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Although the recently published NICE Guideline on the Identification and Management of Familial Hypercholesterolaemia contains no surprises for those involved in running specialist lipid clinics, it is a landmark in establishing the case for a greater recognition of familial hypercholesterolaemia by general practitioners, general physicians, cardiologists and paediatricians and for the need to consolidate and expand lipid clinic services and ensure high clinical standards are maintained. Heterozygous familial hypercholesterolaemia (HeFH) affects 1 in 500 people. This represents some 110 000 of the UK population, similar to the number having type 1 diabetes. The great majority are either undetected or have received incorrect advice from a physician with inadequate knowledge of their condition.1 This is all the more unfortunate because with appropriate treatment the life expectancy in HeFH is now similar to that of the general population2 whereas, untreated, men, in particular, experience symptomatic cardiac ischaemia increasingly from their late 20s. Some 50% of affected men and 15% of women will have died of coronary and aortic root disease before the age of 60 years.3 4
HeFH results from a dominantly inherited defect in low-density lipoprotein (LDL) catabolism, usually an LDL-receptor mutation. The catalogue of LDL-receptor mutations that can cause HeFH is enormous with some 1000 recorded and the number growing.5 Hitherto, a lack of resources for genetic testing and the difficulty of locating many of the mutations have meant that in only a minority of families has a DNA diagnosis been possible. That is set to change with calls for greater NHS investment in this area (both in the NICE report itself and because of the need for something tangible to emerge from investment in the human genome project and new DNA technologies).
Key to the recommendations is that clinicians generally should be more attuned to the recognition of HeFH. Usually the LDL-cholesterol in HeFH is particularly high but, if it is not measured by general practitioners until the age of 40 or 50 years, it will be too late for many people with HeFH. Tendon xanthomas are the diagnostic sign of HeFH.6 However they are rarely sought nor recognised by most clinicians. Achilles tendon xanthomas and tendon xanthomas elsewhere, such as on the dorsum of the hands, are evident in HeFH from the mid-20s. Achilles tenosynovitis can occur earlier.7 Apart from their family history of early-onset coronary heart disease (CHD), people with HeFH generally appear remarkably well, often athletic in appearance, not overweight and free of other cardiovascular disease (CVD) risk factors. Sadly the first indication that anything is wrong is sudden death, acute coronary syndrome or the development of angina, the recognition of which is often delayed because the individual appears so different from the clinical stereotype of coronary-prone patients. Two approaches can overcome the difficulties in achieving early diagnosis. One is to screen all children for high cholesterol.8 HeFH, being entirely genetic, produces a high cholesterol detectable from soon after birth, whereas the more common polygenic/nutritional hypercholesterolaemia is less evident until adulthood. Although, with the accelerating epidemic of childhood obesity, more lipid screening will take place in childhood, it is inconceivable that universal lipid screening will be adopted in the United Kingdom in the foreseeable future. Thus NICE adopts the alternative approach, which is cascade family screening. This relies heavily on patients with a definite diagnosis of HeFH who are already identified and attend a lipid clinic. A detailed family history is taken by a specially trained nurse. This includes contact details of all first-degree relatives. Arrangements are then made directly for cholesterol testing in all available first-degree relatives. Some 50% will, of course, prove to have HeFH. The process is then repeated with any newly diagnosed cases (cascading). In a UK study of 200 first-degree relatives of HeFH patients attending a lipid clinic, 60% were found to be new cases of HeFH. To detect a similar number by population screening over 60 000 tests would have been required. The newly diagnosed individuals were younger than the probands and were generally detected before they had clinically overt atherosclerosis.9 In The Netherlands health service cascade screening for HeFH has already been adopted.10
NICE proposes that in addition to cholesterol testing, an attempt is made to identify the DNA mutations running in HeFH families. Cascade screening is proposed as a nationwide enterprise with relatives eventually able to be contacted by their nearest local centre. It would be possible to envisage general practitioners referring patients with suspected HeFH to clinical geneticists for investigation, but this paradigm would be unworkable on several fronts. First, it presupposes that already overworked general practitioners are suddenly likely to take an interest in HeFH and then open up new lines of referral to clinical genetics centres. Second, clinical geneticists would very rapidly discover that the majority of patients referred did not have detectable LDL-receptor mutations, but that they did have high cholesterol and high cardiovascular risk, requiring investigation and specialised clinical knowledge. Logically therefore suspected HeFH patients should be referred directly to specialist lipid clinics with which general practitioners are already familiar and it is there that cascade family screening and appropriate management should be undertaken. Clinical genetics laboratories will, of course, be invaluable in providing DNA testing. It has already been established that attendance at a lipid clinic does not have the adverse psychological effects that the stigma of a genetic diagnosis can cause.11 Lipid clinics should have a clear line of communication to cardiological services, because many patents will have symptoms of cardiac ischaemia previously overlooked or inappropriately investigated.
Currently the trend in management of HeFH is to make the diagnosis as early as possible and NICE proposes this should be before the age of 10 years. Therefore, not only is an expansion of present lipid clinic services envisaged, but also a much greater involvement of paediatricians with perhaps family or joint clinics. One of the great difficulties in diagnosing HeFH in young people is that serum cholesterol levels fall during the prepubertal growth spurt. It is then in particular that a knowledge of the mutation running in the family can be helpful.
NICE agrees that treatment of HeFH calls for the use of the more potent statins, which are proving remarkably safe even in their highest doses. Indeed, HeFH was key to the development of these drugs, which would have been abandoned back in the 1970s because of concerns that they were carcinogenic and highly myotoxic.12 Only because of clinicians aware of the high mortality and morbidity among HeFH patients were the pharmaceutical companies persuaded to continue. In the event, the fears of toxicity proved to be unfounded and the statins have since gone on to be the most successful medical intervention in terms of the number of people whose lives they can extend.13 Statin treatment is rarely begun before the age of 10 years.14 There is evidence from carotid ultrasound that intima media thickness increases more rapidly in affected children compared to those who have not inherited HeFH15 and that this difference can be ameliorated with statins.16 None the less, lingering concerns about statin safety in childhood mean that, unless the family history is particularly adverse, statins are usually withheld until the age of 18 years in boys. Increasingly, girls are also offered treatment at this age, although in their case the reason is not generally any immediate vascular risk. Rather, it is to take into account that they will discontinue statin treatment while attempting to conceive and during pregnancy and breast-feeding. Although there is no definite evidence that statins harm the conceptus or breast-fed child, it is not a risk to run unnecessarily. Now that many women do not even contemplate pregnancy until their 30s, starting statins early means that the old policy of commencing statin treatment only after a woman is certain that she has completed her family is no longer tenable, because she is then approaching an age when her vascular risk requires statin treatment. If, however, she has protected her arteries for several years before, discontinuing statin treatment for two years or so is likely to be less harmful. Even, if she decides to have a baby in her 40s, she has the reassurance that the progression of atherosclerosis has been impeded for many years before that.
For the clinician consulted by a young patient with symptoms of possible cardiac ischaemia one of the most important messages is not to rush to the conclusion that it is non-cardiac, if there is the possibility that he or she might have HeFH. This diagnosis should be considered by all clinicians in anyone with raised cholesterol and a particularly adverse family history of coronary heart disease. If there is the possibility of HeFH, lipid clinic advice should be sought. For those purchasing healthcare, access to lipid clinic services should be provided throughout the United Kingdom.
Competing interests: None.