Part 1: Historical Narrative of Linguistic Evolution

In the beginning there were three different diseases

Note: Amgen, Regeneron, Sanofi, and Merck have (or had) direct financial interests in the HeFH market. As for Aegerion (Novelion), Madrigal,
Gemphire, and Esperion, there is a mathematical relationship between
the two forms of unequivocal FH: HeFH and HoFH. Thus, when papers
conflate the names of diseases to “double” the quantities of patients with HeFH, the papers also “increase” the estimated prevalence and addressable market of the rarer, HoFH.

A historical narrative of the industry-wide “Language Strategy” to re-define the disease, Familial Hypercholesterolemia (“FH”). (For a one-page summary, click here.)

To understand recent FH prevalence claims, it is more important to trace the linguistic history than to labor over the science as presented today.  Once the scientific record is off course, more power applied to an erroneous assumption only sends us further astray. It’s time to stop and reevaluate where and how this vehicle of science slipped off the road.

“FH” stands for “Familial Hypercholesterolemia.” It is a genetically inherited disease.  Mutations in the LDL receptor (LDLR) account for a disruption of the normal processing of cholesterol, resulting in higher than average levels in the body.  This was first pointed out by Nobel Prize winners Joseph Goldstein and Michael Brown. Think of the LDLR as “trucks” that connect with trailers and haul loads away.  If the truck has a factory defect and breaks down, the loads sit in their trailers and pile up at the depot.  In the same way, if the LDLR is consequent of a mutant gene, then cholesterol can build up in the body. In 1973, Goldstein and others estimated the prevalence of LDLR mutation carriers to be between 1/500 and 1/1,000

Joseph Goldstein, et al, 1973 estimate of FH prevalence
Joseph Goldstein, et al, 1973 estimate of FH prevalence.

Since then other mutations have been found. For example, one mutation involves the gene encoding the ligand Apolipoprotein B-100 (APOB). Its discovery has created the need for an additional disease name, “Familial Defective apoB-100” or also called, “familial ligand-defective apolipoprotein B-100” — slight variations of the name are used, but usage of the acronym is fairly stable, “FDB.”  Think of this mutation as the “hitch” between the truck and the trailer, and which allows the truck to connect with and pull the load.  It is a different problem from the LDLR mutation and was discovered after the calculation of FH-as-LDLR prevalence. FDB prevalence is estimated to be somewhere around 1:1,000.

Problems with PCSK9 have also been found, and this disease went by the name, “FH3.”  Think of this problem in terms of magnetic scrap that the truck must drive through. If too much scrap attaches to the truck, it will weigh it down and prevent it from completing its rounds. Prevalence for FH3 is estimated to be 1:2,500.

Even as late as 2009 Goldstein and Brown continued to define FH by the presence of the LDLR mutation and estimated its prevalence to be 1:500. Here are the Nobel Prize winners in 1985.  Next to the photo is a 2009 paper recounting their history, where prevalence was still calculated to be around 1:500. 

DOI: 10.1161/ATVBAHA.108.179564.

Goldstein and Brown, Familial hypercholesterolemia, LDLR mutation,  prevalence at 1/500
Nobel Prize winners Goldstein and Brown continue to publish FH by the LDLR mutation and put its prevalence at 1/500.

The important point here is that at one time, there was FH-as-LDLR. Later, FDB-as-APOB arrived. Then FH3-as-PCSK9. These are three separate disease names, with three separate populations (and as we will see later, they have different degrees of severity). Changing the labels that are put on these real people — the carriers — does not change their number as a whole. But we need labels of course in order to communicate. So what should we call the entire group of those who inherit one of the three types of mutations? The term “Autosomal Dominant Hypercholesterolemia” (ADH) emerged.  ADH was an umbrella-term under which the three types of diseases would stroll, as it were. And so, given the separate prevalence rates of the separate diseases, what would be the prevalence of all three combined, that is, what is the prevalence of “ADH?”