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Prophylaxis of alimentary hypercholesterolemia
267
Atherosclerosis, 68 (1987) 267-269 Elsevier Scientific Publishers Ireland, Ltd. ATH04055
L e t t e r to the E d i t o r s
Prophylaxis of alimentary hypercholesterolemia * Dear Editors, Eight different causes of human hypercholesterolemia are known. Yet, nearly exclusively, attention is being focused on plasma cholesterol elevation caused by overalimentation. Thus, dietary hypercholesterolemia is being blamed for atherogenesis, that is, for the initiation and evolution of anatomical intimal arterial lesions, and for atherosclerosis, the clinical phase, its symptoms and sequelae, particularly, for coronary artery occlusion and ischemic myocardial infarction. This interest in alimentary hypercholesterolemia has two reasons. Arterial lesions can be initiated and maintained in many animal species by a cholesterol-rich or cholesterol-enriched diet. Clinical atherosclerosis, effort angina and myocardial infarctions are prevalent in populations consuming a high caloric, cholesterol-rich diet. Dietary hypercholesterolemia can be mitigated or controlled in several ways, by restricting ingestion of cholesterol, by various dietary supplements of plant origin, or by medication. The most effective dietary or pharmacal approaches are based on blocking the resorption of cholesterol from the jejunum. The first successful attempts to reduce cholesterol resorption were made in 1951 and 1952. Peterson et al. fed "mixed soy sterols" to chicken; Pollak fed "sitosterol" to rabbits. Neither preparation contained more than 75% of fl-sitosterol, the most important of phytosterols. Experiments with chickens and rabbits yielded the same results. At a ratio of 6 parts of phytosterols to 1 part of cholesterol, the zoosterol, added to the basic feed, there was no rise in serum cholesterol. At a ratio of 2.5 : 1, or even of 2.25 : 1, the serum cholesterol * Published as abstract by Pollak, O.J. and Hasegawa, K., Prophylaxis of Alimentary Hypercholesterolemia. In: IXth International Symposium on Drugs Affecting Lipid Metabolism, Florence, Italy, 19-21 October, 1986.
of rabbits rose only slightly, to too low a level for initiation of intimal lesions. The need for an excess of sitosterol over cholesterol could be explained by the lack of purity of the product used, further, by the fact that fl-sitosterol has to counteract not only dietary cholesterol of various sources but all the cholesterol available for absorption and re-absorption. The experiments with chickens and rabbits were repeated many times with many other species. Some investigators fed sitosterol and cholesterol simultaneously to normocholesterolemic animals; others fed sitosterol in various amounts to animals with elevated plasma cholesterol levels. The original observations were confirmed in well over 200 reports. Encouraged by the results with rabbits, Pollak and his staff ingested sitosterol with each of 3 main meals for 2 weeks. The bulky, crude, chalky, tasteless material was placed between slices of white bread. Such sandwiches were eaten by 26 volunteers whose serum cholesterol ranged between 124 m g / d l and 414 mg/dl. Minimum and maximum reductions were 12.6% and 39%, respectively. The average decrease of the serum cholesterol level amounted to 14-21%. Upon termination of the regimen the cholesterol levels gradually returned to the starting point. Then, after a 40 day pause, a second course of sitosterol ingestion yielded the same results as did the first. The results of the clinical prototype study were confirmed by all the researchers who adhered to the original program. Sitosterol preparations of varying purity were given to well over 2000 subjects on all continents. Sporadic failures were due to often frivolous modifications, such as a single dose of sitosterol, a few minimal doses, too short a trial period, to pre-medication or to a diet lowering the level close to the normal range. At times, selection of subjects was unfortunate: some had a normal plasma cholesterol level, some had endoge-
268 nous, familial hypercholesterolemia of the homozygous type, some had biliary cirrhosis, etc. In spite of satisfactory results as plasma cholesterol depressant, /3-sitosterol was abandoned in medicinal form, sharing such fate with the vast majority of drugs proposed to the same end. This in spite of the fact that, unlike many a drug, vitamin E and fish oils, LDL-cholesterol is lowered by ingestion of/3-sitosterol. In sharp contrast to all the pharmacals proposed to date for reduction of exo- and endogenous cholesterol, /3sitosterol has no adverse effects. Its litholytic action allows for non-surgical treatment of cholelithiasis. Its beneficial effect on prostate adenoma allows for medical treatment of benign prostate hypertrophy. Such effect may be due to its influencing the production of prostaglandins. If, as suggested by Pollak, the effect is due to/3-sitosterol acting as low potency phytoestrogen, it could have a third salubrious side effect, namely on senile osteoporosis. In the past, multiple objections were voiced to the use of /3-sitosterol as plasma cholesterol depressant. All could be easily refuted. At first, the taste was repulsive. Shortly, sitosterol became available as flavored emulsion, in capsules, as tasteless powder, incorporated into tasty cookies, etc. The large dose required was criticised. Since the effect on plasma cholesterol is prompt, the initial trial dose can be quickly reduced to a low maintenance dose. Purification of commercially available products led to further reduction of the effective dose. It has been proven that a daily dose of 3 g, i.e., three 1 g doses ingested with meals, using a highly purified powder, is adequate for most patients. Half that amount, i.e., 1.5 g per day or 2 sitosterol cookies containing 0.75 g each, will, for the time being, suffice for the Japanese. Such doses are considerably smaller than those prescribed for any of the drugs. Next, there was objection to the low potency of fl-sitosterol, a plasma cholesterol reduction by 14-20%. However, such an effect compares favorably with that of currently available drugs, with the effect of a diet high in polyunsaturated fatty acids and that of a vegetable diet. /3-Sitosterol has not a lasting effect on plasma cholesterol unless ingested "forever". This, of course, applies to all known approaches to control of hypercholesterolemia. It
also applies to control of hyperglycemia and of essential hypertension, whether objected to or not. In medicinal form, fl-sitosterol offers a good alternative to pharmaceuticals geared to control hypercholesterolemia. In dietary form, fl-sitosterol offers a good alternative to dietary restrictions of cholesterol, fl-Sitosterol should not be viewed as a drug since it is ubiquitous throughout the flora. It is a natural component of fruits and nuts, vegetables and vegetable oils, seed oils, etc. Prescribing a sitosterol-rich diet is far more difficult than prescribing a cholesterol-poor diet. Knowledge about the amounts of fl-sitosterol in the most common foods is lacking or is incomplete. Vegetable oils are an exception. Moreover, the amounts in various parts of a plant are not the same, vary with seasons and crops, undergo changes with processing, refining, food preparation for consumption, etc. There is an alternative to the therapeutic use of fl-sitosterol, whether in medicinal or in dietary form. It is the prophylactic approach of blending it into butter and margarines, two widely used nutrients. A large bibliography [1,2] provides the background for the proposal. Two classical examples of highly successful prophylactic food additives deserve attention. They are adding potassium iodide to table salt and adding thiamine to rice. Endemic goitre is due to lack of dietary iodine. Iodine was isolated from kelp by Courtois in 1811. It was first used for treatment of goitre by Coindet in 1820. Marine and Kendall suggested iodine for prevention of goitre in 1912. The Michigan State Medical Society endorsed iodization of table salt in 1924, the Goitre Society of Michigan did so in 1935. The American Public Health Association gave its approval in 1941. Finally, in 1942, 30 years after the original proposal had been made, the program was implemented: 0.01% of potassium iodide was added to table salt. This resulted in eradication of endemic goitre. Beriberi is due to dietary thiamine deficiency. In 1886, Takaki reported that beriberi is caused by eating decorticated rice. In 1897, Ejkman prevented polyneuritis in pigeons by feeding them unpolished rice. In 1912, Vedder and Clark prevented beriberi in humans the very same way. That year, Funk discovered vitamins. Vitamin B a,
269 thiamine, was synthesized in 1937 by Williams. He then suggested thiamine as additive to rice. His proposal was promptly approved by the Philippine Medical, Chemical and Pharmacological Societies, the Philippine Government, the U.S. Public Health Service and the Philippine Rice and Corn Corporation. Yet, it took another decade, until 1948, for the original idea to be implemented as the "Bataan Project". Adding 1 mg thiamine per kg of rice led to prompt eradication of beri beri. The relationship between lack of dietary iodine and endemic goitre is linear, as is that between lack of dietary thiamine and beri befi. Atherosclerosis presents a different problem: dietary excess of cholesterol is not the sole cause. However, leading to alimentary hypercholesterolemia, it presents a major risk. One could say that atherosclerosis is partly due to excess of dietary cholesterol. Since fl-sitosterol "neutralizes" cholesterol by blocking its absorption, one can also say that atherosclerosis is partly due to lack of dietary beta-sitosterol. The proposal to utilize flsitosterol as prophylactic food additive is based on the sound nutritional principle of balancing the two dietary sterols. It has been proposed to blend purified flsitosterol into butter and margarines. To add it to other foods would not be practical. Adding it to all margarines, including the cholesterol-free brands of vegetable oil origin, is imperative since cholesterol resorption should be blocked, regardless of its source. In the U.S., a bar of butter or margarine weighs 113.4 g. Scales on the wrappers indicate that each bar can be devided into eight portions, pats or table spoons. Such portions weigh 14.2 g. Similar pats, often individually wrapped, are being served all over the world, in restaurants and in homes. Adding 8 g of fl-sitosterol per bar will provide 1 g per pat. Assuming consumption of 1 pat of butter or margarine with each of 3 main meals, the daily supply of ]~-sitosterol would come to 3 g. A cookie with 0.75 g sitosterol could provide a supplement; 2 cookies could replace 1 pat.
Cholesterol was first isolated from gall stones by Chevreul in 1816. Sitosterol was first obtained from cereal grain by Burifin in 1897. Scarpa, in 1904, described human arterial lesions as "steatomatosis". Anitchkow, in 1912, used the term "cholesterolsteatosis" for arterial lesions induced in rabbits by a cholesterol regimen. In 1951, Pollak prevented such lesions in rabbits by feeding sitosterol together with cholesterol. In 1952, he reported the reduction of serum cholesterol levels of humans ingesting sitosterol with their meals. Thirty-five years later, the proposal was made to utilize fi-sitosterol as a prophylactic food additive. Adding this natural food constituent to butter and margarine is inocuous, safe and effective. Of the Ten Commandments only the two advocating positive behavior are being obeyed. Our "negative" crusade against cholesterol-rich foods is not very successful, and "positive" claims about vegetable margarines actually removing cholesterol from the body will not do. The proposal of prophylactic use of/3-sitosterol as food additive represents a positive approach. The history of using iodine and thiamine as food additives has been sketched to underscore the time lag between proposal and realization of these 2 projects. Time is ripe for all health organizations, agencies and institutions, for the food and the drug industry, the medical profession, the news media and the public to familiarize themselves with the potential of using fl-sitosterol as prophylactic food additive, with the goal of eliminating or, at least, reducing alimentary hypercholesterolemia as a risk factor for atherogenesis and atherosclerosis and myocardial infarction. References 1 Pollak, O.J. and Kritchevsky, D., Sitosterol. In: Monographs on Atherosclerosis, vol. 10, S. Karger, Basel, 1981. (956 references). 2 Pollak, O.J., Effect of plant sterols on serum lipids and atherosclerosis, Pharmac. Ther., 31 (1985) 177 (As chapter in the International Encyclopedia of Pharmacology and Therapeutics, 1987, Pergamon Press, Ltd., Oxford; 115 references).
1203 Delaware Ave., Wilmington, DE 19806, U.S.A.
(Received 18 June, 1987) (Accepted 22 July, 1987)
O.J. P o l l a k
Atherosclerosis, 68 (1987) 267-269 Elsevier Scientific Publishers Ireland, Ltd. ATH04055
L e t t e r to the E d i t o r s
Prophylaxis of alimentary hypercholesterolemia * Dear Editors, Eight different causes of human hypercholesterolemia are known. Yet, nearly exclusively, attention is being focused on plasma cholesterol elevation caused by overalimentation. Thus, dietary hypercholesterolemia is being blamed for atherogenesis, that is, for the initiation and evolution of anatomical intimal arterial lesions, and for atherosclerosis, the clinical phase, its symptoms and sequelae, particularly, for coronary artery occlusion and ischemic myocardial infarction. This interest in alimentary hypercholesterolemia has two reasons. Arterial lesions can be initiated and maintained in many animal species by a cholesterol-rich or cholesterol-enriched diet. Clinical atherosclerosis, effort angina and myocardial infarctions are prevalent in populations consuming a high caloric, cholesterol-rich diet. Dietary hypercholesterolemia can be mitigated or controlled in several ways, by restricting ingestion of cholesterol, by various dietary supplements of plant origin, or by medication. The most effective dietary or pharmacal approaches are based on blocking the resorption of cholesterol from the jejunum. The first successful attempts to reduce cholesterol resorption were made in 1951 and 1952. Peterson et al. fed "mixed soy sterols" to chicken; Pollak fed "sitosterol" to rabbits. Neither preparation contained more than 75% of fl-sitosterol, the most important of phytosterols. Experiments with chickens and rabbits yielded the same results. At a ratio of 6 parts of phytosterols to 1 part of cholesterol, the zoosterol, added to the basic feed, there was no rise in serum cholesterol. At a ratio of 2.5 : 1, or even of 2.25 : 1, the serum cholesterol * Published as abstract by Pollak, O.J. and Hasegawa, K., Prophylaxis of Alimentary Hypercholesterolemia. In: IXth International Symposium on Drugs Affecting Lipid Metabolism, Florence, Italy, 19-21 October, 1986.
of rabbits rose only slightly, to too low a level for initiation of intimal lesions. The need for an excess of sitosterol over cholesterol could be explained by the lack of purity of the product used, further, by the fact that fl-sitosterol has to counteract not only dietary cholesterol of various sources but all the cholesterol available for absorption and re-absorption. The experiments with chickens and rabbits were repeated many times with many other species. Some investigators fed sitosterol and cholesterol simultaneously to normocholesterolemic animals; others fed sitosterol in various amounts to animals with elevated plasma cholesterol levels. The original observations were confirmed in well over 200 reports. Encouraged by the results with rabbits, Pollak and his staff ingested sitosterol with each of 3 main meals for 2 weeks. The bulky, crude, chalky, tasteless material was placed between slices of white bread. Such sandwiches were eaten by 26 volunteers whose serum cholesterol ranged between 124 m g / d l and 414 mg/dl. Minimum and maximum reductions were 12.6% and 39%, respectively. The average decrease of the serum cholesterol level amounted to 14-21%. Upon termination of the regimen the cholesterol levels gradually returned to the starting point. Then, after a 40 day pause, a second course of sitosterol ingestion yielded the same results as did the first. The results of the clinical prototype study were confirmed by all the researchers who adhered to the original program. Sitosterol preparations of varying purity were given to well over 2000 subjects on all continents. Sporadic failures were due to often frivolous modifications, such as a single dose of sitosterol, a few minimal doses, too short a trial period, to pre-medication or to a diet lowering the level close to the normal range. At times, selection of subjects was unfortunate: some had a normal plasma cholesterol level, some had endoge-
268 nous, familial hypercholesterolemia of the homozygous type, some had biliary cirrhosis, etc. In spite of satisfactory results as plasma cholesterol depressant, /3-sitosterol was abandoned in medicinal form, sharing such fate with the vast majority of drugs proposed to the same end. This in spite of the fact that, unlike many a drug, vitamin E and fish oils, LDL-cholesterol is lowered by ingestion of/3-sitosterol. In sharp contrast to all the pharmacals proposed to date for reduction of exo- and endogenous cholesterol, /3sitosterol has no adverse effects. Its litholytic action allows for non-surgical treatment of cholelithiasis. Its beneficial effect on prostate adenoma allows for medical treatment of benign prostate hypertrophy. Such effect may be due to its influencing the production of prostaglandins. If, as suggested by Pollak, the effect is due to/3-sitosterol acting as low potency phytoestrogen, it could have a third salubrious side effect, namely on senile osteoporosis. In the past, multiple objections were voiced to the use of /3-sitosterol as plasma cholesterol depressant. All could be easily refuted. At first, the taste was repulsive. Shortly, sitosterol became available as flavored emulsion, in capsules, as tasteless powder, incorporated into tasty cookies, etc. The large dose required was criticised. Since the effect on plasma cholesterol is prompt, the initial trial dose can be quickly reduced to a low maintenance dose. Purification of commercially available products led to further reduction of the effective dose. It has been proven that a daily dose of 3 g, i.e., three 1 g doses ingested with meals, using a highly purified powder, is adequate for most patients. Half that amount, i.e., 1.5 g per day or 2 sitosterol cookies containing 0.75 g each, will, for the time being, suffice for the Japanese. Such doses are considerably smaller than those prescribed for any of the drugs. Next, there was objection to the low potency of fl-sitosterol, a plasma cholesterol reduction by 14-20%. However, such an effect compares favorably with that of currently available drugs, with the effect of a diet high in polyunsaturated fatty acids and that of a vegetable diet. /3-Sitosterol has not a lasting effect on plasma cholesterol unless ingested "forever". This, of course, applies to all known approaches to control of hypercholesterolemia. It
also applies to control of hyperglycemia and of essential hypertension, whether objected to or not. In medicinal form, fl-sitosterol offers a good alternative to pharmaceuticals geared to control hypercholesterolemia. In dietary form, fl-sitosterol offers a good alternative to dietary restrictions of cholesterol, fl-Sitosterol should not be viewed as a drug since it is ubiquitous throughout the flora. It is a natural component of fruits and nuts, vegetables and vegetable oils, seed oils, etc. Prescribing a sitosterol-rich diet is far more difficult than prescribing a cholesterol-poor diet. Knowledge about the amounts of fl-sitosterol in the most common foods is lacking or is incomplete. Vegetable oils are an exception. Moreover, the amounts in various parts of a plant are not the same, vary with seasons and crops, undergo changes with processing, refining, food preparation for consumption, etc. There is an alternative to the therapeutic use of fl-sitosterol, whether in medicinal or in dietary form. It is the prophylactic approach of blending it into butter and margarines, two widely used nutrients. A large bibliography [1,2] provides the background for the proposal. Two classical examples of highly successful prophylactic food additives deserve attention. They are adding potassium iodide to table salt and adding thiamine to rice. Endemic goitre is due to lack of dietary iodine. Iodine was isolated from kelp by Courtois in 1811. It was first used for treatment of goitre by Coindet in 1820. Marine and Kendall suggested iodine for prevention of goitre in 1912. The Michigan State Medical Society endorsed iodization of table salt in 1924, the Goitre Society of Michigan did so in 1935. The American Public Health Association gave its approval in 1941. Finally, in 1942, 30 years after the original proposal had been made, the program was implemented: 0.01% of potassium iodide was added to table salt. This resulted in eradication of endemic goitre. Beriberi is due to dietary thiamine deficiency. In 1886, Takaki reported that beriberi is caused by eating decorticated rice. In 1897, Ejkman prevented polyneuritis in pigeons by feeding them unpolished rice. In 1912, Vedder and Clark prevented beriberi in humans the very same way. That year, Funk discovered vitamins. Vitamin B a,
269 thiamine, was synthesized in 1937 by Williams. He then suggested thiamine as additive to rice. His proposal was promptly approved by the Philippine Medical, Chemical and Pharmacological Societies, the Philippine Government, the U.S. Public Health Service and the Philippine Rice and Corn Corporation. Yet, it took another decade, until 1948, for the original idea to be implemented as the "Bataan Project". Adding 1 mg thiamine per kg of rice led to prompt eradication of beri beri. The relationship between lack of dietary iodine and endemic goitre is linear, as is that between lack of dietary thiamine and beri befi. Atherosclerosis presents a different problem: dietary excess of cholesterol is not the sole cause. However, leading to alimentary hypercholesterolemia, it presents a major risk. One could say that atherosclerosis is partly due to excess of dietary cholesterol. Since fl-sitosterol "neutralizes" cholesterol by blocking its absorption, one can also say that atherosclerosis is partly due to lack of dietary beta-sitosterol. The proposal to utilize flsitosterol as prophylactic food additive is based on the sound nutritional principle of balancing the two dietary sterols. It has been proposed to blend purified flsitosterol into butter and margarines. To add it to other foods would not be practical. Adding it to all margarines, including the cholesterol-free brands of vegetable oil origin, is imperative since cholesterol resorption should be blocked, regardless of its source. In the U.S., a bar of butter or margarine weighs 113.4 g. Scales on the wrappers indicate that each bar can be devided into eight portions, pats or table spoons. Such portions weigh 14.2 g. Similar pats, often individually wrapped, are being served all over the world, in restaurants and in homes. Adding 8 g of fl-sitosterol per bar will provide 1 g per pat. Assuming consumption of 1 pat of butter or margarine with each of 3 main meals, the daily supply of ]~-sitosterol would come to 3 g. A cookie with 0.75 g sitosterol could provide a supplement; 2 cookies could replace 1 pat.
Cholesterol was first isolated from gall stones by Chevreul in 1816. Sitosterol was first obtained from cereal grain by Burifin in 1897. Scarpa, in 1904, described human arterial lesions as "steatomatosis". Anitchkow, in 1912, used the term "cholesterolsteatosis" for arterial lesions induced in rabbits by a cholesterol regimen. In 1951, Pollak prevented such lesions in rabbits by feeding sitosterol together with cholesterol. In 1952, he reported the reduction of serum cholesterol levels of humans ingesting sitosterol with their meals. Thirty-five years later, the proposal was made to utilize fi-sitosterol as a prophylactic food additive. Adding this natural food constituent to butter and margarine is inocuous, safe and effective. Of the Ten Commandments only the two advocating positive behavior are being obeyed. Our "negative" crusade against cholesterol-rich foods is not very successful, and "positive" claims about vegetable margarines actually removing cholesterol from the body will not do. The proposal of prophylactic use of/3-sitosterol as food additive represents a positive approach. The history of using iodine and thiamine as food additives has been sketched to underscore the time lag between proposal and realization of these 2 projects. Time is ripe for all health organizations, agencies and institutions, for the food and the drug industry, the medical profession, the news media and the public to familiarize themselves with the potential of using fl-sitosterol as prophylactic food additive, with the goal of eliminating or, at least, reducing alimentary hypercholesterolemia as a risk factor for atherogenesis and atherosclerosis and myocardial infarction. References 1 Pollak, O.J. and Kritchevsky, D., Sitosterol. In: Monographs on Atherosclerosis, vol. 10, S. Karger, Basel, 1981. (956 references). 2 Pollak, O.J., Effect of plant sterols on serum lipids and atherosclerosis, Pharmac. Ther., 31 (1985) 177 (As chapter in the International Encyclopedia of Pharmacology and Therapeutics, 1987, Pergamon Press, Ltd., Oxford; 115 references).
1203 Delaware Ave., Wilmington, DE 19806, U.S.A.
(Received 18 June, 1987) (Accepted 22 July, 1987)
O.J. P o l l a k