Familial hypercholesterolaemia: summary of NICE guidance

The NICE guidelines for familial
hypercholesterolaemia (FH) are based on the commonly accepted view that early
coronary heart disease in FH is caused by high cholesterol.¹ Several
observations indicate that it is not that simple.

First, studies including only people with FH
have shown that both the prevalence and future cardiovascular disease are
independent on their blood cholesterol level;^2-7 in one of the
studies mean cholesterol was even lowest in those who had coronary heart
disease (CHD).⁶

In accordance, cholesterol lowering by ileal
surpass⁸ or by non-statin drugs⁹ has no effect in FH, indicating
that the small effect obtained with the statins is due to their pleiotropic
effects. Most likely, it is their effect on the coagulation system,^10-12
as some of the strongest risk factors in FH are high fibrinogen, high  factor VIII,¹³ and high
prothrombin,⁷ because people with FH may have other genetic
aberrations as well.⁷ This interpretation fits well with the fact
that atherosclerosis in FH is mainly located to arteries that are exposed to
mechanical forces, while premature atherosclerosis is absent in the cerebral
arteries, even in homozygous FH.^14,15

Even
more surprising is that according to the The Simon Broome FH Register Group,
the mean life expectancy in FH is as long as for other people; more die from
CHD at a young age, but fewer die from cancer and other diseases later in life.¹⁶
These calculations were based on a selection of FH people with close relatives,
who had died early, and the authors therefore assumed that the prognosis would
have been even better for unselected individuals. Also, before 1900 their life
expectancy was longer than for the general population,¹⁷ probably
because high cholesterol protects against infectious diseases,¹⁸ the
commonest cause of death at that time.

Therefore,
a more appropriate management of FH might be to evaluate the coagulation system
and to find appropriate means to correct possible abnormalities. People with FH
without such abnormalities should also be told that their high cholesterol is
an advantage. The peace of mind following this information should probably be
more beneficial for the prevention of CHD than any cholesterol lowering
measure.

References

1.      Wierzbicki AS, Humphries SE, Minhas R; Guideline Development Group.
Familial hypercholesterolaemia: summary of NICE guidance.BMJ 2008;337:a1095

2.      Miettinen TA, Gylling H. Mortality and cholesterol metabolism in
familial hypercholesterolemia. Long-term follow-up of 96 patients. Arteriosclerosis
1988;8:163-7.

3.      Hill JS, Hayden MR, Frohlich J, Pritchard PH. Genetic and
environmental factors affecting the incidence of coronary artery disease in
heterozygous familial hypercholesterolemia. Arterioscler Thromb
1991;11:290-7.

4.      Ferrieres J, Lambert J, Lussier-Cacan S, Davignon J. Coronary artery
disease in heterozygous familial hypercholesterolemia patients with the same
LDL receptor gene mutation. Circulation 1995; 92:290-5.

5.     
Kroon AA,
Ajubi N, van Asten WN, Stalenhoef AF. The prevalence of
peripheral vascular disease in familial hypercholesterolaemia J Intern Med 1995;238:451-9.

6.      Hopkins PN, Stephenson S, Wu LL, Riley WA, Xin Y, Hunt SE.
Evaluation of coronary risk factors in patients with heterozygous famlial
hypercholesterolema. Am J Cardiol 2001;87:47-553.

7.     
Jansen AC, van Aalst-Cohen ES, Tanck
MW, Cheng S, Fontecha MR, Li J, et al. Genetic determinants of cardiovascular
disease risk in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol
2005;25:1475-81.

8.     
Koivisto
PVI, Leinonen H.Peripheral arterial
disease in heterozygous familial hypercholesterolemia: no difference between
patients with and without partial ileal bypass.  Atherosclerosis 1988;70:21-7.

9.     
Bots ML, Visseren FL, Evans GW, Riley
WA, Revkin JH, Tegeler CH, et al. Torcetrapib and carotid intima-media thickness. Lancet
2007;370:153-60.

10. 
Tremoli
E, Folco G, Agradi E, Galli C. Platelet thromboxanes and serum-cholesterol. Lancet
1979;1:107-8.

11. 
Schrör
K. Platelet reactivity and arachidonic acid metabolism in type II hyperlipoproteinaemia
and its modification by cholesterol-lowering agents. Eicosanoids
1990;     , 67-73.

12. 
Davì G, Averna M, Catalano I,
Barbagallo C, Ganci A, Notarbartolo A, et al. Increased thromboxane biosynthesis in type IIa
hypercholesterolemia. Circulation 1992:85:1792-8.

13. 
Sugrue
DD and others. Coronary artery disease and haemostatic variables in
heterozygous familial hypercholesterolaemia. Br Heart J 1985;53:265-8.

14. 
Postiglione A, Nappi A, Brunetti A,
Soricelli A, Rubba P, Gnasso A, et al. Relative protection from cerebral
atherosclerosis of young patients with homozygous familial
hypercholesterolemia. Atherosclerosis 1991;90:23-30.

15. 
Rodriguez G, Bertolini S, Nobili F,
Arrigo A, Masturzo P, Elicio N, et al. Regional cerebral blood flow in familial
hypercholesterolaemia. Stroke 1994;25:831-6.

16. 
Neil HA, Hawkins MM, Durrington PN,
Betteridge DJ, Capps NE, Humphries SE, et al. Non-coronary heart disease mortality and risk
of fatal cancer in patients with treated heterozygous familial
hypercholesterolaemia: a prospective registry study.Atherosclerosis 2005;179:293-7.

17. 
Sijbrands EJ, Westendorp RG, Defesche
JC, de Meier PH, Smelt AH, Kastelein JJ. Mortality over two centuries in large pedigree
with familial hypercholesterolaemia: family tree mortality study.BMJ 2001;322:1019-23.

18. 
Ravnskov U. High cholesterol may
protect against infections and atherosclerosis. QJM 2003;96:927-34.

Competing interests:
None declared