00:01
Welcome.
00:02
With this talk we're
going to discuss
a really important
entity, cirrhosis.
00:07
So as indicated right
here on the slide,
cirrhosis is end
stage liver damage
with architectural and
functional distortion.
00:14
That is due to liver
scarring or fibrosis.
00:17
I will say the liver has a
remarkable regenerative capacity,
you can cut out 90% of the liver
if there's no
underlying disease,
all of that liver
will regenerate.
00:29
However,
the regenerative capacity of
the liver is not infinite.
00:33
And you can exceed that
with recurrent injury,
as we'll talk about shortly.
00:38
The epidemiology of cirrhosis.
00:41
There are a whole bunch
of different causes,
as we'll see in the next
section of this talk.
00:46
But a significant number
of people in a population,
30 per 100,000,
almost 5 million people in
the United States for example,
are affected with cirrhosis,
which is end stage disease,
you cannot recover
from cirrhosis,
all you can do is
treat what you have.
01:03
Men, probably
because of behavioral
things that they
do like drinking
are more commonly
affected than women.
01:11
It is the eighth leading cause
of death in the United States,
so approximately 50,000 deaths
per year are due to cirrhosis.
01:18
So this is not a trivial disease,
it's not an uncommon disease,
it is not a non lethal disease,
this is a bad disease.
01:26
The three most common causes are
chronic infectious hepatitis,
so that's going to be
hepatitis B and hepatitis C.
01:34
As we increasingly vaccinate
the world's population,
the incidence of hepatitis B
associated cirrhosis
is going down.
01:42
Hepatitis C
in the industrialized nations
of the world is also going down
because we have very good
therapy for hepatitis C.
01:51
But in developing
parts of the world,
Hepatitis C is
still a major cause.
01:56
Alcoholic liver disease,
another very common cause,
and then increasingly with
the obesification,
increasing obesity
of our population,
non alcoholic fatty liver
disease associated with obesity
is becoming probably
the leading cause
is certainly in the industrialized
parts of the world for cirrhosis.
02:20
Elevated iron,
chronic elevated iron,
autoimmune hepatitis,
primary autoimmune disease
involving the biliary tree,
Wilson's disease, which is
a copper metabolic defect,
insufficiency, or
abnormal mutations
in Alpha-1 antitrypsin, etc.
02:41
These are all other causes and there
the list goes on and on and on.
02:44
But remember the top three:
hepatitis, alcohol and
fatty liver disease.
02:49
The pathophysiology
of cirrhosis.
02:51
What is being shown here
is the normal architecture
lining the sinusoids
of our liver.
02:59
The hepatocytes are lined
up in a nice cords,
and then they are
facing onto a sinusoid
which contains the blood supply.
03:09
There is a space in between
called the space of disse,
and in there live
stellate cells.
03:15
The stellate cells are
going to be the precursors
to the hepatocytes,
they're going to be also important
for regulating blood flow.
03:22
They're going to be important
for antigen presentation
and a whole variety of things.
03:26
The stellate cells are
usually a minor player
in the normal hepatic organization
when there isn't much damage.
03:34
And also in the space of disse
but also in the sinusoids
are Kupffer cells.
03:40
These are the liver
version of macrophages.
03:44
So in addition to the endothelial
cells lining the sinusoids,
those are going to be
our four major players
within the hepatic parenchyma.
03:53
When we injure the hepatocytes,
a number of things happen.
03:57
So we have a variety of
inflammatory mediators
that are elicited.
04:02
Macrophages, the Kupffer
cells become activated
and release
inflammatory mediators
such as IL-1, IL-12, IL-18.
04:11
They will drive in concert,
the activation of
the stellate cells
because we've
damaged hepatocytes,
we need to regenerate
hepatocytes
and we need to rev up the
stellate cells to do that.
04:26
While the stellate
cells are also not just
going to help us
regenerate hepatocytes
and be the precursors but
they're also going to initiate
increased extracellular
matrix deposition,
that's part of the body's
way of dealing with injury
is we lay down some scar.
04:42
And with recurrent bouts
of injury to hepatocytes,
you can have so much
stellate cell activation
and so much fibrosis that
you end up with cirrhosis,
and we'll see how that
impacts then liver function
and flow of blood
through the liver.
05:00
Here's our normal
appearing liver overall,
we have the blood vessels,
the sinusoids, lined
by the hepatocytes
and then keeping in
mind the architecture
were in the space of disse sub
stellate cells and macrophages.
05:14
With cirrhosis liver
becomes smaller
and becomes irregularly scarred.
05:20
So you will have zones of
relatively normal hepatocytes
within a ball within a sphere,
trying to regenerate trying
to make the whole new liver
but they will be encased
by bridging fibrosis,
scar that runs from portal
triad to portal triad
and from central
vein to portal triad
and from central
vein to central vein.
05:41
In that way,
we have a diffusely, scarred,
withered liver,
that is the cirrhotic liver.
05:49
So early on,
because liver has such
remarkable regenerative capacity
and we're over engineered
we have much more
liver than we need.
05:58
Small amounts of cirrhosis,
small amounts of scarring
will initially be
able to be compensated
for by the excess liver capacity
and patients will
be asymptomatic.
06:08
However, with time with
increasing amounts of scarring,
then the hepatic function
is going to be compromised.
06:15
And the compromise leading
to the compensation
is predictable based
on what the liver does.
06:20
So for example,
the liver is responsible
for metabolizing blood
that comes out of the GI tract
metabolizing the
contents of the blood
coming out of the GI tract.
06:29
So there is a portal blood flow
from the small and large bowel
that goes through the liver.
06:35
With progressive cirrhosis,
that blood flow is
severely compromised,
it can't flow through
all that scar.
06:43
And as a result, you will
have a mechanical increase
in pressure
and that will lead to ascites,
so accumulation of fluid
within the peritoneal cavity.
06:54
Also there are
portosystemic anastomoses,
so of the portal circulation is
also through venous anastomosis
connected with the
systemic venous return.
07:07
As we obstruct the portal flow,
that blood is shunted into
the systemic venous system
and will get varices,
will get dilated veins in
a variety of locations,
some of which may lead
to significant pathology.
07:21
And we'll cover that
in a subsequent slide.
07:23
The spleen also drains
through the portal system.
07:26
And if the splenic
circulation is compromised,
then you get this big
dilated boggy spleen,
so called hypersplenism that's
associated with platelet retention.
07:39
So you may have a
functional thrombocytopenia.
07:43
The liver is a major
synthetic factory.
07:44
It's making a whole
variety of proteins
as we'll talk about.
07:48
The key amongst those
is going to be albumin.
07:50
And with hypoalbuminemia
due to synthetic defects
in the cirrhotic liver,
you will have systemic
reduction in oncotic pressure.
07:59
And as a result of that,
you will have edema everywhere.
08:02
That's also going to exacerbate
the ascites that's going on
well, liver
metabolizes, bilirubin.
08:08
It metabolizes heme to
bilirubin and beyond.
08:12
And when the liver is not
doing its job in that respect,
the patient will be jaundiced.
08:16
There will be coagulopathy,
liver is the major source for
circulating coagulation factors.
08:22
And when the liver
is dysfunctional,
as in cirrhosis,
you will tend to have bleeding.
08:27
And then with elevated ammonia
and other metabolites that
would normally be activated
and diminished by going
through the liver.
08:37
You will have encephalopathy,
so the patient will have,
will be a little bit crazy.
08:42
So let's talk first about
those portosystemic shunts
and the three main ones
that would have you remember
or think about are
esophageal varices.
08:51
So the portal esophageal
systemic vasculature
with occlusion of the portal
circulation or compromise,
then you get dilation of
the esophageal varices.
09:04
These are very dilated veins
around the distal esophagus
and they just have a
very minimum epithelium
over the surface they're
very easily eroded into
and you can have
fatal exsanguination
from esophageal varices.
09:19
Something called
the Caput medusae,
literally the head of the Medusa
will occur with portal
umbilical anastomoses,
and then you get this very
dilated venous vasculature
around the umbilicus
and it's been likened
to all of the serpents
coming off the head of Medusa.
09:40
And then you can have external
and internal hemorrhoids
that are also part of the
portosystemic anastomosis
and so you may have
rectal bleeding
associated with very prominent
varices in that location.
09:53
The other secondary effects.
09:54
So, the liver besides
making coagulation factors,
and besides making albumin,
makes transport proteins.
09:59
makes transport proteins.
10:01
So things that
will transport fat,
or sex hormones or thyroxine and
retinol are also affected,
so that you may not have normal
amounts of those proteins
and abnormal circulation
to the things
that would normally
bind to them.
10:18
There's abnormal hepatic
glucose metabolism,
you're not able to make
and store glycogen.
10:24
So the patient may actually have
a functional glucose deficiency
because there's
not a sufficient,
sufficient glycogen
stores during fasting.
10:37
On the other hand,
the abnormal glucose metabolism
may also lead to
insulin resistance
and even exacerbation
of a diabetic state.
10:46
And then you can have impaired
metabolism of estrogen
and the precursors to a
number of estrogenic agents
and so you are not metabolizing
those and breaking them down.
10:56
And patients who have cirrhosis
may present with
hyperestrogenism.
11:00
We'll talk about
that in a moment.