Lipid hypothesis
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The lipid hypothesis (also known as the
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
hypothesis) is a medical theory postulating a link between
blood cholesterol Blood lipids (or blood fats) are lipids in the blood, either free or bound to other molecules. They are mostly transported in a protein capsule, and the density of the lipids and type of protein determines the fate of the particle and its influence ...
levels and the occurrence of
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
. A summary from 1976 described it as: "measures used to lower the plasma lipids in patients with
hyperlipidemia Hyperlipidemia is abnormally elevated levels of any or all lipids (fats, cholesterol, or triglycerides) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also used as an umbre ...
will lead to reductions in new events of
coronary heart disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...
". It states, more concisely, that "decreasing blood cholesterol ..significantly reduces coronary heart disease". An accumulation of evidence has led to the acceptance of the lipid hypothesis by most of the medical community.


History

In 1856, the German
pathologist Pathology is the study of the causal, causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when us ...
Rudolf Virchow Rudolf Ludwig Carl Virchow (; or ; 13 October 18215 September 1902) was a German physician, anthropologist, pathologist, prehistorian, biologist, writer, editor, and politician. He is known as "the father of modern pathology" and as the founder ...
first described
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
accumulation in arterial walls, however the initial connection between
arteriosclerosis Arteriosclerosis is the thickening, hardening, and loss of elasticity of the walls of Artery, arteries. This process gradually restricts the blood flow to one's organs and tissues and can lead to severe health risks brought on by atherosclerosis ...
and dietary cholesterol would not be established until the research of Russian pathologist
Nikolay Anichkov Nikolay Nikolayevich Anichkov (russian: Никола́й Никола́евич Ани́чков, often spelled ''Anitschkow'' in German literature) (1885, Saint Petersburg – 1964) was a prominent pathologist of Russian heritage. Anichkov first ...
, prior to
World War I World War I (28 July 1914 11 November 1918), often abbreviated as WWI, was one of the deadliest global conflicts in history. Belligerents included much of Europe, the Russian Empire, the United States, and the Ottoman Empire, with fightin ...
. In 1913, a study by Nikolay Anichkov showed that rabbits fed on
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
developed lesions in their arteries similar to
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
, suggesting a role for cholesterol in
atherogenesis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no sy ...
. Dutch physician Cornelis de Langen noted the correlation between nutritional cholesterol intake and incidence of
gallstones A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of mi ...
in Javanese people in 1916. de Langen showed that the traditional Javanese diet, poor in cholesterol and other lipids, was associated with a low level of blood cholesterol and low incidence of
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
(CVD), while the prevalence of CVD in Europeans living in Java on a Western diet was higher. Since de Langen published his results only in Dutch, his work remained unknown to most of the international scientific community until the 1940s and 1950s. By 1951, it was accepted that, although the causes of
atheroma An atheroma, or atheromatous plaque, is an abnormal and reversible accumulation of material in the inner layer of an arterial wall. The material consists of mostly macrophage cells, or debris, containing lipids, calcium and a variable amount o ...
were still unknown, fat deposition was a major feature of the disease process. "The so-called fatty flecks or streaks of arteries are the early lesions of atherosclerosis and... may develop into the more advanced lesions of the disease."


Ancel Keys and the Seven Countries Study


Ancel Keys

With the emergence of
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
as a major cause of death in the Western world in the middle of the 20th century, the lipid hypothesis received greater attention. In the 1940s, a University of Minnesota researcher,
Ancel Keys Ancel Benjamin Keys (January 26, 1904 – November 20, 2004) was an American physiologist who studied the influence of diet on health. In particular, he hypothesized that replacing dietary saturated fat with polyunsaturated fat reduces card ...
, postulated that the apparent epidemic of heart attacks in middle-aged American men was related to their mode of life and possibly modifiable physical characteristics. He first explored this idea in a group of Minnesota business and professional men that he recruited into a prospective study in 1947, the first of many cohort studies eventually mounted internationally. The first major report appeared in 1963 and the men were followed through until 1981. After fifteen years follow-up, the study confirmed the results of larger studies that reported earlier on the predictive value for heart attack of several risk factors: blood pressure, blood cholesterol level, and cigarette smoking.


Seven Countries Study

Keys presented his diet-lipid-heart disease hypothesis at a 1955 expert meeting of the
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
in Geneva. In response to criticism at the conference, Keys recruited collaborating researchers in seven countries to mount the first cross-cultural comparison, the years-long Seven Countries Study, which is still under observation today. This was to compare the heart attack risk in populations of men engaged in traditional occupations and being from cultures with different diets, especially in the proportion of fat calories of different composition. There was also criticism before the study began: Yerushalmy and Hilleboe pointed out that Keys had selected for the study the countries that would give him the results he wanted, while leaving out data from sixteen countries that would not; they also pointed out that Keys was studying a "tenuous association" rather than any possible proof of causation. Keys then joined the nutrition committee of the American Heart Association (AHA), successfully promulgated his idea, and in 1961 the AHA became the first group anywhere in the world to advise cutting back on saturated fat (and dietary cholesterol) to prevent heart disease. This historic recommendation was reported on the cover of
Time Magazine ''Time'' (stylized in all caps) is an American news magazine based in New York City. For nearly a century, it was published weekly, but starting in March 2020 it transitioned to every other week. It was first published in New York City on Mar ...
in that same year. The Seven Countries Study was formally started in fall 1958 in
Yugoslavia Yugoslavia (; sh-Latn-Cyrl, separator=" / ", Jugoslavija, Југославија ; sl, Jugoslavija ; mk, Југославија ;; rup, Iugoslavia; hu, Jugoszlávia; rue, label=Pannonian Rusyn, Югославия, translit=Juhoslavija ...
. In total, 12,763 males, 40–59 years of age, were enrolled in seven countries, in four regions of the world (United States, Northern Europe, Southern Europe, Japan). One cohort is in the United States, two cohorts in Finland, one in the Netherlands, three in Italy, five in Yugoslavia (two in Croatia, and three in Serbia), two in Greece, and two in Japan. The entry examinations were performed between 1958 and 1964 with an average participation rate of 90%, lowest in the US, with 75% and highest in one of the Japanese cohorts, with 100%. Keys' book ''Eat Well and Stay Well'' popularized the idea that reducing the amount of
saturated fat A saturated fat is a type of fat in which the fatty acid chains have all single bonds. A fat known as a glyceride is made of two kinds of smaller molecules: a short glycerol backbone and fatty acids that each contain a long linear or branched c ...
in the diet would reduce cholesterol levels and the risks of serious diseases due to atheroma. Keys was followed during the rest of the 20th century by an accumulation of work that repeatedly demonstrated associations between cholesterol levels (and other modifiable risk factors including smoking and exercise) and risks of heart disease. These led to the acceptance of the lipid hypothesis as orthodoxy by much of the medical community. By the end of the 1980s, there were widespread academic statements that the lipid hypothesis was proven beyond reasonable doubt, or, as one article stated, ''"universally recognized as a law."''


Consensus

The medical consensus supports the lipid hypothesis as evidence from separate meta-analyses, prospective epidemiologic studies and randomized clinical trials have demonstrated that elevated levels of LDL blood cholesterol are a significant risk factor for cardiovascular disease. Too much LDL (called 'bad cholesterol') can lead to fatty deposits building up in the arteries which increases the risk of cardiovascular disease. A 2017 consensus statement from the European Atherosclerosis Society concluded that "consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD." The consensus statement noted: The 2021 Canadian Cardiovascular Society Guidelines say "We recommend that for any patient with triglycerides > 1.5 mmol/L, non-HDL-C or ApoB be used instead of LDL-C as the preferred lipid parameter for screening (Strong Recommendation, High-Quality Evidence)".


See also

*
Hypercholesterolemia Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (high levels of lipids in the blood), hyperlipoproteinemia (high levels of lipoproteins in the blood), ...
*
Lipid-lowering agent Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins such as cholestero ...
* Fatty acid ratio in food


References

{{reflist Angiology Cardiovascular diseases Diets Medical conditions related to obesity Preventive medicine