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Dear Editor,

Familial hypercholesterolaemia (FH) (perhaps better termed autosomal dominant hypercholesterolaemia due to a defect in LDLR, APOB or PSCK9) is rightly highlighted as an eminently treatable but ‘easily missed’ pathology(1). We would like to highlight three important points raised by the authors.

1. Given the importance of early diagnosis and the prevalence of heterozygous FH we would recommend referral of all adult patients meeting the Simon Broome criteria to a specialist lipid clinic, rather than solely high risk adults. This will facilitate confirmation of the diagnosis, appropriate management and instigation of cascade testing. Despite the latter being undertaken in Northern Ireland, Wales and Scotland, England is currently lagging behind with a lack of structure to perform this, which is recommended in the NICE guideline(2). National implementation of cascade testing with identification of 50% of FH cases could reduce cardiovascular morbidity and mortality in the UK, and £94.7million over a 55 year period could be saved(3). Investment in this approach as recommended by NICE will not only save lives, it is economically viable in the long term(4).

2. Although recommended by NICE, the Simon Broome criteria has some inherent problems. Total and LDL cholesterol levels are used in the guidelines for diagnosis. While FH patients typically have low triglycerides, fasting triglyceride measurements can aid differentiation from other dyslipidaemias such as familial combined hyperlipidaemia, and no mention is made of these within the criteria. The use of LDL cholesterol levels for diagnosis can be problematic as the majority of routine clinical UK laboratories calculate LDL cholesterol using the Friedewald equation(5). This is invalidated with elevated levels of triglycerides (greater than 4.52mmol/L), requires a fasting sample and also importantly is unreliable if a patient is already on treatment. An alternative diagnostic scoring system, the Dutch MEDPED criteria(6) includes a triglyceride cut off at 2.3mmol/L below which the LDL data are valid as part of a scoring system.

3. Treatment involves the use of high intensity statins and although this refers to any lipid lowering drug or combination more potent than Simvastatin 40mg, the recent FDA guidance means that Simvastatin 80mg should be avoided as an initial treatment due to an increase risk of rhabdomyolysis(7). However those patients previously on this medication for over a year without problem may continue with this. As the patent for Atorvastatin expired in May 2012, Atorvastatin 40mg or 80mg should be preferred to Simvastatin 40mg or 80mg(8).

1. Gill PJ, Harnden A, Karpe F. Easily Missed? Familial Hypercholesterolaemia. BMJ 2012;344:40-41.
2. National Institute for Health and Clinical Excellence. Identificaiton and management of familial hypercholesterolaemia. Clinical Guideline 71. NICE,2008.
3. Humphries S, Hadfield G. Department of Health Familial Hypercholesterolaemia Cascade testing Audit Project: Recommendations to the Department of Health. 2007. Accessed online: (June 2012).
4. Heart UK Familial Hypercholesterolaemia guideline implementation team. Saving lives, Saving families. The health, social and economic advantages of detecting and treating familial hypercholesterolaemia (FH). Published: February 2012. Accessed online: (June 2012)
5. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.
6. Mata P, Alonso R, Castillo S, Pocovi M. MEDPED and the Spanish Familial Hypercholesterolemia Foundation. Atheroscler Suppl 2002;2:9-11.
7. US Food and Drug Administration. Accessed online: (June 2012).
8. Smilde TJ, van Wissen S, Awollersheim et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001; 357 (9256): 577-581.

Competing interests: None declared

Stewart J Pattman, ST6 Chemical Pathology/Metabolic Medicine

Dr P. Banerjee, Dr F. Jenkinson, Dr H. Datta.

Dept Clinical Biochemistry, Newcastle upon Tyne Hospitals NHS Trust, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP

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Familial Hypercholesterolaemia

Easily Found

There are now a number of software solutions that allow CCGs to run audits across their CCG. We use one called Audit + from BMJ Informatica.

Search for all patients who have had a Cholesterol over 7.5 or LDL over 4.9 ever. Exclude those diagnosed with Familial Hypercholesterolameia or Possible Familial Hypercholesterolaemia and those already screened against the Simon Broome criteria.

For the rest assess them against the Simon Broome criteria.

A simple audit in the last 8 months across Medway CCG has increased the recorded prevalence of FH or possible FH by 25%, adding 84 patients to the register, a prevalence increase of 0.0025%. Our prevalence is still below the 1 in 500 but we know where to look. Why leave it to chance?

Competing interests: Chair BMJ Informatica Advisory Board

Peter Green, GP

Medway Clinical Commissioning Group, 50 Pembroke Court, Chatham Maritime, Kent ME8 0NJ

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I would like to comment on the comprehensive review of familial hypercholesterolaemia by Peter Gill and colleagues. There are many theories regarding the underdiagnosis of familial hypercholesterolaemia (FH)1,2 including the following:

1)Familial hypercholesterolaemia as a topic has rarely formed part of the curriculum in undergraduate or postgraduate training programmes, and is just beginning in recent years to gain more widespread acknowledgement.

2)A high cholesterol level could be viewed as being at the “tail end” of the general population and FH can be misdiagnosed on cholesterol measurement alone due to the overlap of cholesterol levels in patients with and without familial hypercholesterolaemia3,4.

3)Due to initiatives such as the National Service Framework for Coronary Heart Disease, virtually all practices are computerised and have improved their coding of major diseases5. However, pre-treatment cholesterol results (which might otherwise have aided diagnosis) may only be present in old written notes. Absence of this data may delay the diagnosis in otherwise straightforward cases.

1.Gill PJ, Harnden A, Karpe F. Familial hypercholesterolaemia. BMJ 2012;344:e3228 doi: 10.1136/bmj.e3228

2.Neil HA, Hammond T, Huxley R, Matthews DR, Humphries SE. Extent of underdiagnosis of familial hypercholesterolaemia in routine practice: prospective registry study. BMJ 2000;321:148.

3.Starr B, Hadfield SG, Hutten BA, Lansberg PJ, Leren TP, Damgaard D, et al. Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing. Clin Chem Lab Med 2008;46:791-803.

4.Leren TP, Finborud TH, Manshaus TE, Ose L, Berge KE. Diagnosis of familial hypercholesterolaemia in general practice using clinical diagnostic criteria or genetic testing as part of cascade genetic screening. Community Genet 2008; 11(1):26-35. Epub 2008 Jan 15

5.Gray J, Jaiyela A, Whiting M, Modell M, Wierzbicki AS. Identifying patients with familial hypercholesterolaemia in primary care: an informatics-based approach in one primary care centre. Heart 2008;94:754-758

Competing interests: None declared

Catriona E Brown, ST6 Clinical Genetics

Ferguson-Smith Centre for Clinical Genetics, Glasgow

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Cascade screening for familial hypercholesterolaemia (FH) is only cost effective if it correctly identifies hypercholesterolaemia in family members. [1] It, however, will under-diagnose FH in family members if Simon Broome low-density lipoprotein cholesterol (LDL-C) diagnostic criteria for index individuals are used. [2] NICE guidance recommends using gender- and age-specific LDL-C diagnostic criteria to diagnose FH in affected relatives. [3, 4] This is particularly important in younger individuals (males <25years) in whom the diagnosis of FH may be made on LDL-C concentrations as low as 3.5 mmol/L.


1.Nherera L, Marks D, Minhas R, Thorogood M, Humphries SE. Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies. Heart 2011;97:1175-81.

2.Gill PJ, Harnden A, Karpe F. Familial hypercholesterolaemia. BMJ 2012;344:e3228.

3.National Institute for Health and Clinical Excellence. Identification and management of familial hypercholesterolaemia. Clinical guideline 71. NICE, 2008.

4.Starr B, Hadfield SG, Hutten BA, Lansberg PJ, Leren TP, Damgaard D, et al. Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing. Clin Chem Lab Med 2008;46:791-803.

Competing interests: None declared

Rousseau Gama, Chemical Pathologist

Rouvick M Gama, Susanne E Elliott, Clare Ford

Royal Wolverhampton NHS Hospitals Trust, Wolverhampton. WV10 0QP

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I would like to make a few comments on the very informative article by Peter Gill and colleagues.

1. The Simon Broome Register Group definition of definite familial hypercholesterolaemia requires the presence of tendon xanthoma in the patient or first or second degree relatives or DNA based diagnosis of familial hypercholesterolaemia in the patient (NICE 2008 CG 71).

2. Under key points, the advice should be to consider familial hypercholesterolaemia in patients with a fasting or random total cholesterol >7.5 mmol/L. Fasting is not required as there is no significant difference between fasting and non-fasting total cholesterol. (Langsted A, Freiberg JJ, Nordestgaard BG. Fasting and nonfasting lipid levels. Circulation. 2008, 118, 2047-56.)

3. Under management, the response to lifestyle advice (diet, physical activity, and stopping smoking) should be monitored before starting a statin as some patients with polygenic hypercholesterolaemia achieve a much lower cholesterol with lifestyle change. An initial high dose of simvastatin at 80 mg per day is not advisable in new patients because of the increased risk of myopathy when using this statin at this dose (FDA warning, August 2011).

Competing interests: None declared

Charles VAN HEYNINGEN, Chemical Pathologist

Aintree University Hospitals , Lower Lane, Liverpool L9 7AL, UK

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It is true, as Gill et al. point out in their review about familial hypercholesterolemia (FH),1 that people aged 20-39 years with this genetic aberration have a 100-fold greater risk of dying from coronary disease compared with non-FH adults of the same age. However, this figure may easily mislead because heart mortality is extremely rare at this age. In the study by the Simon Broome Register Group which they refer to, there were only six men between age 20-39 who died during 1318 person-years of observation, and only two women during 1190 person-years of observation. As the participants in their study mainly were individuals who had relatives with cardiovascular disease, mortality is probably even lower among FH individuals without such heredity.

Furthermore, heart mortality in people with FH decreases sharply with increasing age and is close to normal after the age of sixty. According to a more recent paper from the Simon Broome Register Group2 the standardised mortality ratio (SMR) for coronary heart disease was significantly higher in FH than in the general population, but the difference was trivial, the all-cause SMR was the same, and the SMR for non-coronary mortality was significantly lower. It is therefore highly unlikely that statin treatment should be able to prolong the life of people with FH by nine years.

Gill et al. refer to a follow-up study3 said to have shown a delay of atherosclerosis in children and young adults with FH on statin treatment. From this finding it is tempting to conclude, that such treatment should be started already in childhood, but this interpretation is questionable. What the authors found was a delay of carotid intima-media thickness (cIMT) development, but this is not equivalent with a delay of atherosclerosis. For instance, a temporary contraction of the artery wall due to the influence of drugs, cold or stress may simulate an increase of cIMT, and such changes may be much greater than those seen as a result of atherosclerosis progress or cholesterol-lowering treatment. For instance, Brown et al. found that a handgrip sustained for 4,5 minutes resulted in a 35 % reduction of the luminal area of the coronary arteries,3 whereas no cholesterol-lowering trial has been able to change the diameter or the cIMT by more than a few per cent at most.

Other arguments against the interpretation of the follow-up study are, that there is no difference in cIMT between children with FH and normal children,4 and in the ENHANCE trial the cIMT increased, whether cholesterol was lowered a little or very much.5

We have only indirect evidence for the benefit from statin treatment in FH because hitherto no randomised, controlled statin trial including people with FH only has been performed with mortality or major vascular events as outcome, neither in children nor in adults. The question is therefore, whether the benefit from statin treatment outweighs possible adverse effects.

Two years ago Hippisley-Cox and Coupland reported the outcome after statin treatment in more than 200,000 patients treated by the general practitioners.6 More than four per cent had experienced moderate or serious adverse effects from the muscles, liver, kidneys or eyes. These numbers may even have been underestimated. For example, liver damage was recorded only if the alanine transaminase concentration was more than three times higher than the upper limit of normal, and to record muscle problems as a side effect they required the creatine kinase concentration to be four or more times higher than the upper limit of normal. Franc et al. have reported cramps, stiffness and tendonitis-associated pain in about 20 % of patients on lipid-lowering treatment,7 and according to Sinzinger et al. 25 % of those who exercise regularly have muscular problems.8 There is a good reason for these discrepancies, because the large majority of patients with biopsy evidence of structural damage of the muscles have a normal creatine kinase concentration.9 Furthermore, no attempts were done to record diabetes, or sexual or cerebral dysfunction.

Of particular concern is that an increased incidence of cancer has been reported in most animal experiments, in three statin trials and in several cohort and case-control studies, and many cohort studies have found that low cholesterol is a risk factor for cancer,, even after more than 30 years.10

There are no reasons to believe that the number of adverse effects is less common in FH. Statin treatment of an individual with FH should therefore not be started without informing him or her in detail about the risks.

1. Gill PJ, Harnden A, Karpe F. Familial hypercholesterolaemia. BMJ 2012;344:e3228 doi: 10.1136/bmj.e3228
2. Brown BG, Lee AB, Bolson EL, Dodge HT. Reflex constriction of significant coronary stenosis as a mechanism contributing to ischemic left ventricular dysfunction during isometric exercise. Circulation 1984;70:18-24.
3. Scientific Steering Committee on behalf of the Simon Broome Register Group. Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Atherosclerosis 1999;142:105-12.
4. Riggio S, Mandraffino G, Sardo MA, Iudicello R, Camarda N, Ibalzano E, Alibrandi A et al. Pulse wave velocity and augmentation index, but not intima-media thickness, are early indicators of vascular damage in hypercholesterolemic children. Eur JClin Invest 2010;40:250-7
5. Rodenburg J, Vissers MN, Wiegman A, van Trotsenburg AS, van der Graaf A, de Groot E, et al. Statin treatment in children with familial hypercholesterolemia: the younger, the better. Circulation 2007;116:664-8.
6. Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ 2010, 40c2197, doi: 10.1136bmj.c2197.
7. Franc S, Dejager S, Bruckert E, Chauvenet M, Giral P, Turpin G: A comprehensive description of muscle symptoms associated with lipid-lowering drugs. Cardiovasc Drugs Ther 2003; 17: 459-465.
8. Sinzinger H, Wolfram R, Peskar BA. Muscular side effects of statins. J Cardiovasc Pharmacol 2002; 40:163-171.
9. Mohaupt MG, Karas RH, Babiychuk EB, Sanchez-Freire V, Monastyrskaya K, Iyer L et al.. Association between statin-associated myopathy and skeletal muscle damage. CMAJ 2009; 181: E11-18.
10. Ravnskov U. Rosch PJ, McCully KS. The statin-low cholesterol-cancer conundrum. QJM doi:10.1093/qjmed/hcr243

Competing interests: None declared

Uffe Ravnskov, Independent researcher

None, Magle Stora Kyrkogata 9, 22350 Lund, Sweden

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After not clearly defining Familial Hypercholesterolaemia (FH) and suggesting a 100 fold greater mortality risk from coronary disease in this group than in other "20 to 39 year olds" --but without giving an absolute risk--, there are other problems with this article. Their high-dose statin message appears based on expert opinion and population registers but not on randomized data that include mortality, allegedly so greatly increased at least in the young. Two types of data not mentioned deserve attention: 1. It was found in(1) that around the 1850's, families with FH had about 50% the mortality rate than in those not so "afflicted". The authors conclude as to the existence of major "environmental" components in FH. That epoch was before the inventions of the steel roller mill that removes the large majority of homocysteine lowering B-vitamins from grains and of hydrogenation designed to remove the quick spoiling omega-3 fatty acids. 2. The Broome Register reported that the Standardised Mortality Ratio for cancer is about 45% less in the FH group(2). Since statins don't fix the "environment" and randomized mortality studies have not been done, it is time to pay attention to the "environment" and try and come back to the conditions, just possibly the intake of the minor nutrients, that once existed and that appear to give FH's a survival benefit, again. 1) Sijbrands EJG, Westendorp J, Defesche JC, de Meier PHEM, Smelt AHM, Kastelein JP. Mortality over two centuries in large pedigree with familial hyper cholesterolaemia: family tree mortality study. BMJ 2001;322:1019-1023. 2: Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee. Non-coronary heart disease mortality and risk of fatal cancer in patients with treated heterozygous familial hypercholesterolaemia: a prospective registry study. Atherosclerosis. 2005 Apr;179(2):293-7. Medline 15777544

Competing interests: None declared

Eddie Vos, Consulting Engineer, material sciences

publishes, 127 Courser, Sutton QC H3C 2J2 CANADA

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