Optimising strategies for the detection of familial hypercholesterolaemia

Background: Familial hypercholesterolaemia (FH) is an autosomal co-dominant disorder of lipoprotein metabolism characterised by elevated low-density lipoprotein cholesterol (LDL-cholesterol) and premature coronary artery disease (CAD). FH fulfils the screening criteria for a medical condition described by the World Health Organization. However, in spite of this, most countries have not implemented systematic screening programs for FH, and only a minority of individuals with FH are currently diagnosed.

Hypothesis: The care of individuals with FH can be enhanced by employing laboratory, primary care and specialist lipid services.

Aims and scope: To examine the hypothesis, a series of studies were conducted to explore the potential a community laboratory has to screen for FH and to investigate methods to improve FH detection. A survey of general practitioner (GP) awareness and knowledge of FH was conducted, and the GPs ability to accurately use the Dutch Lipid Clinic Network Criteria (DLCNC) to identify individuals at high and low risk of FH assessed. The spectrum of mutations causative of FH in Western Australia was described and assessed in relation to a phenotypic diagnosis of FH. Finally, a study was performed to determine the yield and effectiveness of genetic cascade screening for FH in Western Australia.

Results: Community laboratories perform large numbers of LDL-cholesterol measurements, predominantly requested by GPs (91.8%). An LDL-cholesterol of 6.5 mmol/L (present in 1:398 individuals) was selected to investigate methods to improve FH detection. A secondary cause of elevated LDL-cholesterol was identified in 8.3% of these individuals. Laboratory interpretative comments highlighting the possibility of the diagnosis of FH were associated with significantly greater reductions in LDL-cholesterol than controls, and a trend to increased referral to a specialist. However, specialist referral rates were generally low, and only higher (11.5 vs. 1%, p<0.05) when referral was specifically included in the comment. A telephone call from the chemical pathologist to the requesting GP was associated with increased specialist referral rates (27% vs. 4%, p<0.0001). At follow-up, FH was present in 72% of individuals with an LDL-cholesterol of ≥6.5 mmol/L and 30% had identifiable mutations on genetic testing.

GP awareness of national guidelines and knowledge of hereditability, prevalence and diagnostic features of FH were found to be suboptimal, despite their perception that they were the most effective health practitioners for managing FH. The vast majority of GPs selected appropriate lipid-lowering therapy and preferred interpretative comments to alert them to the possibility of FH. There was good agreement (83.6%) in the DLCNC scores calculated by GPs and specialists. GPs accurately categorised individuals at high (86.7%) and low (94.0%) risk of FH, establishing that the DLCNC is a suitable means to augment FH detection in primary care and ensure appropriate specialist referral.

The mutation spectrum in Western Australia was similar to the UK and France. As expected, the mutation detection rate was highest in individuals with clinically definite (70%) or probable (29%) FH. Genetic cascade testing yielded two new cases of FH per index case, or three new cases if three or more family members were tested. Significant additional reductions in LDL-cholesterol (-25% overall) were achieved in individuals found to have FH despite almost half (48%) already taking statin therapy at diagnosis. Significant improvements were also seen in non-lipid CAD risk factors; 80% of individuals with hypertension attained blood pressure targets and 40% of smokers ceased.

Conclusions: The studies in this thesis collectively demonstrate that laboratory, primary care and specialist lipid services can be employed to enhance the care of individuals with FH, by augmenting the detection and treatment of the condition. Interpretative comments were associated with significant LDL-cholesterol reductions, and a telephone call to the requesting GP of high-risk individuals significantly improved the detection of FH. Identifying individuals with FH remains effective and leads to additional reductions in LDL-cholesterol and improvements in non-lipid cardiovascular risk factors after specialist review. Additional research is required to further investigate methods for optimising the detection of FH and the translation of the findings into effective health policy.