Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemiaBMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7349.1303 (Published 01 June 2002) Cite this as: BMJ 2002;324:1303
All rapid responses
Response to Tyerman & Tyerman
We thank Tyerman and Tyerman for telling us their interesting data on
examining individuals from their general practice records who may have
familial hypercholesterolaemia (FH). If only all general practices were
able to carry out such an exercise, we could certainly make rapid strides
in identifying FH subjects.
We would like to respond to the points they raise as follows:
1. They report that they have found 16 patients/5200 on their list
who have family history (undefined) of fasting cholesterol greater than
7.5 and LDL greater than 4.9. The prevalence of FH is 1/500 so we might
have expected roughly 10 from their patient list. Tyerman and Tyerman have
misunderstood our costings. We do not suggest an incidence of 1 in 938. We
have taken the 1 in 500 prevalence, but allowed for non-attendance at the
various stages of the screening process and thus derived a number needed
to be invited for screening of 938 to find one FH case. Moreover, Tyerman
and Tyerman have failed to take account of the cost of the validation of
diagnosis using a fasting lipid profile and a consultant appointment.
What we (eg ) and many other papers have found is that mutations that
cause FH are present in less than 15% of individuals with high cholesterol
and a family history of premature CHD. The Simon Broome FH register (see
) would define such individuals only “possible” FH. We suspect that a
large proportion of the patients that they have identified do not have
monogenic forms of hyperlipidaemia but have “polygenic” or “environmental”
forms. The additional important FH register criteria for “definite” FH is
the presence in the patient (or a relative), of Tendon Xanthomas, which
serve as a marker of high cholesterol for many years.
2. In patients who have tendon xanthomas, we are still not able to
detect a mutation in 40-50% of subjects (see Heath et al  for a
discussion of possible reasons). However, where a pathogenic mutation can
be identified in a patient this is then the unequivocal cause of
hyperlipidaemia in the patient and their relatives, and quite
straightforward genetic testing (for example on DNA obtained from a
mouthwash sample and sent through the post) can be used to identify all
first and second, and even third, degree relatives who carry the mutation
who are therefore at extremely high risk of FH and early CHD. This is the
principle of cascade testing which has been used so successfully in the
Netherlands  and which we propose for the UK.
3. Although much of the work of identifying new FH probands needs to
be done through primary care , the definitive diagnosis and treatment
must be done in one of the more than 100 active lipid clinics throughout
the UK. A definitive diagnosis of FH cannot be made on a single LDL
4. It is unfortunate that genetic testing for familial
hyperlipidaemia is not currently available in the UK. We set up a pilot
clinical genetics diagnostic service for FH at the Regional DNA Diagnostic
Laboratory at the Institute of Child Health in London in 1997  and
since then samples from over 300 probands have been examined. We would
hope to be able to expand this service if funding were available but at
the present time it is unclear when this will be achieved. It is worth
pointing out that with earlier diagnosis with case finding and screening,
fewer and fewer cases will have xanthomata since these are usually not
evident until at least the fourth decade. Hence a DNA-based test becomes
potentially more important.
4. Tyerman and Tyerman estimate that a family history screen might,
on average, add 30 seconds to the consultation. In our view, this is an
under-estimate. Even recording a response to a simple question would take
more than 30 seconds and this does not constitute taking an adequate
family history for sudden death, premature heart disease, or cancer for
all first degree relatives. To be sure that a family history is properly
assessed, a pedigree should be constructed. We are, as part of our
Department of Health-funded London IDEAS Genetics Knowledge Park
(http://www.gene.ucl.ac.uk/ideas/whatis.html), setting up training courses
for GPs and nurses to take and interpret family histories in a way that
would be most useful, and we would be happy to work with the Tyermans and
other GPs within the UK to pilot some of these approaches.
5. We have no evidence that the frequency of FH varies widely between
different parts of the UK but accept that further research to determine
optimal screening procedures is required.
6. The use of risk tables (eg the Sheffield tables) is inappropriate
for deciding treatment cut-offs for patients with FH. This is clearly
stated in the Sheffield tables and in the British Hyperlipidaemia
Association guidelines . In many cases this part is overlooked by GPs
who therefore do not recommend treatment for young FH subjects, although
these individuals with FH resulting in life-long hypercholesterolaemia
have a substantially elevated risk  should be treated with statins at
least from early adulthood. However at the present time satins are not
licensed for use in children and that affected children and adolescents
should ideally be referred to a specialist clinic.
7. We agree that reduction of smoking is of major importance in the
treatment of FH, as are other lifestyle changes such as increased exercise
and low fat diets. The Family Heart Association
(http://www.familyheart.org) is a family support group for patients with
1. Heath, KE, Gudnason, V, Humphries, SE, and Seed, M, The type of
mutation in the low density lipoprotein receptor gene influences the
cholesterol-lowering response of the HMG-CoA reductase inhibitor
simvastatin in patients with heterozygous familial hypercholesterolaemia.
Atherosclerosis, 1999. 143: p. 41-54.
2. Scientific Steering Committee on behalf of the Simon Broome Register
Group, Mortality in treated heterozygous familial hypercholesterolaemia:
implications for clinical management. Atherosclerosis, 1999. 142: p. 105-
3. Heath, KE, Humphries, SE, Middleton-Price, H, and Boxer, M, A molecular
genetic service for diagnosing individuals with familial
hypercholesterolaemia (FH). Eur.J.Hum.Gen, 2001. 9: p. 244-52.
4. Umans-Eckenhausen, MAW, Defesche, JC, Sijbrands, EJG, Scheerder, RLJM,
and Kastelein, JJP, Review of first 5 years of screening for familial
hypercholesterolaemia in the Netherlands. Lancet, 2001. 357(9251): p. 165-
5. Humphries, SE, Galton, D, and Nicholls, P, Genetic testing for familial
hypercholesterolaemia: practical and ethical issues. Q.J.Med., 1997. 90:
6. British Cardiac Society, British Hyperlipidaemia Association, endorsed
by the British Diabetic Association, Joint British recommendations on
prevention of coronary heart disease in clinical practice. Heart, 1998.
80(suppl 2): p. S1-S29.
Competing interests: No competing interests
We would like to suggest that there is an easier and more cost-
effective method of screening the
population for hyperlipidaemia than that discussed in your article.
The diagnosis of familial hyperlipidaemia requires a family history.
In primary care one
would expect patients to have a blood pressure check at least every 5
years. A family history
screen might on average add 30 seconds to this consultation.
In our practice, (list size 5200) using a cost of £25/hour, this
would produce an additional
cost of £436 if the 2097 eligible patients (age>25,<_55 were="were" screened.="screened." from="from" the="the" _95="_95" we="we" have="have" screened="screened" found="found" _670="_670" patients="patients" with="with" a="a" family="family" history="history" of="of" chd="chd" which="which" _22="_22" cholesterol="cholesterol" greater="greater" that="that" _7.5.="_7.5." using="using" published="published" figure="figure" for="for" primary="primary" care="care" opportunistic="opportunistic" screening="screening" on="on" calculate="calculate" cost="£6927" or="or" _2487="_2487" per="per" caseusing="caseusing" detection="detection" rate="rate" _1="_1" in="in" _938="_938" as="as" compared="compared" to="to" _9072="_9072" article.="article." p="p"/> By using this method we have found 16 patients who have family
cholesterol >7.5and LDL>4.9 - considerably higher than the suggested
incidence of 1 in938.
Genetic testing is not available to us, so we are unable to confirm that
these people have familial
hyperlipidaemia, although many have very convincing family histories.
It would seem obvious that genetically-determined conditions will
occur in clusters, and
therefore the incidence may vary in different areas. This needs further
research to determine
optimal screening protocols.
However, it would appear to us that a combination of opportunistic
screening in primary
care and targeted testing could identify 95% of those at risk within 5
years, as we have done in
our practice. It would also give the primary care team valuable
information on its practice
population so that other CHD prevention targets can be integrated.
We use a computerised screening program which allows us to educate
reduction of all their CHD risk factors, and have achieved considerable
reductions in these. It is
likely that the reduction of smoking in our practice, for example, is
enough to pay for the
screening in terms of life years added. In effect, this means that
detection is achieved at no extra cost.
We believe that if these methods were generally adopted, the plan to
detect all cases of familial
hyperlipidaemia in patients aged >25 by 2010 could be achieved at a
cost which could easily be
P F Tyerman, GV Tyerman
Rotherham road Medical centre,
100 Rotherham Road,
Competing interests: No competing interests
Marks D. et alii (1) state rightly that screening family members of people
with familial hypercholesterolaemia is the most cost effective option for
detecting cases across the whole population. On the other hand,
hypercholesterolaemia plays “notoriously” a primary role in the
pathophysiology of heart ischaemic disease and peripheral occlusive
arterial disorder in western population. In addition, it is well known
that in the United Kingdom, e.g., there are an estimated 110 000 men and
women with familial hypercholesterolaemia, but only a small percentage of
whom have been identified to date. Over half of these people will have a
fatal or non-fatal coronary heart disease event by the age of 50 (men) or
60 (women) without identification and treatment.
Consequently, we have to
face the considerable problem of recognizing (before) and treating (after)
“all” individual involved by hypercholesterolaemia, i.e., on very large
scale, in order to prevent myocardial infarction and a large variety of
other serious arterial disorders, a part a large number of important risk
factors, beside the “sometimes” high blood cholesterol concentration,
including the genetic one, i.e. a mitochondrial functional cytopathology,
Congenital Acidosic Enzyme-Metabolic Histangiopathy (CAEM), I described
previously, which is jet unfortunately overlooked around the world (2, 3,
4, 5) (See: HONCode, ID N. 233736
http://digilander.iol.it/semeioticabiofisica; “Biophysical Constitutions”,
as well as the Page, I hold weekly in the italian site www.katamed.it).
Doctor, learned of biophysical semeiotics, can easily recognize at the
bed-side in a few minutes, as well as in a “quantitative” way, individuals
involved by arteriosclerotic and/or dyslipidaemic and/or hypertensive and
/or diabetic,and/or neoplastic, a.s.o., constitutions. In my opinion,
based on 45-year long “clinical” experience, identifying people with or
without familial hypercholesterolaemia, for instance, nowadays the most
cost effective screening option for all age groups, will be in the near
future a rapid, non expensive, and efficacious enterprise: if we want it,
1) Markd D. et al. Cost effectiveness analysis of different approaches of
screening for familial hypercholesterolaemia. BMJ 2002;324:1303 ( 1 June
2) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. X
Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. Atti, 61. 6-7
3) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica
condizione necessaria non sufficiente della oncogenesi. XI Congr. Naz.
Soc. It. di Microangiologia e Microcircolaz. Abstracts, pg 38, 28
Settembre-1 Ottobre, Bellagio, 1983.
4) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. Una
Patologia Mitocondriale Ignorata. Gazz Med. It. – Arch. Sci. Med. 144,
423, 1985 (Infotrieve).
5) Stagnaro-Neri M., Stagnaro S., Auscultatory Percussion Evaluation of
Arterio-venous Anastomoses Dysfunction in early Arteriosclerosis. Acta
Med. Medit. 5, 141, 1989.
Competing interests: No competing interests