Recently, reports are informing the medical community that HeFH, or “FH,” has a prevalence of 1 in 200. There is a lot of confusion involved with this result. Let’s start with the terminology. The medical community is not settled on the names of the diseases in question. In the screenshot below we can see the FDA indication for the drug Praluent. It clearly designates FH. I don’t see a mention of Familial Defective ApoB100 — “FDB.”
Below is TUFTS Health Plan.  It clearly includes FDB as “FH.”
Culturally, there is some confusion about what FH is and what it isn’t. And one will find FDB and FH both referred to as FH. Strictly speaking, however, FH and FDB are two different inherited diseases. The 1st, Authoritative, 2nd, and Regeneron reports all blend FH and FDB due to available linguistic ambiguity and refer to the natural mathematical result as a larger FH prevalence count.
The established prevalence of FH-as-LDLR mutation is 1:500. Of FDB-as-APOB mutation, it is 1:1000. If I combine FH and FDB, I mathematically derive a prevalence of 1:333. If I call these combined patients “FH,” have I really found more people or have I joined two known populations under a single umbrella-term, “FH,” which then requires that I follow through with the required math?
In a parallel example, due to ambiguous usage, the word “animal” sometimes refers to the entire kingdom of living things, including birds and reptiles, and even protozoans. Other times it means mammals exclusively. So in one context I could speak of cows, sheep, pigs, and geese under the subject of “animals.” In another context I might use the word animal in contrast to birds, in which case it is clear that I use “animal” to refer exclusively to mammals. It would be hoped that I would be responsible and effective in my use of words which are vulnerable to such ambiguities. I have 10 mammals that I call “animals” and 10 birds that I include in a larger count of “animals.” I now have 20 animals and engage in a conversation with someone who, in the context, thinks I’m talking about mammals and so I now have 20 mammals? Could I really say that I had more mammals than previously thought? This is what is happening here. We don’t’ have any more animals or mammals than we had before. We simply played a shell game with definitions.
However, for the uninitiated, the reports create a very real impression that the FH addressable market is much larger than previously thought, taking advantage of the ambiguous cultural usage. The word “FH” has clinical and cultural usages that can refer to all who merely look like they might have an FH mutation in the LDL-Receptor (LDL-R). This includes those who look like FH carriers due to environmental factors but who do not actually have an LDL-R mutation. However, mutations other than the LDLR can affect cholesterol levels in similar ways. One of these is APOB100, the carriers of which are diagnosed with “FDB.”  The FDB mutations are almost exclusively restricted to R3500Q/W. The point here is that they are distinct from FH LDL-R mutations.
Strictly, both FH and FDB fall under the name of “Autosomal Dominant Hypercholesterolemia” or “ADH.” However, this umbrella-term does not seem to have taken hold within the academic and medical communities. The industry still needs to sort out the ambiguous usage of “FH,” which is often used as the umbrella-term itself. With the phenotypic – “looks like” — we have a bird’s eye view of an umbrella with “FH” painted on top and we cannot see the molecular constituents under it. With “ADH,” a molecular perspective, we are at ground level and see that FH and FDB are distinct and under that umbrella.
There is a Clinical Pharmacology Review of Sanofi’s Praluent found on FDA.GOV. In the Appendix it lists two clinical diagnostic systems. In “Simon Broome Register Criteria for Heterozygous Familial Hypercholesterolemia” it includes FDB’s APOB mutation. On the very next page we find the “WHO Criteria (Dutch Lipid Network clinical criteria)” which lists only the LDL-receptor mutation.
In this section of my analysis, I’m not asking a medical question or asking what should and should not be treated; I’m only trying to find a precise definition when moving from one document to another. Which umbrella term should or should not be used? We’ll have to wait that out. The dust has not settled. Many insurance companies are clearly accepting FDB as FH, and it appears that ADH has not dominated as the umbrella term. Where is the FDA on this? As an FDA assigned indication, does FH include FDB? Was an indication added without the paperwork?
But that is not the subject on the current analysis. What
concerns us here is the linguistic conflation. Accounting for it, the
prevalence for HeFH returns to the established 1:500. The claim that more
people have been found is false.
 Pharmacy Medical Necessity Guidelines: PCSK9 Inhibitor Therapy Effective: January 12, 2015. (https://tuftshealthplan.com/documents/providers/guidelines/pharmacy-medical-necessity-guidelines/pcsk9-comm-direct) Other insurance companies are clearly on board with using FH as the umbrella term and setting FDB under it.
 There are a few points peripheral to the current topic but relevant to the entirety of this analysis.
- Only two APOB mutations are considered severe and prevalent enough to be worth screening for. One of these two is nonetheless very rare.
- The more prevalent, R3500Q, is rare outside of central European ancestry.
- They are milder than their FH (LDLR) counterparts, and therefore they are expensive and time consuming to detect. Carriers may not even require risky treatment.
 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 125559Orig1s000 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125559Orig1s000ClinPharmR.pdf