Phosphatidylcholine (lecithin)

In brief

What phosphatidylcholine is

Every cell in the body is wrapped in a film two molecules thick, and the commonest phospholipids in that film are phosphatidylcholine and its close relative phosphatidylethanolamine ⁵. Phosphatidylcholine is a phospholipid, a fat that carries a phosphate group, and its shape explains most of what it does: one end dissolves in water and the other end, two long fatty-acid tails, will not, so that in water the molecules gather with their tails hidden, into the sheets of membranes, the small particles of bile and lipoproteins, and the film that lines the lung ^5,9,23. It also makes up more than 90 percent of the phospholipid in the mucus that coats the inside of the intestine ⁶.

The backbone is glycerol, a three-carbon alcohol; two of its carbons carry fatty acids, and the third carries a phosphate on which sits choline, a small molecule with a nitrogen and three methyl groups that was first obtained in 1862 by heating lecithin from bile ². Choline is the part that matters to nutrition. It is needed to build membrane phospholipids, it is the raw material of the neurotransmitter acetylcholine, and it is an important source of the methyl groups the rest of metabolism uses ³.

Because the two fatty acids can differ, phosphatidylcholine is a family of molecules rather than a single compound ¹. The liver's two routes for making it produce different members of that family: in rat liver cells, the route through CDP-choline, an activated form of choline, made mostly species with medium-length saturated chains, and the route that methylates phosphatidylethanolamine made more long, polyunsaturated chains rich in arachidonic acid, an omega-6 fatty acid with four double bonds ¹. The structure at the top of this page is one representative species, 1-palmitoyl-2-oleoyl-phosphatidylcholine, POPC, with a saturated 16-carbon chain on the first carbon and an 18-carbon chain with one double bond on the second; the lung depends instead on dipalmitoylphosphatidylcholine, DPPC, whose two chains are both saturated ⁹.

The word lecithin is older than the chemistry. Théodore Gobley, working in Paris, described a substance in 1850 that he called lecithine, from the Greek lekithos, egg yolk, and only later was lecithin characterized as phosphatidylcholine ². In commerce the word kept a looser meaning, usually a soybean or egg extract in which phosphatidylcholine travels with other fats, and the cholesterol lowering once claimed for lecithin turned out, on inspection, to be explained by the linoleic acid that comes with it or by other changes in diet ^17,30.

The whole history, including the reversals

Phosphatidylcholine was isolated before anyone knew what a membrane was, and the medicine built on it has been revised repeatedly since ². The entries marked as reversals are the places where a confident claim had to be withdrawn.

Two ways to make it, and why estrogen matters

Every cell can make phosphatidylcholine from choline by the route Eugene Kennedy and his colleagues worked out in the 1950s: choline is activated as CDP-choline, choline joined to cytidine diphosphate, a nucleotide related to the building blocks of RNA, and then attached to the glycerol-and-fatty-acid backbone, the route now called the Kennedy pathway ^2,4,5.

The liver has a second route. An enzyme called phosphatidylethanolamine N-methyltransferase, PEMT, takes phosphatidylethanolamine and adds three methyl groups to its head, which turns it into phosphatidylcholine; Jon Bremer and David Greenberg identified the pathway in 1960 ². It is the only way the body makes a new choline molecule rather than recycling an old one ³². The methyl groups are carried by S-adenosylmethionine, the cell's general methyl donor, and that is how phosphatidylcholine is tied to the metabolism of methionine, betaine and folate ^3,32. Every methyl group handed on in this way leaves behind a molecule of homocysteine, an amino acid whose blood level, when high, is linked to cardiovascular disease, and PEMT is one of the two methylation reactions that normally produce the most of it ⁵². The homocysteine is turned back into methionine by one of two enzymes: betaine-homocysteine methyltransferase, which takes a methyl group from betaine, a molecule the liver makes from choline ⁵³, or methionine synthase, which contains vitamin B12 (cobalamin) and takes its methyl group from folate ⁵². That is why choline, folate and vitamin B12 are bound up in one another's metabolism ⁵². The tie is real but not simple: when a folic acid supplement was tested directly in volunteers on a low-choline diet, it did not change who developed organ damage ¹¹.

The two routes are not interchangeable. In rat liver cells labeled with stable isotopes, the Kennedy pathway made mostly saturated species and the PEMT pathway made more polyunsaturated species containing arachidonic acid ¹. Blocking the liver's synthesis of phosphatidylcholine impairs its secretion of very-low-density lipoprotein, the particle that carries triglyceride out of the liver into the blood, which is one reason a liver short of phosphatidylcholine fills with fat ⁵.

PEMT answers to estrogen. In 2007, primary liver cells from mice and from people treated with estradiol increased PEMT transcription in proportion to the dose, with more enzyme protein and activity, and the gene was found to carry a perfect estrogen response element, a DNA sequence the estrogen receptor binds, about 7.5 kilobases, 7,500 letters of DNA, from its start ¹⁰. That is the mechanism proposed for the finding, in the same laboratory's depletion studies, that premenopausal women were the people least often harmed by a low-choline diet ^10,11. The cell work was done in culture, and the link between it and the women in the feeding study is an inference, though a plausible one ¹⁰.

In the most premature infants, the liver's PEMT route is not yet working. In 31 infants born before 28 weeks, choline tagged with deuterium, a heavy form of hydrogen that can be traced, showed the Kennedy pathway running hard, more than doubling plasma phosphatidylcholine from a median of 481 to 1,046 micromoles per liter in five days, while liver PEMT was essentially inactive ³². The authors read this as an argument for adding choline to the intravenous nutrition of premature infants; that is an inference from a metabolic study, not the result of a trial ³². A 2026 randomized study in 32 infants born at 28 to 32 weeks added choline chloride, choline bitartrate, alpha-glycerophosphocholine (the water-soluble core of phosphatidylcholine without its fatty acids) or egg phosphatidylcholine to their feeds for 48 hours; all four raised plasma choline to a similar extent. It measured blood levels, not growth or development ⁵⁴.

How much choline people need, and why it differs

Choline was not counted as an essential nutrient for humans until someone tested it. In 1991, healthy men in a hospital ate a diet containing no choline for three weeks; their plasma choline and phosphatidylcholine fell by about 30 percent, their alanine aminotransferase (ALT), a liver enzyme that leaks from injured liver cells, rose from 0.42 to 0.62 microkatals per liter, and their cholesterol fell by 15 percent, while men kept on 500 mg a day showed none of these changes ³.

The defining study came in 2007. Fifty-seven adults, 26 men, 16 premenopausal women and 15 postmenopausal women, ate a diet with 550 mg of choline per 70 kilograms of body weight for 10 days and then less than 50 mg for up to 42 days, with or without folic acid; anyone who developed organ dysfunction was given choline back until it resolved ¹¹. Seventy-seven percent of the men and 80 percent of the postmenopausal women developed fatty liver on magnetic resonance imaging or muscle damage, against 44 percent of the premenopausal women ¹¹. Six men developed those signs while still eating 550 mg, the adequate intake set for men, and in all the authors judged that an intake at the adequate intake was not enough to prevent organ dysfunction in 19 participants ¹¹.

Genes explain part of the rest. In the same volunteers, 18 of 23 carriers of one variant, a common spelling difference in the DNA, in the promoter of the PEMT gene, the stretch that switches the gene on, rs12325817, developed organ dysfunction on the low-choline diet, an odds ratio of 25, while a variant in the gene for betaine-homocysteine methyltransferase, BHMT, the enzyme that uses betaine made from choline to recycle homocysteine, was not associated ⁵³. These associations come from 57 people and are signals to be confirmed, not a basis for testing anyone's genes ⁵³.

On average, American adults eat less than the adequate intake. In the National Health and Nutrition Examination Survey from 2003 to 2018, covering 39,925 adults, choline was among the nutrients consistently underconsumed even when supplements were counted ¹². The survey describes intake, not illness, and whether that shortfall harms people who are otherwise well is a question it cannot answer ¹².

In bile: ABCB4, PFIC3 and gallstones inside the liver

Bile salts are detergents, and bile also carries cholesterol that does not dissolve in water ^20,23. Phosphatidylcholine pumped from the liver cell into bile is the carrier and solvent for that cholesterol, and without it the bile ducts are injured ^7,8,23.

The pump's job was found by knocking it out. In 1993, researchers at the Netherlands Cancer Institute disrupted a mouse gene, mdr2, that resembled the drug pumps of cancer cells but did not move cancer drugs; the mice had no phospholipid at all in their bile and developed liver disease, while mice with one working copy had half the normal biliary phospholipid and healthy livers ⁷. The authors proposed that the protein flips phosphatidylcholine across the membrane into bile ⁷. The human version is MDR3, short for multidrug resistance 3 after its resemblance to the drug pumps of cancer cells, now called ABCB4, after the family of membrane pumps, the ATP-binding cassette transporters, to which it belongs ^7,8.

In 1998 the same disease was found in children. Two patients with progressive familial intrahepatic cholestasis, PFIC, a group of inherited diseases in which bile flow fails in childhood, had no ABCB4 protein in the canalicular membrane of the liver cell, the side facing the tiny bile channels, and carried mutations that truncate it; their disease was marked by a high gamma-glutamyltransferase, GGT, and looked under the microscope like the mouse's ⁸. This form is PFIC type 3 ⁵⁵. In a 2022 analysis of 95 cases, GGT was raised in all 88 in whom it was measured, 66.1 percent responded at least partly to ursodeoxycholic acid, a bile acid given as a drug, and 41.1 percent had an unfavorable outcome, including 7 deaths and 27 liver transplants; children with two null variants, which make no working protein, responded in 18.2 percent against 77.1 percent of the others ⁵⁵. In a retrospective series of 65 Arab children with genetic cholestasis, the 25 with PFIC3 had slower progression and longer survival than those with PFIC2, the type caused by loss of the bile-salt pump encoded by ABCB11, and the authors concluded that ursodeoxycholic acid could favorably modify the course of PFIC3 ⁵⁶.

Partial defects matter in adults. In 2001 a group in Paris described six adults with ABCB4 mutations, gallstones inside the liver, symptoms that came back after the gallbladder was removed, and bile with too much cholesterol for its phospholipid; ursodeoxycholic acid prevented recurrence ²³. The condition is now called low-phospholipid-associated cholelithiasis, LPAC ²⁴. A 2025 review from the French national cohort describes gallstones before age 40, symptoms that persist after cholecystectomy, surgical removal of the gallbladder, comet-tail echoes or microspots, small bright ultrasound signals, along the bile ducts inside the liver on ultrasound, ursodeoxycholic acid at 5 to 15 mg per kilogram a day as the reference treatment, and the advice to avoid removing the gallbladder where possible ²⁴. It also states that partial ABCB4 defects explain only half the cases, or fewer ²⁴.

The genetic picture is widening. A 2026 review in Gut regroups the severe childhood PFICs with later and milder conditions such as intrahepatic cholestasis of pregnancy, a build-up of bile acids with severe itching in late pregnancy, and LPAC as a single spectrum of genetic cholestasis, as sequencing becomes cheap enough to find the variants in adults, and discusses which treatments suit which genotypes ⁵⁷.

The first drug trial built around this group of diseases came in 2024. MARCH-PFIC, a phase 3 trial funded by the manufacturer, Mirum Pharmaceuticals, several of whose employees are among the authors, tested maralixibat, a drug that blocks the reabsorption of bile acids from the end of the small intestine, in 93 children aged 1 to 17 with several types of PFIC ⁴⁵. Its main result was in children with deficiency of BSEP, the bile-salt pump behind PFIC2, whose itching and serum bile acids fell more than on placebo; children with MDR3 deficiency were included only in a broader all-PFIC analysis, so the abstract does not establish a benefit for PFIC3 specifically ⁴⁵. Diarrhea affected 57 percent of children on the drug against 20 percent on placebo, mostly mild and transient ⁴⁵. MDR3 deficiency is also being recognized later in life. In 2026 the liver transplant service at King's College Hospital in London described seven adults, first diagnosed after age 16, with genetically confirmed MDR3 deficiency who had liver transplants between 2013 and 2024 at a median age of 31.9 years ⁵⁸. Every one had first been thought to have some other liver disease, only four carried the diagnosis when they were assessed for transplant, and the authors conclude that genetic testing can speed an accurate diagnosis; seven patients from one center show that the condition exists in adults, not how common it is ⁵⁸.

When intravenous feeding leaves out choline

People who cannot absorb food are kept alive by parenteral nutrition, nutrition given directly into a vein, and long-term patients often develop a fatty liver ²¹. In the 1990s Buchman's group found that such patients had low plasma free choline, 4.8 nanomoles per milliliter against a normal of 11.4, and that adding 1 to 4 grams of choline chloride a day to the infusions of four patients for six weeks cleared the fat from their livers on computed tomography (CT); in one patient, the fat had come back after ten weeks of choline-free nutrition ²¹.

A randomized, placebo-controlled trial followed in 2001 ²². Fifteen patients received their usual infusions with or without 2 grams of choline chloride for 24 weeks; liver density on CT improved from week 4, alanine aminotransferase fell, and the fatty liver came back ten weeks after choline was withdrawn ²². It is a small trial, but a design with a placebo, an improvement and a relapse on withdrawal is unusually strong for nutrition, and its authors titled it proof of a human choline requirement ²².

The gap has not closed. A 2025 study, two of whose authors work for Baxter's research division, states that the intravenous lipid emulsions, the fat component of intravenous feeding, now used for newborns contain no choline, and tested a new emulsion containing it in piglets ⁵⁹. In 80 children with short bowel syndrome treated at a German intestinal rehabilitation center between 2021 and 2025, a quarter had markedly low plasma choline and betaine, and the only measured difference between children with and without fatty liver was lower choline and betaine; trimethylamine N-oxide (TMAO), a sign that gut bacteria were consuming choline before it could be absorbed, ranged up to 30 micromoles per liter against a normal below 3 ⁶⁰. The same group found falling choline and frequently high TMAO from infancy in people with cystic fibrosis whose pancreas no longer made digestive enzymes ⁶¹. Both studies are retrospective, and both conclude that trials of choline supplementation are needed rather than claiming that supplements would help ^60,61.

Fatty liver and the PC/PE ratio

Choline deficiency causes fatty liver in animals, as Charles Best showed in the 1930s ². The modern question is whether metabolic dysfunction-associated steatotic liver disease, MASLD, is partly a disorder of phosphatidylcholine ^49,62.

The idea in its sharpest form came from mice in 2006. Mice lacking PEMT and fed a choline-deficient diet developed rapid steatohepatitis, fatty liver with inflammation and cell death, and went into liver failure; the cause was not the fat itself but leaky liver-cell membranes, because the ratio of phosphatidylcholine to phosphatidylethanolamine had fallen ³¹. Mice that also lacked the bile pump, and so stopped losing phosphatidylcholine into bile, kept a normal ratio and escaped liver failure, and the authors added that human livers with steatohepatitis also had a lower ratio than normal livers ³¹.

The human evidence since is consistent but indirect. A 2007 analysis of the lipids in liver biopsies found total phosphatidylcholine reduced in both simple fatty liver and steatohepatitis, while triglyceride rose roughly eight- to tenfold and the ratio of free cholesterol to phosphatidylcholine roughly doubled ⁶². In 664 biopsied patients in the NASH Clinical Research Network (NASH, nonalcoholic steatohepatitis, was the former name for steatohepatitis of this kind), postmenopausal women eating less than half the adequate intake of choline had worse fibrosis, the scarring that determines outcome, but no such association was seen in men, children or premenopausal women ⁶³. A meta-analysis of six studies found the A allele, one of the two versions, of the PEMT variant rs7946 associated with fatty liver, an odds ratio of 1.55, with the association confined to East Asian populations ⁶⁴. And in the Framingham cohort, people in the top third of choline intake had a 31 percent lower risk of new fatty liver on CT over about six years, although egg intake on its own showed no association ⁶⁵.

Each of these is an association, and the choline figures in the two dietary studies come from food questionnaires ^63,65. None of them shows that giving choline or phosphatidylcholine to a person who already has fatty liver reverses it, and the supplement trials that come closest, described next, measured liver fat rather than fibrosis or survival ⁴⁹. Since 2025, mostly animal studies have extended the PC/PE idea. In male mice, a high-fat diet lowered a liver protein, RKIP, that is needed to make PEMT efficiently, and losing it upset the PC/PE ratio and worsened fatty liver; livers from people with MASLD also had less RKIP ⁶⁶. In mice, part of the benefit of sleeve gastrectomy, a weight-loss operation that removes most of the stomach, came from raising the liver's supply of S-adenosylmethionine and restoring PC/PE balance, with supporting human data from only four paired liver biopsies and 42 plasma samples ⁶⁷. Both are studies of mechanism, not of treatment ^66,67.

‘Essential phospholipids’ for the liver: what the trials show

Polyenylphosphatidylcholine, a phosphatidylcholine preparation rich in polyunsaturated fatty acids, is marketed as ‘essential phospholipids’ for the liver ^68,69. Its use in alcohol-related liver disease rested on animal work showing that it prevented alcoholic cirrhosis, and its use in fatty liver has rested mostly on small studies ^16,68.

The largest test was American and negative. The Veterans Affairs Cooperative Study, published in 2003, randomized 789 heavy drinkers at 20 medical centers, 97 percent of them men, who had averaged 16 drinks a day for 19 years and had fibrosis on a baseline liver biopsy, to polyenylphosphatidylcholine or placebo ¹⁶. After two years, with 412 repeat biopsies, there was no difference: 22.8 percent of treated patients and 20.0 percent of placebo patients had advanced at least one stage of fibrosis ¹⁶. The authors also reported a trend favoring the product for liver enzymes and bilirubin at some time points in subgroups, such as drinkers with hepatitis C; that is a secondary finding and does not change the main result ¹⁶. The trial's most striking result was accidental. Drinking fell in both groups, from 16 to about 2.5 drinks a day, through monthly visits with a nurse and brief visits with a physician ⁷⁰. Even at that level, one patient in five progressed ¹⁶.

For fatty liver the evidence is larger in number and weaker in kind. An open-label study of 324 patients in the United Arab Emirates, all of whom received the product, reported falls in liver enzymes and relapse in 43.8 to 63.2 percent when the dose was reduced; with no untreated comparison group, the improvements cannot be credited to the product ⁷¹. A 2020 systematic review and network meta-analysis of ten studies, of 22 to 324 patients each and including non-randomized ones, reported that adding essential phospholipids to diabetes treatment lowered alanine aminotransferase by about 11 units per liter more than diabetes treatment alone; its second author was employed by Sanofi's consumer-health medical affairs department ⁶⁸.

The two newest studies of fatty liver are larger or better controlled than what came before them, and both are commercially tied. A 2025 retrospective analysis of Chinese medical records compared 7,093 patients given polyenylphosphatidylcholine with untreated patients and found a small difference in the FIB-4 index, a fibrosis score calculated from routine blood tests, at 24 weeks, minus 0.12 against plus 0.11; four of its authors list Opella or A. Nattermann & Cie as their employer ⁶⁹. A 2026 phase 4 trial, double-blind and placebo-controlled, randomized 193 patients with MASLD and type 2 diabetes, high blood lipids or obesity; in the 165 analyzed, liver fat measured by controlled attenuation parameter fell more with essential phospholipids at six months ⁴⁹. HbA1c, a blood measure of average blood sugar over the previous two to three months, and the fatigue score also improved, no safety concerns arose, and three of the authors are employees of Opella Healthcare ⁴⁹. The abstract reports that the difference in liver fat was statistically significant but not how large it was, and liver fat is a surrogate: neither study measured fibrosis on biopsy, cirrhosis or survival ^49,69.

The 2026 trial drew two published letters. One, from physicians in Poland, asks in its title whether current data support essential phospholipids in MASLD at all ⁷²; the other, by its title, raises confounding by other metabolic treatments and by changes in weight ⁷³. The reply was written by the trial's first author with Branko Popovic, of Opella, A. Nattermann & Cie, who is also an author of the trial ^49,74. Popovic was second author of the 2020 network meta-analysis ⁶⁸ and an author of a 2025 post hoc analysis of MANPOWER, an observational Russian registry of 2,843 adults with newly diagnosed fatty liver given the product under its brand name, Essentiale ⁷⁵. Five of that analysis's six authors list Sanofi or Opella companies, and with no untreated comparison group described, its falls in liver enzymes and better ultrasound appearance cannot be credited to the product ⁷⁵.

Delayed-release phosphatidylcholine for ulcerative colitis

Ulcerative colitis is an inflammation of the lining of the colon that starts in the rectum and spreads upward ⁶. Wolfgang Stremmel in Heidelberg proposed a cause: phosphatidylcholine makes up more than 90 percent of the phospholipid in intestinal mucus, where it forms a water-repellent layer against bacteria; it is secreted mainly in the small intestine and thins out toward the rectum; and in ulcerative colitis its content in mucus is reduced by about 70 percent, whether or not the bowel is inflamed ⁶. If the barrier is missing, he reasoned, it could be replaced with phosphatidylcholine in capsules built to release it only in the lower bowel ⁶.

The early trials were remarkable. In a 2005 phase 2 trial of 60 patients, 6 grams a day for three months produced clinical remission in 53 percent against 10 percent on placebo ³⁹. In a 2007 trial in 60 patients whose colitis had not responded to steroids and who could not stop them, 50 percent on phosphatidylcholine against 10 percent on placebo came off steroids with low or at least halved disease activity, and 80 percent against 10 percent stopped steroids without a flare ⁴⁰. Both trials were small and run at a single referral center ^39,40. A 2014 multicenter dose-finding trial of the commercial formulation LT-02 in 156 patients, funded by its developer, Lipid Therapeutics, found a benefit on the primary measure only at the highest dose, 3.2 grams, and remission in 31.4 percent against 15 percent, a difference that was not statistically significant ⁷⁶.

The phase 3 program reversed the story. In the induction trial, PCG-2, reported in 2023 with Stremmel among the authors and three employees of the sponsor, Dr. Falk Pharma, 466 patients with mild to moderate colitis that had responded inadequately to mesalamine were randomized before an interim analysis stopped the trial for futility: deep remission at 12 weeks, the trial's primary target, whose exact definition the abstract does not give, occurred in 13.5 percent on placebo, 14.2 percent on LT-02 twice daily and 9.7 percent on LT-02 four times daily ¹⁹. The maintenance trial, PCG-4, enrolled 150 of a planned 400 or so and found remission at 48 weeks in 49.3 percent on LT-02, 50.0 percent on mesalamine and 43.2 percent on placebo, with no significant differences ¹⁹. No safety concerns emerged over the trials' 12 and 48 weeks ¹⁹. It did not work as an induction treatment, and whether it helps keep patients in remission would need a maintenance trial large enough to tell ¹⁹.

Injecting it to dissolve fat: Lipostabil, Lipodissolve and Kybella

In 2001 a physician in São Paulo, P. G. Rittes, reported injecting phosphatidylcholine into the fat pads under the eyes of 30 patients and seeing them shrink, with no recurrence over two years; there was no control group ³⁷. The technique was popularized in Brazil, was wrongly treated as a form of mesotherapy, the European practice of many small injections into the skin, and spread as injections of Lipostabil, a product containing phosphatidylcholine and deoxycholate, and of similar solutions sold under the name Lipodissolve ^29,38,77.

Laboratory work suggests the phosphatidylcholine was largely a passenger. Because phosphatidylcholine does not dissolve in water, the injectable formula contains sodium deoxycholate, a bile salt, to keep it in solution ²⁰. In 2004 Adam Rotunda and colleagues compared the formula, deoxycholate alone and laboratory detergents on cultured cells and pig tissue: the formula and deoxycholate alone caused comparable dissolution of cell membranes and destruction of fat and muscle, as detergents do, and they concluded that deoxycholate was the main active ingredient ²⁰. In seven patients with lipomas, benign lumps of fat, the injections produced acute panniculitis, an inflammation of the fat, with rising inflammatory signals at 48 hours ⁷⁷.

No regulator had cleared these mixtures for fat reduction when they were reviewed in 2009: that review stated that none of the injectable fat-reducing therapies then in use had been cleared by any regulatory authority worldwide ²⁸. A 2011 review described Lipodissolve and phosphatidylcholine-deoxycholate injections as subjects of critical scrutiny by the media and the US Food and Drug Administration ⁷⁸, and a 2013 report from Korea said the injections were still being given in many countries for local fat reduction without legal or scientific evidence of their safety and efficacy, despite a warning from that agency; it described a woman with bleeding spots on her abdomen who developed agitation and metabolic acidosis, a dangerous build-up of acid in the blood, after Lipodissolve injections ⁷⁹. The clinical evidence for the mixture is almost entirely uncontrolled practice experience, such as 1,616 patients treated in two Minnesota practices, reported as satisfactory in 74.5 to 86.5 percent with no serious complications ⁸⁰, and 1,269 treated over 14 years at one practice in Mumbai, reported to respond best on the face and upper arm ⁸¹. The harms that have been documented are those of an unregulated injection: a 2022 case report described a woman injected in both arms who developed painful purulent nodules, pus-filled lumps, from Mycobacterium abscessus, a hard-to-treat environmental bacterium, and three similar infections linked to the same physician's office, and it still described Lipodissolve as not approved by the FDA ²⁹.

The approved drug is the detergent without the phosphatidylcholine ^20,43. Deoxycholic acid injection, ATX-101, sold as Kybella in the United States and Belkyra in Canada, was approved in 2015 for fullness under the chin ⁴³. In REFINE-1, a phase 3 trial whose authors included employees of the developer, Kythera, 70.0 percent of 256 treated patients improved by at least one grade on both clinician and patient scales against 18.6 percent of 250 on placebo, magnetic resonance imaging confirmed a volume reduction in 46.3 percent against 5.3 percent, and 4.3 percent had a temporary weakness of the nerve that moves the lower lip ⁸². Kybella is the licensed, tested form of the ingredient that laboratory work suggests did most of the work in Lipodissolve, and its trials say nothing about the phosphatidylcholine mixtures ^20,38,82.

Phosphatidylcholine itself is being tested again. In 2025 a single-center phase 2 trial in Korea randomized 96 adults to placebo or to AYP-101, a soybean phosphatidylcholine injection, under the chin every two weeks; four weeks after the last session, 69.70 percent on the lower concentration improved by a grade on the evaluator scale against 22.58 percent on placebo, while the higher concentration did less well, at 48.39 percent ⁸³. A 2024 phase 1 trial in 26 volunteers described AYP-101 as 93 percent soybean phosphatidylcholine without naming its other ingredients, and PubMed indexes the phase 2 report under deoxycholic acid as well, so whether it carries a bile-salt solubilizer is not clear from either abstract ^83,84. Every side effect the phase 1 trial recorded was mild, mostly pain and bruising at the injection site, and it reported no systemic exposure after single doses of up to 500 mg ⁸⁴. A single small phase 2 trial in which the higher concentration did worse is a start, not an answer ⁸³. The 2004 conclusion has also been reopened. In 2026 a laboratory study in a standard line of cultured fat cells reported that phosphatidylcholine, at concentrations up to 25 mg per milliliter, set off fat breakdown and programmed cell death through TLR4 (toll-like receptor 4, an immune sensor that normally detects bacteria), which the authors present as a receptor-driven effect beyond detergent damage ⁵¹. Two of its authors list Amipharm Co., Ltd., a company, as an affiliation, two also worked on the AYP-101 trials, and cells in a dish are not a human injection ^51,83,84.

Lecithin for cholesterol and memory, at their true strength

Lecithin was sold for years as a way to lower cholesterol ¹⁷. In 1989 three Dutch nutrition scientists, among them M. B. Katan, examined 24 studies and found that most lacked a proper control group, were small, or allowed other foods to change because of the extra calories; only four balanced the fatty acids of the comparison diets, and none showed an effect of lecithin beyond that of the linoleic acid it contains ¹⁷. A double-blind trial in 20 men with high blood lipids, published in 1998 and divided among three arms, used sunflower oil as a control for the extra fat and found that 20 grams of soy lecithin a day for four weeks changed none of total cholesterol, LDL (low-density lipoprotein) or HDL (high-density lipoprotein) cholesterol, triglycerides, apolipoprotein B (the protein carried on each particle that can enter the artery wall) or lipoprotein(a) (an inherited cholesterol particle linked to heart disease) ³⁰.

A 2025 Russian trial has reopened the question for one product. In 100 patients with combined hyperlipidemia, high cholesterol and high triglycerides together, a water-soluble phosphatidylcholine formulation called Vitaphospholip, 500 mg twice a day for 12 weeks, lowered non-HDL cholesterol by 13.2 percent against 4.3 percent on placebo ⁸⁵. It is a single trial of a proprietary formulation, most of its authors are from the Institute of Biomedical Chemistry in Moscow, and a result for that formulation is not a result for dietary lecithin ⁸⁵.

The memory claim rested on a reasonable idea. People with Alzheimer's disease have been found to lack the brain enzyme that turns choline into acetylcholine, and lecithin supplies choline ¹⁸. The Cochrane review of 2003 found 12 randomized trials, in 265 people with Alzheimer's disease, 21 with Parkinson's dementia and 90 with subjective memory complaints; none showed a clear benefit in dementia, one trial in subjective memory problems reported a dramatic effect, and the reviewers concluded that a moderate effect could not be excluded but that the small trials did not justify a large one ¹⁸. The author of a 2003 trial of alpha-GPC, a choline compound described below, summarized the field in the paper's own background: well-controlled trials had not confirmed any clinical use for choline or lecithin in Alzheimer's disease ⁸⁶.

Lecithin and choline were also among the cholinergic drugs, drugs meant to boost acetylcholine signaling, tried for tardive dyskinesia, the involuntary movements caused by antipsychotic drugs. A 2018 Cochrane review of 14 small trials published from 1976 to 2014, with 5 to 60 people each, rated the evidence low or very low in quality and concluded that cholinergic drugs currently have little place in routine clinical work ⁸⁷.

Gut bacteria, TMAO and the heart

In 2011 Stanley Hazen's group at the Cleveland Clinic screened blood for small molecules that predicted cardiovascular disease and found three that come from dietary phosphatidylcholine: choline, betaine and trimethylamine N-oxide, TMAO ¹⁴. The chain runs through the gut. Anaerobic bacteria, those that live without oxygen, split choline into trimethylamine using a glycyl radical enzyme, a specialized enzyme that breaks the bond between carbon and nitrogen, whose genes were identified in 2012, and the liver's flavin monooxygenases, enzymes that add oxygen, oxidize trimethylamine into TMAO ^13,14. In mice, choline or TMAO in the diet promoted atherosclerosis, germ-free mice made no TMAO, and suppressing gut bacteria blocked the effect of dietary choline ¹⁴. The causal experiments were in mice; in people, the 2011 finding was a statistical prediction ¹⁴.

In 2013 the same group gave healthy people two hard-boiled eggs and a phosphatidylcholine labeled with deuterium: TMAO rose, antibiotics markedly suppressed it and it reappeared once they were stopped, and in 4,007 patients undergoing elective coronary angiography, an X-ray study of the heart's arteries, those in the highest quarter of fasting TMAO had 2.54 times the risk of heart attack, stroke or death over three years of those in the lowest quarter ²⁵. A meta-analysis of 11 cohorts found higher TMAO associated with a 23 percent higher risk of cardiovascular events and a 55 percent higher mortality, the latter possibly inflated by publication bias, the tendency of positive results to reach print more often ⁸⁸. The association persists in high-risk patients: a 2025 meta-analysis of 13 cohorts, 11,279 people who had a coronary stent or angioplasty, found that higher TMAO went with about twice the risk of later major cardiovascular events, hazard ratio 1.99, which is still an association, not proof of cause ⁸⁹. Eggs, with their choline-rich yolks, became suspect ²⁶.

The egg debate that followed was mostly about cholesterol. A pooled analysis of six US cohorts in 2019 linked each extra half egg a day to a 6 percent higher risk of cardiovascular disease, but the association disappeared after adjustment for dietary cholesterol ⁹⁰. A 2020 analysis of three large US cohorts, with a meta-analysis of 1.72 million people, found no association between up to one egg a day and cardiovascular disease, and a lower risk in Asian cohorts ⁹¹. Both are observational, and neither can fully separate eggs from the diets and lives that come with them ^90,91.

Then the Cleveland group tested its own hypothesis and found its weak point. In a randomized trial published in 2021, healthy volunteers with normal kidneys ate four large eggs a day for four weeks, about 467 mg of choline almost all bound in phosphatidylcholine, and their fasting plasma TMAO barely moved, from 2.0 to 2.3 micromoles per liter; phosphatidylcholine capsules behaved the same way; but choline bitartrate tablets supplying similar choline raised TMAO from 1.9 to 11.1 and increased the reactivity of platelets ²⁶. A crossover trial in 23 people with metabolic syndrome, a cluster of obesity, high blood pressure, high blood sugar and abnormal blood fats, found that neither three eggs a day nor choline bitartrate supplying the same 400 mg of choline changed TMAO from baseline, so the contrast between free and bound choline has not been reproduced in every trial ⁹². A 2025 meta-analysis of five randomized trials found no effect of eating eggs on blood TMAO, a pooled difference close to zero (minus 0.08, with a range of minus 0.47 to 0.32), and rated the certainty of that evidence moderate ⁹³. The form of choline matters in the trial that compared them directly: free choline salts reached the bacteria, and choline bound in phosphatidylcholine, it appears, largely did not ²⁶.

Mendelian randomization, which uses inherited gene variants as a natural experiment, points the arrow the other way. In 2019, genetically higher TMAO was not associated with coronary disease, heart attack, stroke, atrial fibrillation, diabetes or kidney disease, while genetic liability to type 2 diabetes and to kidney disease raised TMAO, suggesting that the observational link reflects confounding, a third factor such as kidney disease raising both, or reverse causation ²⁷. TMAO is cleared almost entirely by the kidneys, so failing kidneys raise it ²⁶. The same method found no causal link between TMAO and Alzheimer's disease ⁹⁴. In five Dutch population cohorts of 7,834 people, plasma choline, not TMAO, was associated with cardiovascular disease, fish intake was associated with TMAO, and Mendelian randomization again found no significant association ⁹⁵. A 2024 scoping review counted 26 Mendelian randomization studies of choline-related metabolites, with findings scattered across many different outcomes ⁹⁶. A 2026 critical review concludes that blood TMAO integrates diet, gut bacteria, absorption, liver oxidation and kidney clearance, and that a prognostic association is not proof that TMAO causes heart disease ⁹⁷.

The newest trials are small and do not settle anything. A 2026 secondary analysis of a 12-week trial in 32 Japanese adults, four of whose authors work for the food company Kewpie, found that 3 grams a day of egg phosphatidylcholine raised serum TMAO within the group but not compared with placebo ⁹⁸. A 2026 crossover trial in 41 adults found that six days of plant-based meat instead of red meat lowered TMAO, a reminder that red meat's carnitine and fish's own TMAO feed the same blood measurement ^27,95,99. None of these studies tests whether lowering TMAO prevents heart attacks, the kind of evidence that would most directly show the marker to be a cause ⁹⁷.

In the lung: DPPC and surfactant for premature infants

The air sacs of the lung are lined with a thin layer of water, and the surface tension of water would collapse them at the end of every breath without surfactant, a film of lipid and protein whose key ingredient is dipalmitoylphosphatidylcholine, DPPC, working together with two small proteins, SP-B and SP-C ^9,100. The Swiss physiologist von Neergaard understood surfactant's function in 1929, and his paper was ignored for 25 years; its physical properties were recognized in the early 1950s by Pattle in Britain and by Radford and Clements in the United States, in work that grew out of research on chemical weapons ³³.

In 1959 Avery and Mead established that hyaline membrane disease, the breathing failure of premature newborns now called respiratory distress syndrome, is a deficiency of surfactant ^33,34,101. In 1971 Gluck's group proposed predicting the disease before birth from the phospholipids of amniotic fluid, comparing lecithin with sphingomyelin, another membrane phospholipid ³⁵. In 1972 the obstetrician G. C. Liggins showed that glucocorticoids, steroid hormones, given to the mother could mature the fetal lung, a finding not fully believed for another 20 years ³³; he and his colleague R. N. Howie reported it as a controlled trial of antepartum glucocorticoid treatment to prevent respiratory distress syndrome in premature infants ¹⁰². Three decades later, researchers at the University of Auckland followed up 534 adults whose mothers had taken part in what they describe as the first and largest randomized trial of antenatal betamethasone, and found no difference in lung function or asthma at age 30 ¹⁰³. And in 1980 Fujiwara and colleagues in Japan gave artificial surfactant into the tracheas of ten severely ill premature infants; oxygenation improved, and eight survived, including five of the six who weighed less than 1,500 grams ³⁶.

The phospholipid alone was not enough. Protein-free synthetic surfactants were effective, but a Cochrane review of 15 trials found that animal-derived surfactants, which carry the surfactant proteins, reduced pneumothorax, a leak of air from the lung, with a relative risk, the risk in one group divided by the risk in the other, of 0.65, and modestly reduced death, relative risk 0.89, at the cost of slightly more necrotizing enterocolitis, a dangerous bowel inflammation of premature infants ¹⁰⁴. DPPC is necessary to surfactant but not sufficient: the proteins SP-B and SP-C are part of what lowers surface tension ^9,104.

Surfactant replacement reduces pneumothorax, death and the combined outcome of death or bronchopulmonary dysplasia, and is now standard care ^50,105. The 2022 European consensus guidelines recommend antenatal steroids, non-invasive breathing support from birth and early surfactant ¹⁰⁵. Giving surfactant through a thin catheter to a baby who is breathing on its own, rather than through a breathing tube, reduced death or bronchopulmonary dysplasia, the chronic lung disease of prematurity, with a relative risk of 0.59 in a 2021 Cochrane review ¹⁰⁶. In the OPTIMIST-A trial, in infants born at 25 to 28 weeks and supported with continuous positive airway pressure (CPAP), air pushed gently through the nose to keep the lungs open, minimally invasive surfactant compared with sham treatment did not change death or disability at two years, 36.3 against 36.1 percent, but did reduce hospital admissions for breathing illness, 25.1 against 38.2 percent ¹⁰⁷.

The newest reversals came from adding a steroid and from rethinking timing. Small trials had suggested that budesonide, an inhaled steroid, mixed into surfactant reduced chronic lung disease or death ⁴⁷. But in PLUSS, a trial of 1,059 infants born before 28 weeks in Australia, New Zealand, Canada and Singapore, survival free of bronchopulmonary dysplasia was 25.6 percent with budesonide against 22.6 percent without, a difference consistent with little or no effect ⁴⁶. The US Neonatal Research Network trial BiB was stopped for futility after 641 infants: bronchopulmonary dysplasia or death occurred in 68.5 percent with budesonide against 67.9 percent without, and high blood sugar in 66.7 against 49.8 percent ⁴⁷. A 2025 meta-analysis found no significant reduction in bronchopulmonary dysplasia, relative risk 0.96, on low-certainty evidence ¹⁰⁸. And a 2026 Cochrane review of 10 trials in 3,151 infants reversed an older lesson. Giving surfactant to every at-risk infant immediately after birth reduced death in trials run before antenatal steroids and early CPAP were routine; in infants first stabilized on CPAP, it probably slightly increases mortality compared with giving surfactant only to those who develop the disease, and the reviewers favor that selective approach ⁵⁰. In adults with acute respiratory distress syndrome, where surfactant is inhibited and damaged rather than simply missing, replacement has proven less effective and largely disappointing ¹⁰¹.

Citicoline and alpha-GPC: choline sold as medicine

Two choline compounds are sold as brain medicines in many countries ^41,42. Citicoline is CDP-choline, the intermediate of the Kennedy pathway, and alpha-GPC, L-alpha-glycerylphosphorylcholine or choline alfoscerate, is phosphatidylcholine stripped of both fatty acids, a small water-soluble molecule taken as a precursor of acetylcholine ^44,109,110. Both deliver choline. Oral citicoline raised plasma choline in a dose-related way for 5 to 10 hours and raised uridine by up to 120 percent, while intact cytidine (uridine and cytidine are building blocks of RNA) was barely detectable, so in people it appears to act through choline and uridine rather than as itself ¹⁰⁹. A 2024 study whose authors all work for Otsuka found that a single dose of glycerophosphocholine, the same molecule as alpha-GPC, raised plasma choline without significantly raising TMAO in 12 men ¹¹¹.

As a drug for acute brain injury, citicoline has not survived its large trials. ICTUS, funded by the manufacturer Ferrer, randomized 2,298 patients with moderate to severe acute ischemic stroke and was stopped for futility, with recovery at 90 days essentially identical, odds ratio 1.03 ⁴¹. COBRIT, in 1,213 patients with traumatic brain injury at eight US trauma centers, found no improvement in function or cognition at 90 days, odds ratio 0.98, even though citicoline was approved for brain injury in 59 countries ⁴².

Alpha-GPC has a few positive trials. In 261 patients with mild to moderate Alzheimer's disease, 400 mg three times a day for 180 days improved the ADAS-Cog cognitive score by 3.2 points while it worsened by 2.9 points on placebo ⁸⁶. In 100 Korean patients with mild cognitive impairment, 600 mg a day for 12 weeks improved the ADAS-Cog by 2.34 points, more than placebo, in a trial of a branded capsule, SHCog, with an author from the Suheung Technology Research Institute ¹¹⁰. Both trials were short and modest in size ^86,110.

The stroke signal came from Korea's national health insurance database in 2021 ⁴⁴. Among more than 12 million people aged 50 or older, the 108,877 prescribed alpha-GPC between 2006 and 2008 had a higher risk of stroke over the following decade after matching, an adjusted hazard ratio of 1.43, with risk rising with longer use; the authors proposed TMAO as one possible mechanism ⁴⁴. But people who take a memory medicine differ from people who do not: before matching, users averaged 68.3 years of age against 61.6 for non-users ⁴⁴. A 2025 analysis of the same national database in 508,107 people with mild cognitive impairment found the opposite pattern: lower conversion to Alzheimer's and vascular dementia among users, and lower stroke risk among users who did not progress ⁴⁸. That stroke result held only in a subgroup defined by what happened after treatment began, which makes it harder to read as an effect of the drug ⁴⁸. Two observational studies of one database that disagree in direction are what confounding by indication, the drug looking harmful or helpful because of who is given it, tends to produce, and neither settles the question ^44,48. In 2026 researchers including authors of the 2021 stroke study used the same national database and the same kind of matching in 81,970 users and 409,801 non-users aged 50 or older, and found no association between alpha-GPC and kidney cancer, adjusted hazard ratio 0.95 ¹¹². They had asked the question because earlier cohorts linked dietary choline to less kidney cancer while the TMAO that alpha-GPC can produce has been implicated in kidney injury, and the result is observational as well ¹¹².

What was believed and is not, and what is still unknown

Several claims about phosphatidylcholine were widely held and have been corrected: that lecithin lowers cholesterol by itself rather than through its linoleic acid ^17,30; that it treats dementia ¹⁸; that polyenylphosphatidylcholine slows fibrosis in alcohol-related liver disease ¹⁶; that the phosphatidylcholine in fat-dissolving injections was their active ingredient ²⁰, a conclusion that 2026 cell work from a group with commercial ties has challenged ⁵¹; that delayed-release phosphatidylcholine induces remission in ulcerative colitis ¹⁹; that habitual egg eating raises fasting TMAO ^26,92; that TMAO has been shown to cause heart disease ^27,97; that budesonide mixed into surfactant prevents chronic lung disease in extremely premature infants ^46,47; and that giving surfactant to every at-risk premature infant at birth saves lives in modern care ⁵⁰.

Whether choline or phosphatidylcholine given to people with MASLD prevents fibrosis, cirrhosis or death is untested; the most rigorous trial so far measured liver fat for six months ⁴⁹.

Whether premature infants, children with intestinal failure and people with cystic fibrosis would benefit from routine choline supplementation is open; the evidence so far is metabolic and retrospective, the authors of those studies ask for trials ^32,60,61, and a 2026 randomized study in preterm infants compared supplements only by the blood choline they produced over 48 hours ⁵⁴.

Why half or more of the patients with low-phospholipid-associated cholelithiasis have no ABCB4 defect is not known ^24,57.

Whether delayed-release phosphatidylcholine helps maintain remission in ulcerative colitis would need an adequately powered maintenance trial, which the 2023 authors call for ¹⁹.

Whether alpha-GPC raises or lowers the risk of stroke is unresolved, and a randomized trial would be needed to answer it ^44,48.

Whether drugs that block bile-acid reabsorption help children with PFIC3 specifically, rather than PFIC as a group, has not been shown ⁴⁵.

None of the papers cited on this page carries a retraction or an expression of concern in its PubMed record as of 19 October 2026; commercial ties are named where each study is described.

The tests, one by one

• Plasma free choline (mass spectrometry)Measures choline circulating unbound. In four long-term intravenous-nutrition patients it averaged 4.8 nanomoles per milliliter against a normal of 11.4 ²¹.Mainly research; its use in cystic fibrosis and intestinal failure has been proposed ^60,61In 80 children with short bowel syndrome, malabsorption after loss of much of the small intestine, low choline and betaine were the only measured differences between those with and without fatty liver ⁶⁰.It fell only about 30 percent after three weeks with no choline at all ³, and the 2007 depletion study defined deficiency by organ dysfunction, fatty liver on magnetic resonance imaging (MRI) or muscle damage, rather than by a plasma choline level ¹¹.
• GGT and ABCB4 gene sequencingAmong the progressive familial intrahepatic cholestases, a high gamma-glutamyltransferase (GGT), an enzyme released from injured bile ducts, marks the form caused by failed phospholipid secretion; sequencing ABCB4 confirms it ^8,55.Children with progressive cholestasis; young adults with recurrent or intrahepatic gallstonesGGT was raised in all 88 of 88 children with PFIC3 in whom it was measured ⁵⁵.In low-phospholipid-associated cholelithiasis, a form of gallstone disease, ABCB4 variants explain half the cases or fewer; the diagnosis rests on age, symptoms after gallbladder removal and the comet-tail echoes of stones inside the liver on ultrasound ²⁴.
• Plasma TMAO (mass spectrometry)Measures the oxidized product of bacterial trimethylamine in fasting blood ²⁵.Research cohorts and diet trialsIn 4,007 patients having coronary angiography, an X-ray study of the heart's arteries, the top quarter of TMAO carried 2.54 times the three-year risk of heart attack, stroke or death of the bottom quarter ²⁵; in a 2025 meta-analysis of 11,279 patients who had a coronary stent or angioplasty, higher TMAO went with about twice the risk of later major cardiovascular events ⁸⁹; but in 7,834 people from five Dutch population cohorts it was not associated with cardiovascular disease ⁹⁵.It rises with kidney disease and diabetes and after fish, so a high value may report the kidneys or the last meal rather than a cause ^27,95,97.
• Ceramide-phosphatidylcholine risk score (CERT2)Combines blood levels of several ceramides, a class of signaling fats, and phosphatidylcholine species into one score ¹¹³.Research; several co-authors of the validation are from Zora Biosciences, a companyIn 5,461 people with heart failure from two trials, the highest category carried 2.80 and 2.84 times the risk of cardiovascular death of the lowest ¹¹³.It shows prediction only; the study did not test whether acting on the score changes outcomes ¹¹³.
• Liver fat imaging (computed tomography, magnetic resonance imaging, controlled attenuation parameter)The choline and phosphatidylcholine studies on this page measured liver fat by computed tomography (CT) density, MRI or the controlled attenuation parameter, an ultrasound-based fat reading taken during transient elastography, a liver-stiffness scan ^11,22,49.Trials and clinicsIn four patients, the difference in density between liver and spleen on CT, measured in Hounsfield units, the CT density scale, rose from -14.2 to 8.4 within two weeks of adding choline to intravenous feeding ²¹.Imaging shows fat, not the inflammation and scarring that decide prognosis, which is why the largest trial of polyenylphosphatidylcholine, a polyunsaturated phosphatidylcholine product, used liver biopsies ¹⁶.

Where it connects

Sources

113 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.

1. 1
   DeLong CJ, Shen YJ, Thomas MJ, Cui Z. Molecular distinction of phosphatidylcholine synthesis between the CDP-choline pathway and phosphatidylethanolamine methylation pathway.J Biol Chem · 1999 · 274(42):29683-8doi:10.1074/jbc.274.42.29683 · PMID 10514439

   Stable-isotope labeling in rat liver cells: the CDP-choline route makes mainly saturated species, the PEMT route more polyunsaturated, arachidonate-rich species. Animal cells, not people.

2. 2
   Zeisel SH. A brief history of choline.Ann Nutr Metab · 2012 · 61(3):254-8doi:10.1159/000343120 · PMID 23183298

   Narrative history from Gobley's lecithine (1850) and Strecker's choline (1862) through Best, Kennedy, Bremer and Greenberg to the human feeding studies; written by the investigator who led those studies.

3. 3
   Zeisel SH, Da Costa KA, Franklin PD, Alexander EA, Lamont JT, Sheard NF, Beiser A. Choline, an essential nutrient for humans.FASEB J · 1991 · 5(7):2093-8PMID 2010061

   Three weeks without choline in healthy hospitalized men lowered plasma choline and phosphatidylcholine about 30% and raised ALT; other liver and kidney tests were unchanged. An early controlled feeding study supporting choline as essential. PubMed lists no DOI.

4. 4
   Kennedy EP, Weiss SB. The function of cytidine coenzymes in the biosynthesis of phospholipides.J Biol Chem · 1956 · 222(1):193-214PMID 13366993

   The paper that established the CDP-choline route, now called the Kennedy pathway. PubMed carries no abstract and lists no DOI; the pathway is described here from the reviews that cite it.

5. 5
   van der Veen JN, Kennelly JP, Wan S, Vance JE, Vance DE, Jacobs RL. The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease.Biochim Biophys Acta Biomembr · 2017 · 1859(9 Pt B):1558-72doi:10.1016/j.bbamem.2017.04.006 · PMID 28411170

   Review: phosphatidylcholine and phosphatidylethanolamine are the most abundant membrane phospholipids; liver phosphatidylcholine synthesis is needed for VLDL secretion; abnormal PC/PE ratios are linked to disease, mostly in animal models.

6. 6
   Stremmel W. [Mucosal protection by phosphatidylcholine as new therapeutic concept in ulcerative colitis].Z Gastroenterol · 2013 · 51(4):384-9doi:10.1055/s-0033-1335042 · PMID 23585269

   German-language review with an English abstract, by the originator of the hypothesis: phosphatidylcholine is over 90% of mucus phospholipid and reduced about 70% in ulcerative colitis.

7. 7
   Smit JJ, Schinkel AH, Oude Elferink RP, Groen AK, Wagenaar E, van Deemter L, et al. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease.Cell · 1993 · 75(3):451-62doi:10.1016/0092-8674(93)90380-9 · PMID 8106172

   Mouse knockout: no phospholipid in bile and progressive liver disease; heterozygotes had half the biliary phospholipid and normal livers. Animal evidence.

8. 8
   de Vree JM, Jacquemin E, Sturm E, Cresteil D, Bosma PJ, Aten J, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.Proc Natl Acad Sci U S A · 1998 · 95(1):282-7doi:10.1073/pnas.95.1.282 · PMID 9419367

   Two children with high-GGT progressive familial intrahepatic cholestasis lacked canalicular MDR3 protein and carried truncating mutations: the definition of PFIC3.

9. 9
   Han S, Mallampalli RK. The Role of Surfactant in Lung Disease and Host Defense against Pulmonary Infections.Ann Am Thorac Soc · 2015 · 12(5):765-74doi:10.1513/AnnalsATS.201411-507FR · PMID 25742123

   Review: surfactant is enriched in dipalmitoylphosphatidylcholine, which with SP-B and SP-C lowers surface tension; SP-A and SP-D serve host defense.

10. 10
    Resseguie M, Song J, Niculescu MD, da Costa KA, Randall TA, Zeisel SH. Phosphatidylethanolamine N-methyltransferase (PEMT) gene expression is induced by estrogen in human and mouse primary hepatocytes.FASEB J · 2007 · 21(10):2622-32doi:10.1096/fj.07-8227com · PMID 17456783

    Estradiol raised PEMT transcription, protein and activity in a dose-dependent way in cultured human and mouse liver cells; a perfect estrogen response element lies about 7.5 kb from the start site. In vitro only.

11. 11
    Fischer LM, daCosta KA, Kwock L, Stewart PW, Lu TS, Stabler SP, Allen RH, Zeisel SH. Sex and menopausal status influence human dietary requirements for the nutrient choline.Am J Clin Nutr · 2007 · 85(5):1275-85doi:10.1093/ajcn/85.5.1275 · PMID 17490963

    Controlled depletion of 57 adults: organ dysfunction in 77% of men, 80% of postmenopausal women and 44% of premenopausal women; 6 men affected at the adequate intake; folic acid did not change the response. Small, but the best-controlled human study of the requirement.

12. 12
    Freedman MR, Fulgoni VL, Lieberman HR. Temporal changes in micronutrient intake among United States Adults, NHANES 2003 through 2018: A cross-sectional study.Am J Clin Nutr · 2024 · 119(5):1309-20doi:10.1016/j.ajcnut.2024.02.007 · PMID 38373695

    NHANES data on 39,925 adults: choline was underconsumed throughout, even counting supplements. Intake only, no outcomes; one author is affiliated with Nutrition Impact, a consultancy.

13. 13
    Craciun S, Balskus EP. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme.Proc Natl Acad Sci U S A · 2012 · 109(52):21307-12doi:10.1073/pnas.1215689109 · PMID 23151509

    Identifies the bacterial gene cluster and the carbon-nitrogen bond-cleaving glycyl radical enzyme that turns choline into trimethylamine. Bacterial biochemistry.

14. 14
    Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.Nature · 2011 · 472(7341):57-63doi:10.1038/nature09922 · PMID 21475195

    Human metabolomics identified choline, TMAO and betaine as predictors; the causal experiments (atherosclerosis, germ-free and antibiotic-treated animals) were in mice.

15. 15
    Zeisel SH, da Costa KA. Choline: an essential nutrient for public health.Nutr Rev · 2009 · 67(11):615-23doi:10.1111/j.1753-4887.2009.00246.x · PMID 19906248

    Review: choline was officially recognized as an essential nutrient by the Institute of Medicine in 1998; mean intakes of men, women, older children and pregnant women fall far below the adequate intake.

16. 16
    Lieber CS, Weiss DG, Groszmann R, Paronetto F, Schenker S, et al. II. Veterans Affairs Cooperative Study of polyenylphosphatidylcholine in alcoholic liver disease.Alcohol Clin Exp Res · 2003 · 27(11):1765-72doi:10.1097/01.ALC.0000093743.03049.80 · PMID 14634492

    789 heavy drinkers randomized at 20 VA centers to polyenylphosphatidylcholine or placebo: no effect on fibrosis progression at two years (22.8% vs 20.0%). The strongest trial of the product.

17. 17
    Knuiman JT, Beynen AC, Katan MB. Lecithin intake and serum cholesterol.Am J Clin Nutr · 1989 · 49(2):266-8doi:10.1093/ajcn/49.2.266 · PMID 2916447

    Critical review of 24 studies: no effect of lecithin on cholesterol beyond that of its linoleic acid; most studies were poorly controlled.

18. 18
    Higgins JP, Flicker L. Lecithin for dementia and cognitive impairment.Cochrane Database Syst Rev · 2003 · (3):CD001015doi:10.1002/14651858.CD001015 · PMID 12917896

    Twelve small randomized trials: no clear benefit in dementia; a moderate effect not excluded, but no priority for a large trial.

19. 19
    Dignass A, Stremmel W, Horynski M, Poyda O, Armerding P, Fellermann K, et al. Modified-Release Phosphatidylcholine (LT-02) for Ulcerative Colitis: Two Double-Blind, Randomized, Placebo-Controlled Trials.Clin Gastroenterol Hepatol · 2024 · 22(4):810-820.e7doi:10.1016/j.cgh.2023.09.031 · PMID 37806372

    Phase 3: the induction trial (466 of 762 planned) was stopped for futility and the maintenance trial (150 of about 400) found no significant difference. Three authors are from the sponsor, Dr. Falk Pharma.

20. 20
    Rotunda AM, Suzuki H, Moy RL, Kolodney MS. Detergent effects of sodium deoxycholate are a major feature of an injectable phosphatidylcholine formulation used for localized fat dissolution.Dermatol Surg · 2004 · 30(7):1001-8doi:10.1111/j.1524-4725.2004.30305.x · PMID 15209790

    Cell cultures and pig tissue: deoxycholate alone reproduced the cell lysis of the full phosphatidylcholine formula, like a laboratory detergent. In vitro and animal evidence; challenged in 2026 by cell work on TLR4.

21. 21
    Buchman AL, Dubin MD, Moukarzel AA, Jenden DJ, Roch M, Rice KM, Gornbein J, Ament ME. Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation.Hepatology · 1995 · 22(5):1399-403PMID 7590654

    Four long-term parenteral-nutrition patients with low free choline: steatosis cleared on CT with intravenous choline chloride and recurred in one after it was stopped. Uncontrolled. PubMed lists no DOI.

22. 22
    Buchman AL, Ament ME, Sohel M, Dubin M, Jenden DJ, Roch M, et al. Choline deficiency causes reversible hepatic abnormalities in patients receiving parenteral nutrition: proof of a human choline requirement: a placebo-controlled trial.JPEN J Parenter Enteral Nutr · 2001 · 25(5):260-8doi:10.1177/0148607101025005260 · PMID 11531217

    Randomized and placebo-controlled, 15 patients, 2 g choline chloride for 24 weeks: liver density and ALT improved, and steatosis recurred 10 weeks after withdrawal. Small.

23. 23
    Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis.Gastroenterology · 2001 · 120(6):1459-67doi:10.1053/gast.2001.23947 · PMID 11313316

    Six adults with ABCB4 mutations, intrahepatic stones and recurrence after cholecystectomy: the first description of what is now called LPAC. A case series; it shows the phenotype, not its frequency.

24. 24
    Soret PA, Chazouillères O, Corpechot C. Current approach to diagnosis and management of low-phospholipid associated cholelithiasis syndrome.Curr Opin Gastroenterol · 2025 · 41(2):67-73doi:10.1097/MOG.0000000000001077 · PMID 39782681

    Review from the French national LPAC cohort: onset before 40, persistence after cholecystectomy, comet-tail echoes on ultrasound, UDCA 5-15 mg/kg/day, avoid cholecystectomy; ABCB4 defects explain half the cases or fewer. Built on retrospective cohorts.

25. 25
    Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.N Engl J Med · 2013 · 368(17):1575-84doi:10.1056/NEJMoa1109400 · PMID 23614584

    Egg and labeled-phosphatidylcholine challenge with antibiotic suppression; 4,007 angiography patients: hazard ratio 2.54 for top vs bottom TMAO quartile. Association in a high-risk population.

26. 26
    Wilcox J, Skye SM, Graham B, Zabell A, Li XS, Li L, et al. Dietary Choline Supplements, but Not Eggs, Raise Fasting TMAO Levels in Participants with Normal Renal Function: A Randomized Clinical Trial.Am J Med · 2021 · 134(9):1160-1169.e3doi:10.1016/j.amjmed.2021.03.016 · PMID 33872583

    Read in full text: four eggs a day and phosphatidylcholine capsules did not raise fasting TMAO; choline bitartrate did, with more platelet reactivity. Arms of 10 to 20 young volunteers with normal kidneys; from the group that proposed the TMAO hypothesis.

27. 27
    Jia J, Dou P, Gao M, Kong X, Li C, Liu Z, Huang T. Assessment of Causal Direction Between Gut Microbiota-Dependent Metabolites and Cardiometabolic Health: A Bidirectional Mendelian Randomization Analysis.Diabetes · 2019 · 68(9):1747-55doi:10.2337/db19-0153 · PMID 31167879

    Genetically predicted TMAO not associated with coronary disease, infarction, stroke, atrial fibrillation, diabetes or kidney disease; the findings support diabetes and kidney disease raising TMAO rather than the reverse.

28. 28
    Rotunda AM. Injectable treatments for adipose tissue: terminology, mechanism, and tissue interaction.Lasers Surg Med · 2009 · 41(10):714-20doi:10.1002/lsm.20807 · PMID 20014257

    States that none of the injectable fat-reducing therapies had been cleared for fat reduction by any regulatory authority worldwide; written before deoxycholic acid's 2015 approval.

29. 29
    Kaur H, Reyes-Barron C, Sipprell WH, Cameron A, Louie T, Tsai PR, Scott G. Painful Purulent Nodules Caused by Mycobacterium at Site of Lipodissolve Injections.Am J Dermatopathol · 2022 · 44(4):257-9doi:10.1097/DAD.0000000000002118 · PMID 34999596

    Case report with three linked infections from the same office; describes Lipodissolve as a non-FDA-approved phosphatidylcholine-in-deoxycholate solution developed around 2004.

30. 30
    Oosthuizen W, Vorster HH, Vermaak WJ, Smuts CM, Jerling JC, Veldman FJ, Burger HM. Lecithin has no effect on serum lipoprotein, plasma fibrinogen and macro molecular protein complex levels in hyperlipidaemic men in a double-blind controlled study.Eur J Clin Nutr · 1998 · 52(6):419-24doi:10.1038/sj.ejcn.1600580 · PMID 9683394

    Twenty men for 4 weeks, with sunflower oil as a fat-matched control: 20 g of soy lecithin a day changed no lipid measure. Small.

31. 31
    Li Z, Agellon LB, Allen TM, Umeda M, Jewell L, Mason A, Vance DE. The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis.Cell Metab · 2006 · 3(5):321-31doi:10.1016/j.cmet.2006.03.007 · PMID 16679290

    Pemt-knockout mice on a choline-deficient diet: liver failure from a falling PC/PE ratio and leaky membranes, prevented by also deleting Mdr2. Mouse evidence; the human observation is a single comparison of livers.

32. 32
    Goss KCW, Goss VM, Townsend JP, Koster G, Clark HW, Postle AD. Postnatal adaptations of phosphatidylcholine metabolism in extremely preterm infants: implications for choline and PUFA metabolism.Am J Clin Nutr · 2020 · 112(6):1438-47doi:10.1093/ajcn/nqaa207 · PMID 32778895

    Deuterated-choline study of 31 infants born before 28 weeks: an active CDP-choline pathway and an essentially inactive liver PEMT. A metabolic study; it supports but does not test choline supplementation.

33. 33
    Obladen M. History of surfactant up to 1980.Biol Neonate · 2005 · 87(4):308-16doi:10.1159/000084878 · PMID 15985753

    History from Virchow to Fujiwara: von Neergaard's ignored 1929 insight, the 1950s work of Pattle, Radford and Clements, Avery and Mead's 1959 finding and Liggins's antenatal steroids. Its abstract calls Liggins Australian; no other record opened for this page supports that, so the page does not repeat it.

34. 34
    Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease.AMA J Dis Child · 1959 · 97(5 Part 1):517-23doi:10.1001/archpedi.1959.02070010519001 · PMID 13649082

    The paper that tied hyaline membrane disease to surfactant deficiency. PubMed carries no abstract; its finding is described here from the historical reviews that cite it.

35. 35
    Gluck L, Kulovich MV, Borer RC, Brenner PH, Anderson GG, Spellacy WN. Diagnosis of the respiratory distress syndrome by amniocentesis.Am J Obstet Gynecol · 1971 · 109(3):440-5doi:10.1016/0002-9378(71)90342-5 · PMID 5107880

    The origin of the amniotic-fluid lecithin-sphingomyelin approach to fetal lung maturity. PubMed carries no abstract, so it is cited only for its subject and date.

36. 36
    Fujiwara T, Maeta H, Chida S, Morita T, Watabe Y, Abe T. Artificial surfactant therapy in hyaline-membrane disease.Lancet · 1980 · 1(8159):55-9doi:10.1016/s0140-6736(80)90489-4 · PMID 6101413

    Ten severely ill preterm infants given surfactant into the trachea; eight survived. Uncontrolled.

37. 37
    Rittes PG. The use of phosphatidylcholine for correction of lower lid bulging due to prominent fat pads.Dermatol Surg · 2001 · 27(4):391-2doi:10.1046/j.1524-4725.2001.00282.x · PMID 11298713

    Thirty uncontrolled patients from a São Paulo clinic, treated with phosphatidylcholine injections into the lower eyelid fat pads; no recurrences over two years.

38. 38
    Rotunda AM, Kolodney MS. Mesotherapy and phosphatidylcholine injections: historical clarification and review.Dermatol Surg · 2006 · 32(4):465-80doi:10.1111/j.1524-4725.2006.32100.x · PMID 16681654

    Separates mesotherapy from phosphatidylcholine-deoxycholate injections, which were popularized in Brazil.

39. 39
    Stremmel W, Merle U, Zahn A, Autschbach F, Hinz U, Ehehalt R. Retarded release phosphatidylcholine benefits patients with chronic active ulcerative colitis.Gut · 2005 · 54(7):966-71doi:10.1136/gut.2004.052316 · PMID 15951544

    Phase 2A, 60 patients at one center: clinical remission 53% vs 10% on placebo.

40. 40
    Stremmel W, Ehehalt R, Autschbach F, Karner M. Phosphatidylcholine for steroid-refractory chronic ulcerative colitis: a randomized trial.Ann Intern Med · 2007 · 147(9):603-10doi:10.7326/0003-4819-147-9-200711060-00004 · PMID 17975182

    60 steroid-dependent patients at one referral center: steroid withdrawal with low activity in 50% vs 10%; the authors flag the small size and short duration.

41. 41
    Dávalos A, Alvarez-Sabín J, Castillo J, Díez-Tejedor E, Ferro J, Martínez-Vila E, et al. Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial).Lancet · 2012 · 380(9839):349-57doi:10.1016/S0140-6736(12)60813-7 · PMID 22691567

    2,298 patients; stopped for futility; global recovery OR 1.03. Funded by Ferrer Grupo, the manufacturer.

42. 42
    Zafonte RD, Bagiella E, Ansel BM, Novack TA, Friedewald WT, Hesdorffer DC, et al. Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: Citicoline Brain Injury Treatment Trial (COBRIT).JAMA · 2012 · 308(19):1993-2000doi:10.1001/jama.2012.13256 · PMID 23168823

    Phase 3, 1,213 patients at 8 US trauma centers: no difference at 90 days (global OR 0.98) or 180 days.

43. 43
    Dayan SH, Humphrey S, Jones DH, Lizzul PF, Gross TM, Stauffer K, Beddingfield FC. Overview of ATX-101 (Deoxycholic Acid Injection): A Nonsurgical Approach for Reduction of Submental Fat.Dermatol Surg · 2016 · 42 Suppl 1:S263-70doi:10.1097/DSS.0000000000000870 · PMID 27787266

    Summary of the 2015 approval of deoxycholic acid injection (Kybella, Belkyra) and its 18-study program; written with current and former Allergan employees.

44. 44
    Lee G, Choi S, Chang J, Choi D, Son JS, Kim K, Kim SM, Jeong S, Park SM. Association of L-α Glycerylphosphorylcholine With Subsequent Stroke Risk After 10 Years.JAMA Netw Open · 2021 · 4(11):e2136008doi:10.1001/jamanetworkopen.2021.36008 · PMID 34817582

    Korean national insurance cohort of 12 million: alpha-GPC users had higher 10-year stroke risk (matched aHR 1.43) in a dose-response pattern. Retrospective; open to confounding by indication.

45. 45
    Miethke AG, Moukarzel A, Porta G, Covarrubias Esquer J, Czubkowski P, Ordonez F, et al. Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Gastroenterol Hepatol · 2024 · 9(7):620-31doi:10.1016/S2468-1253(24)00080-3 · PMID 38723644

    93 children at 29 centers in 16 countries: in the BSEP cohort, itch score fell 1.1 points more and serum bile acids 187 µmol/L more than on placebo; MDR3 deficiency only in the all-PFIC cohort; diarrhea 57% vs 20%. Funded by Mirum Pharmaceuticals; several authors are Mirum employees.

46. 46
    Manley BJ, Kamlin COF, Donath SM, Francis KL, Cheong JLY, Dargaville PA, et al. Intratracheal Budesonide Mixed With Surfactant for Extremely Preterm Infants: The PLUSS Randomized Clinical Trial.JAMA · 2024 · 332(22):1889-99doi:10.1001/jama.2024.17380 · PMID 39527075

    1,059 infants born before 28 weeks in 21 units in Australia, New Zealand, Canada and Singapore: survival free of BPD 25.6% with budesonide vs 22.6% (adjusted risk difference 2.7%, 95% CI -2.1% to 7.4%).

47. 47
    Ambalavanan N, Carlo WA, Nowak KJ, Wiener LE, Cosby SS, Bhatt AJ, et al. Early Intratracheal Budesonide to Reduce Bronchopulmonary Dysplasia in Extremely Preterm Infants: The Budesonide in Babies (BiB) Randomized Clinical Trial.JAMA · 2025 · 334(16):1452-62doi:10.1001/jama.2025.16450 · PMID 41026481

    US Neonatal Research Network, 17 centers; stopped for futility at 641 of 1,160 planned: BPD or death 68.5% vs 67.9% (adjusted RR 1.00); hyperglycemia 66.7% vs 49.8%.

48. 48
    Kim HK, Park S, Kim SW, Park ES, Hong JY, Hong I, Baek MS. Association between L-α glycerylphosphorylcholine use and delayed dementia conversion: A nationwide longitudinal study in South Korea.J Prev Alzheimers Dis · 2025 · 12(4):100059doi:10.1016/j.tjpad.2025.100059 · PMID 40155153

    Same national database, 508,107 people with mild cognitive impairment: users had lower conversion to Alzheimer's (HR 0.899) and vascular dementia (HR 0.832) and lower stroke risk among non-progressors. Retrospective.

49. 49
    Stefan N, Hartleb M, Fan J, Demir M, Schattenberg JM, Gietka J, et al. Effect of essential phospholipids in metabolic dysfunction-associated steatotic liver disease: a randomised phase 4 clinical trial.Liver Int · 2026 · 46(5):e70601doi:10.1111/liv.70601 · PMID 41889076

    Double-blind, 193 randomized, 165 analyzed: liver fat by CAP fell more with essential phospholipids at 6 months (p = 0.0269); HbA1c and fatigue improved. Surrogate endpoints only; three authors are employed by Opella Healthcare.

50. 50
    Beijers RJ, Alonso-Fernández S, Soll RF, Rojas-Reyes MX, et al. Prophylactic versus selective use of surfactant for preventing morbidity and mortality in preterm infants at risk of respiratory distress syndrome.Cochrane Database Syst Rev · 2026 · 7(7):CD000510doi:10.1002/14651858.CD000510.pub3 · PMID 42483935

    10 trials, 3,151 infants: prophylactic surfactant reduced mortality only in settings without routine CPAP; with CPAP stabilization it probably slightly increases mortality. Background states that surfactant replacement reduces pneumothorax, death and death or BPD.

51. 51
    Lim DS, Bae KL, Pyo MK, Ko JH, Choi JK, Jung TW, et al. Extracellular phosphatidylcholine functions as a noncanonical TLR4 activator to drive adipocyte lipolysis and apoptosis.Front Pharmacol · 2026 · 17:1783264doi:10.3389/fphar.2026.1783264 · PMID 42137329

    3T3-L1 cultured fat cells only: phosphatidylcholine up to 25 mg/mL caused lipolysis and apoptosis that a TLR4 inhibitor blocked. Two authors list Amipharm Co., Ltd.; two also authored the AYP-101 trials. In vitro evidence.

52. 52
    Brosnan JT, Jacobs RL, Stead LM, Brosnan ME. Methylation demand: a key determinant of homocysteine metabolism.Acta Biochim Pol · 2004 · 51(2):405-13PMID 15218538

    Review: PEMT and guanidinoacetate methyltransferase are normally the largest sources of homocysteine; it is remethylated by betaine-homocysteine methyltransferase or by cobalamin-containing methionine synthase fed from the folate pool. PubMed lists no DOI.

53. 53
    da Costa KA, Kozyreva OG, Song J, Galanko JA, Fischer LM, Zeisel SH. Common genetic polymorphisms affect the human requirement for the nutrient choline.FASEB J · 2006 · 20(9):1336-44doi:10.1096/fj.06-5734com · PMID 16816108

    In the same 57 depletion volunteers, the PEMT promoter variant rs12325817 conferred an odds ratio of 25 for organ dysfunction; the BHMT variant tested was not associated. Small sample; not a basis for testing.

54. 54
    Böckmann KA, Bernhard W, Minarski M, Shunova A, Schwarz J, Poets CF, Franz AR. Choline supplementation in preterm infants: effects of four different supplements on choline plasma concentrations.Eur J Nutr · 2026 · 65(1):20doi:10.1007/s00394-025-03865-w · PMID 41524941

    32 enterally fed infants of 28 to 32 weeks randomized to four choline supplements for 48 hours: all raised plasma choline similarly. Short-term blood levels only.

55. 55
    Chen R, Yang FX, Tan YF, Deng M, Li H, Xu Y, Ouyang WX, Song YZ. Clinical and genetic characterization of pediatric patients with progressive familial intrahepatic cholestasis type 3 (PFIC3): identification of 14 novel ABCB4 variants and review of the literatures.Orphanet J Rare Dis · 2022 · 17(1):445doi:10.1186/s13023-022-02597-y · PMID 36550572

    Thirteen new and 82 published cases: GGT raised in 88 of 88 tested, UDCA response 66.1%, unfavorable outcome 41.1%; biallelic null variants did worst. Pooled published cases are subject to reporting bias.

56. 56
    Al-Hussaini A, Lone K, Bashir MS, Alrashidi S, Fagih M, Alanazi A, et al. ATP8B1, ABCB11, and ABCB4 genes defects: novel mutations associated with cholestasis with different phenotypes and outcomes.J Pediatr · 2021 · 236:113-123.e2doi:10.1016/j.jpeds.2021.04.040 · PMID 33915153

    Retrospective series of 65 Arab children (5 ATP8B1, 35 ABCB11, 25 ABCB4): PFIC2 had shorter survival and faster progression than PFIC3, and the authors conclude that UDCA could favorably modify the course of PFIC3.

57. 57
    Liebe R, Lammert F, Schmidt HH, Krawczyk M. Use of genetic analysis in adult cholestatic liver disease: lessons from progressive paediatric syndromes and cohort studies.Gut · 2026 · 75(11):2267-77doi:10.1136/gutjnl-2025-337027 · PMID 42309808

    2026 review that regroups the childhood PFICs with intrahepatic cholestasis of pregnancy, benign recurrent intrahepatic cholestasis and LPAC as genetic cholestasis, and discusses genotype-guided use of UDCA and bile acid transporter inhibitors.

58. 58
    Nayagam JS, Campbell SM, Chung Y, Heneghan MA, Joshi D. Liver transplantation for adult presentations of MDR3 deficiency.Clin Res Hepatol Gastroenterol · 2026 · 102944doi:10.1016/j.clinre.2026.102944 · PMID 42887767

    Single-center retrospective series from King's College Hospital, London: seven adults with genetically confirmed MDR3 deficiency transplanted 2013-2024 at a median 31.9 years; only four diagnosed by the time of transplant assessment.

59. 59
    Pauline ML, Huynh C, Persad R, Wizzard PR, Nation PN, Rahman R, et al. Fatty acid profiles in blood and tissues of parenteral nutrition-fed neonatal piglets using a novel lipid emulsion containing choline.JPEN J Parenter Enteral Nutr · 2025 · 49(8):942-50doi:10.1002/jpen.70016 · PMID 41015823

    Piglet study whose introduction states that current intravenous lipid emulsions are devoid of choline; tests a new emulsion containing it. Two authors are from Baxter R&D. Animal evidence.

60. 60
    Hilberath J, Shunova A, Heister L, Poets CF, Bernhard W. Choline and choline-related metabolites in pediatric short bowel syndrome.Nutrients · 2026 · 18(10):1553doi:10.3390/nu18101553 · PMID 42197014

    Retrospective study of 80 children: a quarter had markedly low choline and betaine, the only difference between steatotic and non-steatotic patients; TMAO up to 30 µmol/L. Association; the authors call for trials.

61. 61
    Bernhard W, Shunova A, Boriga J, Graepler-Mainka U, Hilberath J. Low plasma choline, high trimethylamine oxide, and altered phosphatidylcholine subspecies are prevalent in cystic fibrosis patients with pancreatic insufficiency.Nutrients · 2025 · 17(5):868doi:10.3390/nu17050868 · PMID 40077735

    162 patients with cystic fibrosis: those with pancreatic insufficiency had falling choline and betaine with age and often high TMAO. Retrospective; no intervention tested.

62. 62
    Puri P, Baillie RA, Wiest MM, Mirshahi F, Choudhury J, Cheung O, et al. A lipidomic analysis of nonalcoholic fatty liver disease.Hepatology · 2007 · 46(4):1081-90doi:10.1002/hep.21763 · PMID 17654743

    Human liver biopsies: total phosphatidylcholine reduced in simple steatosis and steatohepatitis, free cholesterol to PC ratio roughly doubled. Cross-sectional.

63. 63
    Guerrerio AL, Colvin RM, Schwartz AK, Molleston JP, Murray KF, Diehl A, et al. Choline intake in a large cohort of patients with nonalcoholic fatty liver disease.Am J Clin Nutr · 2012 · 95(4):892-900doi:10.3945/ajcn.111.020156 · PMID 22338037

    664 biopsied patients in the NASH Clinical Research Network: intake below half the adequate intake associated with worse fibrosis in postmenopausal women only. Cross-sectional, food-frequency questionnaire.

64. 64
    Tan HL, Mohamed R, Mohamed Z, Zain SM. Phosphatidylethanolamine N-methyltransferase gene rs7946 polymorphism plays a role in risk of nonalcoholic fatty liver disease: evidence from meta-analysis.Pharmacogenet Genomics · 2016 · 26(2):88-95doi:10.1097/FPC.0000000000000193 · PMID 26636496

    Six case-control studies, 792 cases and 2,722 controls: odds ratio 1.55 for the A allele, significant only in East Asians.

65. 65
    Yiannakou I, Long MT, Jacques PF, Beiser A, Pickering RT, Moore LL. Eggs, dietary choline, and nonalcoholic fatty liver disease in the Framingham Heart Study.J Nutr · 2025 · 155(3):923-35doi:10.1016/j.tjnut.2024.10.026 · PMID 39424072

    1,414 Framingham participants followed about 6 years with CT: top choline tertile risk ratio 0.69 for new fatty liver; eggs not associated. Observational; one author also lists Novo Nordisk.

66. 66
    Li M, Ou Q, Qin Q, Chen J, Yang S, Zhao J, et al. Diet-induced RKIP downregulation disrupts PC/PE-ER homeostasis to drive MASLD.Nat Commun · 2025 · 16(1):11092doi:10.1038/s41467-025-65982-8 · PMID 41387436

    Mostly male-mouse work: high-fat diet lowers hepatic RKIP, which is needed for efficient PEMT translation; RKIP loss worsens the PC/PE imbalance and fatty liver. Human livers with MASLD also showed less RKIP.

67. 67
    Tang B, Shen Q, Yuan J, Huang X, Shao Y, Zhu N, et al. Bariatric surgery resolves MASH by enhancing MAT1A-dependent one-carbon metabolism.Nat Commun · 2026 · 17(1)doi:10.1038/s41467-026-75822-y · PMID 42637748

    Male mouse models: sleeve gastrectomy raised MAT1A and S-adenosylmethionine and restored PC/PE balance; human support from 4 paired biopsies and 42 plasma samples. Mechanistic.

68. 68
    Dajani AI, Popovic B. Essential phospholipids for nonalcoholic fatty liver disease associated with metabolic syndrome: A systematic review and network meta-analysis.World J Clin Cases · 2020 · 8(21):5235-49doi:10.12998/wjcc.v8.i21.5235 · PMID 33269259

    Ten studies of 22 to 324 patients, randomized and non-randomized, pooled; ALT and lipids improved. The second author was employed by Sanofi-Aventis Deutschland consumer healthcare medical affairs.

69. 69
    Pan Y, Xue F, Wang S, Zhong B, Zhan Y, Wang Q, et al. A real-world study of polyenyl phosphatidylcholine in the management of patients with metabolic dysfunction-associated fatty liver disease in China clinical practice.Front Med (Lausanne) · 2025 · 12:1610083doi:10.3389/fmed.2025.1610083 · PMID 41001365

    Retrospective records of 7,093 treated patients against untreated controls: FIB-4 change -0.12 vs +0.11 at 24 weeks. Not randomized; four authors are employed by Opella or A. Nattermann & Cie.

70. 70
    Lieber CS, Weiss DG, Groszmann R, Paronetto F, Schenker S, et al. I. Veterans Affairs Cooperative Study of polyenylphosphatidylcholine in alcoholic liver disease: effects on drinking behavior by nurse/physician teams.Alcohol Clin Exp Res · 2003 · 27(11):1757-64doi:10.1097/01.ALC.0000093744.12232.34 · PMID 14634491

    Companion paper: drinking fell from 16 to about 2.5 drinks a day in both arms with nurse-led brief intervention.

71. 71
    Dajani AI, Abu Hammour AM, Zakaria MA, Al Jaberi MR, Nounou MA, Semrin AI. Essential phospholipids as a supportive adjunct in the management of patients with NAFLD.Arab J Gastroenterol · 2015 · 16(3-4):99-104doi:10.1016/j.ajg.2015.09.001 · PMID 26589371

    Open-label study of 324 patients, all of whom received essential phospholipids; with no untreated comparison the improvements cannot be attributed to the product.

72. 72
    Milkiewicz P, Wunsch E, Derezinski T, Marlicz W. Do Current Data Support the Use of Essential Phospholipids in MASLD? A Comment on Stefan et al.Liver Int · 2026 · 46(7):e70728doi:10.1111/liv.70728 · PMID 42249617

    Letter questioning the 2026 phase 4 trial. PubMed carries no abstract; cited for its title and authorship.

73. 73
    Lin Y, Song Y. Confounding Metabolic Therapies and Weight Dynamics in Evaluating Essential Phospholipids for MASLD.Liver Int · 2026 · 46(6):e70689doi:10.1111/liv.70689 · PMID 42124336

    Letter on the 2026 phase 4 trial. PubMed carries no abstract; cited for its title.

74. 74
    Stefan N, Popovic B. Response to Comments on 'Effect of Essential Phospholipids in Metabolic Dysfunction-Associated Steatotic Liver Disease'.Liver Int · 2026 · 46(8):e70776doi:10.1111/liv.70776 · PMID 42385155

    Authors' reply to the two letters; the second author is affiliated with Opella, A. Nattermann & Cie. PubMed carries no abstract.

75. 75
    Dajani AI, Popovic B, Amand C, Tong S, Starostin KM, Goncharuk V. MANPOWER study: Real-world post-hoc analysis assessing essential phospholipids for non-alcoholic fatty liver disease from the Russian registry.World J Hepatol · 2025 · 17(6):103217doi:10.4254/wjh.v17.i6.103217 · PMID 40606927

    Post hoc analysis of an observational registry of 2,843 adults given Essentiale; liver enzymes and ultrasound features improved, with no untreated comparison described. Five of six authors list A. Nattermann, Opella or Sanofi.

76. 76
    Karner M, Kocjan A, Stein J, Schreiber S, von Boyen G, Uebel P, et al. First multicenter study of modified release phosphatidylcholine "LT-02" in ulcerative colitis: a randomized, placebo-controlled trial in mesalazine-refractory courses.Am J Gastroenterol · 2014 · 109(7):1041-51doi:10.1038/ajg.2014.104 · PMID 24796768

    156 patients at 24 centers: only the 3.2 g dose beat placebo on the activity score (p = 0.030); remission 31.4% vs 15% (p = 0.089). Funded by Lipid Therapeutics, two of whose employees are authors.

77. 77
    Bechara FG, Skrygan M, Kreuter A, Altmeyer P, Gambichler T. Cytokine mRNA levels in human fat tissue after injection lipolysis with phosphatidylcholine and deoxycholate.Arch Dermatol Res · 2008 · 300(8):455-9doi:10.1007/s00403-008-0869-7 · PMID 18563422

    Seven patients with lipomas: Lipostabil, described as a phosphatidylcholine and deoxycholate containing substance, caused acute panniculitis with raised inflammatory cytokines at 48 hours.

78. 78
    Duncan D, Rotunda AM. Injectable therapies for localized fat loss: state of the art.Clin Plast Surg · 2011 · 38(3):489-501doi:10.1016/j.cps.2011.02.005 · PMID 21824545

    Notes the critical scrutiny of Lipodissolve and PC/DC injections by the media and the US FDA. The FDA's own 2010 documents could not be reached from the session in which this page was written.

79. 79
    Kyong YY, Choi KH. Woman with hemorrhagic spots on her abdomen.Clin Toxicol (Phila) · 2013 · 51(8):804-5doi:10.3109/15563650.2013.824580 · PMID 23962098

    One-case report from the Catholic University of Korea: agitation and metabolic acidosis after Lipodissolve; its abstract says the injections continued in many countries despite a US FDA warning, which it does not date.

80. 80
    Mahmud K, Crutchfield CE. Lipodissolve for body sculpting: safety, effectiveness, and patient satisfaction.J Clin Aesthet Dermatol · 2012 · 5(10):16-9PMID 23125885

    Experience of two collaborating practices with 1,616 patients; uncontrolled and reported by the treating physicians. PubMed lists no DOI.

81. 81
    Thomas MK, D'Silva JA, Borole AJ. Injection Lipolysis: A Systematic Review of Literature and Our Experience with a Combination of Phosphatidylcholine and Deoxycholate over a Period of 14 Years in 1269 Patients of Indian and South East Asian Origin.J Cutan Aesthet Surg · 2018 · 11(4):222-8doi:10.4103/JCAS.JCAS_117_18 · PMID 30886477

    Retrospective single-practice series without a control group.

82. 82
    Jones DH, Carruthers J, Joseph JH, Callender VD, Walker P, Lee DR, et al. REFINE-1, a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial With ATX-101, an Injectable Drug for Submental Fat Reduction.Dermatol Surg · 2016 · 42(1):38-49doi:10.1097/DSS.0000000000000578 · PMID 26673433

    506 patients: composite one-grade response 70.0% vs 18.6%; marginal mandibular nerve paresis in 4.3%. Authors include employees of the developer, Kythera Biopharmaceuticals.

83. 83
    Choi SY, Abd El-Aty AM, Kim BJ. Randomized, Double-Blind, Placebo-Controlled Phase II Trial of AYP-101 (Soybean Phosphatidylcholine) for Submental Fat Reduction in Asian Adults.Clin Ther · 2025 · 47(10):889-93doi:10.1016/j.clinthera.2025.07.016 · PMID 40850886

    96 patients at one center: one-grade improvement in 69.70% (25 mg/mL) and 48.39% (50 mg/mL) vs 22.58% on placebo at 4 weeks. The abstract does not give the full formulation; PubMed indexes the record under deoxycholic acid as well.

84. 84
    Lee HJ, Jiang X, Abd El-Aty AM, Jeong JH, Chung JY. Phase 1 study of AYP-101 (soybean phosphatidylcholine): safety, pharmacokinetics, and lipid profile effects for reducing submental fat.Lipids Health Dis · 2024 · 23(1):426doi:10.1186/s12944-024-02387-4 · PMID 39732703

    Randomized, double-blind, single-dose phase 1 in 26 adults; describes AYP-101 as 93% soybean phosphatidylcholine without naming other ingredients; all 72 reported reactions mild, mostly injection-site pain and bruising.

85. 85
    Kukharchuk VV, Ponomarenko EA, Lisitsa AV, Romashova YA, Pleshakova TO, Yarovaya EB, et al. Vitaphospholip® (water-soluble phosphatidylcholine) in the treatment of combined hyperlipidemia: a randomized, placebo-controlled clinical trial.Biomed Khim · 2025 · 71(5):364-74doi:10.18097/PBMCR1619 · PMID 41211734

    100 patients for 12 weeks: non-HDL cholesterol -13.2% vs -4.3%. A single trial of one proprietary formulation; most authors are from the Institute of Biomedical Chemistry in Moscow.

86. 86
    De Jesus Moreno Moreno M. Cognitive improvement in mild to moderate Alzheimer's dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double-blind, randomized, placebo-controlled trial.Clin Ther · 2003 · 25(1):178-93doi:10.1016/s0149-2918(03)90023-3 · PMID 12637119

    261 patients for 180 days: ADAS-Cog improved 3.20 points vs a 2.90-point decline on placebo. A single trial; its own background states that earlier controlled trials of choline and lecithin had failed.

87. 87
    Tammenmaa-Aho I, Asher R, Soares-Weiser K, Bergman H. Cholinergic medication for antipsychotic-induced tardive dyskinesia.Cochrane Database Syst Rev · 2018 · 3(3):CD000207doi:10.1002/14651858.CD000207.pub2 · PMID 29553158

    14 small trials (5 to 60 people) of drugs including choline and lecithin: low to very low quality evidence; cholinergic drugs have little place in routine clinical work.

88. 88
    Qi J, You T, Li J, Pan T, Xiang L, Han Y, Zhu L. Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies.J Cell Mol Med · 2018 · 22(1):185-94doi:10.1111/jcmm.13307 · PMID 28782886

    Eleven cohorts: HR 1.23 for cardiovascular events and 1.55 for mortality, the latter possibly inflated by publication bias.

89. 89
    Zhang C, He J, Huo Y, Liu L, Xie Y, Meng Y, et al. Gut microbial metabolite trimethylamine N-oxide as a novel predictor for adverse cardiovascular events after PCI: a systematic review and dose-response meta-analysis.Nutr J · 2025 · 24(1):91doi:10.1186/s12937-025-01159-9 · PMID 40524200

    11 studies, 13 cohorts, 11,279 patients after percutaneous coronary intervention: higher TMAO HR 1.99 for major adverse cardiovascular events. Observational association.

90. 90
    Zhong VW, Van Horn L, Cornelis MC, Wilkins JT, Ning H, Carnethon MR, et al. Associations of Dietary Cholesterol or Egg Consumption With Incident Cardiovascular Disease and Mortality.JAMA · 2019 · 321(11):1081-95doi:10.1001/jama.2019.1572 · PMID 30874756

    Six US cohorts, 29,615 people: each half egg a day HR 1.06 for cardiovascular disease, no longer significant after adjusting for dietary cholesterol. Observational.

91. 91
    Drouin-Chartier JP, Chen S, Li Y, Schwab AL, Stampfer MJ, Sacks FM, et al. Egg consumption and risk of cardiovascular disease: three large prospective US cohort studies, systematic review, and updated meta-analysis.BMJ · 2020 · 368:m513doi:10.1136/bmj.m513 · PMID 32132002

    Three cohorts and a meta-analysis of 1.72 million people: one egg a day not associated with cardiovascular disease (RR 0.98); lower risk in Asian cohorts. Observational.

92. 92
    Thomas MS, DiBella M, Blesso CN, Malysheva O, Caudill M, Sholola M, Cooperstone JL, Fernandez ML. Comparison between Egg Intake versus Choline Supplementation on Gut Microbiota and Plasma Carotenoids in Subjects with Metabolic Syndrome.Nutrients · 2022 · 14(6):1179doi:10.3390/nu14061179 · PMID 35334836

    Crossover in 23 adults with metabolic syndrome: neither three eggs a day nor choline bitartrate (400 mg choline) changed TMAO from baseline.

93. 93
    Aryaeian N, Heydarian A, Tahvilian N, Hosseini H, Ahmadi AR, Davarpanah SH. Effect of egg consumption on circulating choline, betaine, and trimethylamine n-oxide in adults: a systematic review and meta-analysis of randomized controlled trials.Nutr J · 2025 · 24(1):165doi:10.1186/s12937-025-01227-0 · PMID 41146117

    Six randomized trials (five for TMAO): no effect of eggs on TMAO (WMD -0.08, 95% CI -0.47 to 0.32); certainty moderate by NutriGRADE.

94. 94
    Zhuang Z, Gao M, Yang R, Liu Z, Cao W, Huang T. Causal relationships between gut metabolites and Alzheimer's disease: a bidirectional Mendelian randomization study.Neurobiol Aging · 2021 · 100:119.e15-119.e18doi:10.1016/j.neurobiolaging.2020.10.022 · PMID 33280888

    Genetically predicted TMAO and its precursors not associated with Alzheimer's disease (TMAO OR 0.99).

95. 95
    Andreu-Sánchez S, Ahmad S, Kurilshikov A, Beekman M, Ghanbari M, van Faassen M, et al. Unraveling interindividual variation of trimethylamine-N-oxide and its precursors at the population level.iMeta · 2024 · 3(3):e183doi:10.1002/imt2.183 · PMID 38898991

    Five Dutch cohorts, 7,834 people: plasma choline (HR 1.17), not TMAO, associated with cardiovascular disease; Mendelian randomization found no significant association; fish associated with TMAO.

96. 96
    Louck LE, Cara KC, Klatt K, Wallace TC, Chung M. The Relationship of Circulating Choline and Choline-Related Metabolite Levels with Health Outcomes: A Scoping Review of Genome-Wide Association Studies and Mendelian Randomization Studies.Adv Nutr · 2024 · 15(2):100164doi:10.1016/j.advnut.2023.100164 · PMID 38128611

    Scoping review of 27 genome-wide association and 26 Mendelian randomization studies of choline metabolites; one author is with Think Health Group, a consultancy.

97. 97
    Ionescu RF, Cretoiu SM. From Fecal Microbial Potential to Circulating Trimethylamine N-oxide and Cardiovascular Events: A Narrative Review.Cureus · 2026 · 18(9):e115807doi:10.7759/cureus.115807 · PMID 42835796

    2026 critical review: blood TMAO integrates diet, microbes, absorption, liver FMO3 and kidney clearance; prognostic association is not causal mediation; Mendelian randomization and kidney studies challenge a simple causal reading.

98. 98
    Wang W, Takeda Y, Kimura M, Matsuoka R, Hashimoto T, Yanaka N, Sugano M. Association between egg-derived phosphatidylcholine intake and trimethylamine N-oxide in healthy middle-aged and older adults.Lipids Health Dis · 2026 · 25(1)doi:10.1186/s12944-026-02909-2 · PMID 41742272

    Secondary analysis of a 12-week trial in 32 adults: 3 g/day egg phosphatidylcholine raised TMAO within the group but not against placebo. Four authors are employees of Kewpie Corporation, a food company.

99. 99
    Ferreira JP, Marques P, Zhang G, Possik E, Mavrakanas TA, Tsoukas MA, Sharma A. Processed plant-based meat-supplemented diet versus red meat-based supplemented diet randomized cross-over trial Finding Optimal Oral Diet-1 (FOOD-1) trial.Sci Rep · 2026 · 16(1)doi:10.1038/s41598-026-41165-3 · PMID 41813762

    Crossover, 41 adults, 6 days each: plant-based meat lowered TMAO by 0.61 log units against red meat. Short and small.

100. 100
     Agassandian M, Mallampalli RK. Surfactant phospholipid metabolism.Biochim Biophys Acta · 2013 · 1831(3):612-25doi:10.1016/j.bbalip.2012.09.010 · PMID 23026158

     Review: disaturated phosphatidylcholine confers surfactant's surface-tension-lowering activity; phosphatidylglycerol has roles in innate immunity.

101. 101
     Willson DF, Notter RH. The future of exogenous surfactant therapy.Respir Care · 2011 · 56(9):1369-86doi:10.4187/respcare.01306 · PMID 21944686

     Review: surfactant replacement is routine for infant respiratory distress syndrome but has been less effective, and largely disappointing, in acute lung injury and ARDS.

102. 102
     Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.Pediatrics · 1972 · 50(4):515-25PMID 4561295

     The original controlled trial of antenatal glucocorticoids. PubMed carries no abstract and lists no DOI; cited for its subject, design and date.

103. 103
     Dalziel SR, Rea HH, Walker NK, Parag V, Mantell C, Rodgers A, Harding JE. Long term effects of antenatal betamethasone on lung function: 30 year follow up of a randomised controlled trial.Thorax · 2006 · 61(8):678-83doi:10.1136/thx.2005.051763 · PMID 16601084

     University of Auckland follow-up of 534 30-year-olds whose mothers took part in the first and largest randomized trial of antenatal betamethasone: no difference in lung function or asthma.

104. 104
     Ardell S, Pfister RH, Soll R. Animal derived surfactant extract versus protein free synthetic surfactant for the prevention and treatment of respiratory distress syndrome.Cochrane Database Syst Rev · 2015 · (8):CD000144doi:10.1002/14651858.CD000144.pub3 · PMID 26301526

     Fifteen trials: animal-derived surfactant reduced pneumothorax (RR 0.65) and mortality (RR 0.89) against protein-free synthetic surfactant, with more necrotizing enterocolitis (RR 1.38).

105. 105
     Sweet DG, Carnielli VP, Greisen G, Hallman M, Klebermass-Schrehof K, Ozek E, et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update.Neonatology · 2023 · 120(1):3-23doi:10.1159/000528914 · PMID 36863329

     Sixth version of the European guidelines, graded by GRADE: antenatal steroids, non-invasive support from birth, early surfactant.

106. 106
     Abdel-Latif ME, Davis PG, Wheeler KI, De Paoli AG, Dargaville PA. Surfactant therapy via thin catheter in preterm infants with or at risk of respiratory distress syndrome.Cochrane Database Syst Rev · 2021 · 5(5):CD011672doi:10.1002/14651858.CD011672.pub2 · PMID 33970483

     Sixteen trials: thin-catheter surfactant vs endotracheal tube reduced death or bronchopulmonary dysplasia (RR 0.59; moderate certainty).

107. 107
     Dargaville PA, Kamlin COF, Orsini F, Wang X, De Paoli AG, Kanmaz Kutman HG, et al. Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.JAMA · 2023 · 330(11):1054-63doi:10.1001/jama.2023.15694 · PMID 37695601

     486 infants of 25 to 28 weeks on CPAP: minimally invasive surfactant did not change death or disability at 2 years (36.3% vs 36.1%) but reduced respiratory hospitalization (25.1% vs 38.2%).

108. 108
     Phattraprayoon N, Koonrungsesomboon N, Na Takuathung M. Efficacy of pulmonary surfactant with budesonide in infants born at or less than 28 weeks' gestation: a systematic review and meta-analysis.Sci Rep · 2025 · 15(1):45116doi:10.1038/s41598-025-33028-0 · PMID 41430414

     Randomized trials only: no significant reduction in BPD (RR 0.96, 95% CI 0.86 to 1.08; low certainty) or pre-discharge mortality (RR 0.92).

109. 109
     Wurtman RJ, Regan M, Ulus I, Yu L. Effect of oral CDP-choline on plasma choline and uridine levels in humans.Biochem Pharmacol · 2000 · 60(7):989-92doi:10.1016/s0006-2952(00)00436-6 · PMID 10974208

     Twelve subjects, three doses: citicoline raised plasma choline for 5 to 10 hours and uridine by up to 120%; cytidine was undetectable.

110. 110
     Jeon J, Lee SY, Lee S, Han C, Park GD, Kim SJ, Chang JG, Kim WJ. Efficacy and safety of choline alphoscerate for amnestic mild cognitive impairment: a randomized double-blind placebo-controlled trial.BMC Geriatr · 2024 · 24(1):774doi:10.1186/s12877-024-05366-7 · PMID 39300341

     100 patients for 12 weeks: ADAS-cog fell 2.34 points, more than placebo. One author is from the Suheung Technology Research Institute, linked to the capsule tested.

111. 111
     Tanaka-Kanegae R, Kimura H, Hamada K. Pharmacokinetics of soy-derived lysophosphatidylcholine compared with that of glycerophosphocholine: a randomized controlled trial.Biosci Biotechnol Biochem · 2024 · 88(6):648-55doi:10.1093/bbb/zbae031 · PMID 38490741

     Single doses in 12 men: glycerophosphocholine and lysophosphatidylcholine raised plasma choline without significantly raising TMAO. All authors are Otsuka Pharmaceutical employees.

112. 112
     Park YJ, Yu J, Kang JH, Park SJ, Jeong S, Lee G, et al. Association between L-α-glycerylphosphorylcholine use and risk of kidney cancer: A nationwide representative retrospective cohort study.Cancer Epidemiol · 2026 · 103:103152doi:10.1016/j.canep.2026.103152 · PMID 42361543

     Korean national insurance cohort, 1:5 propensity matched, 81,970 users and 409,801 non-users aged 50 or older: no association with kidney cancer (aHR 0.95, 95% CI 0.84-1.08). Retrospective.

113. 113
     Witoslawska A, Meessen JMTA, Hilvo M, Jylhä A, Zannad F, Cerrato M, et al. Ceramide and phosphatidylcholine lipids-based risk score predicts major cardiovascular outcomes in patients with heart failure.Eur J Clin Invest · 2025 · 55(3):e14359doi:10.1111/eci.14359 · PMID 39578928

     CERT2 in 5,461 heart-failure patients from two trials: highest vs lowest category HR about 2.8 for cardiovascular death. Prediction, not treatment; several authors are from Zora Biosciences, which developed the score.