Dear JULES,
Rebutting the cholesterol hypothesis
Executive summary
* This note suggests a rapid rebuttal to the cholesterol hypothesis.
* To get there, it goes through the history of how the cholesterol hypothesis developed and mutated over time. From Russian pathologists to Dr Ancel Keys and to the current focus on saturated fat and Low-Density-Lipoprotein cholesterol (LDL-C).
Introduction
I look after some cats in the village when their owners are away. The owners are very generous, and they bring me gifts from where they’ve been and usually some 85% cocoa chocolate, which they know that I like. After the last pet sit, when the chocolate was given to me, the male in the couple (“B”) remarked “doesn’t that raise your cholesterol?” And I asked “how?”
We got talking and “B” revealed that he was on statins and his cholesterol was now 4 something (mmol/L) and he was thrilled. I asked why. We got talking more and it made me realise that I needed to work out the shortest rebuttal possible for the next time this happens. I’ll share this at the end, but first, we need a bit of history.
The cholesterol hypothesis
The full history of how we came to demonise first cholesterol and then fat and then saturated fat is laid out in chapter two of my PhD. This is the chapter known as “The Review of the Literature” and it reviewed the relevant literature for the whole diet heart hypothesis. This is the potted history…
The cholesterol hypothesis originated in the early years of the twentieth century. While performing autopsies, Russian pathologists noticed build-up in the arteries of deceased people. The build-up contained cholesterol. They hypothesised that the cholesterol had caused the build-up and blocked the artery leading to a sudden death (the term “heart attacks” was not much used before the end of World War II).
An alternative hypothesis would be that cholesterol is a substance made by the body for the repair and health of every cell and thus something else had damaged the artery wall and cholesterol had gone to repair that damage. This is the hypothesis that has the memorable analogy – fire fighters are always found at the scene of a fire. They didn’t cause the fire – they went there to fix it. Ditto with cholesterol. The alternative hypothesis did not occur to the pathologists by all accounts.
The pathologists undertook experiments in rabbits to feed them cholesterol to see if they ‘clogged up’ and sure enough they did. However, rabbits are herbivores and cholesterol is only found in animal foods and thus it’s not surprising that feeding animal foods to natural vegetarians clogged them up. When rabbits were fed purified cholesterol in their normal (plant-based) food, they didn’t clog up. That should have been a red flag to the hypothesis, but it wasn’t.
Dr Ancel Keys
Heart disease, dietary cholesterol and blood cholesterol
The next significant era in the development of the cholesterol/fat hypothesis was when Dr Ancel Keys came on the scene. He had published The Minnesota Starvation Experiment in 1950 and was the man of the moment and keen to stay that way (Ref 1). He turned his attention from the possibility of food shortages due to world war to why men (particularly) were dying from heart disease.
He was aware of the work of the Russian pathologists and picked up their theory that dietary cholesterol increased the levels of blood cholesterol. Keys undertook several experiments on human beings (ethics were not an issue back then). He increased their intake of foods containing cholesterol dramatically and discovered that this had no impact on blood cholesterol levels. In my review of the literature, the most definitive statement that I came across from Keys on his findings was recorded in a 1954 Symposium on Atherosclerosis: “The evidence – both from experiments and from field surveys – indicates that cholesterol content, per se, of all natural diets has no significant effect on either the cholesterol level or the development of atherosclerosis in man” (Ref 2).
Keys thus abandoned research into dietary cholesterol and turned his attention to dietary fat. This premise had a logical flaw. The only foods that contain cholesterol are animal foods: meat; fish; eggs and dairy products. Keys was aware of this: “Cholesterol occurs only in foods of animal origin” (Ref 3). This was reinforced in the 1952 publication, The Cholesterol Problem: “cholesterol is not contained in plants or plant products but it is present in all animal tissues” (Ref 4).
All foods that contain cholesterol contain dietary fat. They all contain all three types of dietary fat: saturated; monounsaturated and polyunsaturated. Only the proportions of each fat vary (Ref 5). To increase the dietary cholesterol in his human subjects, Keys needed to feed them foods of animal origin. This had no impact on blood cholesterol levels, or the development of atherosclerosis in man (Ref 6). Animal foods, per se, had been simultaneously exonerated.
The macronutrient that is largely absent from the foods that contain cholesterol is carbohydrate. Meat and fish have no carbohydrate content (with liver, offal, being an exception for any glycogen stored by the animal at the time of death). Eggs have a trace of carbohydrate. Dairy products approximate to five per cent carbohydrate content. Animal foods are either entirely, or in the main, water, protein and fat (Ref 5).
The logical macronutrient for Keys to have studied was therefore carbohydrate, but attention was turned to fat.
Heart disease and total fat
Total dietary fat was the focus of one of Keys’ best known and most important publications (Ref 7). This publication was first presented at the Mount Sinai Hospital in New York City in January 1953. It is often referred to as the Mount Sinai presentation. This was Keys’ first presentation of a graph of the relationship between mortality from degenerative heart disease and fat calories as a percentage of total calories in the diet for a number of countries, for men aged 45-49 and 55-59 (Ref 8), replicated below. (Degenerative heart disease was defined as coronary disease, angina pectoris, infarction, chronic myocarditis and myocardial degeneration.) Keys presented the graph with data for Australia, Canada, England and Wales, Italy, Japan and the USA. The six data points suggested a strong relationship between fat calories as a percentage of dietary intake and deaths from heart disease for men aged 55-59.
This is the famous six countries graph, which is often confused with the Seven Countries Study and should not be (Ref 9). This graph was presented in 1953 and it showed that Keys was developing his thinking away from ‘cholesterol causes heart disase’ and towards ‘fat causes heart disease’. This graph was comprehensively critiqued by Hilleboe (Ref 10), who presented Yerushalmy’s data for 12 countries for heart disease and calories derived from fat in the diet and then by Yerushalmy and Hilleboe in their co-authored 1957 paper, which presented data for 22 countries (Ref 11). In essence, Keys had omitted several countries for which data were available and the picture looked different when all available data were included.
Heart disease and saturated fat
The 1953 six countries graph set the scene for Keys’ thinking, as he secured funding for the ambitious Seven Countries Study (SCS). The SCS started in 1956, but it wasn’t published until 1970 (Ref 12). The six countries graph helped Keys to select which countries would likely support the fat-heart hypothesis. The seven countries chosen for the SCS included the US and Japan – which defined the ends of the curve above – and included Italy (nicely on the line). The remaining four countries chosen were Yugoslavia, Netherlands, Finland and Greece. Keys was already working with colleagues in these countries and that facilitated collaboration.
Although Keys went into the SCS thinking that fat and deaths from heart disease (in men) were associated, the data did not support this. Instead, Keys concluded that it was saturated fat, and not total fat, that “tended to be related” to both blood cholesterol levels and the incidence of coronary heart disease. The fact that no claims were made against total fat in the SCS is not widely known.
The mutations
Over time, therefore, the hypothesis has mutated from:
– dietary cholesterol raises blood cholesterol and causes heart disease; to
– total fat causes heart disease (no mention of cholesterol); to
– saturated fat and blood cholesterol and heart disease “tend to be related”; to
– lots of variants of a form of a cholesterol hypothesis e.g., total cholesterol causes heart disease and then LDL-cholesterol causes heart disease and then LDL-cholesterol is bad (puh-lease) and HDL cholesterol is good (puh-lease again) and the ratio of LDL (‘bad’) to HDL (‘good’) cholesterol causes heart disease…
We seem to have ended up with the hypothesis that “saturated fat raises LDL-cholesterol and causes heart disease”, although there are variants of this – it’s not just LDL-cholesterol but small dense or large fluffy LDL (I struggle not to laugh when I hear such things).
The mutations have kept the hypothesis alive. As each stage has been disproven, a new variant has emerged, but this may in fact have killed the hypothesis and here’s why…
The short rebuttal
Back to “B” and here’s what I should have said:
1) The chemical formula for cholesterol is C27H46O. There is no good or bad cholesterol, only cholesterol. Do you agree?
2) LDL stands for Low Density Lipoprotein. HDL stands for High Density Lipoprotein. Lipoproteins are not cholesterol. They carry cholesterol – and protein and phospholipids and triglycerides – lipids generally. Think of them as taxis. When ‘they’ talk about LDL-cholesterol and HDL-cholesterol, they are talking about the same cholesterol. Do you still agree?
3) So, you cannot have an issue with LDL-cholesterol and not HDL-cholesterol because the cholesterol is the same. If you have an issue with LDL, you have an issue with the ‘taxi’ and hence you have a lipoprotein hypothesis and not a cholesterol hypothesis. So, ask your doctor what issue s/he has with lipoproteins and can they leave your cholesterol alone?!
By mutating the hypothesis from dietary cholesterol and total blood cholesterol to the cholesterol in one lipoprotein, the cholesterol hypothesis has mutated into a lipoprotein hypothesis. We need to increase awareness of this. Vast sums of money have been invested in the development of the cholesterol hypothesis, to the extent that it is rare to find someone who does not believe that cholesterol is harmful and should be lowered. The hypothesis has moved on but the marketing messages prevail.
Until the next time
All the best – Zoë
p.s. if you are fond of the concept of small dense or large fluffy LDLs – this is still a lipoprotein hypothesis.
References
Ref 1: Keys A, Brožek J, Henschel A, et al. The biology of human starvation: University of Minnesota Press 1950.
Ref 2: Keys A, Anderson JT. The relationship of the diet to the development of atherosclerosis in man. In: National Research Council DoMS, ed. Symposium on atherosclerosis. Washington: National Academy of Sciences – National Research Council. 1954. (P.182 – original emphasis).
Ref 3: Keys A, Mickelsen O, Miller EvO, et al. The Relation in Man between Cholesterol Levels in the Diet and in the Blood. Science 1950. (P.79).
Ref 4: Keys A. The cholesterol problem. Voeding 1952. (P.542).
Ref 5: Harcombe Z, Baker J, Davies B. Food for Thought: Have We Been Giving the Wrong Dietary Advice? Food and Nutrition Sciences 2013.
Ref 6: Keys A, Anderson JT. The relationship of the diet to the development of atherosclerosis in man. In: National Research Council DoMS, ed. Symposium on atherosclerosis. Washington: National Academy of Sciences – National Research Council. 1954.
Ref 7: Keys A. Atherosclerosis: a problem in newer public health. J Mt Sinai Hosp N Y 1953.
Ref 8: Keys A. Atherosclerosis: a problem in newer public health. J Mt Sinai Hosp N Y 1953. (Fig. 2, P.134).
Ref 9: https://www.zoeharcombe.com/2017/02/keys-six-countries-graph/
Ref 10: Hilleboe HE. Some epidemiologic aspects of coronary artery disease. J Chronic Dis 1957.
Ref 11: Yerushalmy J, Hilleboe HE. Fat in the diet and mortality from heart disease; a methodologic note. N Y State J Med 1957.
Ref 12: Keys A. Coronary heart disease in seven countries I. The study program and objectives. Circulation 1970.
