PPC, a soya extract for treating liver disease

Polyenylphosphatidylcholine or PPC, is extracted from soya. It is approved in many countries as a treatment for chronic liver disease. Scientific evidence increasingly suggests that PPC’s benefits extend beyond the liver to the stomach, pancreas and cardiovascular system. Its efficacy may be explained in part by its antioxidant potency.

Antioxidant effects 3 One of PPC’s key mechanisms of action lies in its antioxidant effect. Despite being rich in polyunsaturated linoleic acid, PPC has been shown to be effective both at reducing the oxidative stress produced by alcohol in the liver and pancreas, and lowering levels of oxidised LDL-cholesterol. A study on baboons showed that PPC mitigates alcohol-induced oxidative stress, which partly explains its protective action against alcoholic liver damage (Liber C.S. et al., 1997).

High alcohol consumption is harmful to the liver and increases oxidation of LDL-cholesterol. In new research on baboons, PPC clearly reduced alcohol-induced LDL oxidation, and may thus help protect heavy drinkers from this key promoter of atherosclerosis (Navder K.P. et al., 1999). PPC also protects the liver from alcohol toxicity.

Drinking alcohol increases apoptosis (self-destruction) of hepatocytes. Enzymes such as P450E1, which are used to detoxify alcohol, become dangerous when over-stimulated. They generate significant quantities of free radicals and it is therefore important to control their activity. In one study, 28 male rats were given a liquid food with 30% of calories in the form of alcohol or carbohydrates, for a 28-day period. Half the animals received PPC (3g/l) and the other half a similar quantity of linoleate or stearate.

An additional dose of alcohol was given to the animals 90 minutes before their livers were removed. The results showed that alcohol absorption increased apoptosis of liver cells five-fold compared with controls, but that the PPC almost halved the rate of alcohol-induced apoptosis. The study suggests that PPC supplementation limits alcohol-induced apoptosis of hepatocytes, an effect which may be due in part to PPC’s protective effect against liver damage as well as to an antioxidant action through control of cytochrome induction (Liebert C.S. et al., 2000).
One way in which PPC helps prevent alcohol-induced liver damage is by inhibiting an enzyme involved in alcohol metabolism called CYP2E1, which is increased by chronic alcohol consumption. This leads to oxidative stress and production of acetaldehyde which places stress on antioxidant defences and depletes glutathione levels. CYP2E1 increases production of toxic metabolites in drugs such as acetaminophen and promotes carcinogenesis. CYP2E1 inhibitors protect the liver from alcohol-induced damage but drugs tested for this purpose have been found to be too toxic for daily use. PPC, however, has been shown to significantly inhibit CYP2E1 activity (Lieber C.S., 1999; Aleynik M.K. et al., 1999), thus offering a non-toxic alternative to addressing this problem.

Fibrosis, cirrhosis and alcohol

A characteristic of liver disease, whatever its cause, is an increase in deposits of collagen, a protein in connective tissue. This accumulation of connective tissue can result from stimulation of collagen biosynthesis and/or a reduction in its breakdown. It appears that PPC increases collagen breakdown by promoting activity of collagenase in liver cells, thus preventing the development of fibrosis and cirrhosis (Li J. et al., 1992). A number of studies have been conducted on PPC and its effects on collagen and fibrosis. Confirming earlier results, one recent study on baboons (Lieber C.S. et al., 1994) showed that giving the animals ethanol (a form of alcohol) resulted in hepatic fibrosis and cirrhosis even when combined with an adequate diet. This effect may be prevented by supplementing the diet with a 94-96% pure PPC preparation. None of the eight animals fed alcohol with PPC for up to 6 years showed any development of fibrosis or cirrhosis, which was not the case with 10 of the 12 unsupplemented baboons.
In another study on rats (Ma X. et al., 1996) PPC was shown to reduce hepatic fibrosis induced by carbon tetrachloride or human albumin.

Not only did it prevent the development of fibrosis, it also accelerated the regression of pre-existing fibrosis.
. This study suggested PPC’s protective effect against fibrosis is due, at least in part, to increased collagen breakdown. Research conducted on 18 alcoholic patients recently confirmed PPC’s benefits in the treatment of liver disease, suggesting it may stop or even reverse hepatic fibrosis. Following administration of PPC or a placebo, fibrosis was shown to have progressed two years later in five of the nine placebo patients, whereas in the nine taking PPC, the disease had either not progressed or had slightly improved.

Hepatic steatosis

Hepatic steatosis is characterised by the accumulation of fat in liver cells (hepatocytes) without causing specific symptoms. It is a chronic condition which can occur in association with a wide range of other diseases, toxins and drugs, although in current clinical practice, the majority of cases are due to excessive alcohol intake, diabetes or obesity. Much less commonly, acute steatosis can develop during pregnancy or in response to administration of tetracycline, acetaminophen or other drugs or toxins.

Steatosis, also known as fatty liver, was for some time thought to be a benign and reversible condition but detailed clinical studies have shown that, whether alcohol-related or not, it can lead to inflammation, cell death, fibrosis (steatohepatitis) and possibly even cirrhosis.

Cirrhosis is the irreversible end result of fibrous scarring, a response by the liver to a variety of long-term inflammatory, toxic, metabolic and congestive damage.

Alcohol is by far the most common cause of steatosis and cirrhosis in Western societies. However, the degree of damage produced by excessive alcohol intake varies widely between individuals. There appears to be no clear correlation between the incidence and severity of hepatic steatosis and the amount, nature or duration of alcohol abuse. It has yet to be determined why in some people, steatosis never develops into steatohepatitis or cirrhosis, whatever its cause.

There is increasing evidence to suggest that oxidation of fat in the liver leads to the development of liver damage, and free radicals have been shown to play a key role in the hepatotoxicity of a number of substances. Fat oxidation takes place within a chain reaction called lipid peroxidation which compromises anatomical and functional membrane integrity and creates new toxins, exacerbating the damage. As demonstrated in research conducted in the Czech Republic, PPC’s antioxidant effect may help explain its efficacy in treating hepatic steatosis (Horejsova M. et Urban J., 1994).

The study of 28 women with various-cause steatosis showed PPC to be a highly effective treatment. The women were given PPC alongside polyunsaturated fatty acids and low doses of vitamins B and E. After six months, tests showed eight of the women no longer had any signs of steatosis, thirteen had improved, while in seven, there was no change. Abnormal hypertrophy of the liver (hepatomegaly) had decreased significantly and parenchyma had become more homogenous in 10 of the 11 cases where it had been abnormal. Laboratory tests showed highly significant reductions in all liver enzymes measured (ALT, AST and GMT). Bilirubin, cholesterol and triglycerides were also significantly lower. Overall, 54% of patients showed improvements in all the parameters studied, 43% showed improvement in lab tests and subjective evaluation, and only 3.6% showed no objective improvement.

PPC and viral hepatitis

PPC was initially shown to reduce serum aminotransferases in experimental hepatitis. A multi-centre, randomised, placebo-controlled clinical trial evaluated the effects of PPC combined with interferon alpha (IFN) in patients with hepatitis B and C (Niederau et al., 1998). Interferon is a standard treatment for such diseases but only 50% of patients with hepatitis B, and 20-30% of those with hepatitis C, respond to this anti-viral drug with long-term normalisation of serum aminotransferases. Even when hepatitis C patients do respond to IFN treatment, there is a relapse rate of at least 50%.

176 patients completed the study protocol. All were given the same dose of IFN and were randomly assigned to also receive either 1.8g of PPC or a placebo for the 24-week test period. A biochemical response to the treatment was defined as a decrease of at least 50% in ALT compared with pre-treatment values.

The results showed that PPC increased the response rate to IFN in viral hepatitis C (71% compared with 51% in the placebo group). PPC administration was prolonged in the responders for 24 weeks after interferon was stopped. This produced a tendency towards an increase in the sustained response rate in patients with hepatitis C (41% compared with 15%). PPC did not, however, improve the response rate to interferon in patients with hepatitis B. The reason for this difference in response rate is unclear and needs further investigation, but the study nevertheless shows that PPC may be a valuable adjunct to interferon treatment for hepatitis C, and that it continues to provide benefits in reducing the risk of relapse after interferon therapy has ceased.

Alcohol and the pancreas

The pancreas is essential for digestion and glucose control. It secretes digestive enzymes into the duodenum for the digestion of proteins, carbohydrates and fats, and produces large quantities of sodium bicarbonate to neutralise stomach acid in the duodenum. Islets of Langerhans in the pancreas produce insulin and the related hormones glucagon and somatostatin.

Pancreatitis or inflammation of the pancreas, is caused by excessive alcohol consumption in around 80% of cases. Ethanol produces significant oxidative stress in the pancreas, probably due an increase in free radicals and a fall in levels of glutathione and other antioxidants
In particular, alcohol consumption, like pancreatitis, is associated with an increase in the CYP2E1 enzyme in the pancreas.

Protection for the stomach

In Western societies, we take more non-steroidal anti-inflammatories including aspirin than any other kind of drug because of their relative effectiveness at treating pain and inflammation. Recent evidence showed that people who took NSAIDs had a lower risk of developing Alzheimer’s disease, cardiovascular disease and some cancers. It seems a number of common age-related diseases are caused by a chronic inflammatory cascade and that daily ingestion of NSAIDs offers considerable protection against such conditions.
However, these drugs are far from unproblematic because they induce gastrointestinal damage in the form of erosion, bleeding, ulceration or perforation.

As little as 30mg of aspirin can suppress production of protective prostaglandins in the gastric mucosa. A study in which gastric ulcers were induced experimentally in rats (Dunjic B.S. et al, 1993) showed that mucosal lesions were significantly reduced when a single dose of PPC was given before and after the damaging factor, in this case, ethanol or an NSAID.

A recent clinical study compared the gastrointestinal effects of aspirin with those of aspirin chemically associated with PCC (Anand B.S. et al., 1999). Sixteen healthy subjects were given 10 doses of aspirin or an aspirin/PCC complex for 72 hours. After a washout period, the subjects crossed over treatments for a further 72 hours.
The researchers counted the number of gastroduodenal erosions in each subject. Those taking aspirin had an average of 8.75 erosions, while those taking the aspirin/PCC complex had only 2.81. The protective effect of PPC was more apparent in those who were most sensitive to aspirin damage and did not interfere with the therapeutic effect of the aspirin.

Reduction of cholesterol and angina pectoris

The benefits of PPC on blood lipoproteins have been demonstrated in a series of animal and human studies. A clinical trial conducted in St Petersburg in Russia, (Klimov A.N. et al., 1995) compared the effects of PPC with those of niacin in angina pectoris patients with hereditary elevation of cholesterol and triglycerides. Niacin is considered a standard treatment for this disease but side-effects are quite common and include flushing, skin dryness, itching, gastrointestinal upsets, elevated liver enzymes, and decreased glucose tolerance and excretion of urine and uric acid.
100 patients were randomly assigned to receive either PPC or niacin for a six-month period. Both groups were required to eat a low-fat diet and to stop any lipid-lowering medication they had been taking previously four weeks before the start of the trial. For the first two weeks of the study, PPC was given intravenously (500mg/day) and thereafter in 600mg capsules three times a day.

Both treatments reduced the frequency of angina attacks - from 2.3 per week to 0.9 in the niacin group, and from 3.8 per week to 0.9 in the PPC group. Eight of the niacin group patients (16%) left the study due to the treatment’s side-effects while the PPC subjects suffered no such problems. An improvement in exercise tolerance was observed in the PPC group only.
Unlike niacin, PPC significantly reduced oxidation of lipoprotein apoB. Both treatments produced similar improvements in the patients’ total lipid profile.

PPC lowered total and LDL-cholesterol levels by almost 15% and triglycerides by 32%. It also increased levels of ‘good’ HDL-cholesterol by 10%.

HDL and longevity

We now know the most protective sub-fraction of HDL-cholesterol is HDL2B – the sub-fraction with the largest particles. When rhesus monkeys were placed on a low calorie diet to slow the ageing process, their HDL2b levels increased significantly (Verley R.B. et al., 1997). A study of female centenarians has provided convincing proof of the importance of this HDL sub-fraction in protecting cardiovascular health (Barbagallo C.M. et al., 1998). These subjects’ lipoprotein profiles were compared with those of healthy, middle-aged women and older women of the same weight. There was no significant difference between the centenarians and the younger women in the series of tests conducted which included plasma lipids and apoliprotein, except for levels of HDL3a and HDL2b. While levels of total HDL were almost the same, those of HDL2b were significantly higher, and those of HDL3a significantly lower among the centenarians in comparison with those of the other groups. Researchers are calling for further studies on the distribution of HDL sub-fractions as potential markers of longevity.

In the previously-mentioned Russian study, an equally significant change in the HDL sub-fractions from HDL3a into HDL2b occurred in the PPC group but not the niacin group. Thus, while there was a modest increase in HDL levels following PPC supplementation, the HDL2b sub-fraction increased preferentially due to the 2a and 3a sub-fractions evolving into the highly anti-atherogenic 2b sub-fraction.

High lipid levels are frequently found in people with diabetes (in around 50% of cases) with a significant effect on coronary disease. In a double-blind study on the lipoprotein profile of diabetics (Kirsten et al., 1994), 30 non-insulin dependent diabetics with secondary hyperlipidaemia were given 2.7g of PPC or a placebo every day for two months. Levels of LDL-cholesterol and triglycerides decreased significantly compared with the placebo group while HDL-cholesterol levels increased. In the control group, values remained the same throughout the study.

It has been demonstrated that moderate alcohol consumption improves the profile of lipoproteins and in particular, increases HDL-cholesterol levels. A study on rats showed that PPC sustains alcohol’s HDL-elevating effects while reducing post-prandial levels of LDL- and VLDL-cholesterol (Navder K.P. et al. 1997).