Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, primarily of the low-density lipoprotein type.
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.
Analyses of mortality rates show a large variation of atherosclerosis risk between families. This means that doctors must not always assume high risk but must consider the family history and treat accordingly.
The genetic factor involved is usually the gene for LDL receptor protein or apolipoprotein B, both charged with removing LDL from the 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 CV 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.
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.
Genetic counseling is also appropriate to all FH patients of childbearing age as well as screening children of all new adult patients. The usual counsel regarding exercise, weight, smoking and diet should apply as they are relevant for all those at high risk of heart attack or stroke.
One must be aware of the, at times, highly variable and sometimes subtle side effects of the present statin drugs. Doctor, patient and family are desperate to inhibit cholesterol synthesis and reduce circulating blood levels. Be advised that side effects may be severe and disabling with no real evidence that changing statins does any good.
Side effects may be cognitive, emotional or neurodegenerative. A relatively normal cholesterol level at a cost of permanent disability is too big a price.
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