- So I'm gonna speak to you
today a little bit about
a few abstracts coming
from the liver meeting
about non-alcoholic fatty liver
and alcoholic liver diseases.
Dr. Lock said alcoholic liver diseases,
my area of research interest
and what I work in mostly,
but we tend to group
these two things together.
Obviously the causative
factor of fat in the liver
in these two conditions
is quite different,
but pathophysiologically
they look the same
under the microscope.
And importantly for all of us to realize
is that these are behaviorally
mediated liver diseases.
Obesity with non-alcoholic fatty liver,
in addition to diabetes and
some of the metabolic syndrome
and then obviously alcohol use
and sever alcohol use disorders
are the behaviors that mediate this.
So important for us to understand
because as Dr. Fontana pointed out,
we are kind of getting rid of Hepatitis C.
I'm not gonna say we've got it
completely cured, or completely treated,
but all of the projections indicate that
in the coming years we're not
going to see as much of this
because the direct acting antivirals
are so effective at getting rid of it.
And so what is rising to take its place?
It's these two diseases.
It's non-alcoholic fatty liver
and alcoholic liver disease.
And as we'll talk about, I
tried to select some abstracts
from a very large group of
abstracts, over 500 abstracts
in these two areas that
might have the most
clinical relevance for us
right now in clinical practice
and ways to think about how
we care for these patients,
how we diagnose and what
implications that has for us
as we take care of them.
So starting off with non-alcoholic
fatty liver or NAFLD.
As we all know, NAFLD
is really a spectrum.
It's beginning with just fat in the liver
and then progressing on to
those who have inflammation
or non-alcoholic steatohepatitis
and in some of those patients,
a percentage of them will
go on to develop cirrhosis.
This was an article
from Dr. Allen at Mayo,
looking at the cardiovascular risk,
as it relates to gender in
patients who have NAFLD.
What we all know and
are quite familiar with
is that in general, prior to menopause,
women are generally
protected compared to men.
They tend to have lower risk
of hard cardiovascular outcomes,
like heart attacks,
stroke, AFib, et cetera.
But what Dr. Allen's abstract looked at
was whether or not NAFLD
influences this risk separately.
What we also know is in general,
in epidemiologic studies
and studies of cardiovascular outcomes,
NAFLD gives you an excess
risk above and beyond
diabetes, hypertension,
hyperlipidemia, smoking,
those types of things,
not only for hard cardiac outcomes,
but also for some of the
intermediate measures that we have
of cardiac outcomes like
coronary artery calcium,
cardiac intima-media thickness
or carotid intima-media thickness.
In all ways, it seems to be a separate
and independent risk factor.
And what Dr. Allen wanted to do
was explore sex related differences
in that cardiovascular
risk in NAFLD to see if
women versus men had differential risk
and if it tended to
give you an excess risk.
So this was a long term study.
Again, retrospective from the Rochester
Epidemiologic Project
looking back at NAFLD patients
in the Mayo Clinic area in Olmsted County.
And they looked at incident
cardiovascular disease events
after the NAFLD diagnosis.
So your time point was the NAFLD diagnosis
and their heart outcomes were
as they typically are in these studies.
Angina, myocardial
infarction, heart failure,
AFIB and stroke.
They matched them four to
one with cases and controls.
And they matched them in all the things
you would want to match on
for cardiovascular risks.
Their age, gender and then
cardiovascular risk factors,
as well as any baseline
known cardiovascular disease.
And they had just over 4,000 subjects,
with the median age of about
52, and about half were women.
So they had a good, well
characterized cohort.
And what they found is that
the risk of these incident
cardiovascular events
all total was about 1,600
over the course of this study.
And I can tell you, having
done one of these studies
in the Framingham Health System,
it can be a little bit
difficult to get that number
of incident cardiovascular outcomes.
You really have to follow
people for a long time
to be able to get that level
of incident cardiovascular disease.
They had enough and enough
power to be able to tell this.
And what they found here was that in men,
men with NAFLD, did not
appear to increase the risk
of incident cardiovascular events,
but for women it did.
And it increased it, and not greatly,
but definitely statistically
significantly up
in all events to about 1.21 here
and then when they looked
at individual events,
angina, MI and heart
failure, you can see here,
that they had some slightly
differential effects,
but all significant.
For AFIB and stroke,
that actually wasn't
significant for gender.
And they also found that these events
tended to occur more
frequently and earlier
compared to the general population.
So what you're seeing here is,
this doesn't project as
well as I would like, but,
the solid lines are the people with NAFLD
and the dashed lines are their controls.
And the controls, you can see,
it's the progression
that we typically see.
It's related to age,
it progresses in almost a
linear fashion across age
and men greater than women as you age.
But with NAFLD, it tended
to here be earlier.
So you had more
cardiovascular events earlier
and women were greater than men here.
That crossed over as they got older.
So men, again, had more
cardiovascular events with NAFLD
compared to women with NAFLD,
but both of these were higher
than any of the controls,
up until you hit about the age of 65,
when those lines began to converge.
So really the takeaway is here,
again, this is retrospective,
so it does have retrospective
study limitations,
but there do appear to be
an attenuation of those cardiovascular
protective affects of gender.
And what this means for us clinically
is to be aware of this
and to really focus on
the cardiovascular risk
protection in people,
maybe even at a younger age
than we might normally think about it.
Checking lipid profiles
and being aggressive about
diet and exercise,
controlling blood pressure,
diabetes and hyperlipidemia to try
until we get effective
treatments for NAFLD and NASH
to help with the cardiovascular
risks of these patients.
So the next abstract that was presented
in one of the parallel sessions was about
okay, so how do we find these people?
There's multiple different
ways of diagnosing fatty liver
and obviously we wanna not just
diagnose fatty liver on its own,
but we want to try to diagnose
the more advanced forms as well.
So NASH and obviously cirrhosis.
We want to find these people.
And one of the ways that has
been looked at to do this
is with Fibroscan.
This has been used quite
extensively throughout
and this study looked
at how feasible was it
to do this in a primary care clinic?
So in people who are just walking in
and don't have pre-existing liver disease
and you're looking at whether
or not they have NAFLD.
Can you do this and what
are some of the issues
with screening in a primary
care clinic for this?
They looked three months prospectively.
All patients who came in
to a primary care clinic in California,
so this was a population
in Coronado, California,
they consented just over 800 patients
and everybody underwent
Fibroscan in this clinic.
Nobody had liver disease.
They excluded people who had pre-existing
or known liver disease,
HEP B, HEP C, et cetera,
and they used what most
frequently is called Fibroscanner
or Vibration Controlled
Transient Elastography.
This is a method of determining,
essentially, liver stiffness.
You're looking for how stiff is the liver
as a shear wave is passed
through the liver tissue.
And there's a calculation
based on Hook's Law.
we can dig that out of our physics classes
from undergraduate.
I knew that that would
come in handy some day.
I didn't know it at the
time, but now it has.
There's a buncha math that gets done here.
And they calculate how stiff is the liver.
And in the proper context,
acknowledging some of the
limitations of the study,
of the use of this,
which we'll talk about,
you can measure how stiff that liver is,
how much fibrosis or scar
tissue is in the liver.
There also is now a
relatively newer technology
within the last couple of years
called Controlled Attenuation Parameter,
which again, looks at the attenuation
of the tissue under ultrasound.
The takeaway from that is it
gives you an estimate of fat.
You can look at both fat
and fibrosis in the liver with Fibroscan.
In general, the multiple
studies that have been done
on this technology show that
it's actually pretty good
for distinguishing the extremes.
You can distinguish, you
can say cirrhosis or not.
You can say a lot of
fat or very little fat.
When you get into the
gradations of fibrosis,
we generally measure
it f zero, no fibrosis
or f four is cirrhosis,
when you can kind of get
into those gradations
of f one, f two, it
doesn't do quite as well.
So we use this a lot of times
to say do ya have cirrhosis
or do ya not have cirrhosis?
And that seems to be where
it functions the best.
Some caveats to it, are that
if you're going to use it
you want to make sure that
there's not gonna be anything
going on with the patient
that's going to falsely
elevate the stiffness
or is going to have too much tissue
or too much distance in between the probe,
which sits right here between the ribs
and that liver.
The more distance you
have, between the probe tip
which sits right at
the skin and the liver,
the greater the degree of error
that you're going to have with that study.
People who have ascites.
We don't use it in
people who have ascites.
If you have heart failure,
and you have passive
congestion in the liver,
it's going to look
stiffer when it may not be
just because of the backflow.
If your ALT is too elevated, over 100,
that can indicate more
inflammation in the liver
and inflammation, as you might imagine,
might give you a greater
degree of stiffness,
not truly reflective of scar tissue.
We want people to be fasting,
'cause if you eat, it's
gonna increase blood flow.
Again, you might have more stiffness
that's not necessarily
reflective of scar tissue.
Very severe steatosis
actually can be a confounder.
So having the CAP method
with this can be helpful.
And then obesity, BMIs 30 or
above, can be confounding,
again 'cause we have this distance
in between the liver tissue,
so there is an XL probe
that comes along with this, is
being used increasingly now.
The technology of which
is a design to help us
be able to more accurately
sense true stiffness
across a greater distance in between
if you have more
subcutaneous tissue there.
What they found in their study was
that about 2/3 of the patients
were female, they're fairly
young, only about 45.
Mostly Hispanic and they
had quite a few people
who had BMIs over 30,
but they didn't really comment extensively
about if they used the M or the Xl probe,
so have that in your mind.
About 13% had diabetes and
13% had hyperlipidemia.
And they found that
about a third of people
had significant fatty liver.
They're kind of above 290 on their CAP
and then for the fibrosis score,
they also found that they
had about 4% of people
had a score over 15, which
is very clearly cirrhosis
in this population.
About 12% had a score from
anywhere from seven to 15,
which is consistent with advanced fibrosis
or kind of the f three to f four scale.
The takeaways from this were
really that it's feasible
to do this in a PCP clinic
and you might actually be
able to identify some people
who have more advanced
fibrosis and cirrhosis
and then get them into
appropriate screening
with HCC screening protocols et cetera.
It may help your patients be
more motivated to lose weight.
Sometimes when patients
have a knowledge of
negative consequence of something,
so you have liver disease, you
have more advanced fibrosis,
those types of things can be
motivational for some people,
to help them lose weight
and with NAFLD and NASH,
weight loss is bar none the best way
to help this get better.
There have been studies
that have been presented
a couple of years ago where
10% of the body weight
or greater in patients lost and kept off
in paired biopsy studies led to resolution
of fatty liver and NASH in as
many as 80% of those patients.
Generally if they're in
the cirrhosis category
that's not going to go away,
but it's pretty powerful
to be able to tell your patients
that if they could lose 10%
of their body weight or more
and keep it off, they
might actually see healing
of their fatty liver and some
of their fibrosis over time
as they keep that off.
They didn't really do alcohol
use questioning in this
and that's actually quite important
because alcohol use can,
as you might imagine,
cause inflammation and
falsely elevate that score.
If people are using alcohol,
you may want to not do a
Fibroscan right away on them
but give them some time
in abstinence first
before you go back and Fibroscan them
to see how much scar
tissue is in the liver.
This is just a nice graphic
from our own Dr. Tapper,
who's gonna be speaking later
on the things to know about Fibroscan
and how to use it.
The first, most important
thing, is that you need to know
what that underlying disease
is because your cutoffs
for what is and isn't high
grade fibrosis or cirrhosis
change based on your disease process.
So as you can see here,
some of these kilopascal scores
for cirrhosis or fibrosis,
they're different depending upon
what the validation studies have shown
in these various different liver diseases.
Knowing that allows you
to interpret that result.
And again, you wanna obviously
pair this with your history
and physical pair it with your labs.
If, for whatever reason, you
feel you can't do a Fibroscan,
then you wanna be considering other ways
to potentially assess
for advanced fibrosis,
both with blood testing,
some of the cirrhologic scoring systems.
We offer an MR Elastography
at the University of Michigan now
that can be helpful for obese patients
for whom Fibroscan is
not going to be accurate.
Functions in a similar
way with elastography,
meaning vibration through the liver,
but it's not a probe
that's gonna be impacted
by that distance in between
your liver and your skin.
So that's another option if
you're dealing with people
whose BMI is too great
and you feel it's not
going to be accurate.
Moving on to alcoholic liver disease.
The first abstract that we'll talk about
is actually one that
came out of our center
looking at the burden
of alcoholic cirrhosis
in the United States.
As many of you are aware of,
we really have a huge problem
with alcohol use disorders
and there was recently a large article
in the JAMA Psychiatry that
looked at a very big study
of the epidemiology of
alcohol use disorders.
It's called the NESARC and
it's a large survey study,
very, very good survey
study that the NIAAA,
the Alcohol Research arm of the NIH
runs about every 10 years or so.
And what they found was that the rate
of alcohol use disorders in the U.S.,
the alcohol use disorder
being the more severe form
of alcohol use problems had gone up by 50%
over the course of the past 10 years.
And in women, it was 80%.
We're seeing more alcohol use problems,
but because of the nature of the American
Health Care System, and our datasets,
it's hard to really estimate
how big of a problem
is alcoholic cirrhosis in the U.S.
Anecdotally, we see this a
lot and I'm sure you do too.
Certainly it's the second leading
cause for liver transplant
and that's going up, not
down, across the nation.
There've been studies about that as well.
And so our aim with this
was to try to estimate
the health care burden overall
in privately insured
alcoholic cirrhosis patients.
Why privately insured?
The Center for Medicare and Medicaid,
where many of these patients
are probably located
in terms of insurance,
had eliminated substance
abuse related claims
from their dataset because
of concerns about privacy,
so that makes that dataset
tough to use, obviously,
if you're going to be studying
a very substance abuse related disorder.
We looked at a large
dataset called MarketScan,
which is tens of millions of patients
with employer sponsored insurance
across the nation.
And it comes with a weighting strategy
that allows you to make estimates to
50% of the U.S. population,
so 150 million people roughly,
who have insurance bought and
paid for by their employer.
It's a big dataset, it's
very well characterized
and it gets us this larger
sense of what's happening
with these patients across the nation.
We looked at this from 2009 to 2015.
We defined it by ICD nine codes,
which is how most administrative
claims datasets are done,
where you look at the ICD nine code
and define it in that sense.
At baseline, these patients'
ages were roughly similar.
We had about 66,000 patients
who had alcohol related cirrhosis
and about 100,000 that had
non alcohol related cirrhosis.
The women were about a third
of the alcoholic cirrhosis patients
as compared to about 50% of those patients
who did not have it.
They had long term coverage,
so we had a lot of data
in terms of their coverage
and Elixhauser is a co-morbidity score
to detect how sick someone
is in another sense,
how many other co-morbidities they have.
And alcoholic cirrhosis patients
tended to be slightly
sicker than non alcoholic.
When we looked at the prevalence
across this time frame,
so looking at how big of a problem is this
and is it growing, what we found was that
it actually is growing
by about just over 40%
across this relatively short time frame
and that alcoholic
cirrhosis patients, again,
made up just over a third
of that total burden.
When we did some subgroup analysis to see
was this going up in men versus women,
it was slightly higher in
terms of rate for women,
but we found that in the young population,
people under the age of 45,
it had actually tripled
across that time frame,
even though the numbers were quite small.
Anecdotally it kind of matched
some of what we were
seeing in our own hospital,
where very, very young patients
are coming in in their early 30s,
sometimes even their late 20s,
with advanced alcohol
related liver disease.
Alcoholic hepatitis and
alcoholic cirrhosis,
even at that young age.
We looked at event rates,
meaning how many decompensating events
did these patients have?
Trying to see, are these
patients sicker at presentation?
And effectively, the
takeaway from this slide
is that they are.
When they show up with
their first diagnosis,
they are more likely to have ascites,
hepatic encephalopathy, a
variceal bleed and kidney injury
and when we project this out
to two years, that holds true.
They tend to have more
decompensating events
and to just be sicker
when they're showing up
for the first time and that
stays that way over time.
Obviously the data doesn't tell us this,
but it makes one wonder, are
we missing these patients
or are we missing these patients?
Was there an opportunity for
us to help them stop drinking,
which might help them
not decompensate as much.
They're admitted more
frequently certainly,
for all reasons and also for cirrhosis,
alcohol and readmissions as well.
So not only are they sicker,
but they're using up more
or being admitted and readmitted more.
Just overall sicker patients.
And in terms of the cost, when
we look at per person costs,
the highlighted line is for
one alcoholic cirrhosis patient
compared to a non
alcoholic cirrhosis patient
and it's almost double.
Single patient to single
patient, almost double.
What you see here in
the subsequent lines is
an isolation of ascites by itself,
so comparing any person with ascites,
to any person with cirrhosis without it.
And what this tells us
is that as expected,
these complications, regardless
of where they're occurring,
are costing more in these patients.
The cost of alcoholic cirrhosis patients
is really coming from
their decompensation.
It's coming from the fact
that they have more ascites,
they have more bleeding,
they have more encephalopathy in HCC.
And overall, they cost about
over half of the total cost
to the health care system
in these privately insured patients.
It's about $9.5 billion in 2015
and just over half of that was coming from
our alcoholic cirrhosis patients.
The takeaway of this
was that we really have
a defined now population,
even in the privately insured cohort,
where we might expect
them to be healthier.
Again, remember, this is
in people who are employed,
or have employer sponsored insurance
or their dependents.
This isn't in Medicaid, Medicare patients
or in the VA system where
often these patients
might move into those systems
once they become too sick to work.
We expect that this is actually
the floor of the problem
and that if we were look
and see a Messer, Vijay date
it would actually get worse.
We're gonna see more
costs and more illness
with a consequence of this.
Once of the other areas of debate
that comes along with advanced
alcoholic liver disease
is should we or should we
not be transplanting patients
who have alcoholic hepatitis?
Alcoholic hepatitis often co-occurs
on top alcoholic cirrhosis.
This is a very severe
inflammation of the liver
that comes about from
heavy, heavy alcohol use
and then results in a
systemic inflammation
and extremely high mortality.
As high as 50% at three months
in patients who have alcoholic hepatitis.
And as you might imagine,
it's prompted people to ask
should we be transplanting these patients?
And by way of background,
one of the seminal papers
that was published about
five, six years ago
in the New England Journal
came out of the French study
that looked at transplanting
highly selected patients
with alcoholic hepatitis
and looking at how they did.
They did actually fairly well.
When you look at the survival curves here,
looking out one to two
years, about 3/4 were alive
compared to those alc hep patients
who didn't get transplanted,
who actually died.
Of course as you might imagine,
this is not without controversy.
Not every center does this.
We at Michigan do not transplant
acute alcoholic hepatitis,
but other centers are beginning to look at
larger scale studies of how people do.
What this initial study looked at was
how do these patients do
compared to status 1A patients.
Your status 1A patients
are your acute liver failure patients
who come in suddenly very sick,
they get listed, they go
to the head of the class
right away because they are so sick
and they get allocated organs first
before anyone else on the
list because they are so sick
and their mortality is so high.
So they compared these alc hep
with status 1A patients
to see how they did.
And this group looked
at five years of UNOS
or United Network for Organ Sharing data,
which collects data on
all liver transplants
that occur in the United States.
They compared waitlisted alc hep patients
with status 1A patients
and they divided those into effectively
Tylenol and non-Tylenol
related acute liver failure
because Tylenol is the number one cause
of acute liver failure in the U.S.
And they looked at 90
day waitlist mortality,
a 90 day transplant rate
and then one and five year
post transplant survival,
which are really our
standard outcome metrics
for transplant.
And what they found was that here,
if you look at the acute alc hep,
the takeaways are that
their transplant rate
was comparable to the non DILI group,
but greater than those for Tylenol.
This may be a consequence of
potentially Tylenol patients
who were listed, then
recovering, it's hard to know
'cause they didn't present that data.
But their one and three year
post liver transplant survival
were actually quite
good and in this study,
better than those who were transplanted
for ALF of whichever cause.
The takeaway from that
is that the outcomes
actually look like they
may be just as good.
In this study, which is called
the Accelerate-AH Study,
they provided us with a
little more granular detail
about a rather large group of patients
who had been transplanted
across multiple centers
with acute alcoholic hepatitis.
Again, the aim was roughly the same,
to determine how do these people do
when we transplant them.
Should we continue doing that or not?
They looked at 12 transplant centers
across eight UNOS regions.
Again, transplant is by region,
by geographic region across the U.S.,
so they had a good coverage of the U.S.
And they looked at a time
frame of just over 10 years.
Anybody who'd had alcohol use
within six months of transplant
and met the clinical definition
of alcoholic hepatitis
was included in their cohort.
Note that they also had
to have no other prior
liver disease diagnosis
and no prior history of
alcoholic hepatitis episodes.
This gets at the choice of these patients.
What you see in these studies
and in transplant centers
that are transplanting alcoholic hepatitis
is it is a very select group
of alcoholic hepatitis patients
that meet the criteria
that they've assessed
and typically if they've had
any other alcohol related liver disease
in the past and drank over it,
people typically won't
transplant those individuals.
If they had that before, they
did not transplant them here
and they looked at survival.
They also, importantly,
really importantly for these studies,
they looked at alcohol use post transplant
and they did a nice job of mirroring
the addiction medicine literature
and looking at slips,
where you go back to some alcohol use,
but you return to abstinence quickly,
versus relapse, where you
go back to heavy alcohol use
and there is not a return
to abstinence quickly.
One of the challenges with this literature
is that frequently we
conflate those things.
And in the hepatology literature
we put it all together.
Any alcohol use is considered the same,
but that isn't true and
it isn't evidence based
with the addiction medicine literature.
They did a nice job in
making it evidence based
with our addiction medicine colleagues
and distinguishing
between slip and relapse.
They had 147 recipients with alc hep.
147 over 12 centers over 10 years.
That gives you an idea of how rare it is
for an alc hep patient
to qualify for this.
Most were male and white,
2/3 were privately insured,
some of which may relate
to some of the requirements
for substance use that are attached
to other forms of insurance.
The median pre-transplant
abstinence was 55 days.
Much less from the typical six months
that you've heard about
that, we often hear about.
Over half had received steroids
before they were transplanted
and we'll talk about
this a little bit later
in the subsequent talk, but Prednisolone,
as many of you know, is used often
in acute alc hep in certain scenarios
to see if people improve and if they do,
they go on to have potentially
a month's worth of Prednisolone
to try to help them recover from alc hep.
If they don't, these were often the people
who got in to this study
to be transplanted.
Their median meld was really
high at transplant, so 39.
The meld caps out at 40.
These patients were very, very sick
and they followed them for
just about a year and a half.
What they found was that
there were approximately
about 25% used alcohol
afterward in some form.
At one year, about a
quarter would've used it,
but that increased at three years
to about a third of the
patients who had used it.
And the median time to that first drink
was about 160 days after
they left the hospital.
Factors that were predictive of this
was a lack of self admission
at the hospitalization
predictive of drinking.
If they're not saying yep,
yep, yep, this is alcohol
and not having that level of insight
that was predictive of
going back to drinking,
but the survival at one and
three years was 94% and 84%,
even with that level of slip
versus slip and relapse.
I should also distinguish here,
the slips versus the relapses again.
Relapses were slightly
less common than slips.
If we miss a slip, it
can turn into a relapse,
so it's important for us to
catch those types of things
in our patients who have
this kind of an issue.
Predictors of death then afterward
were if you had more
than 10 drinks per day
prior to coming in to the hospital,
so the heavy, heavy drinkers,
more than 10 drinks.
And if you had any alcohol
use at all post transplant,
that was slip or relapse, that
was also highly predictive
and this was really one of the only things
that was predictive on multi-vari analysis
of post transplant death.
They had 18 deaths overall.
Nine of them actually occurred
within three months of transplant
and most of those patients,
eight out of the nine,
had received steroids and
five of them died of sepsis.
This gets at the infectious
complications of alc hep
and of the steroids that we sometimes use
as being an issue in that
early post transplant period.
When you get out to one
year after transplant,
it's alcohol, seven out
of nine of the patients
who died after a year was
because of alcohol use
and because they had
gone back to drinking.
The take home from this, for me,
is that it's possible to do this,
and it is possible to do it
with relatively good outcomes long term.
However, you do have to have very robust
alcohol cessation
efforts after transplant.
You have to follow people very carefully
and be very selective about doing this.
Again, we do not transplant these patients
at University of Michigan currently,
but centers that are choosing to do so
really need to be aware of these issues
of post transplant alcohol use
and that it isn't insignificant.
It's one of the biggest reasons why
these patients die long term.
It really points out the need for us
to be able to better manage
that alcohol use disorder in the long run
and come up with some better
management strategies,
medications, and behaviorally
to help these patients
stay off alcohol.
Thank you.
