FH: a syndrome?

In a recent article in Atherosclerosis , colleagues Masana et al. on behalf of the Spanish Atherosclerosis Society have floated the idea of a new FH classification (Masana et al., 2019). They introduce the umbrella term "Familial Hypercholesterolemia Syndrome," which encompasses all of the above-mentioned designations for FH. Read about the research and the opinions of T.R. Tromp, L.F. Reeskamp, and Prof. E. Stroes here.

When do we refer to familial hypercholesterolemia (FH)? The answer to this question is not entirely clear. Classically, we know of monogenic FH, in which an increased risk of cardiovascular disease due to greatly elevated LDL cholesterol (LDL-c) is caused by a functional variant in one of the three FH genes (LDLR, ApoB, PCSK9). Due to the autosomal dominant inheritance pattern, family members are almost always affected, which is why it is also referred to as autosomal dominant hypercholesterolemia. A very rare exception is autosomal recessive hypercholesterolemia, in which two affected alleles of the LDL receptor adaptor protein (LDLRAP) causethe FH phenotype.

But how can significantly elevated cholesterol be explained without a monogenic basis?

In recent years, there has been a lot of attention for 'polygenic FH'. The FH phenotype can be explained by the sum of common genetic variants, each of which minimally increases LDL-C. Genetic risk scores have been developed that appear to predict LDL-C (Talmud et al., 2013) or future risk of coronary heart disease (Khera et al., 2018), but their applicability in the consulting room has yet to be proven.

Not every patient with hypercholesterolemia fits into the category of "monogenic" or "polygenic" FH. For pragmatic reasons, therefore, the term "phenotypic FH" is used, defined on the basis of scoring systems such as the DLCN score (WHO, 1999), MED-PED, or Simon Broome criteria (Chan et al., 2018).

The way FH is defined is also relevant in the Netherlands, as PCSK9 inhibition with monoclonal antibodies is only reimbursed for primary prevention when an FH mutation is detected. Masana et al. hope that patients with phenotypic FH will not be denied additional therapy due to the fact that the underlying metabolic explanation for the elevated LDL-c cannot (yet) be found. In our opinion, however, a collective term such as 'FH Syndrome' does not offer a solution but rather obscures the issue. It seems to run counter to the clarification of individual risk classification (e.g., through combinations of imaging and proteomics) and therefore does not serve the individual patient with monogenic, polygenic, or phenotypic FH.