The Great FH Debate: Reinforcing the fact that “Time is Plaque”

Currently a debate rages in the world of Familial Hypercholesterolemia (FH).  Old school thinking is that this lipid disorder – typically caused by a mutation in one of three genes – is exceedingly rare. The initial teaching stated that the homozygous form (two mutations – one from mother and one from father, HoFH) occurs at a rate of one in a million, while the heterozygous form (one mutation from just one parent, HeFH) occurs at a rate of one in 500. Recent explosions in not only genetics, but also the acquisition of large volumes of patient data have put this prior supposition in question. Now, a recent study published in the European Heart Journal by Sjouke et al truly proves that we have grossly underestimated the prevalence of FH. Examining over 100,000 patients who were referred for genetic analysis, the authors found 74 patients with clinically significant mutations consistent with the homozygous form of FH (HoFH). Being abundantly cautious in their interpretation of data, the authors pared the number down to just 45, from which they conducted a mathematical calculation of the prevalence of FH. (Their minimalist rationale is beyond the scope of this blog, but suffice it to say that had they included all patients, the disease prevalence would be far greater). Their restrained assessment revealed the prevalence of HoFH in an unselected population to be 1 in about 300,000 while the prevalence of HeFH, 1 in 244.

Perhaps more striking and even earthshattering is what the authors discovered about the wide range of HoFH LDL-C levels. Older belief systems had maintained that the LDL-C in untreated HoFH should always exceed about 450 mg/dL. In their comprehensive and novel analysis however, the authors discovered untreated HoFH patients with LDL-C levels as low as 170 mg/dL. 170 mg/dL overlaps not only the HeFH population, but the non-FH population as well. The bottom line here once again is that as in diagnosing all other diseases, clinicians must maintain open minds when diagnosing FH. When considering FH, we must always look for a family history of premature vascular disease, very high LDL-C levels, signs of the disorder on physical examination, and the presence of aggressive coronary artery or cerebro-vascular disease in the patient we are evaluating. Most important is for all clinicians to keep FH on the tips of our tongues. Without considering the diagnosis, we will never make it. And without making the diagnosis, we will never treat it. Early treatment can be life saving so early diagnosis is of course paramount. In no other lipid disorder is the concept that “Time is Plaque” more apparent. FH patients bathe in their own LDL-C in utero and beyond. The longer they remain untreated the worse they do. So let’s think of FH and treat it when we see it. By doing so we can hope to prolong the lives of more than a million people right here in the USA.

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