00:02
Welcome!
In this talk,
we're going to be covering
Nonalcoholic Fatty Liver Disease.
00:07
What is this?
So NAFLD or Nonalcoholic
Fatty Liver Disease
is chronic liver pathology that's
associated specifically with obesity
and also with hepatic steatosis.
00:18
And it may or may not have
associated inflammation and fibrosis.
00:22
It's essentially got many
of the same mechanisms
and much of the same appearance
as alcohol associated
liver disease,
just without the alcohol.
00:33
The types of non alcoholic
fatty liver disease.
00:35
So you can have just non
alcoholic fatty liver,
this is just hepatic steatosis
and there's no inflammation.
00:42
You can also have non
alcoholic steatohepatitis,
easier to abbreviate that
as NASH, which is steatosis.
00:50
But there's lobular inflammation,
degenerating hepatocytes
and lots of accumulated,
a both acute and chronic
inflammatory cells.
01:00
The epidemiology.
01:03
This is now in the United States
the most common cause of
chronic liver disease,
it exceeds alcohol,
and it exceeds hepatitis
due to viral injury.
01:14
It affects up to 25% of adults
and it's increasing as the
obesity epidemic kind of expands,
no pun intended,
to the adult population
in many industrialized nations.
01:28
Patients are usually affected
in their 40s and 50s.
01:30
So this is after a period
of time with obesity.
01:33
It doesn't happen instantaneously
in their 20s and 30s
when they become fat.
01:38
But later on, after
a couple of decades
of persistent accumulation of
extra cholesterol and lipids.
01:48
It can also lead to cirrhosis.
01:50
So in the same way that alcoholic
liver disease can progress
through alcoholic
steatohepatitis
and then eventually to cirrhosis
so too can occur in non
alcoholic fatty liver disease
and the incidence of
fat of liver cancer
is up to 3% when
cirrhosis does develop.
02:10
Risk factors for this overall.
02:12
So metabolic syndrome and you
may recall the metabolic syndrome
involves insulin resistance,
central obesity with a
large abdominal girth,
hypercholesterolemia,
and hypertension.
02:27
Other associated risk factors
even if the patient doesn't
have insulin resistance, etc,
just central obesity puts
them at increased risk
for non alcoholic
fatty liver disease.
02:37
Type 2 diabetes,
probably as a marker
for obesity and
insulin resistance
is also a risk factor as is
hypertension and hypertriglyceridemia.
02:46
Other risk factors,
so rapid weight gain,
okay, that kind of makes sense.
02:51
You're just pouring
on the calories
and you have
increased fat content,
but also rapid weight loss
by mobilizing fat and
proteins from the periphery
and mobilizing and
sending them to the liver
may also give rise to non
alcoholic fatty liver disease.
03:09
Hypothyroidism by changing metabolic
rates may be a risk factor.
03:14
Certainly polycystic
ovarian syndrome
is also associated with,
although the
mechanisms overlapping
between obesity and
polycystic ovarian syndrome.
03:25
And then some of the
endocrine derangements
that lead to PCOD,
Polycystic Ovarian disease
are a little bit complex.
03:34
Some of the other
endocrinopathies.
03:36
So Cushing syndrome
with an elevated ACTH
leading to elevated glucocorticoids
and then medications.
03:43
Amiodarone is known to cause
non alcoholic fatty
liver disease,
glucocorticoids,
doxycycline and there
are a host of others.
03:52
The pathophysiology here.
03:54
Again, this is very similar
to what is happening
overall associated with alcohol
and the metabolism of alcohol
except in this case,
it is increased oxidative stress
due to the increased chronic
metabolism of free fatty acids.
04:11
In metabolizing
free fatty acids,
in the setting of obesity
and type two diabetes
and other things,
we are creating increased amounts
of reactive oxygen species,
and those in particular
drive an oxidative stress
that will in turn,
induce lymphocyte
and kupffer cells,
macrophages within the liver,
to increase their production
inflammatory mediators
that increased
triglyceride metabolism
also leads to lipid toxicity.
04:40
So as we're metabolizing a
whole bunch of triglycerides,
we may not efficiently get down
to two carbon acetate subunits,
but in fact, we may
have intermediates
that are also
potentially lipotoxic.
04:54
When that occurs, the
poor hepatocytes respond
by not metabolizing
lipid appropriately.
05:01
And they accumulate it.
05:02
So that's recognized the steatosis
are non alcoholic fatty liver,
and with recurrent injury,
or recurrent bouts of this
or just chronic obesity
and chronic steatosis.
05:15
You may eventually get
such degree of lipotoxicity
and activation of kupffer
cells and lymphocytes
that you now get
NASH, steatohepatitis,
and with prolonged NASH
that can then lead
into cirrhosis.
05:31
And as we've already seen,
cirrhosis over time may develop
into hepatocellular carcinoma.
05:36
So that's kind of the pathway.
05:38
So the progression from a
healthy liver to a liver,
the past cirrhosis or even
hepatocellular carcinoma
is as indicated here.
05:48
With the lipotoxicity, the
reactive oxygen species,
the accumulation of fat,
we can get steatosis,
that's completely reversible.
05:55
And if we lose weight,
if we reduce the oxygen toxicity
associated with
reactive oxygen species,
we're good to go.
06:04
With persistence steatosis,
we may activate lymphocytes
and macrophages.
06:10
So we did get a degree of
inflammation or steatohepatitis.
06:15
That's also
incredibly reversible
and we can get back to
even a healthy liver.
06:21
However, once we
progress to fibrosis,
through the activity,
through the activation
of stellate cells,
who are driven by
inflammatory mediators,
once we have that cirrhosis,
then that's in stage and
we can't ever revert.
06:38
And in that setting,
as we've already talked about,
there is an increased
risk for the development
of hepatocellular carcinoma.
06:46
How does the patient present?
So with early steatosis,
the patient is often
quite asymptomatic,
there may be subtle levels
of fatigue and malaise.
06:56
There may be a little bit of
right upper quadrant discomfort,
that's because as the
liver expands with fat,
it will stretch glistens capsule
and that will lead to some
sensation of discomfort.
07:08
There will be hepatomegaly,
you can formally
feel the liver edge
below the right costal margin,
indicating that the
liver is enlarged.
07:16
And with more
progressive disease,
we may see elements or
symptoms related to cirrhosis.
07:25
I would refer you back to other
talks within this Lecturio series
to see what cirrhosis
presents with.
07:33
How are we going to
make the diagnosis?
Liver biopsy is probably
the gold standard
but is not usually performed.
07:41
If the diagnosis is unclear,
if there might be other
etiologies for fatty liver disease
or for hepatitis
or even cirrhosis,
we may do that.
07:52
The biopsy will help
us to distinguish
whether we just have fatty liver
disease with accumulation of fat,
or whether we've progressed
on to hepatosis with NASH.
08:02
An ultrasound will often give
us some of that same information
and is non invasive,
and a very echogenic liver
indicates that there's
lots and lots of fat
that is reflecting
the ultrasound waves.
08:13
And on the image that
you're seeing here,
the normal renal parenchyma
is indicated on the
right hand side.
08:20
That darker color should be
what the liver looks like.
08:23
And here's a liver is
looking much wider,
indicating greater fat content.
08:28
Laboratory tests can be
somewhat confirmatory,
they're not going to be
absolutely diagnostic.
08:34
So you may see elevated
Aspartate Aminotransferase, AST,
or elevated Alanine
Aminotransferase or ALT,
but they may also be normal,
particularly if there
is no steatohepatitis.
08:48
There will certainly be elevated
triglycerides and cholesterol
but this is actually part and
parcel of the primary process.
08:54
These patients are obese.
08:56
So their serum triglycerides
and cholesterol
are usually elevated
just on that basis,
whether they have
liver disease or not.
09:04
We do want to rule out other
causes of chronic hepatitis.
09:08
So we want to make sure that
this isn't due to alcoholism.
09:11
And we do that with history
and some of the biomarkers
and I would refer
you to the talk
in this series about
alcoholic liver disease.
09:20
We want to make sure
it's not viral hepatitis
because we have some
therapies for that,
particularly viral hepatitis C.
09:26
Wilson's disease
or hemochromatosis
due to either copper or
iron overload respectively,
on autoimmune hepatitis,
so we want to rule those out.
09:35
This is just an
example of what things
would look like
histologically on biopsy.
09:39
On the left hand side
is mostly steatosis.
09:43
We have enlarged hepatocytes
with nuclei out to the periphery
and a massive expansion with
intracellular triglycerides.
09:52
It's basically a big bubble
of fat that is reversible.
09:56
On the right hand side,
we are seeing hepatocytes
with triglyceride accumulation,
but now we see a lot of
little blue cells in between.
10:06
That's the hepatitis.
10:07
So we have steatohepatitis.
10:10
And stage we will get cirrhosis.
10:12
And again, I refer you to those
talks on cirrhosis in this series.
10:18
How are we going to manage it?
So easier said than done,
tell your patient
to lose weight,
help them with
that, be supportive.
10:26
But it can be very difficult.
10:28
You want to control a
lot of the comorbidities.
10:31
So if diabetes is associated
with their metabolic syndrome,
that's leading to this,
we want to control
that with insulin,
or other agents that are
going to help them control
and give them good
glucose blood control.
10:45
We want to avoid
other toxicities,
we don't want to exacerbate
what is already going on
due to the lipotoxicity
and the reactive oxygen species.
10:53
So avoid alcohol,
avoid smoking,
avoid other things that
can injure the liver.
11:01
We want to make sure that
they're immunized and up to date
so that they don't
get hepatitis.
11:05
And if they do have hepatitis,
such as hepatitis C,
we want to be sure that we treat
that quickly and effectively.
11:12
For non alcoholic
fatty liver disease,
so just steatosis
and this steatohepatitis,
there is no specific
pharmacologic therapy,
we just do the things that are
at the top part of this slide.
11:26
And for end stage disease,
where the patient has
developed cirrhosis,
but is driven to lose weight
and otherwise maintain
good glycemic control, etc.
11:39
Then liver transplantation
can be considered.
11:42
With that, non alcoholic
fatty liver disease