Chronic Liver Injury

Front 1

What three things is chronic liver injury usually associated with? (think process, response to process, and final response of process). What is the liver's way of scarring? (term)

What is a common cause of chronic liver injury?

Back 1

Front 2

Chronic viral hepatitis usually causes a
predominantly _____ cell inflam-
matory infiltrate composed of macro-
phages, lymphocytes and _____ cells,
that preferentially involves _____ (what part of liver).

There is often some _____ inflammation
that tends to be focal, with dead or dying
hepatocytes, often surrounded by
_____.
The single layer of hepatocytes
immediately adjacent to the portal triad
is called the _____ plate, a concept
used in the description of hepatitis.

Back 2

Chronic viral hepatitis usually causes a
predominantly mononuclear cell inflam-
matory infiltrate composed of macro-
phages, lymphocytes and plasma cells,
that preferentially involves portal triads.

There is often some lobular inflammation
that tends to be focal, with dead or dying
hepatocytes, often surrounded by
lymphocytes.
The single layer of hepatocytes
immediately adjacent to the portal triad
is called the limiting plate, a concept
used in the description of hepatitis.

Front 3

Back 3

Front 4

Where is the localization of most of the inflammatory infiltrate?

Back 4

Front 5

Back 5

Front 6

In some cases of hepatitis B,
the cytoplasm of some hepatocytes
is packed full of _____ particles.
These hepatocytes often develop a
“_____” cytoplasmic
appearance.

The presence of virions in the
hepatocyte cytoplasm can be
demonstrated with immunostain
for _____.

Back 6

In some cases of hepatitis B,
the cytoplasm of some hepatocytes
is packed full of viral particles.
These hepatocytes often develop a
“ground glass” cytoplasmic
appearance.

The presence of virions in the
hepatocyte cytoplasm can be
demonstrated with immunostain
for hepatitis B viral antigens.

Front 7

Back 7

Front 8

In some cases of chronic hepatitis
the inflammation is not confined
to the _____, but extends
beyond them, destroying or
at least obscuring the hepatocytes
that form the limiting plate.

This is _____ hepatitis.

It has also been
called “___ ___.”

Back 8

In some cases of chronic hepatitis
the inflammation is not confined
to the portal triads, but extends
beyond them, destroying or
at least obscuring the hepatocytes
that form the limiting plate.

This is interface hepatitis.

It has also been
called “piecemeal necrosis.”

Front 9

What type of hepatitis (infection type)?

Back 9

Interface hepatitis effacing the limiting plate

Front 10

Can you tell where the limiting plate is?

Back 10

Front 11

It was thought for many years that
patients with _____ hepatitis
(“chronic active hepatitis”) had a
____ (better or worse) prognosis than those with
inflammatory infiltrates
confined to the portal triads
(“chronic persistent hepatitis”).

In fact, many people came to
regard chronic _____ hepatitis as
a specific disease entity.

Back 11

It was thought for many years that
patients with interface hepatitis
(“chronic active hepatitis”) had a
worse prognosis than those with
inflammatory infiltrates
confined to the portal triads
(“chronic persistent hepatitis”).

In fact, many people came to
regard chronic active hepatitis as
a specific disease entity.

Front 12

When quantitative blood testing for
viral ____ came along, this provided
a way to see the activity of chronic
viral hepatitis. For HCV, this showed
that __ to __ months after
infection, patients started having
fluctuations between periods of
minimal clinical activity (normal or
near normal liver enzyme levels)
and periods with clinical activity
(elevated liver enzymes).

Back 12

When quantitative blood testing for
viral RNA came along, this provided
a way to see the activity of chronic
viral hepatitis. For HCV, this showed
that two to four months after
infection, patients started having
fluctuations between periods of
minimal clinical activity (normal or
near normal liver enzyme levels)
and periods with clinical activity
(elevated liver enzymes).

Front 13

Interface depends on viral activity at time of biopsy.

Back 13

Front 14

Does the finding of interface hepatitis have any predictive value regarding the evolution of the disease?

What does it reflect?

Back 14

Front 15

Back 15

Front 16

With acute injury, mature
adult hepatocytes can
_____ the cell cycle
and undergo cell division
_____ the mass
and function of the liver,
even after loss of ____%
of the liver.
With chronic injury, the
repair response messes
up _____,
resulting in architectural
abnormalities that can
profoundly impair function

Back 16

Front 17

The key players in the hepatic
hepatic repair response are
the _____ cells (___ cells).

They differentiate into
_____ and secrete
collagen and other extra-
cellular matrix substances
into the _____.

Back 17

The key players in the hepatic
hepatic repair response are
the stellate cells (Ito cells).

They differentiate into
myofibroblasts and secrete
collagen and other extra-
cellular matrix substances
into the space of Disse.

Front 18

The initial deposition of fibrous
tissue takes place at the site of
predominant _____.

In chronic hepatitis
the deposition takes place
in the _____ region

and this is described as
fibrous portal expansion.

Back 18

The initial deposition of fibrous
tissue takes place at the site of
predominant injury.

In chronic hepatitis
the deposition takes place
in the periportal region

and this is described as
fibrous portal expansion.

Front 19

What type of expansion?

Back 19

Fibrous portal

(Trichrome stain)

Front 20

In cases where the chronic injury
is predominately in centrolobular
areas, as with chronic _____
liver disease, the fibrosis
develops around the ____ veins.

This is a frequent change in
chronic alcoholics

and this is described as
___ ___.

Back 20

In cases where the chronic injury
is predominately in centrolobular
areas, as with chronic alcoholic
liver disease, the fibrosis
develops around the central veins.

This is a frequent change in
chronic alcoholics

and this is described as
central sclerosis.

Front 21

What type of sclerosis?

Back 21

Central sclerosis

Front 22

With ongoing chronic injury, the
amount of _____ increases.

Eventually, the fibrosis in one part
of a lobule can connect with the
fibrosis in another part or with
the fibrosis in an adjacent lobule.

This is _____ fibrosis,
which can be portal-to-portal,
portal-to-central, etc.

Back 22

With ongoing chronic injury, the
amount of fibrosis increases.

Eventually, the fibrosis in one part
of a lobule can connect with the
fibrosis in another part or with
the fibrosis in an adjacent lobule.

This is bridging fibrosis,
which can be portal-to-portal,
portal-to-central, etc.

Front 23

What type of fibrosis?

Back 23

Bridging

Front 24

Timing of fibrosis (early or late)?

Back 24

Front 25

More advanced fibrosis

Back 25

Yep

Front 26

What type of fibrosis?

Back 26

Bridging fibrosis

Front 27

What does the collagen type in the space of Disse change to with chronic injury?

Back 27

Front 28

What is really the only thing that the stellate cells do normally?

With chronic injury, what activates stellate cells to make myofibroblasts => collagen?

Back 28

Front 29

Activated stellate cells produce _____ factors, chemokines and
cytokines, especially _____, stimulating their own proliferation
and _____ synthesis. (autocrine function?)

TNF is considered the major cytokine effector of liver injury
due to _____, although IL-1, IL-6 and IL-8 are also given
some credit. ________ and microbial
products are the main stimulants of cytokine production
in alcoholic liver injury. 30% of patients with alcoholic
liver disease also have _____ (double whammy).

Like fibrosis anywhere, in the liver, fibrosis is a _____ process.
There is a continuously shifting balance between matrix metallo-
proteases and their tissue _____, so that remodeling can
cause what is called “___ ___”.*

Back 29

Activated stellate cells produce growth factors, chemokines and
cytokines, especially TGF-beta, stimulating their own proliferation
and collagen synthesis.*

TNF is considered the major cytokine effector of liver injury
due to alcohol, although IL-1, IL-6 and IL-8 are also given
some credit. Reactive oxygen species and microbial
products are the main stimulants of cytokine production
in alcoholic liver injury. 30% of patients with alcoholic
liver disease also have hepatitis C (double whammy).

Front 30

Eventually, the fibrosing repair
process creates nodules of
______ hepatocytes
surrounded by ______ tissue
with loss of the normal lobular
architecture and hence loss of
the normal vascular and biliary
hookups, so _____ cannot get
in properly and blood and bile
cannot get out properly.

Back 30

Eventually, the fibrosing repair
process creates nodules of
regenerating hepatocytes
surrounded by fibrous tissue
with loss of the normal lobular
architecture and hence loss of
the normal vascular and biliary
hookups, so blood cannot get
in properly and blood and bile
cannot get out properly.

Front 31

What is this end-stage of liver disease?

Back 31

Cirrhosis

Front 32

What can you see here?

Back 32

The regenerative nodules of cirrhosis.

Front 33

What is the nodule surrounded by?

Back 33

Regenerative nodule surrounded by fibrous tissue

Front 34

You can think of regenerative
nodules as like little cities
where the roads, sewers and
electricity are all misarranged
in a haphazard manner, and
the cities are surrounded by a
war zone of chronic inflam-
mation and scorched earth.

Back 34

You can think of regenerative
nodules as like little cities
where the roads, sewers and
electricity are all misarranged
in a haphazard manner, and
the cities are surrounded by a
war zone of chronic inflam-
mation and scorched earth.

Front 35

What are the manifestations of cirrhosis?

Alk phos?

AST and ALT?

Bilirubin?

Serum albumin

Prothrombin time?

What is the most important manifestation of cirrhosis?

Back 35

Front 36

Back 36

Front 37

What are these lesions?

Back 37

Spider angiomas (spider telangiectasias, spide nevi, or just spiders)

Front 38

Spider angiomas:

They are vascular lesions consisting of a central arteriole surrounded by many smaller vessels, most frequent on the trunk, ___ and arms.
The central arteriole can be seen
_____ when compressed with a
glass slide.
They are not totally specific
for _____.
The pathogenesis is not
clear, but their number and size
correlate with the _____ of cirrhosis.

Back 38

They are vascular lesions consisting of a central arteriole surrounded by many smaller vessels, most frequent on the trunk, face and arms.
The central arteriole can be seen
pulsating when compressed with a
glass slide.
They are not totally specific
for cirrhosis.
The pathogenesis is not
clear, but their number and size
correlate with the severity of cirrhosis.

Front 39

What two things is Dupuytren contracture (palmar fibromatosis) associated with?

Back 39

Diabetes mellitus and cirrhosis (particularly alcoholic)

Front 40

What are the four most common causes of cirrhosis?

What percent of alcoholics get cirrhosis?

Back 40

Front 41

Draw the pathways of hepatitis C

Back 41

Front 42

Non-Alcoholic Steatohepatitis (NASH)
subset of non-alcoholic fatty liver
disease (NAFLD)

Liver disease that looks like _____
liver disease but is caused by _____.

Associated with elevated levels of
inflammatory cytokines (TNF, IL-6
and _____) consistent with the idea
that obesity is an inflammatory
disease.

Back 42

Non-Alcoholic Steatohepatitis (NASH)
subset of non-alcoholic fatty liver
disease (NAFLD)

Liver disease that looks like alcoholic
liver disease but is caused by obesity

Associated with elevated levels of
inflammatory cytokines (TNF, IL-6
and MCP-I) consistent with the idea
that obesity is an inflammatory
disease.