Phosphatidylcholine in Liver

Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996

Copyright©1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

Phosphatidylcholine: A Superior ProtectantAgainst Liver Damage

Parris M. Kidd, Ph.D.

AbstractPhosphatidylcholine (PC) is one of the most important support nutrients for the

liver. PC is a phospholipid, a large biological molecule that is a universal building blockfor cell membranes. A cell’s membranes are its essence: they regulate the vast majorityof the activities that make up life. Most liver metabolism occurs on cell membranes,which occupy about 33,000 square meters in the human. More than 2 decades ofclinical trials indicate that PC protects the liver against damage from alcoholism,pharmaceuticals, pollutant substances, viruses, and other toxic influences, most ofwhich operate by damaging cell membranes.

The human liver is confronted with tens of thousands of exogenous substances.The metabolism of these xenobiotics can result in the liver’s detoxicative enzymesproducing reactive metabolites that attack the liver tissue. Dietary supplementationwith PC (a minimum 800 mg daily, with meals) significantly speeds recovery of theliver. PC has also been shown to be effective against alcohol’s liver toxicity in well-controlled studies on baboons.

PC has other qualities that enhance its usefulness as a dietary supplement. PCis safe, and is a safer means for dietary choline repletion than choline itself. PC is fullycompatible with pharmaceuticals, and with other nutrients. PC is also highly bioavailable(about 90% of the administered amount is absorbed over 24 hours), and PC is anexcellent emulsifier that enhances the bioavailability of nutrients with which it is co-administered. PC’s diverse benefits and proven safety indicate that it is a premier livernutrient. (Alt Med Rev 1996;1(4):258-274)

Phosphatidylcholine (PC) is a phospholipid nutrient that is a major building block forall known cells.1 PC is the most abundant constituent of cell membranes, the thin and delicateyet dynamic surfaces on which cells carry out most of their activities (Fig. 1). The “workhorse”parenchymal cells that make up the liver are especially reliant on their membranes,2 and it hasbeen estimated that the human liver as a whole encapsulates some 33,000 square meters of cellmembrane.3 The liver’s wide range of functions, as well as its capacity for ongoing renewal,hinge on its ability to make new cell membranes, which are on average 65% PC. Decades ofbasic and clinical research on this nutrient indicate that it is critical for optimal liver function.


Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 59

In its programmed efforts to rid thebody of potential toxins, the liver paradoxi-cally generates toxins that can damage the livertissue. This can happen because evolution hasbeen tricked: manmade foreign substancesactivate the liver’s natural enzyme detoxifica-tion pathways, but often the metabolites thatthe liver generates from them via such“bioactivation” are more toxic than the start-ing substrates. Whether their toxicity occursdirectly or following bioactivation, virtuallyall of the agents that damage the liver do so byway of attack on the membrane systems of theparenchymal cells.

Membrane systems are central to thesurvival and specialized functioning of allcells. In order to carry out its metabolic re-sponsibilities, the liver parenchymal cells aredensely packed with membranes. Given thiscentral role of membranes in the liver’s func-tions, the demonstrated superiority of PC insupporting the liver against damage is thor-oughly consistent with the known mechanismsof liver homeostasis, toxic liver damage, andthe liver’s recovery processes. Out of thiscomes a dramatic conclusion: PC is the singlemost important nutrient for the liver.

The Human Liver, theDetoxification Paradox, and PC

The liver is the body’s main organ fordisarming and disposing of toxins, yet isitself vulnerable to toxic attack. Such toxicattack is both endogenous (from toxinsgenerated in the liver), and exogenous (dueto toxins coming from the outside). Simi-lar metabolic mechanisms are employedto deal with the toxins coming from eithersource, but due to the stressful influencesof modern life, toxic overload is a con-stant possibility.

The healthy liver is the body’s largestorgan and is probably also its most meta-bolically versatile. The liver carries outhundreds, if not thousands, of sophisti-cated enzymatic reactions along numerous

metabolic pathways. Enzymes residing withinthe membranes of the parenchymal cells pro-duce biological molecules by synthesis fromsmaller molecules, by the modification of pre-existing metabolites or from newly-absorbednutrients. The parenchymal cells also processhormones and many other metabolic wasteproducts into water-soluble compounds forsubsequent excretion. With the myriad of func-tions that it performs, the liver plays a pivotalrole in maintaining homeostasis, i.e., healthin all its aspects. But these routine liver func-tions do generate intrinsic, potentially toxicmetabolites.

Normally the parenchymal cells arewell equipped with protective antioxidantenzymes and with water-soluble antioxidantssuch as glutathione, cysteine, and taurine toneutralize endogenous toxic metabolicproducts. However, with the additionalchallenge posed to the liver’s defenses by food-borne toxins and by the bioactivation productsof xenobiotics, including lifestyle-relatedsubstances such as alcohol the liver’sdetoxification enzyme systems can be divertedto the compulsive generation of toxicmetabolites that attack their maker. Last but

Phosphatidylcholine

CELL INTERIOR

CELL EXTERIOR

CHOLINE

PHOSPHATE

GLYCEROL

FATT

Y A

CID

FATTY ACID

1 2

Head

Tail

figure 1

Figure 1. Phosphatidylcholine, major constituentof cell membrane systems. Left: Molecular planof PC. Middle: PC, membrane building block.Right: the basic membrane plan, with proteinsinterspersed in a lipid matrix.



not least, by being the first way-station for theblood draining the intestines (via the portalcirculation), the liver tissue is directly exposedto preformed toxins that enter by the oral route.

It is highly doubtful that the humanliver is evolutionarily equipped to cope withthe tens of thousands of toxins generated bymodern circumstances: pharmaceuticals, pol-lutants, and other toxins associated with a self-abusive lifestyle. As the liver becomes over-burdened with such toxins, its stores of pro-tective antioxidants are progressively de-pleted.4 Parenchymal cells die, and cell deathspreads zonally. Left unchecked, necrotic andinflammatory damage comes to threaten wholeregions of the liver.

Overall Clinical Benefits of PC for theLiver

A large number of controlled clinicaltrials, conducted mostly in Europe, have in-

vestigated PC for the management of liverdamage coming from a variety of toxic insults.In a landmark study published in 1973,Wallnoefer and Hanusch in Germany followed650 subjects with various degrees of liver dam-age for at least 5 years.6 This trial relied onbiopsy, conducted in conjunction with bloodanalyses and clinical tests, to assess the scopeand character of liver damage.7 The subjectsreceived PC for periods that ranged from 4weeks to several years. The distributions ofsubjects, listed in groups according to approxi-mate degree of damage severity, was as fol-lows: fatty degeneration, n=130; acute inflam-mation, n=157; persistent inflammation (sub-acute and chronic), n=41; chronic inflamma-tion, n=122; chronic aggressive inflammation,n=70; advanced fibrotic damage, n=130. Allsubjects were begun on intravenous PC (950mg*) along with oral PC (450-700 mg*), un-til blood parameters began to return to nor-mal; they were then shifted to oral PC only.

Figure 2. Schematic of the liver parenchymal cell, showing the internal functionalunits or organelles. Those superscriptedM are made up of membranes or rely onmembranes to function. Modified from Sherlock S, Dooley J. Diseases of the Liver andBiliary System. Oxford: Blackwell Scientific Publications; 1993.

Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 261


All the groups of subjects in this studybenefited from receiving PC. Of those withmild damage, more than half (51.1%) showedexcellent improvement, and many subjects ex-perienced reversal of their fatty degeneration.In the acute inflammation group, lab measuresand biopsy indicated PC accelerated recoveryby about 10 days. In the group with persistentinflammation, PC returned the enzyme param-eters to normal after 30 days. In chronic ag-gressive inflammation , more than one-third(35.3%) experienced benefit and among thosewith advanced fibrotic damage, 17.5% ben-efited. In this last group with liver damage ofthe greatest severity, recovery was better whenPC was given intravenously as well as by theoral route.

Notably, some of the subjects with per-sistent inflammatory damage included in thistrial had failed to benefit from milk thistle ex-tract (“silymarin”) or steroid drugs, but ben-efited from PC. The investigators commentedthat for the best chance of success, the man-agement of advanced liver damage should becontinued for years rather than weeks ormonths; and that in their clinical experiencePC proved to be the best single means formanaging liver damage.

Sorrentino and collaborators (1982)studied 42 subjects with liver damage stem-ming from varied causes and exhibiting all de-grees of severity.8 They divided the subjectsinto 2 groups of 21 each, then provided con-ventional management (diet, B vitamins) toone group. To the other group, they gave PC(1350 mg), fortified with B1, B2, B6, B12,and E. Blood samples and clinical assessmentswere taken after 1 month, then at 2 months(the end of the trial). The results were sub-jected to a customized best-fit, least squaresstatistical analysis. After the first month, thedata on 7 of the 8 parameters were clearly in

favor of PC (5 of the 7 were 95% significant),then at month 2 the eighth parameter—SGOT—also became significant in favor ofPC. In suggesting that PC can benefit the vari-ous stages of liver damage, these findings areconsistent with those of Wallnoefer andHanusch6.

Clinical Assessment of PC InAlcoholic Liver Damage

Excessive alcohol consumption is stillthe single most common cause of toxic liverdamage in Western societies. Alcohol dam-ages the liver by various mechanisms.9 First,it increases oxidative stress: the ethyl alcoholmolecule becomes metabolized by the livercell to acetaldehyde, which is a reactive oxi-dant (“two-electron stealer”). Acetaldehydecombines with antioxidants, often into a mo-lecular complex (an “adduct”), thereby drain-ing the liver cells of their antioxidant power.Acetaldehyde also reacts with enzymes andother proteins and with DNA, damaging theseand sometimes causing mutations. Membranephospholipids and their associated fatty acidsalso can be damaged or destroyed by thehighly reactive acetaldehyde, which can do asmuch damage as many free radicals (techni-cally, one-electron stealers).

Being a weak polar solvent, alcoholhas a dispersive/disruptive effect on the lipidsthat make up the matrix of cell membranes.9Alcohol can literally dissolve PC and otherphospholipids from the membrane, therebyinactivating the membrane proteins thatdepend on the lipids for activity andweakening the membrane to the point ofrupture. By this means and through theacetaldehyde pathways, alcohol also attacksthe mitochondria, the liver cell organelles thatnormally generate energy. By impairing

*Footnote: The PC preparations used in clinical trials were soy lecithins enriched in PC, sometimes also with RDA-range levels of added B vitamins and vitamin E (herein termed fortified PC). In this text the actual PC intakes are stated,as calculated and rounded to the nearest 50 milligrams (mg).

Phosphatidylcholine



mitochondrial function, chronic alcoholexposure robs the cell of precious energyresources needed for maintenance and formore sophisticated functions. As the cellbecomes more energetically compromised, itsdeath becomes inevitable.

Mitochondrial damage is the mostlikely toxic basis for the early clinical stage ofalcoholic liver damage termed “fatty liver.”9,10

The mitochondria are the organelles that nor-mally burn fats (triglycerides) to make energyfor the cell. When the mitochondrial mem-branes become destroyed by alcohol, the pa-renchymal cells can no longer adequatelymetabolize fats. Pools of triglycerides thenbecome deposited within hepatocytes through-out the liver tissue. It is thought that as thesefatty deposits grow, they can come to occludethe important functions of the cell and causemore severe functional damage.

Clinically, the fatty liver state repre-sents a relatively mild degree of alcoholic dam-age to the liver, which can often be reversedthrough diligent personal commitment. How-ever, if the individual continues to consumealcohol the fat-laden parenchymal cells canbegin to die off in large numbers. An inflam-matory situation then develops: in response tosubstances exuded from dying liver cells, im-mune cells migrate into the liver tissue fromthe circulation and attempt to “mop up” thedebris. However, with the liver’s energeticsand antioxidant adaptability now compro-mised, the stage is set for the inflammatoryprocess to get out of hand and usher in achronic inflammatory state.9

If liver inflammation develops fromalcohol toxicity and is not controlled, as withthe continuation of alcohol consumption, cellsin the liver called lipocytes are transformedand begin to produce collagen, which is theprimary molecular basis for connective tissuedeposition and fibrosis. At first the liver mayadapt, accelerating its removal of collagen tokeep pace with the rate of new deposition. If

the liver’s functional state cannot be improved,however, the rate of collagen removal eventu-ally falls behind the rate of collagen deposi-tion, and progressive collagen accumulation(fibrosis, scarring) begins to obscure ever-en-larging regions of the liver. Beyond this point,the liver’s many functions become seriouslycompromised as it develops advanced, cir-rhotic damage.10

Clinical trials conducted with PCagainst alcoholic liver damage have consis-tently produced favorable findings. Knuechelreported in 1979 on a double blind trial con-ducted in Germany on 40 male subjects whohad fatty deposits in the liver resulting fromalcohol intake, as verified by biopsy.11 A ma-jority of these subjects also likely had “Stage2” inflammatory involvement, as indicated byabnormally-elevated serum iron, elevated im-munoglobulin-A (IgA), and values of SGOTand SGPT 3-5 times higher than normal.

The subjects were taken off all phar-maceuticals and randomly divided into 2groups of 20 each. One group received a pla-cebo and the other, 1350 mg of fortified PCper day. Liver damage was monitored at days14, 28, and 56 after beginning the treatment,based on the levels of SGGT, SGOT, SGPT,AP, LDH, Chol, TG, and BR. In addition LAP,immunoglobulins, platelets, reticulocytes, andthe blood fatty acid spectrum were measured,but only at the beginning and at the end of thetrial (day 56).

In this trial, measurable benefits fromPC intake were apparent at the first timepoint—2 weeks after the start. At 4 weeks,most of the indicators of liver damage wereclearly more improved for the PC group thanfor the placebo group. By 8 weeks, the trial’sculmination, all the main parameters of liverfunction were significantly improved (p<0.05). The parameters LAP and IgA-IgG-IgM, measured only at the end of the trial, alsowere significantly improved.



A blind clinical evaluation was con-ducted at the end of the trial, by a qualifiedinvestigator not informed of the randomiza-tion code. Of the PC group of 20 subjects, 6were judged very good and 14 good. Of theplacebo group, none was very good, 7 weregood, 8 were moderate, and 5 showed nochange. The differences were statisticallyhighly significant in favor of the PC group.No side effects from the PC were observed. Inthis 2-month trial, PC definitely benefited sub-jects with alcoholic liver damage. It did notcompletely resolve the more severe inflamma-tory indicators, which perhaps could have beenachieved had the trial gone for a longer pe-riod.

In Madrid in 1985, Schuller Perez andSan Martin organized a double-blind trial.12

They drew 20 subjects with alcohol-inducedfatty liver deposits from a population and com-pared them with 20 matched control subjects.As in the Knuechel study just described, forti-fied PC was given at 1350 mg per day. Thetrial went for 12 weeks, and blood sampleswere taken at the beginning and at the end ofthis trial period. Initially the indicators SGGT,SGOT, SGPT, AP, and bilirubin all were higherin the PC group than in the controls, but bythe trial’s end they were significantly reducedand were lower than the controls. Alpha-2-globulin was also significantly increased(p<0.01). Clinical assessment at the trial’s enddetermined that in the PC group 3 subjectswere good, 14 were average, while 3 had notimproved. In the placebo group, 0 subjectswere good, 9 were average, and 11 (more thanhalf) had experienced no benefit. The authorsconcluded, “it is our view that the use ofhighly-unsaturated phosphatidylcholine fortherapy of alcohol-dependent steatoses [fattyliver] is very productive.”

The above two double-trials just sum-marized establish the benefits of PC as an oralnutritional supplement for the earliest clini-cally-characterized stage of liver damage fromalcohol abuse - the presence of fatty deposits

in the liver. These findings are consistent withthose from Buchman and collaborators (1992),who gave PC double-blind to 15 subjects withfatty liver of non-alcoholic origin as part ofan intravenous feeding regimen (TPN).13

The next and more serious stage ofliver damage by alcohol is inflammation,which if left untreated can become life-threat-ening. In 1990, Panoz and collaborators re-ported on a double-blind trial conducted inEngland.14 The researchers divided 46 subjectswith liver inflammation from alcohol abuse(verified by biopsy) into two groups. The PCgroup were placed on a high intake—about 4.6grams daily—of fortified PC, in contrast to theplacebo group, and both groups were periodi-cally assessed for 2 years. By the end of thetrial there had been deaths in both groups, buta trend was seen toward increased survival inthe PC group (p=0.086, short of the p<0.05required for statistical significance). The groupthat seemed to benefit the most was the inter-mediate stage of severity (Pugh’s B classifi-cation). Tolerance of the relatively high intakeof PC was good.

The findings from these and otherclinical trials conducted on human subjectswith alcoholic liver damage are generally con-sistent with a large body of data from animalexperiments.

The evolutionary strategy for normalliver “detoxification” seemingly is to makepotentially problematic substances water-soluble, suitable for later excretion into the bileor the urine. Therefore the healthy liverattempts to first use the P450 enzymecomplexes and related pathways, to put acharge on the molecule. It then attempts toconjugate this charged, more reactive“activated” metabolite with glucuronic acid orwith glutathione or other antioxidants to renderit water-soluble.4 If the first phase enzymesystems become induced, generating copiousamounts of exceedingly reactive activatedmolecules, then the resources for conjugation

Phosphatidylcholine



can become insufficient. When this happens,activation can still proceed but conjugationfails, and the liver tissue becomes a sitting duckfor oxidative attack by the activatedmetabolites. Alcohol and many xenobioticscan actually induce, i.e., turn on, the Phase 1systems, thereby racking up the potential forthe system to overproduce activatedmetabolites. This can explain why combinedintakes of alcohol and/or drugs and/orpollutants or other xenobiotics can be severelythreatening to the liver’s integrity.4,9,10 In thisscenario any agent that turns on Phase 1 of thedetoxification system, can cause the systemto concurrently convert excessive amounts ofa second (or third) agent to reactive, oxidantmetabolites.

The Baboon Model of Alcoholic LiverDamage

Animal studies have helped elucidatethe means by which PC exerts its impressive

clinical benefits against liver damage frommany causes. In the case of alcohol, the mostclinically relevant animal research to date hasbeen the “baboon model” of alcoholism de-veloped by Leiber and his colleagues at theMount Sinai School of Medicine and theBronx Veterans Affairs Medical Center in NewYork City, for more than 2 decades.10,15,16,48

Their findings constitute compelling evidencethat dietary supplementation with PC is effec-tive against alcoholic liver damage. In earlyexperiments they fed alcohol to rats, and foundthat it impaired phospholipid synthesis in therat liver. This partially accounts for fats accu-mulating in the liver cells (“fatty liver”), sincePC and other phospholipids are needed to me-tabolize triglycerides. Then, for an “experi-mental model” closer to the human state, theyturned to research on baboon primates (Fig. 3).

Lieber and his associates placed ba-boons on a daily regimen of alcohol intake.Over a period of years most of the baboonsdeveloped features of alcoholic liver damage

Perivenularand/orIntersititialFibrosis

SeptalFibrosis

Cirrhosis

Normal

Fat++++++

Perivenularand/orIntersititialFibrosis

SeptalFibrosis

Cirrhosis

0 1 2 3 4 5 6 7 8YEARS

0 12 24 MONTHS

PolyunsaturatedLecithin

Figure 3. Inhibition of alcoholic liver damage in baboons fed an adequate diet with ethylalcohol. Left: alcohol given daily along with PC to six baboons results in minimal fibroticdamage, stable for up to 8 years. Right: after PC is removed from the diet of three babbons,damage progresses to end-stage fibrosis (“cirrhosis”) in 1-2 years. From Lieber et al.15



that closely resembled those seen in humans,making this is a good “animal model” for hu-man liver disease. The researchers also de-veloped sophisticated methods for quantitat-ing the tissue changes seen in liver biopsysamples, and refined biochemical analyses foruse on small amounts of biopsy material.

Subsequently, using a blinded trial de-sign, they set up two main groups of baboons,one of which received alcohol along with PC,the other receiving only alcohol.15 After run-ning this primate trial for several years anddecoding their results, Lieber’s group foundthat the baboons fed alcohol with PC devel-oped fatty liver and mild fibrosis, but did not

progress to advanced liver damage for sixyears or longer. In contrast, the majority ofbaboons fed alcohol without PC progressedto advanced fibrosis (p < 0.005). While PCdid not block the development of fatty liver inbaboons that continued to receive alcohol, itdramatically slowed the progress to advanced

disease.Three of the baboons with fatty liver

were subsequently taken off PC while continu-ing to be fed alcohol. These baboons rapidlyprogressed to extensive liver fibrosis (equiva-lent to advanced liver damage). From thisstudy and a follow-up study using a similardesign17, Lieber’s group were able to firmlyconclude that PC is an effective means forhalting (not merely slowing) the progressionfrom early-stage alcoholic liver damage intolate-stage generalized fibrosis (cirrhosis). (Fig-ure 3) PC is unique among both nutrients anddrugs, as was pointed out in a supportive peereditorial,18 in its ability to halt the clinical pro-

gression of alcoholic liver damage.Subsequent in vitro experiments by

Lieber’s group16 showed that the lipocytes, theliver cells that normally store moderateamounts of fats, under the influence of alco-hol become transformed to collagen-produc-ing cells (called “transitional cells”). In the

Phosphatidylcholine

Figure 4. Summary of the mechanisms of liver damage by drugs. Note the lipid peroxidationevents that result in cell membrane damage. From Hoyumpa and Schenker.19

Genetic and environmental

influenceP450

Drug

Metabolite

Free radical

Lipid peroxidation

Cell injury

Covalent binding

Superoxide anion

Redoxcycling

Lipid peroxidationProtein-thiol oxidation

Electrophile

}



intact, alcohol-treated liver these transitionalcells intensify collagen production, but initiallythe liver keeps up by breaking down collagenfaster (via increased collagenase enzyme ac-tivity). As alcohol damage progresses, thebalance shifts: the liver’s collagenase activitydrops and continued collagen production bythe transitional cells results in progressive col-lagen deposition and extensive fibrosis. Thiseventually deprives the liver of most of itsfunction (the state of cirrhosis). It may wellbe that in the baboons fed PC along with alco-hol, excessive collagen production was par-tially blocked by PC, and collagen breakdownwas increased for a sustained period (also viaincreased collagenase). Ongoing dietarysupplementation with PC seemingly restorednormal collagen balance in the transitionalcells, thereby blocking further fibrosis and pro-tecting the baboons for several years and po-tentially longer.

These findings with primates stronglysuggest that advanced liver damage in humans,clinically expressed as cirrhosis, may proveamenable to dietary PC. As a result of thisresearch breakthrough by the Lieber group, ex-citement developed in the U.S. research com-munity around the potential of PC to slow, tostabilize, and perhaps in some cases even toreverse, alcoholic liver damage. An editorialin the journal Alcoholism: Clinical and Experi-mental Research discussed PC as a possible“magic bullet” for this purpose.18 The Lieberbaboon studies also established that cholinedoes not have comparable benefits to PC forthe liver. The small choline molecule is actu-ally part of the headgroup of the large PCmolecule, but when free choline was added tothe baboon diet it proved toxic to the alcohol-damaged liver.48

Benefits of PC Against Other LiverToxins

Further clinical evidence indicates thatPC supports liver cells against attack by a va-

riety of toxic agents other than alcohol. Thetrials reported in this category are sparse be-cause of the difficulties in assembling victimsof toxic exposures. However, some clinicaltrials have been accomplished, and their find-ings indicate PC is also unique in its protec-tion of the liver against toxins other than al-cohol.

As discussed earlier, the liver is di-rectly vulnerable to foreign substances(“xenobiotics”) entering the body. Blood car-rying newly-absorbed molecules proceeds di-rectly to the liver from the intestines. Sub-stances as diverse as drugs, whether legal orillegal; anesthetics; herbs, foods, and pollut-ants can be rendered more toxic after reach-ing the liver, due to bioactivation by the liverP450 and related enzyme pathways (see Fig.4). Almost all of these substances are livertoxins because of their conversion into reac-tive oxidants, which deplete the antioxidantsand other Phase 2 conjugation resources. Thisunfortunate lack of discriminative activity bythe liver underlies most of the notorious livertoxicity of pharmaceuticals. Excessive intakeof substances from any xenobiotic categorycan predispose the liver to damage in responseto otherwise-reasonable intakes of substancesfrom other categories. A classic example isalcohol intake potentiating the metabolism ofpharmaceuticals.

• Drug Xenobiotics. Both prescription andover the counter pharmaceuticals can becomeactivated to toxic metabolites in the liver.4,19

The most heavily consumed among these arethe painkillers acetaminophen, aspirin (acetyl-salicylic acid), ibuprofen, carbamazepine, in-domethacin, phenylbutazone; the antibiotictetracycline; the anti-arrhythmic drugsamiodarone, perhexiline, and hexestrol; theblood pressure drug alpha-methyldopa; theanticlotting medication sulfinpyrazone;the barbiturate phenobarbital; the chemo-therapy drug methotrexate; the gout drug al-



lopurinol; the anti-tuberculosis drug isoniazid(particularly in combination with rifampin);the CNS stimulant amineptine; the tricyclicantidepressant tianeptine; the anti-epilepticsphenytoin and valproic acid; and the benzodi-azepine sedative chlordiazepoxide. Anesthet-ics that are potentially toxic to the liver in-clude halothane. Of the illicit drugs, cocainehas been extensively studied for its toxicity tothe liver by bioactivation.

Marpaung and colleagues did a 1988double-blind trial for which they assembled101 tuberculous subjects who earlier had suf-fered liver damage from rifampin and 2 otheranti-tuberculosis pharmaceuticals.20 The PCgroup received 1350 mg of fortified PC daily,versus placebo for 3 months. Both groupsshowed good clinical improvement, but in thePC group SGOT and SGPT were significantlylower when compared with the group that re-ceived the placebo. Kuntz and collaboratorshad made a similar finding in 1979, by givingPC via the intravenous route.21

Long-term intakes of certain of theantiepileptic drugs, especially phenytoin, posea high risk of liver damage. Hisanaga andcollaborators (1980) in Japan followed 38 sub-jects who had received phenytoin and otherantiepileptic drugs for an average of fiveyears.22 A subgroup with the highest degreeof damage (assessed by SGGT enzyme eleva-tion), after being given PC orally for 6 months,experienced remarkable benefits.

• Other, non-Pharmaceutical Xenobiotics.Chemicals produced by industry currentlynumber at least sixty-five thousand. One ofthe chemical classes most toxic to the liver isthe chlorinated and related halogenated hydro-carbons, of which carbon tetrachloride hasbeen extensively researched as an experimen-tal model. Included in this class is the drycleaning solvent trichloroethylene, along withmany commonly used herbicides and pesti-cides. In 1965 Kuntz and Neumann-Mangoldt

documented an antidotal effect from PCagainst acute oral trichloroethylene poison-ing.23 Also, non-halogenated organic solvents,allyl alcohol, carbon disulfide, ethionine, andthioacetamide all are markedly liver-toxic, bymechanisms similar to those illustrated in Fig.4. Numerous case histories have been pub-lished that document the benefits of PC in othertypes of xenobiotic toxicity.

Among plants that can be mistaken asfoods, the deathcap mushroom (Amanitaphalloides) carries toxins that are some of themost lethal agents known. Esslinger used PC,at first intravenously then also orally, to avertdeath in victims of deathcap poisoning.24 InEsslinger’s experience, PC worked againstdeathcap mushroom toxicity after milk thistleextract had failed to show benefit. He calledPC “a valuable extension to therapy for thisgrave form of poisoning.”

• Natural plant toxins. In addition to thedeathcap mushroom, aflatoxin from moldypeanuts is also one of the most toxic naturalsubstances, and also becomes operative viabioactivation. Constituents of herbs also canbe liver-toxic by bioactivation, the most noto-rious of these being the pyrrolizidine alkaloidsfound in comfrey and at least 59 other plants.

• Radiation exposure. Klemm and Pabst in1964 gave PC to 161 subjects who had previ-ously undergone radiation treatment.25 Radia-tion scattered from the head-neck area tendedto damage the liver, and PC afforded partialbut clinically-meaningful protection againstthis occurrence.

• Other toxic insults to the liver, such as fromhigh galactosamine intake or partialhepatectomy (the surgical removal of livertissue), and a variety of other sources, haveproven amenable to improvement by PC in

Phosphatidylcholine



studies conducted with laboratory animals.

Controlled Trials with PC in ViralLiver Damage

A number of viruses can damage theliver, by precipitating widespread inflamma-tory breakdown which is further complicatedby overactivation of the immune system (au-toimmune complications). Once successfullyinstalled in the liver parenchyma, such virusescan become chronic and very hard to dislodge.Liver viruses (here simply called LV) canwreak havoc with the liver’s functions. Medi-cal weapons for eliminating LV from the liver,or for ameliorating their progressive damage,have been limited. Controlled clinical trialshave unequivocally established PC as safe andreliable nutritional support for the liver againstthe damage initiated by LV.

Mueting and collaborators in 1972gave 16 subjects with chronic, aggressive LVa relatively high intake of PC (2,050 mg perday) for an average 8 months.26 A numberof clinical parameters improved, includingmeasures of the liver’s detoxification pathwaysthat metabolize amino acids and phenols, andthe authors concluded that PC was having a“normalizing” effect on the liver as a whole.From their large open study reported in 1973,over the course of which some subjects re-ceived PC for up to 5 years, Wallnoefer andHanusch noted a success rate for chronic, ag-gressive LV infection of 35.3 percent.7

Hirayama, Yano and collaborators con-ducted a double-blind trial in Japan in 1978,using 124 subjects with various LV.27,28 Theygave PC (1350 mg per day) to a group of 58subjects and placebo to 66 subjects, for twelveweeks. The PC group experienced significantreductions in SGOT and SGPT levels whencompared with the placebo group; those withhigher enzyme values to begin with appearedto benefit the most. A subsequent blinded bi-opsy assessment after 6 months confirmed thatin the PC subjects, the liver parenchymal tis-

sue had partially recovered from its earlierdamage; focal necrosis/cell death was lessenedin the PC group, and these subjects showedsigns of liver regeneration.

In 1981, Kosina and collaborators con-ducted a sophisticated trial in Czechoslova-kia that compared PC against drugs for themanagement of viral-related liver inflamma-tion. They recruited 80 subjects with pre-sumed acute LV infection (viruses hepatitis Aand hepatitis B), and divided them into fourgroups of 20 subjects each.29 The first 2groups were drawn from subjects whose bi-lirubin levels were low (below 250 micro-moles per liter) and were judged “moderatelyserious.” Subjects in Group I were adminis-tered fortified PC (1350 mg) along with the“standard treatment” that involved diet, rest,vitamins, and glucose; Group II received thestandard treatment only. Groups III and IVwere judged “serious,” with bilirubin levelsabove 250 micromoles per liter. Group IIIreceived fortified PC and 580 mg daily of theimmunosuppressive drug prednisone (a drugoption for the suspected immune systemoveractivation from LV); Group IV receivedprednisone plus the standard treatment.

PC had a clearly favorable effect in thistrial. Concerning the resolution of viral dam-age, both Group I subjects (less severe) andGroup III (more severe) had their liver testsreturn to normal markedly faster than the cor-responding groups that did not receive PC.Subjects who did not receive PC were morelikely to relapse (10% in the less severe, 25%in the severe), while no relapses occurred inthe PC groups. Upset stomach, jaundice, andliver swelling, as well as the lab tests, all re-solved faster in the groups treated with PC.There was a trend towards lower occurrenceof the hepatitis B surface antigen (HBsAg) inthe PC groups as treatment progressed.

Jenkins and collaborators at King’sCollege, London did a double-blind trial in1982 on 30 subjects with progressing liver



damage from chronic LV (hepatitis B virus,negative for HBsAg), as verified by biopsy.30

They randomly divided the subjects into twogroups of 15 each, kept them on the standardimmunosuppressive therapy (prednisolone orazathioprine), then gave one group PC (2,300mg per day) and the other placebo, for 1 year.At the end of this period, the group given PChad no clinical changes, while the placebo(control) group had worsened. Biopsies re-vealed significant improvement of the liverstructure in the PC group, versus no improve-ment for the controls. More of the PC sub-jects reported improved well-being than didthe controls (62% versus 43%). In 3 of the 15subjects given PC the viral infection wasjudged to be inactive at the end of the trial,while no subjects were judged inactive fromthe placebo group. Thus in this small con-trolled trial, PC halted and partly reversedchronic LV damage, improved overall well-being, and “turned off” the virus in as many as20% of the subjects.

In 1985, Visco and collaborators as-sembled 60 subjects who were positive forhepatitis B virus (assessed as presence ofHBsAg) and who had acute LV liver damage,and divided them into two groups.31 Within10 days from the onset of jaundice, on adouble-blind basis the subjects were started oneither fortified PC (1350 mg) or placebo cap-sules. Lab tests were conducted frequently,and immune evaluations and clinical examswere done at 30, 90, and 180 days (6 months,end of trial).

By the 30-day mark, the group givenPC was significantly more improved than theplacebo group, with 50% being negative forHBsAg versus 25% for the controls (p<0.05).PC improved the rate of clearance of virusantigen from the blood. The immune param-eters were not significantly different, thoughliver enzyme tests showed trends favoring PC.

In 1990, Hantak and collaborators inYugoslavia used PC to manage 24 subjects

with LV (hepatitis B virus).32 All the subjectswere chronically infected—they all had beenvirus carriers for at least 6 months. Seven hadviral antigens (HBeAg) which indicated a rela-tively high degree of active infection. Theother 17 subjects had no viral antigens and hadantibodies to the virus (anti-HBeAg), indicat-ing that they were in a stage of relative viralinactivity. All subjects received 900 mg offortified PC per day. After 4 months, the lessseverely affected, antibody-positive subgroupshowed statistically significant improvementsin SGOT, SGPT, albumins, gamma-globulins,and other biochemical measures. The sub-group that began the study with active virushad statistically significant improvements inimmune measures, suggestive of clinical ben-efit from PC. The effects of PC in this smalland not well controlled trial were judged en-couraging, and might have been more dramatichad the daily intake been as high as in othertrials (a minimum 1350 mg of fortified PC,rather than the 900 mg that was given).

Controlled Trials with PC AgainstSevere Liver Damage

This category of liver damage is char-acterized by extensive fibrosis, which effec-tively stifles whole zones of the liver. Some-times aggressive inflammatory changes arealso present. This stage can be reached as aconsequence of persistent alcohol intake, per-sistent viral infection, or the unchecked toxiceffects of any of the many other agents thatcan damage the liver. Given the severity ofthe structural and functional damage to theliver at this stage, lesser benefits are to be ex-pected from PC supplementation than at ear-lier stages. Yet still PC proved beneficial.

Fassati and collaborators in 1981 in acontrolled trial conducted in Prague, Czecho-slovakia, studied 61 subjects with moderatelysevere to severe functional breakdown of theliver.33 The degree of advanced liver damage(extensive fibrosis, inflammation, elevated en-

Phosphatidylcholine



zymes) was assessed by biopsy and by a widerange of blood biochemical tests. Thirty-four(34) subjects were given fortified PC (900 mgper day), and 27 subjects served as controls.The trial ran for 4 months, with each patientserving as their own control for statisticalanalysis.

Biochemical re-testing conducted atthe end of the trial showed that except for thebilirubin values, all the other biochemical in-dicators were significantly improved (p<0.01).These included the albumin/globulin ratio, al-bumin, bromsulfalein (BSP) clearance, SGPT,and SGOT. The number of subjects positivefor HBsAg in the blood moved from 8 of 34to 3 of 34 in the PC group; that of the controlsmoved from 7 of 27 to 6 of 27. The trendapparent in the PC group was not statisticallysignificant due to the small numbers ofHBsAg-positive subjects in both groups fromthe beginning of the trial. The investigatorscommented that fortified PC was the only in-tervention they were aware of that seemed tobring down viral antigen levels, and they urgedfurther investigation of this possible benefitwith larger groups of subjects.

In 1991, Ilic and Begic-Janev con-ducted a randomized, double-blind, placebo-controlled trial.34 They recruited 50 subjects,all positive for HBsAg (hepatitis B virus anti-gen) who had extremely severe liver damageas verified by biopsy and immunologic test-ing. The test group was administered 1350mg of fortified PC, and the control group re-ceived a placebo. Both groups were followedfor 1 year, with periodic sampling for lab as-sessments, then at the end of the 12 monthsthey were biopsied again.

After 12 months the subjects given PChad experienced considerably greater benefit,as assessed both from the structural biopsyfindings and from the lab findings (p <0.001).Among the PC group, 20 of 25 were judgedgood to moderately good, versus 6 of 25 be-ing moderately improved in the placebo group.Six of the 25 in the PC group also lost the

HBsAg viral antigen, versus only 3 of 25 forthe placebo group. Such “seroconversion”indicated marked clinical improvement forthese fortunate subjects. A number of cell-structural, biochemical, immunologic, andhematologic parameters were significantlyimproved in the PC group as compared withthe placebo group. Improvement in the PCgroup continued well past the end of the trial.

As a rule, researchers working withsuch severely affected subjects obtained bet-ter results by maintaining the subjects on com-bined intravenous PC and oral supplementa-tion until substantial improvement had begun.

Other trials with severe liver damage,though not controlled, are worthy of note.Wallnoefer and Hanusch in their pioneeringstudy administered PC both intravenously andorally to 130 subjects with advanced, fibroticliver damage.7 Once the clinical indicatorsbegan returning to normal, they switched topurely oral administration at relatively lowintakes (450-700 mg), which was continuedfor months to years as necessary. PC producedbenefits for 17.5% of these subjects, as con-firmed from normalized enzyme levels andimproved tissue structure on biopsy. Using asimilar strategy, they achieved benefit for 35.3percent of their subjects with chronic viral in-fection of a kind that was positive for viralantigen and has an aggressive tendency toprogress to severe liver damage. Kuntz re-ported in 1989 on 10 subjects to whom he gavePC intravenously at 2,800 mg per day.3 Im-provements were seen as early as the seventhday, and at the end of the 28-day trial period 3subjects showed “dramatic, life-saving” im-provement, 2 had “increasingly rapid improve-ment,” 2 had gradual improvement, 2 had nochange; and 1 of the 10 subjects had died.

Kalab and Cervinka worked with 30subjects who had advanced liver damage forwhich pharmaceutical treatments had failed.35

Orally administered fortified PC (1350 mgdaily) produced clinical improvement after 6



months, with favorable effects on the usualenzyme indicators of liver damage.

In summary, the experiences from theclinical trials discussed above concur withfindings from others36-40 to paint a clear pic-ture of PC as an effective and safe nutrient forliver damage of all degrees of severity.

PC Benefits the Liver PrimarilyThrough Cell Membranes

The efficacy of PC in protecting theliver against toxic attack can be attributed toits important role in cell membranes. Themembrane systems are among the cell con-stituents most vulnerable to toxic attack, andthe diverse array of hepatotoxic substancesoperates through common pathways: free radi-cal or other oxidative attack that depletes an-tioxidants, leading to oxidative overload andsubsequent peroxidative damage to the cell’smembranes.4 The ultimate consequence is thedeath of the cell.

The phospholipids of cell membranesare partially unsaturated, and by being packedtightly next to each other in the membrane theyare highly vulnerable to oxidative attack fromfree radicals and other highly reactive, oxidanttoxins. Under excessive or sustained attack,the membrane phospholipids become de-graded (“peroxidized”), mainly through theirfatty acid tails. As the phospholipidsperoxidize, membrane continuity is inter-rupted. Holes begin to develop in the cell’souter membrane, resulting in loss of controlover internal conditions. Enzymes and otherlarger bio-molecules begin to leak out, homeo-stasis fails, and the death of the cell becomesimminent.

Viral attack on the liver follows amodel similar to chemical attack: viral inva-sion of the parenchymal cells initiates releaseof pro-inflammatory, oxidizing substances.Immune cells arrive in the area and begin re-leasing more oxidants via their “respiratoryburst.” These activities initiate cascades of

peroxidative membrane damage to the livercell membranes, and the damage spreads toneighboring zones within the tissue.

PC plays crucial roles in supporting themembrane-based structure and functions of theliver’s parenchymal cells. When orally admin-istered to experimental animals, in quantitiesusually equivalent to 1-3 grams per day forthe human, PC had the following liver-pro-tective effects:

• Leakage of “indicator” enzymes fromthe liver tissue was lessened

• Lipid peroxidation from free radical/oxidant insult was lessened

• Membrane damage was slowed,membrane integrity was conserved

• Cell death, fibrosis, and fatty infil-tration of the liver tissue were diminished

• Cell synthesis of RNA and proteinincreased, suggesting regeneration

• Liver metabolism improved

This documented range of benefitsfrom PC is consistent with its functions at thecell membrane. PC is required for the struc-tural integrity of all the body’s cell membranesystems, and is essential to their functional-ity.41-45 PC is crucial both for the internalmembranes to do their housekeeping and spe-cialized functions, and for the cell’s “masterswitch”—its outer membrane. The outer mem-brane interfaces with both the external envi-ronment and the internal environment of thecell; PC supports the membrane receptors that“hear” these molecular messages and carrythem across the membranes in both directions.This outer membrane is also the cells’ reser-voir for the eicosanoids and other phospho-lipid derivatives that act as outgoing vocabu-lary, speaking the language of that cell to oth-ers.

The accumulated findings from de-cades of research are that PC is an importantprotective nutrient for the liver, primarilythrough being a building block for cell mem-

Phosphatidylcholine



branes. PC is essential for the liver’s baselinehomeostatic housekeeping functions, for theliver’s recovery following toxic damage, andnot least to support the sophisticated livermetabolism that determines the individual’slevel of health and freedom from disease.

PC is highly bioavailable (about 90%of the administered amount is absorbed over24 hours),46 and PC represents a far morepleasant means for dietary choline repletionthan choline itself. Lastly, even as the PC mol-ecule is efficiently absorbed, it also is an ex-cellent emulsifier that enhances thebioavailability of nutrients with which it is co-administered. Antioxidant nutrients and es-pecially the flavonoids are likely to be betterabsorbed in combination with PC,47 as are Bvitamins, minerals, and numerous other nutri-ents.

Conclusion:From the many controlled clinical

studies conducted on thousands of human sub-jects to date, PC’s confirmed clinical benefitsinclude:

• Successful improvement of specificindicators of liver damage

• Faster functional and structural re-covery of the liver tissue

• Accelerated restoration of subjects’overall well-being

In the trials cited in this review, PC wasvery well tolerated at oral intakes that rangedup to 4.6 grams per day, and was found to bemore effective the earlier it was administered.Subjects who are started on PC after their liveris already severely damaged are more likelyto benefit from higher oral intakes of PC (upto or exceeding 4.6 grams per day). The mostsevere cases are likely to thrive with the helpof intravenous PC, administered in combina-tion with a high oral dose.

Lieber and colleagues’ elegant studieswith baboons as a primate model of alcoholic

liver damage have established that PC canstave off steadily-worsening damage fromchronic alcohol consumption; improvementfrom PC is far more likely if the subject’s al-cohol consumption is ceased. The small cho-line molecule is actually part of the headgroupof the large PC molecule, but when free cho-line was added to the baboon diet it provedtoxic to the alcohol-damaged liver. Phosphati-dylcholine is a highly bioavailable form ofcholine; it is also the most biologically sig-nificant and (for damaged livers, at least) thesafest source of choline.

PC is undoubtedly a critically impor-tant nutrient for the liver, both because it isthe primary cell membrane building block andbecause the liver is so functionally dependenton its estimated 33,000 square meters of mem-brane surface. Whether the liver has beendamaged by alcohol, by other toxic chemicals,by pharmaceuticals, or by viruses, dietarysupplementation with PC significantly speedsrecovery. The clinical studies demonstrate thatdietary PC in sufficient amounts revitalizeswhole zones of cells in the recovering liver.

PC has other qualities that further en-hance its remarkable usefulness as a dietarysupplement. PC is well documented as safeto take, and seems fully compatible with phar-maceutical regimens and with other nutrients.The PC molecule enhances the bioavailabilityof nutrients with which it is co-administered,is highly bioavailable and represents a far bet-ter means for dietary choline repletion thancholine itself.

The jury is still out on whether PC istruly a “magic bullet” for alcoholic liverdisease, but its benefits against variousseverities of liver damage and its proven safetyindicate that for the liver it is a nutrient ofmajor importance.

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