Q J Med
2011; 104:867–870. doi:10.1093/qjmed/hcr087 Advance
Access Publication 20 June 2011
The great cholesterol myth; unfortunate consequences
of Brown and Goldstein’s
mistake
D.D.
ADAMS’—Converted from the PDF http://qjmed.oxfordjournals.org/content/qjmed/104/10/867.full.pdf#
From the Faculty
of Medicine,
University of Otago,
Dunedin,
New Zealand.
Address correspondence to
Dr
Duncan Adams, Faculty of Medicine, University of Otago, P.O. Box 913, Dunedin, New Zealand. email:
duncan.adams@stonebow.otago.ac.nz
Received 16
March 2011
and in revised form 3 May
2011
Summary
Following their
Nobel
Prize-winning
discovery
of
the defective gene causing familial hypercholesterolaemia,
Brown and Goldstein
misunderstood the mechanism involved in the pathogenesis of
the associated arterial disease. They
ascribed this
to an effect of
the
high
levels
of cholesterol circulating
in the blood.
In reality, the accelerated arterial damage is likely
to be a consequence of
more brittle arterial
cell walls, as biochemists
know
cholesterol to be a component of
them which
modulates
their fluidity, conferring
flexibility and hence resistance
to damage from the ordinary
hydrodynamic blood forces. In the absence of efficient receptors for
LDL cholesterol, cells
will be unable to use this component
adequately for the manufacture
of normally
resilient arterial cell walls, resulting
in accelerated arteriosclerosis. Eating
cholesterol is
harmless,
shown by its failure
to produce
vascular
accidents in laboratory animals, but its avoidance
causes
human malnutrition from lack
of
fat-soluble
vitamins,
especially vitamin D.
Introduction
When post-mortem
examinations
are made of elderly people, opening
of the aorta and smaller
arteries often reveals
atheroma, rough
yellow plaques disfiguring the smooth pink lining of these blood vessels
and impinging on the lumen. Often
the
extent
of
the atheroma formation makes
one
marvel
at how long the patient has lived before succumbing to a vascular
accident
from obstruction or rupturing of an
important artery.
Atheromatous
plaques contain cholesterol. Accordingly, research
workers have repeatedly fed laboratory
animals
large amounts of cholesterol
in their diets,1 expecting this to produce vascular accidents. It never
has, which
shows that despite the presence of cholesterol in atheromatous
plaques
these lesions are not caused
by eating cholesterol. Before describing the strong evidence that hydro- dynamic stresses cause the arterial degeneration responsible for ischaemic
heart disease
and strokes, we
shall recount
description2 of the spectacular
deviation from
reality caused by a mistaken interpretation
made
by Goldstein and
Brown after
they had brilliantly
discovered the defective gene that causes familial
hypercholesterolaemia (FH).
Familial hypercholesterolaemia
A famous book is Victor McKusick’s Mendelian Inheritance
in Man.3 This is a
catalogue
of thousands
of inherited diseases
caused
by mutations in germ-line
genes. The diseases are divided into three classes, depending on
whether the defective
gene is dominant, recessive
or sex-linked. One of these genetic diseases is FH, where
blood
cholesterol
levels are raised.
Heterozygous cases,
with one
normal gene and one
defective gene, have blood cholesterol levels
of
250–450 mg/dl, whereas 
homozygotes
with
both alleles defective
have levels >500, compared to normal people with
levels
of
150–250. There
is accelerated arteriosclerosis with premature deaths from vascular accidents in the forth and fifth decade in heterozygotes and earlier in homozygotes. In most populations
the frequency
of the
homozygotes is 1 in a million and that of
the heterozygotes about 1 in 500, comparable
to
the frequency of the
defective gene causing
cystic fibrosis.
Brown and Goldstein’s
discoveries4,5
One of
the most famous ever
partnerships in medical research
was that of Michael
Brown and Joseph Goldstein, who received the 1985 Nobel Prize
in Physiology and Medicine for
discovering that the defective gene in FH codes for a cell surface
receptor for cholesterol
in the form of low-density
lypoprotein (LDL). In a
succession of
brilliant research achievements, Brown
and
Goldstein
developed a
culture technique for skin from both normal individuals and
patients with
FH.
The
cultured skin cells were then analysed biochemically by
Brown. In 1973, Brown
and
Goldstein discovered the rate-limiting enzyme
in
cholesterol production,
3-hydroxy-3-methylglutaryl coenzyme A (HMG- CoA)
reductase, which could be regulated in cultured normal skin
fibroblasts by the amount
of LDL in the medium. Adding LDL
to
the
normal
cells switched off HMG-CoA reductase and
the cells
ceased making cholesterol.
However, the
skin cells
from FH patients
continued to make cholesterol
with
even very high levels of LDL in the medium.
Brown and Goldstein
correctly concluded
that the genetic mutation must
involve
a
receptor that bound LDL and enabled
cholesterol to enter the cell. Drugs were developed
that would inhibit HMG-CoA reductase and thus decrease the cellular
production of cholesterol. Lovastatin [Mevacor] was
the first
such drug marketed
in the hope of decreasing the occurrence of heart attacks, on the mistaken
assumption that high
blood cholesterol caused
such attacks.
Brown and Goldstein’s
mistake,
the cholesterol hypothesis4–6
Unfortunately, Brown and Goldstein failed to realize that it is the loss of a functional
cholesterol receptor,
causing impaired ability to absorb
and
use cholesterol, which is the probable
cause of the accelerated
arteriosclerosis occurring in
FH.
Instead, they assumed that the cause
is the high level of blood cholesterol,
which
‘salts out’ into the arterial walls, causing the vascular impairment. This was an understandable
mistake, because as mentioned
above, the atheromatous plaques
of arteriosclerosis contain
cholesterol, which causes
a bulge impinging on the lumen. In angioplasty, cardiologists use mechanical
pressure
to
flatten
such
bulges,
with
therapeutic
benefit to the flow of blood.
However, pathologists realize
that
deposition of cholesterol
in the arterial walls seems to be secondary
to hydro- dynamic
damage,7 followed by inflammation, with cell multiplication
and somatic gene
mutation. The first awareness of this came from the finding that it is not possible
to produce arteriosclerosis by feeding excessive amounts
of cholesterol to laboratory animals.
Only
harmless
‘fatty streaks’
are produced,1 never a vascular accident.
Biochemists know that cholesterol is a component of cell walls that modulates
their fluidity.8 With the loss of the cholesterol
receptor, the impaired
ability to absorb cholesterol is likely
to impair flexibility of cell walls in arteries, making them
more
brittle
and
therefore more liable to hydrodynamic damage.
This
accounts for deaths from occurrence of
vascular accidents
in the fourth and fifth
decades in patients
with heterozygous
FH,
including two cousins
of the
author,
who were identical
twins, thereby doubling the misfortune.2
Evidence for the haemodynamic hypothesis of arteriosclerosis
1. Hypertension causes accelerated
arteriosclerosis and vascular accidents.
2. The absence of
arteriosclerosis in the pulmonary circulation that
has one third of
the pressure of the systemic circulation. Furthermore, in cases of pulmonary
hypertension typical fibrous atheromatous
plaques occur in the pulmonary
artery and its major branches.7
3.
The
sites of arterial
damage are where
hydrodynamic forces act,
e.g.
left anterior descending
coronary,
where a powerful
jet of blood
from the aorta hits the wall of the branch
artery.
4. Race
horses
with
high
blood
pressure
during
daily hours
of training die around
20 years of age compared to
40 years for untrained
horses.
False claim from the Lipids Research
Clinics Primary Prevention Trial
In 1985, every doctor
in New Zealand received a report
saying it was now proven
that lowering blood cholesterol
levels in normal people reduces the risk of coronary heart disease.
The report cited a study in which a group
of 1906 men took
the bile sequestrant, cholestyramine resin, for 7 years in comparison with 1900 men who took a placebo. L’Abbe
and colleagues in Toronto9 noted with disapproval that the investigators had made
a post hoc relaxation of the level of significance from the originally
proposed <0.001 to <0.05. Check of the statistics, showed that even
this low level of
significance had not been reached.10 The investigators
had cheated by using a
one-tailed Student’s t-test instead of the proper
two-tailed one.
Lenfant’s complaint
In a flush of success,
Brown and Goldstein6 wrote
a 1996 editorial for Science
entitled, ‘Heart
attacks: gone with the century?’ In the year 2000, Claude Lenfant, Director,
National
Heart Institute, National Institutes of Health,
wrote
the Forward
to a book by Grundy
evaluating clinical trial evidence for benefit of cholesterol-lowering therapy. Dr Lenfant asks rhetorically if
Brown and Goldstein’s prediction had been
fulfilled and stated,11 ‘Unfortunately, the
answer is no’.
Unfortunate
consequences of Brown and
Goldstein’s mistake
Brown and Goldstein’s burst of fascinating information dazzled the
medical profession, most of whom consequently accepted
the false cholesterol hypothesis. This has led to unfortunate
consequences that
include:
1. Waste of money on misdirected
research.
2. Waste of money
on blood cholesterol tests.
3. Waste of money
on statins.
4. Malnutrition from lack of fat-soluble vitamins
(A,D,K,E) present in butter, full-cream milk and animal fat
but lacking in margarine and skim milk (green-top bottles in New Zealand).
5. Fear of eating eggs, contributing
to unhealthy, starchy diets.
6. Ricketts in middle-aged
men
from lack of vitamin
D due to use of margarine and skim-milk.
7. Distortion of the Dairy Industry, causing unnecessary
marketing of skim milk.
8. Distortion of the Meat Industry
with unnecessary
production of lean meat.
Discussion
Recently,
LaRosa et al.12 reported on a huge study
by thousands of people, comparing the therapeutic efficacy of two doses of
Atorvastin, 80 mg/day
and
10 mg/day,
on
the
frequency of adverse
cardiac
events. Notably, there was no difference in overall
mortality between the two
doses. However, LaRosa drew a graph
depicting cardiovascular event percentage
and LDL cholesterol level, in patients
from four statin trial groups and his
own study. The graph, in
his Figure 4, is misleading. It shows a rising slope
for
cardiovascular events against LDL cholesterol
levels. However, all the statin groups, in black, are on the left of the graph and
all the placebo groups
in white are on the right of the
graph,
so
the
slope
simply depicts the cholesterol-lowering
effect
of
the statins. To test whether
statins reduce the cardio- vascular events, the
statin and
placebo sections of the individual trials must
be compared. Reading by eye
from the graphs, the statin
components of the four trials average
13 events compared to
17 events from the placebo components, Student’s
t-test showing no significant difference. The fact that of
the thousands of people involved
in achieving this spurious result did not
include a
single elementary mathematician with intellectual
independence is
in accord with the whole sorry story of the great
cholesterol myth, starting with the false statistics used in analysing the Framingham data.10 The meta-analysis of Ray et al.,13 showing no prolongation of life by use of statins
in randomized controlled trials involving
65 229 participants, is the
final nail in the coffin of
the great cholesterol myth. [One needs to do more than merely look at a
graph to ferret out pharma’s marketing deception. For example, a minor
endpoint, such as angina,
is added to the list to MI and death, for to get the marketing answer, benefit.
Adams merely took LaRosa’s evidence at face value, though Adams has
uncovered deliberate deception by LaRosa--why not more?—jk.]
There is a popular fear
of eating fat, triglycerides, which was reduced to fear of
saturated
fats to accommodate the finding
that
Eskimos, the Inuit people, were found to
eat much unsaturated
fat
without early heart disease. It seems likely that fear of fat is
unreal based on
a carry-on of the cholesterol fear.
In
the world of religion, it is often taught that
it is virtuous to believe something without adequate proof and virtuous to
convert others to the same misbelief.
This
has
overlapped
into Medicine in
regard
to
the
cholesterol
hypothesis,
as
described
in
my
previous paper.2 The great
strength of Medicine
is its scientific basis,
which
we
must all have the courage
and intellectual flexibility
to preserve.
Acknowledgement
The author is indebted to Pro-Vice Chancellor Peter Crampton for encouragement
and administrative
support.
Conflict of interest: None declared,
References
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DF,
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JR. Muir’s
Textbook of Pathology. th edn.
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MS, Goldstein JL. How LDL
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1984;
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5. Brown
MS, Goldstein JL. A receptor-mediated pathway for
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Science
1986;
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6. Brown
MS, Goldstein JL. Heart
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gone
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7. Benditt EP, Schwartz SM. Blood vessels. In: Rubin E, Farber JL, eds, Pathology. 2nd edn. Philadelphia,
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DD. Lowering cholesterol
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