Phosphatidylcholine: a superior protectant against liver damage

Phosphatidylcholine: A Superior Protectant
Against Liver Damage
Parris M. Kidd, Ph.D.
Phosphatidylcholine (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. PC is 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 for all 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.
Page 258 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission The Human Liver, the
CELL INTERIOR
Detoxification Paradox, and PC
PHOSPHATE
GLYCEROL
disarming and disposing of toxins, yet is itself vulnerable to toxic attack. Such toxicattack is both endogenous (from toxins FATTY ACID
generated in the liver), and exogenous (due to toxins coming from the outside). Simi- lar metabolic mechanisms are employedto deal with the toxins coming from either CELL EXTERIOR
source, but due to the stressful influencesof modern life, toxic overload is a con- Figure 1. Phosphatidylcholine, major constituent
of cell membrane systems. Left: Molecular plan The healthy liver is the body’s largest of PC. Middle: PC, membrane building block.
organ and is probably also its most meta- Right: the basic membrane plan, with proteins bolically versatile. The liver carries out hundreds, if not thousands, of sophisti-cated enzymatic reactions along numerous metabolic pathways. Enzymes residing within body of potential toxins, the liver paradoxi- the membranes of the parenchymal cells pro- cally generates toxins that can damage the liver duce biological molecules by synthesis from tissue. This can happen because evolution has smaller molecules, by the modification of pre- existing metabolites or from newly-absorbed activate the liver’s natural enzyme detoxifica- nutrients. The parenchymal cells also process tion pathways, but often the metabolites that products into water-soluble compounds for “bioactivation” are more toxic than the start- subsequent excretion. With the myriad of func- ing substrates. Whether their toxicity occurs tions that it performs, the liver plays a pivotal directly or following bioactivation, virtually role in maintaining homeostasis, i.e., health all of the agents that damage the liver do so by in all its aspects. But these routine liver func- way of attack on the membrane systems of the tions do generate intrinsic, potentially toxic survival and specialized functioning of all well equipped with protective antioxidant cells. In order to carry out its metabolic re- enzymes and with water-soluble antioxidants sponsibilities, the liver parenchymal cells are such as glutathione, cysteine, and taurine to densely packed with membranes. Given this central role of membranes in the liver’s func- tions, the demonstrated superiority of PC in challenge posed to the liver’s defenses by food- supporting the liver against damage is thor- borne toxins and by the bioactivation products oughly consistent with the known mechanisms of xenobiotics, including lifestyle-related of liver homeostasis, toxic liver damage, and the liver’s recovery processes. Out of this detoxification enzyme systems can be diverted comes a dramatic conclusion: PC is the single most important nutrient for the liver.
metabolites that attack their maker. Last but Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 259
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Figure 2. Schematic of the liver parenchymal cell, showing the internal functional
units or organelles. Those superscriptedM are made up of membranes or rely on
membranes to function. Modified from Sherlock S, Dooley J. Diseases of the Liver and
Biliary System. Oxford: Blackwell Scientific Publications; 1993.
not least, by being the first way-station for the vestigated PC for the management of liver blood draining the intestines (via the portal damage coming from a variety of toxic insults.
circulation), the liver tissue is directly exposed to preformed toxins that enter by the oral route.
Wallnoefer and Hanusch in Germany followed 650 subjects with various degrees of liver dam- liver is evolutionarily equipped to cope with age for at least 5 years.6 This trial relied on the tens of thousands of toxins generated by biopsy, conducted in conjunction with blood modern circumstances: pharmaceuticals, pol- analyses and clinical tests, to assess the scope lutants, and other toxins associated with a self- and character of liver damage.7 The subjects abusive lifestyle. As the liver becomes over- received PC for periods that ranged from 4 burdened with such toxins, its stores of pro- weeks to several years. The distributions of tective antioxidants are progressively de- subjects, listed in groups according to approxi- pleted.4 Parenchymal cells die, and cell death mate degree of damage severity, was as fol- spreads zonally. Left unchecked, necrotic and lows: fatty degeneration, n=130; acute inflam- inflammatory damage comes to threaten whole mation, n=157; persistent inflammation (sub- acute and chronic), n=41; chronic inflamma-tion, n=122; chronic aggressive inflammation, Overall Clinical Benefits of PC for the
n=70; advanced fibrotic damage, n=130. All subjects were begun on intravenous PC (950mg*) along with oral PC (450-700 mg*), un- til blood parameters began to return to nor- trials, conducted mostly in Europe, have in- mal; they were then shifted to oral PC only.
Page 260 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission favor of PC (5 of the 7 were 95% significant), benefited from receiving PC. Of those with mild damage, more than half (51.1%) showed SGOT—also became significant in favor of excellent improvement, and many subjects ex- PC. In suggesting that PC can benefit the vari- perienced reversal of their fatty degeneration.
ous stages of liver damage, these findings are In the acute inflammation group, lab measures and biopsy indicated PC accelerated recovery by about 10 days. In the group with persistentinflammation, PC returned the enzyme param- Clinical Assessment of PC In
eters to normal after 30 days. In chronic ag- Alcoholic Liver Damage
gressive inflammation , more than one-third (35.3%) experienced benefit and among those the single most common cause of toxic liver with advanced fibrotic damage, 17.5% ben- damage in Western societies. Alcohol dam- efited. In this last group with liver damage of ages the liver by various mechanisms.9 First, the greatest severity, recovery was better when it increases oxidative stress: the ethyl alcohol PC was given intravenously as well as by the molecule becomes metabolized by the liver cell to acetaldehyde, which is a reactive oxi- dant (“two-electron stealer”). Acetaldehyde sistent inflammatory damage included in this combines with antioxidants, often into a mo- trial had failed to benefit from milk thistle ex- lecular complex (an “adduct”), thereby drain- tract (“silymarin”) or steroid drugs, but ben- ing the liver cells of their antioxidant power.
efited from PC. The investigators commented Acetaldehyde also reacts with enzymes and that for the best chance of success, the man- other proteins and with DNA, damaging these agement of advanced liver damage should be and sometimes causing mutations. Membrane phospholipids and their associated fatty acids months; and that in their clinical experience PC proved to be the best single means for highly reactive acetaldehyde, which can do as much damage as many free radicals (techni- studied 42 subjects with liver damage stem- ming from varied causes and exhibiting all de- has a dispersive/disruptive effect on the lipids grees of severity.8 They divided the subjects that make up the matrix of cell membranes.9 into 2 groups of 21 each, then provided con- Alcohol can literally dissolve PC and other ventional management (diet, B vitamins) to one group. To the other group, they gave PC (1350 mg), fortified with B1, B2, B6, B12, and E. Blood samples and clinical assessments were taken after 1 month, then at 2 months (the end of the trial). The results were sub- acetaldehyde pathways, alcohol also attacks jected to a customized best-fit, least squares the mitochondria, the liver cell organelles that statistical analysis. After the first month, the data on 7 of the 8 parameters were clearly in *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).
Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 261
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission the liver’s functional state cannot be improved, exposure robs the cell of precious energy however, the rate of collagen removal eventu- ally falls behind the rate of collagen deposi- more sophisticated functions. As the cell tion, and progressive collagen accumulation becomes more energetically compromised, its (fibrosis, scarring) begins to obscure ever-en- larging regions of the liver. Beyond this point, the liver’s many functions become seriously likely toxic basis for the early clinical stage of compromised as it develops advanced, cir- alcoholic liver damage termed “fatty liver.”9,10 The mitochondria are the organelles that nor- mally burn fats (triglycerides) to make energy against alcoholic liver damage have consis- for the cell. When the mitochondrial mem- tently produced favorable findings. Knuechel branes become destroyed by alcohol, the pa- reported in 1979 on a double blind trial con- ducted in Germany on 40 male subjects who metabolize fats. Pools of triglycerides then had fatty deposits in the liver resulting from become deposited within hepatocytes through- alcohol intake, as verified by biopsy.11 A ma- out the liver tissue. It is thought that as these jority of these subjects also likely had “Stage fatty deposits grow, they can come to occlude 2” inflammatory involvement, as indicated by the important functions of the cell and cause abnormally-elevated serum iron, elevated im- and SGPT 3-5 times higher than normal.
sents a relatively mild degree of alcoholic dam- age to the liver, which can often be reversed through diligent personal commitment. How- groups of 20 each. One group received a pla- ever, if the individual continues to consume cebo and the other, 1350 mg of fortified PC alcohol the fat-laden parenchymal cells can per day. Liver damage was monitored at days begin to die off in large numbers. An inflam- 14, 28, and 56 after beginning the treatment, matory situation then develops: in response to substances exuded from dying liver cells, im- AP, LDH, Chol, TG, and BR. In addition LAP, mune cells migrate into the liver tissue from immunoglobulins, platelets, reticulocytes, and the circulation and attempt to “mop up” the the blood fatty acid spectrum were measured, debris. However, with the liver’s energetics but only at the beginning and at the end of the mised, the stage is set for the inflammatory process to get out of hand and usher in a PC intake were apparent at the first time point—2 weeks after the start. At 4 weeks, most of the indicators of liver damage were alcohol toxicity and is not controlled, as with clearly more improved for the PC group than the continuation of alcohol consumption, cells for the placebo group. By 8 weeks, the trial’s in the liver called lipocytes are transformed culmination, all the main parameters of liver and begin to produce collagen, which is the primary molecular basis for connective tissue <0.05). The parameters LAP and IgA-IgG- deposition and fibrosis. At first the liver may IgM, measured only at the end of the trial, also adapt, accelerating its removal of collagen to keep pace with the rate of new deposition. If Page 262 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission in the liver. These findings are consistent with ducted at the end of the trial, by a qualified those from Buchman and collaborators (1992), investigator not informed of the randomiza- who gave PC double-blind to 15 subjects with tion code. Of the PC group of 20 subjects, 6 fatty liver of non-alcoholic origin as part of were judged very good and 14 good. Of the placebo group, none was very good, 7 were change. The differences were statistically which if left untreated can become life-threat- highly significant in favor of the PC group.
ening. In 1990, Panoz and collaborators re- No side effects from the PC were observed. In ported on a double-blind trial conducted in this 2-month trial, PC definitely benefited sub- England.14 The researchers divided 46 subjects jects with alcoholic liver damage. It did not with liver inflammation from alcohol abuse completely resolve the more severe inflamma- (verified by biopsy) into two groups. The PC tory indicators, which perhaps could have been group were placed on a high intake—about 4.6 achieved had the trial gone for a longer pe- grams daily—of fortified PC, in contrast to the placebo group, and both groups were periodi- cally assessed for 2 years. By the end of the San Martin organized a double-blind trial.12 trial there had been deaths in both groups, but They drew 20 subjects with alcohol-induced a trend was seen toward increased survival in fatty liver deposits from a population and com- the PC group (p=0.086, short of the p<0.05 pared them with 20 matched control subjects.
required for statistical significance). The group As in the Knuechel study just described, forti- that seemed to benefit the most was the inter- fied PC was given at 1350 mg per day. The mediate stage of severity (Pugh’s B classifi- trial went for 12 weeks, and blood samples cation). Tolerance of the relatively high intake were taken at the beginning and at the end of this trial period. Initially the indicators SGGT, SGOT, SGPT, AP, and bilirubin all were higher clinical trials conducted on human subjects in the PC group than in the controls, but by with alcoholic liver damage are generally con- the trial’s end they were significantly reduced sistent with a large body of data from animal and were lower than the controls. Alpha-2- globulin was also significantly increased (p<0.01). Clinical assessment at the trial’s end liver “detoxification” seemingly is to make determined that in the PC group 3 subjects potentially problematic substances water- were good, 14 were average, while 3 had not soluble, suitable for later excretion into the bile improved. In the placebo group, 0 subjects or the urine. Therefore the healthy liver were good, 9 were average, and 11 (more than half) had experienced no benefit. The authors concluded, “it is our view that the use of charge on the molecule. It then attempts to highly-unsaturated phosphatidylcholine for therapy of alcohol-dependent steatoses [fatty “activated” metabolite with glucuronic acid or with glutathione or other antioxidants to render it water-soluble.4 If the first phase enzyme marized establish the benefits of PC as an oral systems become induced, generating copious nutritional supplement for the earliest clini- amounts of exceedingly reactive activated cally-characterized stage of liver damage from molecules, then the resources for conjugation alcohol abuse - the presence of fatty deposits Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 263
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Figure 3. Inhibition of alcoholic liver damage in baboons fed an adequate diet with ethyl
alcohol. Left: alcohol given daily along with PC to six baboons results in minimal fibrotic
damage, 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
can become insufficient. When this happens, clinical benefits against liver damage from activation can still proceed but conjugation many causes. In the case of alcohol, the most fails, and the liver tissue becomes a sitting duck clinically relevant animal research to date has been the “baboon model” of alcoholism de- metabolites. Alcohol and many xenobiotics veloped by Leiber and his colleagues at the can actually induce, i.e., turn on, the Phase 1 systems, thereby racking up the potential for Bronx Veterans Affairs Medical Center in New York City, for more than 2 decades.10,15,16,48 metabolites. This can explain why combined Their findings constitute compelling evidence that dietary supplementation with PC is effec- pollutants or other xenobiotics can be severely tive against alcoholic liver damage. In early threatening to the liver’s integrity.4,9,10 In this experiments they fed alcohol to rats, and found scenario any agent that turns on Phase 1 of the that it impaired phospholipid synthesis in the detoxification system, can cause the system rat liver. This partially accounts for fats accu- to concurrently convert excessive amounts of mulating in the liver cells (“fatty liver”), since a second (or third) agent to reactive, oxidant PC and other phospholipids are needed to me- tabolize triglycerides. Then, for an “experi-mental model” closer to the human state, they The Baboon Model of Alcoholic Liver
turned to research on baboon primates (Fig. 3).
boons on a daily regimen of alcohol intake.
Over a period of years most of the baboons the means by which PC exerts its impressive developed features of alcoholic liver damage Page 264 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission that closely resembled those seen in humans, making this is a good “animal model” for hu- man liver disease. The researchers also de- were subsequently taken off PC while continu- veloped sophisticated methods for quantitat- ing to be fed alcohol. These baboons rapidly ing the tissue changes seen in liver biopsy progressed to extensive liver fibrosis (equiva- samples, and refined biochemical analyses for lent to advanced liver damage). From this use on small amounts of biopsy material.
study and a follow-up study using a similar design17, Lieber’s group were able to firmly sign, they set up two main groups of baboons, conclude that PC is an effective means for one of which received alcohol along with PC, halting (not merely slowing) the progression the other receiving only alcohol.15 After run- from early-stage alcoholic liver damage into ning this primate trial for several years and late-stage generalized fibrosis (cirrhosis). (Fig- decoding their results, Lieber’s group found ure 3) PC is unique among both nutrients and that the baboons fed alcohol with PC devel- drugs, as was pointed out in a supportive peer oped fatty liver and mild fibrosis, but did not editorial,18 in its ability to halt the clinical pro- Figure 4. Summary of the mechanisms of liver damage by drugs. Note the lipid peroxidation
events that result in cell membrane damage. From Hoyumpa and Schenker.19
progress to advanced liver damage for six years or longer. In contrast, the majority of Subsequent in vitro experiments by baboons fed alcohol without PC progressed Lieber’s group16 showed that the lipocytes, the to advanced fibrosis (p < 0.005). While PC did not block the development of fatty liver in amounts of fats, under the influence of alco- baboons that continued to receive alcohol, it hol become transformed to collagen-produc- dramatically slowed the progress to advanced ing cells (called “transitional cells”). In the Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 265
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission intact, alcohol-treated liver these transitional riety of toxic agents other than alcohol. The cells intensify collagen production, but initially trials reported in this category are sparse be- the liver keeps up by breaking down collagen cause of the difficulties in assembling victims faster (via increased collagenase enzyme ac- of toxic exposures. However, some clinical tivity). As alcohol damage progresses, the trials have been accomplished, and their find- balance shifts: the liver’s collagenase activity ings indicate PC is also unique in its protec- drops and continued collagen production by tion of the liver against toxins other than al- the transitional cells results in progressive col- lagen deposition and extensive fibrosis. This eventually deprives the liver of most of its function (the state of cirrhosis). It may well (“xenobiotics”) entering the body. Blood car- be that in the baboons fed PC along with alco- rying newly-absorbed molecules proceeds di- hol, excessive collagen production was par- rectly to the liver from the intestines. Sub- tially blocked by PC, and collagen breakdown stances as diverse as drugs, whether legal or was increased for a sustained period (also via illegal; anesthetics; herbs, foods, and pollut- ants can be rendered more toxic after reach- supplementation with PC seemingly restored ing the liver, due to bioactivation by the liver normal collagen balance in the transitional P450 and related enzyme pathways (see Fig.
cells, thereby blocking further fibrosis and pro- 4). Almost all of these substances are liver tecting the baboons for several years and po- toxins because of their conversion into reac- tive oxidants, which deplete the antioxidants and other Phase 2 conjugation resources. This suggest that advanced liver damage in humans, unfortunate lack of discriminative activity by clinically expressed as cirrhosis, may prove the liver underlies most of the notorious liver amenable to dietary PC. As a result of this toxicity of pharmaceuticals. Excessive intake research breakthrough by the Lieber group, ex- of substances from any xenobiotic category citement developed in the U.S. research com- can predispose the liver to damage in response munity around the potential of PC to slow, to to otherwise-reasonable intakes of substances stabilize, and perhaps in some cases even to from other categories. A classic example is reverse, alcoholic liver damage. An editorial alcohol intake potentiating the metabolism of in the journal Alcoholism: Clinical and Experi- mental Research discussed PC as a possible“magic bullet” for this purpose.18 The Lieber • Drug Xenobiotics.
baboon studies also established that choline over the counter pharmaceuticals can become does not have comparable benefits to PC for activated to toxic metabolites in the liver.4,19 the liver. The small choline molecule is actu- The most heavily consumed among these are ally part of the headgroup of the large PC the painkillers acetaminophen, aspirin (acetyl- molecule, but when free choline was added to salicylic acid), ibuprofen, carbamazepine, in- the baboon diet it proved toxic to the alcohol- domethacin, phenylbutazone; the antibiotic tetracycline; the anti-arrhythmic drugsamiodarone, perhexiline, and hexestrol; the Benefits of PC Against Other Liver
blood pressure drug alpha-methyldopa; theanticlotting medication sulfinpyrazone; the barbiturate phenobarbital; the chemo- therapy drug methotrexate; the gout drug al- PC supports liver cells against attack by a va- Page 266 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission lopurinol; the anti-tuberculosis drug isoniazid (particularly in combination with rifampin); against acute oral trichloroethylene poison- the CNS stimulant amineptine; the tricyclic ing.23 Also, non-halogenated organic solvents, antidepressant tianeptine; the anti-epileptics allyl alcohol, carbon disulfide, ethionine, and phenytoin and valproic acid; and the benzodi- thioacetamide all are markedly liver-toxic, by azepine sedative chlordiazepoxide. Anesthet- mechanisms similar to those illustrated in Fig.
ics that are potentially toxic to the liver in- 4. Numerous case histories have been pub- clude halothane. Of the illicit drugs, cocaine lished that document the benefits of PC in other has been extensively studied for its toxicity to foods, the deathcap mushroom (Amanita double-blind trial for which they assembled phalloides) carries toxins that are some of the 101 tuberculous subjects who earlier had suf- most lethal agents known. Esslinger used PC, fered liver damage from rifampin and 2 other at first intravenously then also orally, to avert anti-tuberculosis pharmaceuticals.20 The PC death in victims of deathcap poisoning.24 In group received 1350 mg of fortified PC daily, Esslinger’s experience, PC worked against deathcap mushroom toxicity after milk thistle showed good clinical improvement, but in the extract had failed to show benefit. He called PC group SGOT and SGPT were significantly PC “a valuable extension to therapy for this lower when compared with the group that re- ceived the placebo. Kuntz and collaboratorshad made a similar finding in 1979, by giving • Natural plant toxins. In addition to the
peanuts is also one of the most toxic natural antiepileptic drugs, especially phenytoin, pose substances, and also becomes operative via a high risk of liver damage. Hisanaga and bioactivation. Constituents of herbs also can collaborators (1980) in Japan followed 38 sub- be liver-toxic by bioactivation, the most noto- jects who had received phenytoin and other rious of these being the pyrrolizidine alkaloids antiepileptic drugs for an average of five found in comfrey and at least 59 other plants.
years.22 A subgroup with the highest degreeof damage (assessed by SGGT enzyme eleva- • Radiation exposure. Klemm and Pabst in
tion), after being given PC orally for 6 months, 1964 gave PC to 161 subjects who had previ- ously undergone radiation treatment.25 Radia-tion scattered from the head-neck area tended • Other, non-Pharmaceutical Xenobiotics.
to damage the liver, and PC afforded partial but clinically-meaningful protection against number at least sixty-five thousand. One of the chemical classes most toxic to the liver isthe chlorinated and related halogenated hydro- • Other toxic insults to the liver, such as from
carbons, of which carbon tetrachloride has been extensively researched as an experimen- hepatectomy (the surgical removal of liver tal model. Included in this class is the dry tissue), and a variety of other sources, have cleaning solvent trichloroethylene, along with many commonly used herbicides and pesti-cides. In 1965 Kuntz and Neumann-Mangoldt Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 267
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission studies conducted with laboratory animals.
sue had partially recovered from its earlierdamage; focal necrosis/cell death was lessened Controlled Trials with PC in Viral
in the PC group, and these subjects showed Liver Damage
ducted a sophisticated trial in Czechoslova- liver, by precipitating widespread inflamma- kia that compared PC against drugs for the tory breakdown which is further complicated management of viral-related liver inflamma- by overactivation of the immune system (au- tion. They recruited 80 subjects with pre- toimmune complications). Once successfully sumed acute LV infection (viruses hepatitis A installed in the liver parenchyma, such viruses and hepatitis B), and divided them into four can become chronic and very hard to dislodge.
groups of 20 subjects each.29 The first 2 Liver viruses (here simply called LV) can groups were drawn from subjects whose bi- wreak havoc with the liver’s functions. Medi- lirubin levels were low (below 250 micro- cal weapons for eliminating LV from the liver, moles per liter) and were judged “moderately or for ameliorating their progressive damage, serious.” Subjects in Group I were adminis- have been limited. Controlled clinical trials tered fortified PC (1350 mg) along with the have unequivocally established PC as safe and “standard treatment” that involved diet, rest, reliable nutritional support for the liver against vitamins, and glucose; Group II received the standard treatment only. Groups III and IV were judged “serious,” with bilirubin levels gave 16 subjects with chronic, aggressive LV above 250 micromoles per liter. Group III a relatively high intake of PC (2,050 mg per received fortified PC and 580 mg daily of the immunosuppressive drug prednisone (a drug of clinical parameters improved, including measures of the liver’s detoxification pathways overactivation from LV); Group IV received that metabolize amino acids and phenols, and prednisone plus the standard treatment.
the authors concluded that PC was having a PC had a clearly favorable effect in this “normalizing” effect on the liver as a whole.
trial. Concerning the resolution of viral dam- From their large open study reported in 1973, age, both Group I subjects (less severe) and over the course of which some subjects re- Group III (more severe) had their liver tests ceived PC for up to 5 years, Wallnoefer and return to normal markedly faster than the cor- Hanusch noted a success rate for chronic, ag- responding groups that did not receive PC.
Subjects who did not receive PC were more likely to relapse (10% in the less severe, 25% ducted a double-blind trial in Japan in 1978, in the severe), while no relapses occurred in using 124 subjects with various LV.27,28 They the PC groups. Upset stomach, jaundice, and gave PC (1350 mg per day) to a group of 58 liver swelling, as well as the lab tests, all re- subjects and placebo to 66 subjects, for twelve solved faster in the groups treated with PC.
weeks. The PC group experienced significant There was a trend towards lower occurrence of the hepatitis B surface antigen (HBsAg) in compared with the placebo group; those with the PC groups as treatment progressed.
higher enzyme values to begin with appeared to benefit the most. A subsequent blinded bi- College, London did a double-blind trial in opsy assessment after 6 months confirmed that 1982 on 30 subjects with progressing liver in the PC subjects, the liver parenchymal tis- Page 268 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission damage from chronic LV (hepatitis B virus, with LV (hepatitis B virus).32 All the subjects negative for HBsAg), as verified by biopsy.30 were chronically infected—they all had been They randomly divided the subjects into two virus carriers for at least 6 months. Seven had groups of 15 each, kept them on the standard viral antigens (HBeAg) which indicated a rela- immunosuppressive therapy (prednisolone or tively high degree of active infection. The azathioprine), then gave one group PC (2,300 other 17 subjects had no viral antigens and had mg per day) and the other placebo, for 1 year.
antibodies to the virus (anti-HBeAg), indicat- At the end of this period, the group given PC ing that they were in a stage of relative viral had no clinical changes, while the placebo inactivity. All subjects received 900 mg of (control) group had worsened. Biopsies re- fortified PC per day. After 4 months, the less vealed significant improvement of the liver severely affected, antibody-positive subgroup structure in the PC group, versus no improve- showed statistically significant improvements ment for the controls. More of the PC sub- in SGOT, SGPT, albumins, gamma-globulins, jects reported improved well-being than did the controls (62% versus 43%). In 3 of the 15 group that began the study with active virus subjects given PC the viral infection was had statistically significant improvements in judged to be inactive at the end of the trial, immune measures, suggestive of clinical ben- while no subjects were judged inactive from efit from PC. The effects of PC in this small the placebo group. Thus in this small con- and not well controlled trial were judged en- trolled trial, PC halted and partly reversed couraging, and might have been more dramatic chronic LV damage, improved overall well- had the daily intake been as high as in other being, and “turned off” the virus in as many as trials (a minimum 1350 mg of fortified PC, rather than the 900 mg that was given).
sembled 60 subjects who were positive for Controlled Trials with PC Against
hepatitis B virus (assessed as presence of Severe Liver Damage
HBsAg) and who had acute LV liver damage, and divided them into two groups.31 Within acterized by extensive fibrosis, which effec- tively stifles whole zones of the liver. Some- double-blind basis the subjects were started on times aggressive inflammatory changes are either fortified PC (1350 mg) or placebo cap- also present. This stage can be reached as a sules. Lab tests were conducted frequently, consequence of persistent alcohol intake, per- and immune evaluations and clinical exams sistent viral infection, or the unchecked toxic were done at 30, 90, and 180 days (6 months, effects of any of the many other agents that can damage the liver. Given the severity of the structural and functional damage to the PC was significantly more improved than the liver at this stage, lesser benefits are to be ex- placebo group, with 50% being negative for pected from PC supplementation than at ear- HBsAg versus 25% for the controls (p<0.05).
lier stages. Yet still PC proved beneficial.
PC improved the rate of clearance of virus antigen from the blood. The immune param- controlled trial conducted in Prague, Czecho- eters were not significantly different, though slovakia, studied 61 subjects with moderately liver enzyme tests showed trends favoring PC.
severe to severe functional breakdown of the liver.33 The degree of advanced liver damage (extensive fibrosis, inflammation, elevated en- Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 269
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission zymes) was assessed by biopsy and by a wide HBsAg viral antigen, versus only 3 of 25 for range of blood biochemical tests. Thirty-four the placebo group. Such “seroconversion” (34) subjects were given fortified PC (900 mg indicated marked clinical improvement for per day), and 27 subjects served as controls.
these fortunate subjects. A number of cell- The trial ran for 4 months, with each patient structural, biochemical, immunologic, and serving as their own control for statistical hematologic parameters were significantly improved in the PC group as compared with the end of the trial showed that except for the group continued well past the end of the trial.
bilirubin values, all the other biochemical in- dicators were significantly improved (p<0.01).
such severely affected subjects obtained bet- These included the albumin/globulin ratio, al- ter results by maintaining the subjects on com- bumin, bromsulfalein (BSP) clearance, SGPT, bined intravenous PC and oral supplementa- and SGOT. The number of subjects positive tion until substantial improvement had begun.
for HBsAg in the blood moved from 8 of 34 to 3 of 34 in the PC group; that of the controls though not controlled, are worthy of note.
Wallnoefer and Hanusch in their pioneering apparent in the PC group was not statistically study administered PC both intravenously and orally to 130 subjects with advanced, fibrotic HBsAg-positive subjects in both groups from liver damage.7 Once the clinical indicators the beginning of the trial. The investigators began returning to normal, they switched to commented that fortified PC was the only in- purely oral administration at relatively low tervention they were aware of that seemed to intakes (450-700 mg), which was continued bring down viral antigen levels, and they urged for months to years as necessary. PC produced further investigation of this possible benefit benefits for 17.5% of these subjects, as con- improved tissue structure on biopsy. Using a ducted a randomized, double-blind, placebo- similar strategy, they achieved benefit for 35.3 controlled trial.34 They recruited 50 subjects, percent of their subjects with chronic viral in- all positive for HBsAg (hepatitis B virus anti- fection of a kind that was positive for viral gen) who had extremely severe liver damage antigen and has an aggressive tendency to as verified by biopsy and immunologic test- progress to severe liver damage. Kuntz re- ing. The test group was administered 1350 ported in 1989 on 10 subjects to whom he gave mg of fortified PC, and the control group re- PC intravenously at 2,800 mg per day.3 Im- ceived a placebo. Both groups were followed provements were seen as early as the seventh for 1 year, with periodic sampling for lab as- day, and at the end of the 28-day trial period 3 sessments, then at the end of the 12 months subjects showed “dramatic, life-saving” im- provement, 2 had “increasingly rapid improve- ment,” 2 had gradual improvement, 2 had no had experienced considerably greater benefit, change; and 1 of the 10 subjects had died.
as assessed both from the structural biopsy findings and from the lab findings (p <0.001).
subjects who had advanced liver damage for which pharmaceutical treatments had failed.35 good to moderately good, versus 6 of 25 be- Orally administered fortified PC (1350 mg ing moderately improved in the placebo group.
daily) produced clinical improvement after 6 Six of the 25 in the PC group also lost the Page 270 Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission months, with favorable effects on the usual peroxidative membrane damage to the liver cell membranes, and the damage spreads to neighboring zones within the tissue.
clinical trials discussed above concur with findings from others36-40 to paint a clear pic- membrane-based structure and functions of the ture of PC as an effective and safe nutrient for liver’s parenchymal cells. When orally admin- liver damage of all degrees of severity.
istered to experimental animals, in quantitiesusually equivalent to 1-3 grams per day for PC Benefits the Liver Primarily
the human, PC had the following liver-pro- Through Cell Membranes
• Leakage of “indicator” enzymes from liver against toxic attack can be attributed to • Lipid peroxidation from free radical/ its important role in cell membranes. The stituents most vulnerable to toxic attack, and the diverse array of hepatotoxic substances • Cell death, fibrosis, and fatty infil- operates through common pathways: free radi- tration of the liver tissue were diminished cal or other oxidative attack that depletes an- tioxidants, leading to oxidative overload and subsequent peroxidative damage to the cell’s membranes.4 The ultimate consequence is thedeath of the cell.
from PC is consistent with its functions at the are partially unsaturated, and by being packed cell membrane. PC is required for the struc- tightly next to each other in the membrane they tural integrity of all the body’s cell membrane are highly vulnerable to oxidative attack from systems, and is essential to their functional- free radicals and other highly reactive, oxidant ity.41-45 PC is crucial both for the internal toxins. Under excessive or sustained attack, membranes to do their housekeeping and spe- cialized functions, and for the cell’s “master graded (“peroxidized”), mainly through their switch”—its outer membrane. The outer mem- brane interfaces with both the external envi- peroxidize, membrane continuity is inter- ronment and the internal environment of the rupted. Holes begin to develop in the cell’s cell; PC supports the membrane receptors that outer membrane, resulting in loss of control “hear” these molecular messages and carry over internal conditions. Enzymes and other them across the membranes in both directions.
larger bio-molecules begin to leak out, homeo- This outer membrane is also the cells’ reser- stasis fails, and the death of the cell becomes voir for the eicosanoids and other phospho- lipid derivatives that act as outgoing vocabu- lary, speaking the language of that cell to oth- model similar to chemical attack: viral inva- sion of the parenchymal cells initiates release of pro-inflammatory, oxidizing substances.
cades of research are that PC is an important Immune cells arrive in the area and begin re- protective nutrient for the liver, primarily leasing more oxidants via their “respiratory through being a building block for cell mem- burst.” These activities initiate cascades of Alternative Medicine Review ◆ Volume 1, Number 4 ◆ 1996 Page 271
Copyright1996 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission branes. PC is essential for the liver’s baseline liver damage have established that PC can homeostatic housekeeping functions, for the liver’s recovery following toxic damage, and not least to support the sophisticated liver from PC is far more likely if the subject’s al- metabolism that determines the individual’s cohol consumption is ceased. The small cho- level of health and freedom from disease.
line molecule is actually part of the headgroup of the large PC molecule, but when free cho- of the administered amount is absorbed over line was added to the baboon diet it proved 24 hours),46 and PC represents a far more toxic to the alcohol-damaged liver. Phosphati- pleasant means for dietary choline repletion dylcholine is a highly bioavailable form of than choline itself. Lastly, even as the PC mol- choline; it is also the most biologically sig- ecule is efficiently absorbed, it also is an ex- nificant and (for damaged livers, at least) the bioavailability of nutrients with which it is co- administered. Antioxidant nutrients and es- tant nutrient for the liver, both because it is pecially the flavonoids are likely to be better the primary cell membrane building block and absorbed in combination with PC,47 as are B because the liver is so functionally dependent vitamins, minerals, and numerous other nutri- on its estimated 33,000 square meters of mem- brane surface. Whether the liver has beendamaged by alcohol, by other toxic chemicals, Conclusion:
by pharmaceuticals, or by viruses, dietary supplementation with PC significantly speeds studies conducted on thousands of human sub- recovery. The clinical studies demonstrate that jects to date, PC’s confirmed clinical benefits dietary PC in sufficient amounts revitalizes whole zones of cells in the recovering liver.
hance its remarkable usefulness as a dietary supplement. PC is well documented as safe to take, and seems fully compatible with phar- • Accelerated restoration of subjects’ maceutical regimens and with other nutrients.
The PC molecule enhances the bioavailabilityof nutrients with which it is co-administered, In the trials cited in this review, PC was is highly bioavailable and represents a far bet- very well tolerated at oral intakes that ranged ter means for dietary choline repletion than up to 4.6 grams per day, and was found to be more effective the earlier it was administered.
Subjects who are started on PC after their liver truly a “magic bullet” for alcoholic liver is already severely damaged are more likely disease, but its benefits against various to benefit from higher oral intakes of PC (up severities of liver damage and its proven safety to or exceeding 4.6 grams per day). The most indicate that for the liver it is a nutrient of severe cases are likely to thrive with the help of intravenous PC, administered in combina-tion with a high oral dose.
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