How to

Finding Familial High Cholesterol Before You Know You Have It

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Thank you for coming out. I know it's game night. And I know that this is a
relatively specific talk on a disease that's near
and dear to my heart. And I hope to
educate you about it so you can educate your
friends and your family. I know that there'll be some
questions from the audience, probably not specifically
pertaining to this exact topic, maybe on heart health
or something like that. And so I'll keep this
talk relatively brief– probably about 40 minutes.

And then we'll have some time
for questions at the end. I do have some disclosures. I'm a volunteer. And I volunteer as the
chief medical officer for a patient-led
charity for individuals with this particular
form of heart disease that I'm going to
be talking about. It's called the FH Foundation. And the more you click on our
website, the better we like it.

So go to our website
and check it out. I have received grant
support from many places. I'm going to give
you a pre-talk quiz. And we'll see how you do
pre- and post-talk to see how I've done. How common is– so
you guys got pens. Many of you have pens. "How common is FH in
the general population?" Does it happen 1 in 1,000 of us? 1 in 500? 1 in 200? Think about your answer. How many say 1 in 1,000? How many say 1 in 500? How many say1 in 200? So everybody will
know, "FH patients are at what fold increased
risk of a heart attack?" How many say five? Familial
hypercholesterolemia– FH– familial hypercholesterolemia. You don't know about that. But by the end, you
will know about that. "What is cascade screening? What is the goal
LDL cholesterol?" And what are the
three genes that are caused to have mutations? And so many of you will
not know– probably most of you will
not know the answers to any of these questions.

And by the end, I hope
you'll know the answers to these questions. And not only will you know the
answers to these questions. You'll know the answers to
what these questions mean because probably many
of you don't even know what some of these things are. So I always like to
start with the case because cases– this is one
of our patients at Stanford. It's a 45-year-old male. He didn't have any
problems as a child. At 26 he was told that his
cholesterol level was 350 and that he needed to be
on medications for that. And then for about 10 years
he didn't have any problems. But then he started
having chest pain when he worked out in the gym.

And he went to his doctor. And they said, well,
you need to stress test. And so he did that. And that was not a
good news for him. His stress test was positive. And so then he had an angiogram. They took pictures of
this coronary arteries. And they said, you
need a bypass surgery. Your arteries are all blocked. And the next day he
had a bypass surgery. So it's shocking. He was in his early
40s at the time. And then he had to have
surgery on his carotid arteries that lead to his brain.

And this unfortunately is
not atypical for FH patients. FH patients, as
you'll learn, have extremely elevated
cholesterol levels that places them at hugely
increased risk of heart disease. And so he's on lots
of medications now to control his cholesterol. He's on four medications
to control his cholesterol. He's on medications to
prevent heart attacks. And if I can leave you with
only one message going forward, it's that FH– the most
important thing that we say is we don't ever find
individuals with FH. We only find families
with FH because if you look with his family,
here he is over here. He had a bypass surgery. It turns out his
wife also had FH.

She didn't know it at the time. And all three of their
children have FH. And so with medicine
in America, we forget about the
family a lot of times. And that's something that
we need to keep in mind. So what is FH. We call it familial
hypercholesterolemia– family high cholesterol. So we say FH because
it's hard to say that. So just remember that term– FH. Now we know that heart
disease is the leading cause of death in the world. And it's certainly
the leading cause of death in the United States. Heart disease– mostly
blockage of the arteries that feed the heart.

And we know that over
the last 10 years, we've done a good job. We've done a good job in
lowering heart disease in older individuals older than 65. But in younger individuals, we
haven't done such a good job and part of the reason for this
is that we're not identifying these young people that have
particular problems that make them at hugely increased
risk of heart disease. How common is FH? How many of you had heard of
FH before I started this talk? One– because you've
done some articles on it. Now how many of you have
heard of cystic fibrosis? How many of you heard
of Marfan Syndrome? How many of you have heard
of multiple sclerosis? So everybody's heard of Marfan
Syndrome, multiple sclerosis, cystic fibrosis.

FH is orders of magnitude more
common than those conditions. But none of you've
heard about it. And that's a big problem. And not only of none of
you've heard about it. But in the United States,
we estimate that only 1% of the people in the country
that have FH know they have FH. And so if you don't
know you have something, you can't treat it. And so that's also
a big problem. And that's one of the reasons
that I give these kind of talks to try to get the word out. Now the irony of this is that
if all these patients knew about it, and they
treated it, we could get rid of their risk–
their excess risk of heart disease. They basically would
go back to being just like the general population. If we start treatment,
this is a graph that shows years and chances
of event-free survival. And so, basically, if
you have a statin– if you take an FH patient
and you put them on a drug to control their
cholesterol, they live a long,
healthy normal life. If you don't find an
FH patient and put them on cholesterol-lowering
medications, they have heart attacks.

And they die early. Is everybody
following me so far. So it's imperative that we
identify these people early. In the old days before
we had statin-controlling medications– medications
to control cholesterol– if you had FH, and you weren't
treated, and you were a man, there's a 50% chance
you'd have a heart attack by the time you were 50. And so that is a
huge increased risk– more than 20-fold increased risk
versus the general population. And the other problem
about that is it causes 12,000 heart attacks
a year in the United States. And how many know what it costs
to care for personal– if you have a heart attack
and they take you to Stanford, how much does it
cost to put a stent in and care for you in the hospital just for
that immediate hospitalization? Anybody have any idea? Just throw some numbers out.

$100,000. Not $100,000– not even $50,000. It's probably about
$25,000 just for the immediate hospitalization. So if you imagine that if this
is causing 12,000 heart attacks a year, the immediate health
care costs for all of us are huge. So how does this present? And why it is FH such a problem? And how is it different than
regular high cholesterol? So most of us were born. And when we're born, we have
very low cholesterol levels. Our LDL– our bad cholesterol
levels are about 50 milligrams per deciliter. And over time because
we eat a bad diet and we don't exercise
much, over time our cholesterol
levels gradually rise. And that's not the case in FH. In FH you're born with very,
very high cholesterol levels. And those cholesterol levels
go even higher as we age. And so they have a cumulative
effect of a lifelong exposure to very high cholesterol levels. And that's what puts them
at heart disease risk. And so that's what
this graph represents– how much cholesterol they've
had for how many years.

And so individuals
without FH– they have a gradual increase
in their cholesterol. And they start to develop heart
disease in their 50s, 60s. If you have FH, you start
to develop heart disease in your 30s. And if you're unlucky
enough that you inherit a mutation– an FH mutation
for mom and from dad– instead of your cholesterol levels
being double or triple normal, their 10 times normal. And those people have– those
kids– they're very, very rare– happens very rare. But those kids often have
to have bypass surgery in their teenage years. So when I say that cholesterol
levels are very different, what does that mean? Well, an average cholesterol
level for an FH patient might be 250 or 290
milligrams per deciliter. An average patient– if you
don't have FH in this room, your LDL cholesterol might
average about 130 to 150– so hugely increased. This is the curve– some FH
patients are a little less affected than others. But in general, there's
a huge difference in the cholesterol levels
between FH patients and non-FH patients.

People following me so far? So how do we diagnosis FH? Well, it turns out that one
of the most important things is how high is your cholesterol. It's also important to know
what your family history is. Has there been a family
history of early heart disease? How high is the history
of– how high is the cholesterol in the family? There's also physical exam
findings that people with FH get. They get cholesterol deposits in
their tendons that we can see. They get cholesterol
deposits around their eyes that we can see. They get little–
this is called arcus. They get discolorations
of the iris. And if we look at all these
and we look at the cholesterol, we can make a pretty
fair statement about whether a person has FH or not. Or we can simply
plug it into an app. There are apps now that
allow us to calculate this. And it's very important. Now, what causes FH? Why are there some
people around? Why are there people around
that are walking around with these astronomically
high cholesterol levels? And this is a genetic condition. And the genetic
condition means it's passed in families from
parent to child– from parent to offspring.

And how many genes do we have? How many genes are
in the human genome? 5,000? 10,000? or 20,000? Who says 5,000? Who says 10,000? Who says 20,000? There's about 20,000
genes in the human genome. That controls what
I look like, what you look like– how we all–
how we all are built. In FH, individuals have a single
gene that's mutated. And that single
gene that's mutated are genes that are mostly
active in the liver. This is meant to
represent a liver cell. This is the blood up here. This is the liver cell here. This is the membrane
of the liver. And your liver has
a recycling program. The recycling program it
has is for cholesterol. And so normally the
liver makes cholesterol, but it also recycles
cholesterol. And LDL cholesterol,
the bad cholesterol, floats around in
the bloodstream. And it's recyclable. It's actually basically waste. And so your liver likes
to take up that waste and actually put it
into your GI tract. And you poop it out. But in FH, the
liver has mutations in these receptors that normally
bind to these cholesterol particles.

And so you cannot pull
cholesterol from the blood and get rid of it, recycle it. Instead, the cholesterol
levels remain very high end in the blood. Is everybody
following that so far? In FH, you can either
have a mutation in the gene that binds
to the cholesterol– the protein that binds
to the cholesterol. You can have a mutation
in the protein that binds to the receptor. And it also turns out you can
have a mutation in the gene here that helps to
degrade this receptor.

So if you have– if this
gene here is overactive and it degrades
this LDL receptor so this is not there anymore,
again, the LDL levels can remain very
high in the blood. So it's a genetic disease. If one individual in a
family– if a parent has it, every child that they
have has a 50% chance of having it and further
on down the line. So it's very– it' s transmitted
in families very strongly. And that has been–
being a genetic disease has pluses and minuses. The minuses are
obviously that you can have lots of people in the
family suffer consequences.

But the pluses are that it
can make it easier potentially to find it if you look for it. And so in Holland,
in the Netherlands, they've made FH a
national priority. They realized that this was
a big health care burden. And they have a
program where if they find one individual
in a family with FH, they actually send public health
nurses to that person's house. And they take a blood sample. And they confirm that they
have high cholesterol. And they also take
a blood sample and they use that
for a DNA test. And if they find the DNA
mutation in that individual, then they can use
that DNA mutation to screen all of the rest
of the family members for that DNA mutation. And so they started with
5,000– over 30 years, they accumulated about 5,000
individuals that had FH.

And they screened 60,000
family members– that's brothers, sisters, parents. And if we forecast that
FH would affect one in two, how many of 60,000
would we have expected to find? Half, 30,000. They didn't find 30,000. They found 27,000. What happened to
the other 3,000? Maybe they died or
something like that. Now, it turns out that
using this genetic testing improves the ability
to find FH patients. And so it turns out that it's
incredibly cost-effective to find FH patients and treat
them because the medications that we use generally
are pennies a day. And you are preventing big
heart attacks at an early age. So the cost-effectiveness
per year of life saved was about 8,000 euros. And who knows in
the United States what we judge in general
cost effectiveness to be. How much is the United States
in general willing to spend on treatments per
year of life saved? $5,000? $50,000? Or $500,000? It's $50,000. In general, the
standard for what we're willing to spend per year
of life saved for an individual is about 50,000.

And that's based on the
cost of dialysis per year. Medicare pays for dialysis. It costs about $50,000
per year per patient– highly cost-effective. And it also turns out
that when you give people genetic information, it might
actually improve outcomes. And the reason for
that is not very clear. But there's this idea
that maybe people respond to genetic
information differently. So in the Netherlands,
they did this study where they said– they
took individuals and said, you have FH. You have LDL cholesterol of 300. You've got a family
history of heart disease. You need to be on
cholesterol-lowering medications. And then took another group
of patients and they said, you have FH. You've got an LDL
cholesterol of 300. You've got a family
history of heart disease. You need to be on
cholesterol-lowering medications. And by the way, we've
done a genetic test that proves you have FH.

And it turned out
that the people that had the genetic
information over time had lower cholesterol levels. Now, is that because
it motivated them? Is that because it
motivated their physician? We don't know. But it certainly helped
control their disease. And for this reason,
the CDC– the Center for Disease Control
in Atlanta– has said we need to be paying
much more attention to FH. It's a genetic condition
with a high societal cost. And they've actually
looked through all the genetic conditions that
affect individuals in the US. And they've ranked three
diseases as tier one– as tier one indications for
use of genetic information. And who might guess– I'm
telling you one of them is familial
hypercholesterolemia, FH. The others are things
that are probably much more familiar
to you– hereditary breast cancer like Angelina
Jolie– and hereditary colon cancer. So everybody's heard
of breast cancer. Everybody has family
members that have had a history of breast cancer. Many people have
had family members with colon cancer and disease
that has similar burden is FH.

But nobody's heard about it. And so we're now doing a trial
where we're taking people. This foundation I work
with this is working with a group at Pennsylvania. And they're doing this
trial in the United States where they're saying, you
have high cholesterol. It's important to get
your relatives checked– to tell your relatives to get
their cholesterol checked. And then we are taking
other individuals and say, you have high cholesterol. And you have a particular
genetic mutation.

That means that you really need
to get your relatives checked. And we're going to
see if it motivates people to get their
relatives screened. Following me so far? So how do we treat FH patients? Well, the first
thing that we all do is we say you need to
eat a healthy diet. And you need to
exercise regularly. And the most important thing
about lowering your cholesterol in terms of the diet is
reducing saturated fat. So that's processed
foods– that's McDonald's. That's fast food. That's pastries– high fiber–
referral to a dietitian. And then we get people
on medications– statins. And those statins are drugs like
Lipitor and Zocor and Mevacor and Crestor. Those are the
mainstays of therapy. But most FH patients
will require more than one medication
to lower their cholesterol. And that's a big difference
than most people. Most people that
have high cholesterol can do with one medication. FH patients always
need more than one. We always need to consider FH
patients at very high risk. One of the big things
that we have to deal with is patients not wanting
to take medications.

And we have to convince
them that if they don't take medications, their chances
of having bad problems are very high. And so we don't treat FH
patients like a garden variety high cholesterol patient. We also always use statins
and non-statin drugs. And the important
information that we give them is that if we get
you on therapy, and we get you on
therapy early enough, your risk of heart disease
dramatically decreases. This is another figure,
I've shown you this earlier, where they took
individuals with FH. This was in the Netherlands. Statins– these statin
drugs didn't come out in the Netherlands until 1990. And what they did
then is they said they had 2,400 patients with FH.

And they started with 2,100. And then they looked at the ones
that ended up taking statins. This is the ones that
didn't take statins. And if you had FH
and you took statins, your morbidity and
mortality was very good. And if you didn't take
statins by 10 years later, 25% had died. It also turns out that FH
doesn't just affect adults. Obviously, it affects children. And it turns out that when kids
have high enough cholesterol, there's a good rationale
for treating them with medications as well. The cholesterol has
to be very high. But in the Netherlands
they've also done studies where they've taken FH kids. And when they started, this is
their– in their teenage years or earlier– their
cholesterol 237 already compared to their siblings
that didn't have FH. So their cholesterol is
already double normal. And then they put
them on medications.

And 10 years later, they looked. And the normal kids–
everybody's cholesterol goes up as we age. So they went from 100 to 124. And the kids on statins
went from 237 to 173. And it turns out
that their measure of the plaque– their
atherosclerotic buildup also normalized. So getting kids on
medications early can save potentially
stabilized down the line. Now one of the big
problems with FH is that we'd like to get people
to have cholesterol levels that are optimal. And optimal cholesterol
levels– LDL cholesterol levels are less than 100. Everybody defines that. Most people don't have
cholesterol levels that are optimal. But we'd like to get FH
patients to an optimal level to compensate for
that past burden.

But only 20% of FH patients,
even with all the medications we can use, ever get there. And only 40% of patients
ever get to an LDL of 130. So this is a big problem. They can also develop
muscle toxicity to statins. About 10% or 15%
have that problem. And so there's been
at this urgent need for new medications. And I don't know, very
serendipitously for this talk I guess, how many
of you have heard the story about these
new cholesterol-lowering medications that have
gotten a lot of press in the last two days. The FDA basically had hearings. And the committees
recommended the approval of two new medications
for high cholesterol. Have any of you seen that press? It was in the New York Times.

It was in the Washington Post. It was on PBS. And here is the founder
of the FH Foundation. This is a woman that I've been
working with for three years. She has FH. Her daughter has FH. She had a heart
attack in her 30s. And she founded this
charitable organization. And these are some of the
CEOs of these companies that have these new
cholesterol drugs. This is an article in the
New York Times that came out. And they were nice enough
to quote me in that article because I think that these
medications are potentially game changers for FH. And these drugs are
called– I'm not going to ask you remember this. You'll never remember this. But these are called
PCSK9 inhibitors. And they are a poster child. And the quote that I
had about these drugs is they are a triumph of the
modern genetic revolution.

So this is your tax
dollars at work helping to discover these drugs. So how did this happen? Well, about simultaneously
families in France were found to have mutations in
PCSK9 that caused this enzyme to be overactive. And, again, when this
gene is overactive, it degrades LDL receptors. And the cholesterol levels
remain very elevated in the blood. So overactive PCSK9 is bad. About the same time
in studies that were helped to be funded by
charity, but also by the NIH, individuals in Texas were found
to have naturally occurring mutations. That means they are born with
these natural mutations that cause an inactive PCSK9. And these inactive PCSK9
folks have extremely low LDL cholesterol. They're born with
low cholesterol. And they remain with low
cholesterol their whole life. Their PCSK9 does not work. And their cholesterol
levels are much lower than the normal people. The average cholesterol
was about 70. Here the average
cholesterol was about 130. But their risk for heart
disease– those people that had the mutation was 90% gone.

So they had a 90% reduction in
their risk of heart disease. And you could never tell
that these individuals had a problem. Their LDL cholesterol
levels were very low. And they're only
side effect seemed to be they lived a long time. They didn't have heart disease. So these drug
companies are not dumb. And they said, well, this
sounds like a good target. We're going to develop drugs
to treat this condition. And we're going to develop
inhibitors of this enzyme. And they have. And these are antibodies. They're injectable drugs. And if you inject them once
every two weeks or once every month, these are
plots of cholesterol levels. So here our cholesterol
levels in FH patients– these are FH patients. These are FH patients that
did not get the active drug. Their cholesterol level over
time remained about 182– their LDL cholesterol. If they did get the
active drug, look there is a dramatic drop
in their LDL cholesterol. And that remained
for over a year. And so the FDA has
weighed the evidence and said for
certain populations, it looks like these drugs are
going to be very promising. They haven't
conclusively demonstrated that they increase lifespan
or reduce heart attacks.

But those studies will come out
in the next couple of years. So that's the landscape. And there remains a lot
of challenges for FH. And I'm just going to talk
to you about a few of them that we're helping to
address at Stanford and how we're doing it. So what are the problems? Well, lack of public awareness. Nobody here knew what it was–
underestimate of how serious it is. There is no active registry. There's no specific
ICD-9 diagnostic code. So I can't go to the
health care system and say pull out all the
people that have a code for FH. And we have a fractured
health care system. One family member
gets care one place. One family member gets another. And so if we're tackling
family diseases, it's hard. And so the FH Foundation–
I work with them. We're trying to address these. We have trained a
lot of FH patients.

These are all FH
patients that are being trained to go into the
community and educate people. We've applied for
a specific code that doctors can
use to code an FH patient in the medical record. We've started a
National Registry. And the last thing
I want to talk about is this project we're doing–
a big data project that has gotten some awareness here. So we're trying to increase
awareness through social media. We have a website that
gets 10,000 hits a month. And, again, all of
these are FH patients. They are all passionate
about getting the word out to prevent future problems. We have a national summit
that we host every year. So what are we starting to
learn from our patients that are participating in research? And this is a new trend
in the United States. It's patient participation
in research– patient participation in care–
patient autonomy– patients driving improved outcomes. And so these are representative. These blue ones
are representative of clinics where patients are
being enrolled to participate in our registry at Stanford.

We have about 100
patients that have enrolled at the University
of Pennsylvania. They have about 350 patients. And we're starting to learn
some really interesting things. The average age of these
FH patients is about 55. But the average age of
diagnosis is about 45. So they've gone 45 years without
knowing they have something that's potentially deadly. By the time they get the
registry, if you count it all up, about 35% have already
had a heart attack or a stroke or a bypass surgery.

And the average cholesterol
level is about 250 in these folks. And they, again, are not
getting to healthy levels even with currently available
drugs despite the fact that at least about
55% of them are taking more than one
cholesterol lowering medication. I noticed the charts–
they always show the LDL. Do they ever talk
about how their HDL looks in this prototype? No. HDL is a new– there's a lot
of controversy about HDL. And it turns out that it's
not nearly as important as we once thought it was. And really LDL is the driver. HDL is a marker of good
overall health– good diet, good exercise. But it turns out that treating
people with drug to raise HDL levels is not effective. And so FH patients have
HDL levels that are just like the general population. Now, it also turns out
that even if there's lots of gaps in knowledge.

So we also have asked all
these patients questionnaires. And these are patients
that are being seen even at leading lipid centers. And so we're asking
them how well they understand their disease. So how many of these
FH patients have a full understanding of all
their available treatment options? Only 34%. How many understand
your personal risk for heart disease? Only 60%. How many understand why
screening family members is important? Only 71%. So there's lots of gaps
that need to be addressed across the United States. In the last couple
of minutes before we get to your questions,
I'm just going to talk about one big
data project about FH. And this is called the
find FH initiative.

And Stanford is a
partner with this. And so this is the irony of FH. Normally, when we're
looking for a disease, we're looking for small signals. The needle is small. The haystack is big. It's hard to find the disease. But that really shouldn't
be the case for FH. FH is a big needle
in a small haystack. And we should be able
to find FH patients if we look hard enough. And the irony is that we
should be able to find that. But we're not finding it. I've told you that only 1% of
people in the United States with FH know they have it. And it's hard to do it
again because there's no specific code for FH. So doctors can't put
into the medical record I have a patient with FH. They can only put in I have a
patient with high cholesterol.

And so we're taking
a big data approach to try to change that at least
at Stanford and hopefully across the world. So what does big data mean? And it's a word that's getting–
it's this phrase that's getting a lot of press lately. It can mean volume,
variety, velocity, variability– veracity. But another explanation
that I think is cute is one of our
scientists said big data is like teenagers and sex.

Everybody talks about it. Nobody really
knows how to do it. Everyone thinks everyone
else is doing it. And so everyone claims
they are doing it too. So big data is this sexy topic. Everybody says we're doing
things with big data. But the most important
thing is whether the data is big enough to solve
the problem that you're interested in. And so I'll give you another
example of how this is might work. Anybody can tell me what
this is a picture of? No. Nobody can tell me what
that's a picture of. Now if I take this
slice of the data, anybody tell me what
that's a picture of? No. Nobody knows what this
is because this is not the right slice of data. Now what if I change
this slice of data? Instead of showing you–
this is 5% of the image. What if I show you
a different 5%? Anybody know what that is? No, because it's still not
the right 5% of the data.

But what if I showed you 5%
of the data in another way? Now, how many people
know what that image is? The selfie at the Oscars– the
most tweeted photo ever, right? So if you have the right 5% of
the data, you can learn a lot. And so that's analogous to
what we're trying to do. How many know who
this person is? So everybody knows who
Ellen Degeneres is. So how do we find the
right 5% of the data? And so what we
we're trying to do is look across the
huge medical records that we now have at
Stanford and look and try to find FH
patient's within the electronic medical record. And how are we going to do that? Well, we're going to use
some fancy techniques, which are called machine learning and
natural language processing.

And natural language
processing means using a computer to
read text, basically, for the purposes
of this lecture. So wouldn't it be nice if
you could go to a computer and say read all the
doctor's notes that have ever been at Stanford and
pull out all the patients where a doctor said they have
familial hypercholesterolemia. That will be amazing. And what is machine learning? Well, machine learning
is another fancy. Thing but it's
not– intuitively, it's not that hard
to understand. It's software that
learns by example. And, basically, you give the
computer a bunch of examples. And you say, learn what this is.

And an example of
that might be you go– you buy a bunch of
stuff using your credit card for two or three years. And then a few years– so the
credit card company computer learns what you buy normally. Then if a diamond ring shows
up on your credit card that was purchased in
Brazil, then you get a call from the
credit card company saying this looks anomalous. This does not look
like the patterns that you normally have. And this is an automated voice
message from your credit card company. Did you actually make this call? So credit card companies
use machine learning. You show a bunch of examples
to do credit card fraud. If any of you have Netflix
accounts or Amazon accounts, they learn what your
preferences are just by you purchasing things.

And then it speeds you
examples of what you like. The US Postal Service also
uses machine learning. There's not a person that
looks at your envelope that says I want to send this to
Sue Smith at zip code 27514. The machines read
those envelopes now. And they read the
envelopes by being shown thousands and thousands
and thousands of examples of handwriting. So they know what things mean. So we're going to
do the same thing in the electronic
medical record. We're going to take that 100
FH patients that we follow. We're going to show the
entire medical record of these patients to a computer. And we're going to
say, show me– learn what these patients look like. Learn what the patterns
of these patients are through the medical record. And then once you
learn that, show me all the other patients that
are in the medical record that look like that.

I hope people are
following me so far. And then we're going to
look at the demographics. Their medical history–
their family history. We're going to look at
structured and unstructured data. Structured data is
things like lab results or blood pressure or numbers. Unstructured data as
things like text or things not put in a spreadsheet. And so we're going to take
these known FH patients. And we're going to say– we're
going to look in clinic nodes. We're going to look
in lab results– pharmacy claims, prescriptions,
procedures that they've had.

And we're going to say
what is common for FH patients among this. And then show me all the
other examples of that. So we're just starting
this project now. And so maybe in a
year or two I'll come back and show you
what the– show you what the results are. So that's really the end
of what I wanted to say. And the most important thing
is for FH– the time is now. And I gave you pre-talk quiz. So now I'm going to give
you a post-talk quiz? "How common is FH in
the general population?" Who says 1 in 1,000? Who says 1 in 500? Who says 1 in 250? 200? Come on, people got
to raise your hands. A. OK, it's not 1 in 1,000. So I failed on that. It's somewhere between
1 in 200 and 1 in 500. "FH patients are
what-fold in 20?" Right.

Cascade screening. Cascade screening
is family tracing. It's screening all the relatives
of a family member that has FH. "What is the goal
of LDL cholesterol?" How low do I want it to be? 100. Yes, 100– at least 100. "Mutations in what
three genes cause FH?" LDL receptor– we know that one. PCSK9, we know that one. So it's gotta be this, right? Because this is the
only one with PCSK9.

Now you know more. I'm going to show
you how well you did. So in September, 2013,
500 cardiologists were surveyed about what
they understood about FH. 80% were unaware
of the prevalence. 70% did not recognize it
when given an example. 60% did not realize that
it was autosomal dominant. And none realized that they
were at 20-fold increased risk of heart attack. So already you
know more than 80% of the cardiologists in
the country about FH.

So that's all I had to say. And I'm happy to take questions
about that or other topics. So you said at the beginning
that it is very difficult to diagnose and
find the patients when they are very young
that have high cholesterol. When people start
having a physical, they always check the
cholesterol if it's normal or not. But it turns out they don't. In the United States,
the pediatric guidelines recommend all kids have
their cholesterol checked between ages 8 and 11. And that's almost never done. So we're missing
a huge opportunity to find those kids
because people don't adhere to the guidelines. That should be an easy fix. Well, it should be an easy fix. But convince the
parent or a physician that they need to draw blood
from an eight-year-old. It's not that easy. How difficult is it to
develop a FCA-9 code? The ICD-10? Yeah, it's not easy.

To get a code, you actually
have to make an application to the Center for
Medicaid Services. So you call these physicians. And you make a petition. And people are making
petitions all the time. And then you have
to go and explain why you think this is important. And so we, a few years ago, went
to Baltimore and represented. And we think that it
will get approved. But as you know,
ICD-10 codes were supposed to be implemented
in the US last year. And they've been put off.

They keep getting
put off because it's going to cost health
care systems money to implement them. But ultimately, it
will go, we think. Are there consequences for kids
being on statins for decades? Yeah, excellent
question that's one of the reasons the
pediatricians don't measure it because they say well
of what I did it what do I do about it if I find it. I'm not going to put
kids on medications. And so we know– statins have
been around since the mid '80s. So we don't know
consequences for 60 years because we only have
35 years worth of data. But so far, the for patients
like– for FH kids– the major side effect
that we can find is that they just don't
develop vascular disease.

So they develop normal
sexual maturity. They have normal
muscle strength. They have normal
exercise tolerance. They have normal mentation. So we can't find any
major side effects. Do we know about 60 years? No. We don't know whether it prevent
heart attacks, obviously, because these kids
are not old enough to have had heart attacks yet. But we're presuming that
if their vasculature looks a lot better that it
will prevent heart attacks. Those kind of studies
are extremely difficult. You'd have to study
thousands and thousands and thousands and thousands of
kids that were put on statins follow them for 60 years. And nobody can afford
those kind of studies. The patient– do they need–
in addition to the medication, do they need to
follow a good diet? Absolutely. A diet that's low in saturated
fat and high in fiber is really important. Exercise daily is
very important. All the same things that
we would tell everybody, we would tell the
FH patients too. So what about eating
foods with cholesterol? Now, it's OK? Like eggs? Yeah, so that's also something
somewhat controversial.

The question is what about foods
that have cholesterol in them like eggs? And there's been
some press about that recently because the American
Heart Association changed their recommendations. And it turns out
after years of study, we've been able to determine
that cholesterol that you eat in foods like eggs
doesn't turn into cholesterol in your bloodstream. What turns into cholesterol
in your bloodstream is saturated fat that you eat. And so if you want to
have lower cholesterol levels in your blood,
the most important thing is to eat a diet that's low
in saturated fat– that's animal fat and in general. And so occasionally– the
AHA is really backed– and these dietary
guidelines have become less strict
about things like eggs, which is appropriate
or shellfish, which I think is
appropriate too. They are talking about
butter also was OK. Yeah, a little bit of butter–
butter is saturated fat. So a little– the advice
your grandmother gave you about most this stuff, which
is everything in moderation, is probably the
best information.

Are there certain
populations that are at higher risk
for FH in the same way that metabolic syndrome
tend to run in populations? Yeah, there are what we
call in the genetics field founder affects. And what that means
is that if you happen to have a small
population at one time in which a few people had FH and
that population then expanded, there's a lot of people
in that population that are going to get FH just
because the number of people that founded that population
was small to begin with. And there are founder
populations for FH. So for instance, in the general
population, we think about 1 in 200 to 1 in 500 have FH. But in Ashkenazi Jews,
it's more like 1 in 100. If you happen to
live in South Africa and be a Dutch Afrikaner,
it's more like 1 in 80. If you're a Christian from
Lebanon, it's more like 1 in 150. So there are certain–
the Amish it turns out probably have the
highest population. The Amish in Pennsylvania
have extremely high prevalence of FH.

Is that due to primarily
to inbreeding essentially? Well, it's just
a small community that was founded by a
small number of people. And in that small
number of people, there happened to
be a few– these are Huguenots that came over. And there's a few Huguenots
that had apoB mutations. So there there's a
very high prevalence of FH in the Amish population. If these new drugs
are approved, which you are hoping that they
will be and fast tracked, will they always be injectable– There's three companies that
have these PCSK9 inhibitors.

Two are very close to–
they'll get approved this. Those are injectable. The third is also injectable. And then there's a few
other companies that are trying to develop pills. But they're very
expensive medications. And the way that they currently
work is there are antibodies. You can't take an
antibody by mouth. It will get degraded
in the stomach. And so not clear whether
that's going to happen or not. They're going to be very
expensive– $10,000 a year. And so they're only going to be
used in the most severe cases hopefully. Is there any research going
on for tissue engineering stem cells to override
the liver function? Well actually, was there
any engineering– tissue engineering that's
going on stem cells? And it turns out
that's probably not going to be necessary
because the drugs that we have are so
effective we don't need to use genetic
engineering to correct this.

Now there is one form
of genetic engineering that you probably
haven't thought of. But in homozygous
patients– that is they get a bad copy
of the gene from mom and a bad copy the
gene from dad– their cholesterol levels are
10 times normal– 500 or 1,000 milligrams per deciliter. And there their livers
just don't work at all. And so the gene therapy that's
used rarely for those kids now is liver transplantation
because if you take a normal liver
and you substitute it, then that everything's
back to normal. But that is very rare
because the medications that we have a fairly effective. What's the contribution
of this physical exercise to cure the FH patients? It helps modestly. We think that diet and exercise
can lower your LDL cholesterol by, on average, about 15%. And for FH patients, if
you need 60% reduction, it's only part of the equation. For a normal person, that
might be very, very effective. But for FH, it's a
fallacy for those patients to think they can get away
with just diet and exercise. It's not their fault. You
just can't exercise your way to lower cholesterol. So you mentioned
earlier that you're taking HDL– your total
cholesterol, LDL, HDL, and then ratios.

So now HDLs are
playing a lesser part? It's a little bit more
nuanced than that. HDL is clearly associated
with a decreased risk of heart disease. If you have high HDL,
you have a decreased risk of heart disease. And that reflects the fact
that you're eating a nice diet. And you're exercising. And maybe you're a woman who
hasn't gone through menopause. What I was speaking
to rather was the fact that we have never
been able to find a drug that raises HDL levels
that results in protection. And probably that's
because HDL is not causally associated with a decreased
risk of heart disease. It just reflects an
overall better lifestyle.

So it represents lifestyle
more than genetics. Yeah, rather than a target
for therapies so far as we understand it. So we don't give FH
patients medications to raise their HDL
because it doesn't work. We hear sometimes some
of the athletic people. Suddenly they get a heart
attack, and they die. Is it possible they have FH? Actually, the other
people I take care of are people like that–
people with other inherited forms of heart disease. And if you look broadly at
athletes who die suddenly, there's about five or
six things that happen. FH is pretty rare for that. More commonly they
have actual diseases of the heart muscle–
hypertrophic cardiomyopathy where the heart muscle
is very, very thick. Or they have diseases of the
electrical system of the heart.

So they get arrhythmias–
things like long QT syndrome or Brugada syndrome
rather than FH. So you might have mentioned it. But do you look at–
is the general you look at then is total cholesterol. Or do you look at it– Total cholesterol– mostly we
treat LDL cholesterol for FH. FH is really a disease of
LDL cholesterol metabolism. And so the most important
number to know for FH patients is their LDL. And what type of
cholesterol numbers are you usually seeing in
these FH patients– total cholesterol? You mean what kind of
total cholesterol numbers? Yes, so, in general a
total cholesterol over 300 is very, very suspicious for FH. Total cholesterol 300–
LDL cholesterol of 200. This is the ballpark
numbers that you'd think about– so very high. Is the web page for
your non-profit– does it receive funding
based on clicks on it? Not yet. I wish it did. Not yet. I wish it– but
indirectly it does because the FH
Foundation raises money from all kinds of sponsors. And the more we can
show there are clicks, the more the sponsors are
interested in sponsoring us.

It's nice if you like it on
Facebook and things like that. Yeah, absolutely, yeah. [INAUDIBLE] Then you can
go to Facebook and like it. Right, absolutely. And share it with your friends. I would love for you to do that. Any other questions? I think this is
probably the end of it. But Dr. Knowles,
thank you for a really informative and wonderful talk. Oh, yeah, thanks for having me. Thank you all for coming. [APPLAUSE] .

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