Abstract
In September 2007 familial hypercholesterolaemia (FH) was thrown into the media spotlight when Wald et al. proposed a screening strategy for all children as young as 15 months. Their work, an ambitious meta-analysis of 13 independent studies, including a total of 1907 people with FH and 16,221 controls, was published in the BMJ. They present clear age-related differences in the ability to distinguish between affected and unaffected individuals based upon serum cholesterol measurements. The greatest discrimination appeared at ages 1–9 years and declined with increasing age.
Currently in the UK, identification of children and young adults with FH relies greatly upon reflex testing, instigated as a result of identifying the condition in a first-degree relative. Wald et al. rightly point out that such approaches will not identify index cases in the population. Adults aged 20–39 with the condition have a 100-fold increased risk of dying from coronary heart disease. It is believed that only a small proportion of these are being detected at present. Wald et al. propose a screening approach that addresses both the child and the parent. They boast a detection rate in the child of 88%, with a false-positive rate of 0.1% and subsequently in the parent of 96%. They use the simple assumption that, given the autosomal dominant nature of the condition, the parent with the higher cholesterol concentration is likely to be the affected one. This is clearly an idealistic viewpoint and relies upon a number of caveats being true. It also means that without genetic confirmation of an affected state, the false-positives are amplified by applying the diagnosis to the parents. In their paper, they propose that treatment is not initiated in the child until it reaches adulthood; indeed the long-term safety of lipid lowering treatments in young children has not been established. However, in reality this delayed treatment is something that would be a challenge to follow up and implement with complete confidence in a mobile population.
They state that their ‘strategy fulfils eight out of the 10 requirements for a worthwhile screening programme,’ with cost effectiveness one of the major factors that remains to be determined. The costs involved in such a project are likely to be substantial, not only in monetary terms but also, as in any genetic condition, the medico-legal implications and public education must be considered. Eliminating false-positives through DNA analysis for LDL receptor mutations would in theory be preferable. However, this has its own limitations as some cases will be missed due to the presence of as yet unidentified mutations. It is also likely to dramatically raise costs and meet with some hostility. In response to an article on this topic that appeared in the Daily Mail newspaper, one reader's comment was simply ‘It's one way to extend the DNA database.’. As usual, we are left to weigh up the arguments for such a programme, and consider the impact that this may have on us as a laboratory service. This is certainly a paper that will prompt a lot of discussion and has raised the profile of FH in the public eye.