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PAPERS: Dalya Marks, David Wonderling, Margaret Thorogood, Helen Lambert, Steve E Humphries, and H Andrew W Neil Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia BMJ 2002; 324: 1303 [Abstract] [Full text]

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Overlooked Bed-Side Screening of familial Hypercholesterolaemia

Sergio Stagnaro   (31 May 2002)

GP screening a different way

Peter F Tyerman, Gillian V. Tyerman   (11 June 2002)

Re: GP screening a different way

Dalya Marks, David Wonderling, Margaret Thorogood, Helen Lambert, Steve E Humphries, and H Andrew W Neil   (22 June 2002)

Overlooked Bed-Side Screening of familial Hypercholesterolaemia 31 May 2002
Sergio Stagnaro, Specialist in Blood, Gastrointestinal and Metabolic Research. Researcher in Biophysical Semeiotics. Via Erasmo Piaggio 23/8 160037 Riva Trigoso (Genoa) Italy Send response to journal: Re: Overlooked Bed-Side Screening of familial Hypercholesterolaemia	Sirs, 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, of course. 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 Novembre, Siena,1981. 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.
GP screening a different way 11 June 2002
Peter F Tyerman, GP Rotherham road Medical Centre Barnsley S703QF, Gillian V. Tyerman Send response to journal: Re: GP screening a different way	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 screened. From the 95% we have screened we found 670 patients with a family history of CHD of which 22 have cholesterol of greater that 7.5. Using the published figure for primary care opportunistic screening on the 670 we calculate a cost = £6927 or £2487 per case(using the detection rate of 1 in 938) as compared to the £9072 in the published article. By using this method we have found 16 patients who have family history, fasting 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 patients in 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 familial hyperlipidaemia 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 justified. P F Tyerman, GV Tyerman Rotherham road Medical centre, 100 Rotherham Road, Barnsley S71 1UT Tyerman@medcal.co.uk
Re: GP screening a different way 22 June 2002
Dalya Marks, Research Fellow London School of Hygiene & Tropical Medicine, David Wonderling, Margaret Thorogood, Helen Lambert, Steve E Humphries, and H Andrew W Neil Send response to journal: Re: Re: GP screening a different way	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.