Hey everyone, welcome to the drive
podcast. I'm your host Peter Aia.
>> Peter, welcome to another AMA. How you
doing?
>> Very good, thanks.
>> Awesome. So, today we are doing the
whole episode around one topic, which is
the liver and metabolic health. In the
past, you've described the liver as the
quote unquote canary in the coal mine
for metabolic dysfunction. So, I think
it'd be helpful to start with kind of
talking about what you mean by that and
why you think the liver is so important.
>> Well, the liver sits sort of at the
center of systemic metabolism for every
macronutrient, glucose, fat, protein, as
well as cholesterol. And by the way,
let's not forget ethanol or alcohol
there as well. So it's also one of the
very first places to both promote and
respond to stress from anywhere in the
system. If circulating triglycerides are
high, the liver gets involved. If
glucose regulation is deteriorating, the
liver is involved. If APOB or LDL
cholesterol is climbing, the liver made
those particles. And the flip side is
equally true. If we look at the liver
and see that it's under stress, we know
that these metabolic systems are also
under stress. It's a two-way mirror
between systemic metabolic health and
what's happening in the liver. And
that's also why I think about liver
disease less about a standalone organ
problem. Um, dysfunction of the liver is
more of a parallel expression of
systemic metabolic dysfunction. The
leading cause of death in people with
liver disease isn't liver failure. It's
cardiovascular disease. Because a liver
under metabolic stress is overproducing
apo containing particles and amplifying
the insulin resistance that drives
atherosclerosis throughout the body. And
so that's why um this is a metabolic
episode as much as a liver one. Uh and I
guess we should also name it upfront
when we're talking about fatty liver
disease, we're talking about a disorder
that is estimated to affect more than
38% of the world's adult population. uh
which is hard to believe. Um this isn't
something that happens to some
unfortunate person that you'll never
meet. Um it will happen to nearly anyone
in the developed world who isn't paying
some attention. And I think it's worth
kind of early on talking about what the
liver does, right? So I think for a lot
of people when they think of the liver,
they usually think about processing
alcohol. So before we get too much into
metabolic disease, can you frame in a
little more detail what the liver is
doing in the body?
>> Sure. Um and you're right, the alcohol
framing dominates. Um and and that's a
bit of an underscell. Um as our past
guest, uh Julia Waterrell says the liver
has over 300 functions. Um which is sort
of staggering. Obviously, we're not
going to talk about many of those today.
Um, but I find it useful to
conceptualize all of those as fitting
into four main categories. So the first
is detoxification. The liver breaks down
alcohol just as it virtually just as it
would break down virtually any toxin
that's m that makes its way into the
body from food, drink, pharmaceuticals,
inhalation, any toxin that reaches the
blood, the liver plays a central role in
clearing it. Uh, second, it is an immune
organ. So the first place blood from the
gut goes is to the liver. All blood from
the gut winds its way back into the
portal system to the liver. So it's one
of the first responders to ingested
toxins or bacterial leakage from the
gut. Third is protein processing and
secretion. The liver is the site of
synthesis for many of the most common
proteins in our blood. something as
ubiquitous as albamin and as vital as
clotting and platelet stimulating
factors, apo, peptide hormones like
IGF-1. The fourth category is where
we're going to spend most of our time
today and that is on energy metabolism.
The liver plays a central role in the
uptake and synthesis of circulating fats
and cholesterol and is one of the most
important organs if not the most
important organ for the balancing act of
maintaining blood sugar. It's, you know,
you could think of it as the met
metabolic headquarters of the body,
which is why when it's harmed, the
damage is not just confined to the organ
itself.
>> And so, you mentioned there about the
liver and blood sugar. Can you walk us
through more the liver's relationship
with controlling blood sugar?
>> Yeah, it sounds simple, but the
precision required to regulate blood
sugar is extraordinary. Uh, and it never
ceases to amaze me. It's one of my
favorite things to explain to a patient.
After a meal, uh, glucose rises, the
pancreas releases insulin, and insulin
tells the liver to absorb glucose and
stored as glycogen.
Now, when you've been fasting for some
period of time and glucose dips, insulin
falls and then the liver does the
opposite. It breaks glycogen back down
and releases glucose into the
circulation. And when glucose runs
really low, it can actually just
manufacture glucose on its own. So if
you're, you know, going more than a day
without eating, the liver turns into a
glucose making organ. If there's too
much sugar to store as glycogen, the
liver converts it into triglycerides,
packages it into apa lipoproteins,
um, and ships them out. So what I want
people to appreciate though is the scale
of this. So everybody, you know, think
about you go to the doctor, you get a
blood draw and it's, you know, it's a
fasting blood draw, right? And you you
you get back a number. And so let's say
that number you get back says 90
milligrams per deciliter. That was your
blood glucose that morning when you
showed up at the lab. If that's the
case, your entire bloodstream in that
moment contained only about 4 and a half
grams of glucose. That's roughly a
teaspoon, not a tablespoon, just a
teaspoon. Um, yet a single meal,
especially if it's a meal that I'm
eating, may contain many times that,
easily 90 grams of glucose, right? So 20
times that amount in one meal. And yet,
despite that, a healthy person rarely
moves more than a teaspoon above
baseline. Right? In fact, I'm trying to
think of all the times I wore a
continuous glucose monitor if I ever saw
a blood glucose level uh that would have
been north of about 160 milligrams per
deciliter.
Um someone with type 2 diabetes would
rarely go above a teaspoon and a half at
fasting. And when we can go hours
without eating, our glucose still stays
in that range. In fact, if you go days
without eating, it might only dip to say
50 mg per deciliter. This is a
monumental homeostatic achievement. And
that reserve capacity to titrate out
glucose in such fine amounts is exactly
why early dysfunction is very easy to
miss, which is something we'll I'm sure
talk about. Yeah. And so let's dive into
more metabolic disease and how that
affects the liver. And so when looking
at that, is there a framework that you
typically use typically talk through
with patients in explaining it? Yeah, I
think the most useful framing is to
consider metabolic liver disease moving
through four stages.
So in the first stage the liver becomes
metabolically stressed. Um and then the
second stage in response to that it
starts storing excess excess energy that
is as fat and that's a condition known
as steattosis.
And then the third stage is uh stato
heepitis and that is just a fancy word
for excess fat being stored in the liver
tips the liver into inflammation and
then the liver begins to injure itself
and then the fourth stage is the
response to that injury where it starts
to lay down scar tissue and that's a
term that uh people have probably heard
called fibrosis in the liver. So those
first three stages uh are largely
reversible. It's fibrosis
um that is a little trickier. Um it is
biologically reversible to varying
degrees especially if caught on the very
very early side of things but once the
scarring accumulates
into such that the liver's architecture
uh is disrupted that's the point that
becomes irreversible.
Now, the presence of fibrosis is what
predicts the outcomes that we typically
care about, especially cardiovascular
disease, cancer, and even liver specific
mortality. Um, so as we kind of go
through this exercise, I'll keep
pointing back to where we are on that
four-part scheme. And you previously
said that, you know, chronic calorie
surplus is a primary driver of metabolic
dysfunction. And so can you walk us
through the chain of the events from
caloric surplus to ultimately at the end
liver damage?
>> Yeah, it starts relatively simply. Um if
you consume more calories than you
expend consistently, the body has to put
that excess energy somewhere and the
liver converts much of it into
triglycerides through a process of
denovo lipogenesis. It packages them
into these apo containing particles,
namely VLDLs and LDLs, and ships them to
atapost tissue for long-term storage.
And again, that is a normal healthy
physiologic response. If we didn't have
that capacity, uh we wouldn't be here
today. You and I wouldn't be talking
together. Our species would have gone
extinct because we had to be able to
store energy when energy um was abundant
and we had to be able to draw from that
when energy was scarce. So, so far this
is this is normal. It's obviously, as
you can see, it's going to become
abnormal at some point. So, think of a
fat cell as a warehouse. Um, for a
while, they will accept every shipment.
Um, but as they become progressively
overfilled, they stop responding
normally to insulin, which is kind of
the most important hormone that's
involved in this process. And one of the
molecular hallmarks of that process is
the accumulation of a lipid intermediate
called dasalog glycerol or DAG or DAG
which interrupts insulin signaling. So
once that happens the warehouse starts
malfunctioning instead of simply storing
fat those particular fat cells or
atyposytes begin releasing fatty acids
back into the bloodstream. exactly what
you don't want unless you're about to
use them immediately. The problem is
there's already too much energy in
circulation. So, the last place you want
more triglycerides is being released
back into the bloodstream. So, now the
liver has to deal not only with the
excess calories coming in from the diet,
but also the excess fat coming back into
the circulation from those defective fat
cells.
>> And what happens to the free fatty acids
in the blood? So the liver picks up
those fatty acids as well as the fats
from our diet because that's one of the
primary jobs is energy balance. Um but
eventually the same process develops
here. So lipid intermediates begin to
accumulate. Insulin signaling becomes
impaired and the liver becomes insulin
resistant. Now, people may recall back
to the podcast that we did uh with Ralph
Defrono on this, and it was a it's one
of my favorite podcasts of the past year
or two because it's just a you know, a
master class in all of the different
types of insulin resistant and insulin
resistance in the muscle versus the fat
cell versus the pancreas versus the
liver. They all look a little bit
different. I'm not going to get into
that now, but if you if anybody wants to
sort of get really brushed up on that,
that's where we'll go and we'll link to
that in the podcast. But here's the part
that's really important. Insulin
normally tells the liver to do two
things. Stop releasing glucose into the
bloodstream and stop making new fat
cells. Why? Because if insulin is high,
you've just been fed. And if you're fed,
you don't need to be putting glucose uh
into the bloodstream or making new fat.
Um but as insulin resistance develops,
the first signal fails before the
second. So the liver continues releasing
glucose even when blood sugar is already
high while the pancreas responds by
making more insulin which still drives
fat production. So that's called
selective hpatic insulin resistance and
it's one of the defining features of
metabolic disease. At first the liver
exports those triglycerides in these apo
containing particles and again that just
means LDLs and VLDLs which is why
dysipidemia always accompanies this and
eventually production outpaces export.
So fat accumulates inside the liver and
now we've reached stage two of our
little linear progression. This is now
steattosis.
And so what are the liver diseases that
you're concerned about as a result of
that metabolic dysfunction?
>> Well, the name changed recently updated
to
reference the cause of the disease and
move away from the fat in the name. um
because fat is at the is basically the
end result of caloric excess but that
that excess isn't usually fat itself. So
excess calories are often in the form of
anything. It could be carbohydrates,
glucose, fructose. So basically earlier
um we called this disease nafal D
non-alcoholic fatty liver disease and
then if it progressed to the
inflammation damage stage it was nash
which just stood for non-alcoholic stato
hepatitis by the way the NA in both of
those non-alcoholic is just so that we
try to understand that this was uh
driven more through uh excess energy but
not through the damage specifically of
alcohol because you can also get
alcoholic fatty liver disease and
alcoholic stato hepatitis. Um, okay.
Now, these things are called mazeld,
m-asld, and mash, not the TV show. And
what does that stand for? That stands
for metabolic dysfunction associated
stotic liver disease and stato heepitis.
So, basically, it's the same disease,
just new names. And I'm going to
apologize in advance. I will
occasionally still refer to these as
naffy and nash as opposed to masled and
mash. Uh again, apologies in advance for
that, but please understand it's just
new nomenclature to try to more
accurately reflect the process of the
disease.
>> And on that, so once fat is built up, is
that the point at which the liver starts
to suffer actual damage?
>> Well, ctosis is a giant warning sign.
It's not liver damage yet, though, but
you're you're sort of now on the path to
liver damage. So, think of it as the
liver stuffing excess energy inventory
into the manager's office because the
shelves are full. Uh, something is
clearly wrong, but at the packaging
facility, nothing is breaking yet. If
that analogy helps, it might not. Masle
D is diagnosed when that steattosis is
accompanied by another cardiomatabolic
risk factor such as hypertension uh
pre-diabetes defined by hemoglobin A1C
or even just type 2 diabetes itself
dysipidemia
elevated BMI or obesity um again these
are just sort of poor man's proxies but
you get the point right which is liver
fat accompanied by some other metabolic
dysfunction is what we're looking for
and so that's our second stage both
metabolic stress as well as fat in the
liver. The real damage begins when that
fat burden triggers inflammation. Uh
hpatocytes loaded past their limit
actually start to die. Hpatocytes are
just the cells that make up the liver.
Their death recruits immune cells which
release inflammatory signals that spread
to neighboring cells. And it's that
inflammation
um that starts to disable insulin
signaling through a second separate
pathway. So the resistance is now coming
from two directions at once. Um with
even more insulin resistance, the
neighboring cells now accumulate more
fat and die too. And then you get a
spreading wave where each cell death
drives the next. So as you can see this
becomes a feed forward kind of amplified
loop. That transition fat accumulating
to active inflammation is the move from
stage two to stage three what we call
mASH. And the liver responds to dying
cells the way any tissue does. It lays
down scar tissue. That's called
fibrosis. It's our final stage of
thinking about metabolic disease in the
liver. As fibrosis accumulates, the
liver moves towards cerosis. That's the
end stage scarring where so much
functioning tissue has been replaced
that the liver can't even do its job
anymore. And you have to think back to
all those other things I talked about
making proteins and clotting factors and
doing detoxification. all that stuff
starts to go out the window. This is
also where cancer risk starts to climb
dramatically. Fibrosis is where the
really durable uh clinical risk lives.
And when talking about metabolic
dysfunction, we often hear visceral fat
as well. So, what do we know about
visceral fat and the liver? Does
visceral fat affect the liver
specifically?
>> Yes, it's one of the most significant uh
modifiers of liver risk. Not all fat is
meaning or metabolically um equal. Uh
fat stored around your organs is
actually more prone to releasing fatty
acids even at baseline. But the bigger
factor is definitely location. So
visceral fat um fat around the abdominal
organs drains directly into the portal
vein which is the one of the two blood
supplies that goes to the liver. Um it's
the one that drains the GI tract. So all
of the gut and all of the uh metabolites
that come from digestion. So
subcutaneous fat uh releases fatty acids
that diffuse through through the entire
circulation first. So it's just far less
concentrated in terms of a shot directly
into the liver. Visceral fat bypasses
all of that. And so it's the difference
between, you know, someone yelling at
you from across the house versus like
shouting directly into your ear. Same
signal, um but just much higher
intensity because of where it's coming
from. And the the data bear this out. So
in one cohort visceral fat area which
could be estimated by CT scans um
predicted steattosis independent of BMI
and liver enzymes.
So patients with greater than 200 cm
squared of visceral fat had a 7 and a
halffold greater increase of liver
steattosis when compared to people below
100 cm squared. And if you looked at the
NHANES database among people with
diagnosed mass D, the all-c cause
mortality ratio in the top quartile of
visceral atyposity was nearly three and
a half times that in the lowest
quartile. So visceral fat predicts liver
pathology and in the people who already
have liver disease, visceral fat
predicts a dramatically higher risk of
death. And in the past when talking
about metabolic health, you've often
talked about the importance of
resistance training. So what do we know
about how does resistance training
interact with the role of the liver in
metabolic dysfunction? Well, even more
so than the liver, skeletal muscle is a
major glucose sink in the body. In fact,
it is hands down the largest sink of
glucose in the body. So it pulls blood
sugar out of circulation and stores it
as glycogen. So roughly speaking about
3/4 of your total capacity to store
glucose is in your muscle and about a
quarter of it's in your liver. Um and
that's again storing it as glycogen. So
less muscle means what? It therefore
means less capacity to buffer glucose.
So more of that burden lands on your
liver. Um it's why you see metabolic
liver disease in people that actually
have normal BMI but are very you know
low in muscle mass. um sarcopenic
obesity uh is the technical term for
that or what people call skinny fat and
multiple longitudinal cohorts point the
same thing out. More muscle predicts
both fewer new cases of mazeld and
higher rates of resolution. The single
most striking
uh figure comes from a large 7-year
Korean cohort. People who gained the
most muscle over the study resolved
their masled at more than four times the
rate of those who gained the least
muscle. We'll include all of this in the
show notes. So whether it's prevention
or reversal, the direction here is
pretty unambiguous, which is why
resistance training is kind of a
non-negotiable if you're trying to
address metabolic dysfunction. And do we
know anything about if fructose may be
more harmful than glucose?
>> This is a very interesting question and
one that it's it's very easy to get
wrapped around the axle on this one. Um,
the cleanest human experiment.
Um, and I only want to focus on the
human experiments because you could we
could spend the entire day on this
question, Nick, if we wanted to talk
about all of the animal stuff. But uh
the cleanest human experiment is a
randomized trial in 94 healthy men who
drank moderate amounts of fructose
um which is again just the pure sweet um
an antimer sucrose which is the 50/50
mix of of fructose and glucose or
glucose sweetened beverages um for seven
weeks at weight stability. So, it's very
important when you do these studies that
you have to keep the subject's weight
stable because if you don't, it
confounds everything.
In this study, fructose and sucrose
roughly doubled the liver's baseline
fat-making machinery. This so-called
denovo lipogenesis pathway. Denovo just
means new li and lipogenesis means fat
creating. While glucose did not. So at
least in this study, fructose can behave
differently from glucose in the human
liver. And where that shows up most
cleanly is in these measurements of
denovo lipogenesis.
But on the harder outcome, actual
steattosis, controlled feeding studies
show the dominant driver is excess
calories and not fructose itself. So if
you swap fructose isocalorically for
other carbohydrates, liver fat barely
moves. So calorie for calorie, the
honest fructose specific signal is on
lipogenesis which is an intermediate
measure but not the final outcome. Where
fructose earns its reputation is in the
form that it arrives in. Liquid sugar in
soda for example or other you know high
fructose corn syrup laden beverages
which are very calorie dense don't make
you feel full and are trivially easy to
consume and the cohort data do link
sugar sweetened beverages to higher
nafal risk or masle risk. So the
practical advice holds cutting sugar
sweetened beverages is absolutely one of
the higher yield dietary moves for
someone with insulin resistance or liver
disease. But it's really the chief uh
reason for that is that it's um going to
have its downstream effect on less
calorie reduction. So, one of the things
I absolutely would counsel somebody on
who has fatty liver disease is don't
drink calories at all and especially
don't drink carbohydrate calories and
especially don't drink fructose
containing calories. A
>> lot of especially there in that
statement. Sounds like it was super
important. Um, all right. So, going now
to what we talked about earlier on,
which is when people think about the
liver, they think about alcohol. So, how
should we think about alcohol here as it
relates to the liver? Yeah, alcohol is a
pretty clean story. You'll recall a
second ago I said that you the reason we
have to put the NA non-alcoholic or you
know whatever in front of those is to
differentiate it. Um it can cause fatty
liver on its own. So alcohol associated
liver disease um which by the way is
more common than than we give it credit
for. It's very easy to just focus on the
non-alcoholic metabolic versions. But if
you actually look at the people
requiring liver transplants, um I don't
remember the latest numbers, but the
last time I looked, I was very surprised
at how many I think more of those came
from uh alcohol consumption than than
non-alcoholic consumption. Again, I I
could be off on that, but I just
remember being sort of surprised. Um
now, that said, it works through a
different mechanism than caloric excess,
but it turns out the outcome is almost
the same. you pass through these these
categories of steattosis, insulin
resistance, fibrosis, ultimately
cerosis. Uh different mechanism um which
is why it's very harmful if you combine
it with metabolic dysfunction as is
often the case. So now you're getting
basically a twopronged synergistic
attack when you have calorie excess and
alcohol co-occurring. The combination of
metabolic dysfunction and alcohol
consumption recently earned its own
designation which I frankly I think
we're getting a little ahead of
ourselves which is metabolic and alcohol
associated liver disease or metal.
I'm not going to say that ever again.
There's a a very telling cohort study
from the NHANES database in patients
with existing cardiometabolic risk
factors. If you already had a risk
factor, steattosis alone wasn't
associated with increased all-c cause
mortality. But steattosis plus what they
described as moderate and I might call
moderate plus alcohol consumption
produced hazard ratios of 1.4 for all
cause mortality, 2.35
for cancer mortality,
and a whopping 15, please check that
number again. Yes, 15 X for liver
specific mortality versus people with no
steotic liver disease. So to put those
into actual relative risks, that's um a
cause of death from anything is up 40%.
Death from cancer is up 135%.
And from liver specific disease, death
is up 1,400%.
So again, the purpose of me sharing this
is not to tell you never to have another
drink. It's to explain that when you add
alcohol to liver disease, it gets really
bad. Now, if we look at the pattern of
drinking um there might be some again
something to glean here. So acetal
aldahhide is the primary driver of
alcohol's harm on the liver and it
accumulates faster the more you exceed
about one drink per hour. Therefore
mechanistically I get asked this
question all the time but I think what
we could say is seven drinks in one
evening is probably worse for you than
one drink per night. seven, you know,
consecutive nights. Um, again, I haven't
seen the data for that, but when you
understand the mechanism of action, I
think that makes sense. Um, but but
that's basically, I think, the point
here is that, you know, human data
directly comparing binge versus daily
drinking don't exist for the metabolic
disease. And I suspect we're not going
to have an RCT for that. But, but that's
kind of the point on alcohol and
metabolic liver disease. And to follow
up on the NHANES study, do we know how
much alcohol they were actually
drinking?
>> Yeah, again, everything is
self-reported. So, it's possible that
this is what they were drinking. It's
also possible this is a slight
underestimate. I believe the men were
drinking something to the tune of 40 to
60 grams a day and the women would have
needed to be a bit less than that. We'll
put the exact numbers in the show notes
page, but that means that these are
people that are self-reporting three at
least three drinks a day, maybe four
drinks a day. Um because again, 60 grams
of ethanol is technically uh for
normalsized drinks or potentially less
if you're drinking, you know, if you're
pouring it yourself. Sorry. I I mean
that the point I would also add to that,
Nick, is there are lots of people who
can drink that amount and they're
totally functional. So I I I don't want
the interpretation to be this is only
for people, you know, who are rampant
alcoholics because there lots of people
can be drinking three drinks a day um
and and obviously have, you know, no
obvious uh side effects of that. Moving
beyond just lifestyle factors, so when
looking at the liver, are there any
people who are at greater risk at the
baseline, whether that's from genetics,
hormones, or something else? Yep. I I
would put these into two buckets. The
inherited genetic piece and then
obviously the hormonal piece which can
fluctuate over time. So on the inherited
side, the most important single gene
variant here is something called uh
PNPLA3.
And people who carry two copies of a
particular variant here tend to have
about 2x the risk of uh or the the
likelihood of accumulating liver fat.
And then with that comes the elevated
risk of inflammation and fibrosis even
after accounting for standard metabolic
risk factors. Um there are also variants
that appear protective especially a loss
of function variant in a gene called
HSD17B13
which is associated with lower liver
enzymes and fibrosis risk and it may
actually partially offset the uh PNPA3
associated risk. There are other
variants as well. Again, we'll kind of
list them in the um show notes for
completeness, but I think the larger
point here is that there is an absolute
genetic predisposition and even some
protection that we see. Um and it I mean
I think any clinician can attest to
this, right? You've got that patient who
for whatever reason two people doing the
exact same things and they have
completely different liver health. Um,
it's also why ancestry can show up in
population level risk, though, you know,
we have to be careful not to overstate
it. So, the PMPA3 risk variant is much
more common in people with Hispanic
ancestry. So, that's why at the
population level, we know that Hispanics
are much more uh sensitive to and
therefore susceptible to uh masold and
mash. Um, and it's actually the exact
opposite in people of African ancestry.
So that likely cont contributes to what
we see clinically. But again, that
doesn't mean at the individual level.
That's always the case. So I don't want
someone who's listening to this who's
black to think, great, I can't get mas,
you know, away I go. And I don't want
someone who's Hispanic to listen to this
and say, "Oh, well, great. This is my
destiny." Um, it's just, again, it's
it's it's a predisposition, but it's
it's, you know, it's not destiny. So I
mean there are also now body composition
differences that standard labs and BMI
stuff can always miss. So for example um
many people who are of Asian ancestry
develop metabolic risk at lower and
normal BMIs in part again because
visceral atyposity can be higher at a
given body weight in a in a in a group
of people who otherwise don't
genetically accumulate much subcutaneous
fat. So again, this is why I think body
weight and BMI while at the population
level are useful tools at the individual
level offer nothing. I wouldn't be able
to tell you the BMI of one of my
patients, but I can tell you virtually
every one of their uh total body fat,
visceral fat, and other measurements
that are more nuanced. So that's that's
what really matters. The other major
baseline modifier uh is menopause. So
premenopausal women are relatively
protected. uh the net effect of estrogen
here appears to be restraining visceral
and epatic fat accumulation. Uh of
course after menopause that protection
starts to fade and it can do so quite
quickly and then fatty liver becomes
more common and can progress uh actually
more aggressively. So again, all of
these things, ancestry, family history,
genotype, um, all menopause status, all
of these things belong in the risk
assessment. Um, but again, none of them
replaces the core question, which is
what is the person's actual metabolic
phenotype. So I don't want to get too
hung up on knowing what increases or
decreases risk beyond, you know, what I
just said. I think what we really want
to focus on is how do you actually
measure it objectively in yourself
unambiguously? Peter, let's move into
that, which is how people figure out
kind of their liver health in a way. So,
I think if you ask most people, they
would assume that if they go get annual
blood work done and their liver enzymes
come back normal, everything is fine
with their liver. So, first and
foremost, would you say that is true?
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