Higher FH prevalence in IHD and severe hypercholesterolemia subpopulations
Worldwide Prevalence of Familial Hypercholesterolemia: Meta-Analyses of 11 Million Subjects
Introduction and methods
Studies over the last years have estimated the prevalence of FH at 1:200 to 1:250 in the general population [1-6]. Especially when looking at IHD and hyperlipidemia subpopulations, FH is relatively common. However, overall FH prevalence estimates in these subpopulations are not available, leaving a probable worldwide underdiagnosis of FH.
The present study conducted systematic reviews and meta-analyses to estimate the prevalence of FH in the general population, subjects with IHD, subjects with premature IHD, and subjects with severe hypercholesterolemia (LDL ≥190 mg/dL). IHD was defined as a composite of fatal and nonfatal MI, angina pectoris, and coronary revascularization. Premature IHD was distinguished from IHD if the investigators stated that IHD was premature or if an age cutoff (explored in sensitivity analyses) for included subjects was defined. Peer-reviewed studies and conference abstracts were identified by searching PubMed (MEDLINE), Embase, and the Web of Science until June 3, 2019. Combinations of following terms were used as keywords and/or Medical Subject Heading terms for the search: “familial hypercholesterol(a)emia,” “prevalence,” “frequency,” and “screening.”
- Included in the meta-analyses were 104 publications (>11 million subjects and >37,000 patients with FH), including 44 studies (n=10,921,310) covering FH prevalence in the general population, 28 studies (n=84,479) covering subjects with IHD, 32 studies (n=31,316) covering subjects with premature IHD and 7 studies (n=17,728) covering subjects with severe hypercholesterolemia.
- Using random-effects meta-analyses, pooled estimates of FH prevalence were 0.32% in the general population (95%CI: 0.26-0.39%; corresponding to 1:313), 3.2% for subjects with IHD (95%CI: 2.2-4.3%; [1:31] ), 6.7% for subjects with premature IHD (95%CI: 4.9-8.7%;[1:15]) and 7.2% for subjects with severe hypercholesterolemia (95%CI: 4.6-10.8%; [1:14]).
- In the general population, there was concordance in prevalence between clinical and genetic criteria for FH (0.32% vs 0.34%). In subjects with IHD, lower prevalence was found with genetic FH criteria compared with both clinical criteria and overall prevalence (0.7% vs. 3.6% vs. 3.2%, respectively). In subjects with premature IHD, genetic FH criteria showed lower prevalence compared with overall prevalence (2.1% vs. 6.7%).
- FH prevalence in the general population has been reported in only 17 of 195 countries in the world. FH prevalence was primarily reported in studies from Europe, North America, East Asia and Australia. Prevalence of FH is therefore unknown in 90% of countries in the world.
Prevalence of FH was 1:313 among subjects in the general population, 1:31 among subjects with IHD, 1:15 among subjects with premature IHD and 1:14 among subjects with severe hypercholesterolemia. The overall FH prevalence estimates should be interpreted with caution, because of large heterogeneity among studies. FH prevalence in the general population is unknown in 90% of countries in the world.
Kastelein et al.  comment that the higher FH prevalence estimates found by Beheshti et al. need to be interpreted with caution, as they might be biased by the inclusion of studies relying solely on clinical rather than molecular criteria. FH prevalence in the studied subpopulations on the basis of DNA testing appears to be lower compared with studies using only clinical criteria (IHD: 4.8-fold higher instead of 10-fold higher; premature IHD: 3.7-fold higher instead of 20-fold higher; severe hypercholesterolemia: 2.0-fold higher instead of 23-fold higher). In patients with FH, a genetic cause is not identified in 12% to 58% of patients as identified by clinical criteria . Furthermore, as Kastelein et al. comment, clinical scores are automatically inflated when using diagnostic criteria in a cohort that is partly selected on the basis of those same criteria. Finally, another possible confounding factor is that patients with very high levels of lipoprotein(a) (Lp(a)) may be misclassified as having FH, as cholesterol in Lp(a) is measured as part of LDL-c in the Friedewald formula . Using data from whole-exome sequencing results would overcome the potential clinical biases. For example, when combining 3 studies in which whole-exome sequencing was performed in unselected cohorts, including a recent study from the UK not included in the meta-analysis, a genetic diagnosis-based FH prevalence of 1:207 is observed among 113,205 subjects in the general population [3, 9, 10]. Overall, the present study shows that FH is a prevalent disorder. Early detection and treatment are important as initiation of statin treatment in children with FH reduces the risk of CVD .