By Duane Graveline, MD, MPH
Familial hypercholesterolemia (FH) is a genetic disorder characterized by substantial elevations of low-density lipoprotein cholesterol (LDL) with an inflammatory predisposition, unrelated to diet or lifestyle.
In many families, there will be an associated high risk of premature cardiovascular disease even with cholesterol control, indicating the presence of other inflammatory and pro-thrombotic factors.
Estimates indicate that as many as 1 in 500 people of all ethnicities and 1 in 250 people of Northern European descent may have FH; nevertheless, the condition remains largely undiagnosed.
The genetic factor involved is usually the gene for LDL receptor protein or apolipoprotein B, both charged with removing LDL from blood circulation. People who have one copy of the abnormal gene–the relatively common heterozygous familial hypercholesterolemia–may have premature cardiovascular disease.
However, a single abnormal copy (heterozygote) of FH causes cardiovascular disease by the age of 50 in only about 40% of cases, suggesting the frequent co-existence of other factors yet to be identified. Having two abnormal copies–the relatively rare homozygous familial hypercholesterolemia–may be associated with severe cardiovascular disease, even in childhood.
Of particular interest is the well-known observation that premature cardiovascular disease does not always follow from heterozygous hypercholesterolemia. There exist family lines where the cardiovascular disease risk is no different than the rest of the population. It is also well established that reduction of cholesterol levels through the aggressive use of statins and other cholesterol lowering agents in hypercholesterolemia is not always associated with risk reduction.
Naturally such observations point to the presence of risk factors far more important than cholesterol levels and are entirely in agreement with growing awareness of the frequent presence of other factors leading to increased cardiovascular disease risk.
Common abnormalities of prothrombin, apolipoprotein(a) and angiotensin-converting enzyme genes all have been found in genetics studies on selected familial hypercholesterolemia (FH) families. Additionally, both C-reactive protein and lipoprotein(a), a powerful pro-thrombotic factor, are now well known to be very relevant to risk assessment. This applies equally to familial cases as well as to the more ordinary, non-genetic cases of cholesterol elevation.
Some people with FH have normal cardiac histories while others have an elevated risk for premature cardiac events. We have learned that the reason is not cholesterol, it is inflammation and a predisposition to arterial thrombosis completely unrelated to cholesterol levels.
Ideally people with elevated cholesterol levels should be screened for this inflammatory predisposition, with the most appropriate test today being the high-sensitive C-reactive protein (hs-CRP) test for the presence or absence of the underlying inflammation causing atherosclerosis.
A dramatic demonstration of the effectiveness of this test was demonstrated in the JUPITER trial of 2009. In this study investigators selected a large group of men and women having normal cholesterol but elevated hs-CRP levels. They then equally divided the group giving a statin to one half and placebo to the other.
Nineteen months elapsed before the incidence of “hard” atherosclerotic events in the placebo group prompted the ethics committee to stop the study. The lead author of the study had personal involvement with the development of the hs-CRP test and it rapidly became controversial but two very significant truths emerged from this study–cholesterol is irrelevant to cardiac risk determination and statins help reduce this risk.
Familial hypercholesterolemia must be differentiated from common hypercholesterolemia, the quasi disease triggered by Ancel Keys in the fifties. This was definitely NOT a disease. When I graduated from medical school in 1955, cholesterol was a regular blood constituent with a normal range of 100 - 300 mg. Now the upper limit of normal for this completely innocent substance has become 200mg.
The food industry saw millions to be made from conjuring up low cholesterol foodstuffs while the pharmaceutical industry was giddy at the prospect of developing cholesterol lowering drugs from which they would make fortunes. Even doctors were excited about another chronic disease to treat.
This turned out to be one huge con-job in which cholesterol was innocent. Just as with FH, inflammation is the cause of atherosclerosis and only if inflammation was present will statins drugs benefit.
If you want to screen for something, screen for hs-CRP. If positive, it means arterial inflammation and a high risk for atherosclerosis. Particularly if other risk factors are present–like hypertension, obesity and diabetes–most doctors would start statins in addition to counseling about regular exercise, if sedentary in habits, and smoking cessation if a smoker.
Statins now are well known to be powerful anti-inflammatory drugs in addition to their cholesterol reducing role and become an even more important treatment option when considering these other contributory factors.
It is reassuring to note the findings of a British registry showing improvement in familial hypercholesterolemia mortality beginning in the early 1990s, when statins first were introduced. One would expect the anti-inflammatory effect of statins to be making a contribution here. Perhaps it is better to use a fixed low dose of statin rather than "treat to level" thereby minimizing adverse reactions from collateral blocking of CoQ10 and dolichols, while still giving anti-inflammatory protection. This is a judgment call all doctors must make.
Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor