Familial Hypercholesterolaemia; Brown and Goldstein

Brown and Glodstein won the 1985 Nobel Prize for medicine.
You can download their acceptance address as a pdf here.

Their work was primarily based around familial hypercholesterolaemia.

The world is full of genetic problems where the heterozygote, with one copy of an affected gene, has an advantage over people in whom neither copies of the gene is affected. Being a carrier (heterozygote) for sickle cell anaemia protects you from malaria without any disadvantage. Being the far rarer homozygote (both genes affected) is bad news because your haemoglobin polymerises under hypoxic conditions and your red blood cells become dysfunctional. Not nice. Hurts like hell, apparently.

There are lots of types of familial hypercholesterolaemia but I'll stick to the type where the receptor for LDL particles is fully dysfunctional. Get one copy of the gene and you have elevated cholesterol levels but are at no excess risk for CVD, unless you come from a family which has a history of premature CVD. Get two copies of the FH gene and, as for sickle cell disease, you are potentially in trouble. Why is part of a future AGE, RAGE and ALE post, so I'll leave it there for the time being.

Brown and Goldstein came up with a therapy for managing heterozygous familial hypercholesterolaemia.

Heterozygous FH (hFH) people make a lower number of functional LDL receptors because one of their genes for this protein is naff. The other gene is fine. B and G noted that the level of cholesterol within our cells controls the expression of the genes for the LDL receptor. Lower intracellular free cholesterol and you up regulate the LDL receptor gene, to grab extra cholesterol from passing LDL particles. Get enough functional receptors on to cell surface and you behave as if you are normal, LDL-wise.

So they put in place the concept of lowering plasma LDL by up regulating the LDL receptor expression by inhibiting cholesterol synthesis within the cell. You can particularly target the liver by, in addition, depriving it of bile acids. These cholesterol derivatives are fiendishly important and normally get very efficiently recycled. Treating with cholestyramine guarantees, along with gut ache, that most bile acids go down the loo. Now the liver REALLY needs cholesterol (partly to make more bile acids) but also because HMG CoA, the rate controlling enzyme cholesterol synthesis, can be blocked by a mould fungus (eventually to be marketed as lovastatin). So it sticks out lots of LDL receptors and normalises plasma LDL.

And all heart problems disappear. But B and G worked in the 1970s. At that time it had not occurred to anyone that it is only those hFH people with heart disease that get heart disease. The rest are fine. The heart disease cannot be from the elevated LDL, because the non CVD families have similar LDL yet stubbornly have no heart disease. Back in the 1970's no one thought to look for healthy hFH "victims", all of the hFH patients were found through cardiology clinics..........

So the basic principle which was used to usher in lovastatin was based on a mistake. Very clever science, but based on a mistake non the less. Who gave B and G the idea that elevated LDL cholesterol caused heart disease? Who do they cite as the source of elevated cholesterol being the cause of heart disease in their nobel acceptance address?

Well, you can bet it wasn't Yerushalmy and Hilleboe.

Oh, you've never heard of Yerushalmy and Hilleboe? Obviously neither had B and G.

B and G cited Ancel Keys and his seven countries study linking saturated fat to heart disease via elevated cholesterol:

"Extensive epidemiologic studies performed in many populations in many countries over the past three decades have pointed strongly to a general association of high blood cholesterol levels with heart attacks. Among the most striking examples is the seven-country study of coronary artery disease directed by Ansel Keys (116)"

ref 116 is to a text book published in 1980. The original publications were in the 1950s, this one comes from 1953. Unfortunately papers this old are not freely available so I'll personally have trust to Dr Ravnskov to have seen the actual paper based papers.

Yerushalmy and Hilleboe, in 1957, pointed out that Keys had selected his countries to fit his hypothesis and that inclusion of all of the data available at the time showed no association between saturated fat and blood cholesterol, let alone heart disease. Really, that should have been the end of the diet heart hypothesis.

But what is MUCH more interesting (than their believing Ancel Keys) is B and G's opinion about homozygous FH. It was obvious to them that you CANNOT up regulate the effective LDL receptors of homozygous FH patients because they DO NOT HAVE ANY GENES FOR EFFECTIVE LDL RECEPTORS AT ALL. Quote from B and G:

"The principles applied to treatment of FH heterozygotes cannot, unfortunately, be applied to homozygotes, especially those who have totally defective LDL receptor genes. These individuals do not respond to the above-mentioned drugs because they cannot synthesize LDL receptors"

Oh.

So why give statins to homozygous FH patients? Remember, statins are used, in B and G's scenario, to upregulate LDL receptors.

Clearly there is no logic to this.

You could say medicine has been very lucky in the multitude of unsought after beneficial effects from the fungal toxin lovastatin, in addition to it's very unpleasant ability to inhibit HMG CoA reductase and along side a few other rather nasty effects which negate any overall mortality benefit.

Or maybe you could say science has been held back for 25 years by that fluke and that medicine is no closer today to the real causes of heart disease than it was in 1953. Thanks again to Dr Keys.

Peter