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 [1]) 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 [2]) 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 [3] 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 [4] 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 [5], 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 cholesterol measurement.

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 [3] 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 [6]. 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 [2] 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 inherited hyperlipidaemia.

References 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- 12. 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- 68. 5. Humphries, SE, Galton, D, and Nicholls, P, Genetic testing for familial hypercholesterolaemia: practical and ethical issues. Q.J.Med., 1997. 90: p. 169-81. 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.