Article from Larry Husten Polygenic vs. Monogenic FH

How Many People

Really Have Familial Hypercholesterolemia

– And Does It Matter?

March 14, 2016 by Larry Husten Leave a Comment

A new study estimates that about 834,000 adults in the US
have genetically high cholesterol levels,
otherwise known as familial hypercholesterolemia (FH).

The prevalence of FH, which the authors calculate as 1 in 250 American adults,
is twice the size of earlier assumptions.

But the authors acknowledge
that the criteria for FH used in their study did not include genetic testing and therefore
may capture a large number of people who have other reasons
for elevated cholesterol levels than more strictly diagnosed FH.

Once obscure, FH has been a big and growing topic of discussion in recent years,
since FH patients are the best candidates
for the newly approved PCSK9 inhibitors.

A great deal of research– much of it performed with industry support–
has sought to expand the population of people eligible for PCSK9 inhibitors.

However, it is unclear what impact the new study, published online in Circulation,
will have on this ongoing debate.

Outside experts argue that an FH diagnosis is not important in the clinical setting,
since treatment decisions should be made on the basis of cholesterol levels and
other relevant clinical factors.

Sarah D. de Ferranti (Boston Children’s Hospital) and colleagues
analyzed data from nearly 37,000 participants
in the National Health and Education National Surveys (NHANES).

Using a modified version of the Dutch Lipid Clinic criteria,
which classifies people with either definite or probable FH based on

1- LDL cholesterol levels,

2- physical examination,
3-genetic criteria, and

4-personal and family history of premature cardiovascular disease.

The authors calculated that 0.40% of US adults, or
about 1 out of every 250, had probable or definite FH.

Few people (0.02%), or 1 in 4,023) were classified with definite FH.

Many more people (0.38%, or 1 in 267) were classified with probable FH.

Older people and obese people were more likely to have probable/definite FH.

“It’s more common than we thought and
it’s important to look for it at a young age
because someone with FH may have no symptoms until there is serious heart disease.,”
said de Ferranti, in an American Heart Association press release.

“A common story might be someone who develops chest pain or
has a heart attack in their 30s or 40s –
even though they look healthy, eat well, and are thin and fit.”

A very loose definition of FH is a key limitation of the study, however.

Because it is not collected in NHANES, genetic information
was not included in this analysis. ”
Genetic testing for FH,” the authors note,
“is not a usual part of clinical practice in the United States, and
the clinical implications of genotype-positive/milder-phenotype FH
are uncertain and require additional research.”

They acknowledge that the clinical definition used in their study
“could have identified familial combined hyperlipidemia
or polygenic hypercholesterolemia
with metabolic syndrome, along with FH.”

“I do not think the focus should be on
whether someone has ‘FH’ or does not have ‘FH’,”
commented Allan Sniderman (McGill University).

“The issue should be whether there is severe hypercholesterolemia,
regardless of whether it is ‘FH’ or not ‘FH’.
That is, the clinical consequences of a markedly elevated LDL-C relate to the
markedly elevated level of LDL-C, not to the cause of the marked elevation of LDL.”

FH, said Sniderman, refers to a clinical syndrome that involves
a genetic defect in the functioning of the LDL receptor, PCSK9 or apoB.

“These are all monogenic disorders.

But there are polygenic disorders of function of the LDL receptor.

These patients are at extremely high risk also.
Not all will have positive FH. Not all will qualify by the Dutch criteria.”

Sniderman argues that the diagnosis of FH,
instead of severe hypercholesterolemia,
only confuses the issue.

“By making the diagnosis FH instead of severe hypercholesterolemia (SHC),
the diagnostic process gets more complex and
more chance for patients who need to be treated not to be treated.”

He thinks that “everyone with SHC due to elevation of LDL needs to be treated.”

Sniderman agrees with the ACC/AHA threshold of LDL cholesterol level of 190 mg/dl.

James Stein, University of Wisconsin, largely agrees with Sniderman

.”The risk of hypercholesterolemia is manifested by
its phenotype, not its genotype.”

Therefore, “knowing about a genetic defect
is not particularly useful for clinical risk prediction.

I worry that ‘More FH’ = ‘more unnecessary genetic testing’.”