Simon Broome criteria for familial hypercholesterolaemia

Clinical background

Familial hypercholesterolaemia (FH) is an autosomal dominant lipid disorder with a prevalence of approximately 1 in 250 in its heterozygous form. Untreated, the raised LDL cholesterol level present from birth leads to premature atherosclerotic disease, and mortality from coronary artery disease is markedly increased, particularly in young adults [1]. The diagnosis is made clinically using combinations of lipid values, physical findings, family history and genetic testing, since genetic testing is not available or cost-effective for all patients in the first instance. The Simon Broome criteria for familial hypercholesterolaemia constitute one of several established diagnostic systems, developed in British clinical practice and still among the most widely used in both Europe and North America [2, 3].

The tool serves the decision on whether a patient with hypercholesterolaemia should proceed to genetic testing, cascade testing of relatives and intensified lipid-lowering treatment. Without a structured criteria set, the boundary against polygenic hypercholesterolaemia becomes arbitrary, and there is a substantial risk that FH is either overlooked or overdiagnosed.

Applying the Simon Broome criteria

The criteria rest on two lipid thresholds for adults (≥16 years):

$$\text{Total cholesterol} > 7{.}5 \text{ mmol/L} \quad \text{or} \quad \text{LDL cholesterol} > 4{.}9 \text{ mmol/L}$$

If either threshold is met, the patient is classified further according to clinical and family findings:

• Definite FH: The lipid threshold met plus tendon xanthomas in the patient or in a first- or second-degree relative, or a DNA-confirmed LDLR, APOB or PCSK9 mutation in the patient or a relative.
• Possible FH: The lipid threshold met plus a family history of myocardial infarction before the age of 60 in a first-degree relative or before the age of 50 in a second-degree relative, or a family history of total cholesterol >7.5 mmol/L in a first- or second-degree relative.
• If the lipid threshold is not met, a diagnosis of FH is unlikely on these criteria.

For children under 16 years, lower lipid limits apply in the original criteria (total cholesterol >6.7 mmol/L and LDL cholesterol >4.0 mmol/L), but this calculator uses the adult limits.

The derivation cohort consisted of 526 patients (282 men, 244 women) aged 20 to 74 years with heterozygous FH, recruited from 11 British lipid clinics and followed prospectively during the 1980s. The standardised mortality ratio (SMR) for coronary death was 386 (95% CI 210 to 639) compared with the population of England and Wales, and was highest in the 20 to 39 year age group (SMR 9686) [1]. The cohort comprised patients with clinically manifest FH and therefore reflects a population already referred to specialist care, not an unscreened general population.

Interpretation in practice

A patient classified as definite FH should not wait for a genetic result before lipid-lowering treatment is intensified. Tendon xanthomas are a pathognomonic finding that in itself argues strongly for FH, and their presence has the highest predictive value for an underlying mutation [4].

Validation and performance

In an Australian comparative study of 885 patients referred to a lipid clinic for genetic testing, a pathogenic FH-causing mutation was identified in 30%. The Simon Broome criteria for definite FH had an odds ratio of 11.7 for predicting a mutation, comparable to the Dutch Lipid Clinic Network (DLCN) (OR 9.4) and MEDPED (OR 10.5), but a lower Youden index (0.274) than DLCN (0.487) and MEDPED (0.457). The AUC was significantly lower for Simon Broome than for DLCN and MEDPED [4]. This means that in a specialist-referred population Simon Broome has less discriminatory power than competing systems, chiefly because of lower specificity.

In a primary care-based validation study from the United Kingdom with 260 participants and genetic testing as the reference standard, the Simon Broome criteria had a detection rate of 11.3% (95% CI 6.0 to 20.0) and a specificity of 70.9% (95% CI 64.8 to 76.5), but a higher sensitivity (56.3%, 95% CI 29.9 to 80.2) than DLCN (37.5%). The lower cut-off for Simon Broome means that the tool captures more cases, but at the cost of more false positives [5].

A large-scale retrospective analysis from the USA applied the Simon Broome lipid criteria to 121 million lipid panels from 58.4 million patients. Of these, 3.2% were classified as possible FH on the lipid thresholds alone, but only 0.02% of these patients had undergone genetic testing [3]. The study illustrates that lipid-based screening according to Simon Broome can be used within the laboratory system to flag patients, but that the clinical yield of genetic testing is low when only the lipid threshold is met without additional clinical findings.

In the follow-up Simon Broome register, which comprised 2,929 patients with definite or possible FH followed from 1992 to 2016, coronary mortality remained raised despite statin treatment, with an SMR of 220 (95% CI 184 to 261) for patients with severe FH and 144 (95% CI 98 to 203) for non-severe FH. After adjustment for traditional risk factors, the hazard ratio for the difference between groups was no longer significant (HR 1.22, 95% CI 0.80 to 1.87), indicating that the excess risk remaining in treated FH is largely explained by smoking, previous coronary artery disease and untreated LDL cholesterol [2].

Limitations

The criteria are designed for adults with heterozygous FH and do not apply to homozygous FH, in which lipid levels and the clinical picture are different. They are further intended to be applied to untreated lipid values; statin treatment already under way can mask the lipid threshold and lead to incorrect classification as unlikely FH. In clinical practice, untreated values are often difficult to obtain, particularly in patients already identified in primary care and started on treatment.

Tendon xanthomas are a strong criterion but appear relatively late in the course of the disease and are often absent in younger patients, so sensitivity for definite FH is low in the early stages. Family history data depend on the patient's knowledge of relatives' medical history and may be incomplete or inaccurate, particularly for second-degree relatives.

The Simon Broome criteria have not been evaluated in the specifically Swedish setting in larger studies. In Swedish practice, the DLCN criteria are often used in specialist care, while simpler cholesterol-based thresholds may be applied in primary care to identify patients who should be referred. Access to genetic testing for FH varies between regions, and cascade testing is not systematised in the way it is in, for example, the Netherlands or the United Kingdom.

References

1. Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholesterolaemia. BMJ 1991. PMID: 1933004
2. Humphries SE et al. Coronary heart disease mortality in severe vs. non-severe familial hypercholesterolaemia in the Simon Broome Register. Atherosclerosis 2019. PMID: 30458964
3. Fleming JK et al. A strategy to increase identification of patients with Familial Hypercholesterolemia: Application of the Simon Broome lipid criteria in a large-scale retrospective analysis. Am J Prev Cardiol 2025. PMID: 39896055
4. Chan DC et al. A Comparative Analysis of Phenotypic Predictors of Mutations in Familial Hypercholesterolemia. J Clin Endocrinol Metab 2018. PMID: 29408959
5. Qureshi N et al. Comparing the performance of the novel FAMCAT algorithms and established case-finding criteria for familial hypercholesterolaemia in primary care. Open Heart 2021. PMID: 34635577