Transcript Cellular Basis of Disease CH057

Biology of Disease CH0576
Irreversible Cell Injury & Death
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Irreversible Cell Injury
• Cells can adapt to worsening environmental
conditions and persistent injuring factors.
• However, there is a limit to the extent of
the adaptations which are possible
• If the acute stress is > capacity to adapt
then the resulting changes in both
structure and function will inevitably lead
to cell death
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Irreversible Cell Injury
• The theoretical ‘point of no return’ is
passed.
• The injury becomes irreversible
• The cell will inevitably proceed to cell
death.
• Cell death is almost always accompanied
by a series of morphological changes
which can be recognised in the light
microscope
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Irreversible Injury & Cell
Death
• These recognisable changes are usually
referred to as Coagulative Necrosis.
• We are unable to recognise when a cell
is irreversibly injured until it is dead,
and the feature of necrosis are
apparent.
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Morphology of Coagulative
Necrosis
• Coagulative necrosis involves changes in
the cytoplasm, nucleus and membrane.
• When stained with H & E, the cell
cytoplasm is much more eosinophilic than
normal.
• Initially the nucleus of a necrotic cell
shows clumping of the chromatin,
followed by a redistribution around the
periphery of the nuclear membrane.
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Nuclear Changes in CN.
• The nucleus becomes
smaller and stains
more basophilic as
the chromatin within
it continues to clump
• This is referred to
as PYKNOSIS.
• Basophilia indicating
the end of DNA
transcription
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Normal v Pyknotic Cell
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Nuclear changes in CN.
• Necrotic process
continues, with the
action of nucleases,
causing the nucleus
to fragment.
• The fragments
become scattered
throughout the
cytoplasm.
– KARYORRHEXIS
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Karyorrhexis
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Nuclear Changes in CN.
• The pyknotic or
fragmented nucleus
may be actively
extruded from the
cell or it may undergo
further and complete
dissolution, a process
known as:– KARYOLYSIS
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Normal v Necrotic Cell
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Pathogenesis of Necrosis
• The necrotic cell is left as a mass of
partly denatured protein, still having
the same rough cellular outline as the
surrounding cells.
• The cytoplasm is deeply eosinophilic.
• Coagulative necrosis is the same no
matter what the cause of cell death:
virus, radiation or ischaemia, for
example.
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Pathogenesis of Necrosis
• A characteristic of living cells is that
they maintain large differences
between their internal and external
environments.
• These differences are maintained by
the plasma membrane.
• With cell death, these characteristic
differences in ionic concentrations
are dissipated or lost.
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Pathogenesis of Necrosis
• One of the most significant gradients
maintained across a living cell
membrane is that of Ca2+.
• The concentration of Ca2+ in the
external fluid is in the millimolar range.
• Concentration within the cell is around
10,000 times lower.
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Pathogenesis of Necrosis
• This gradient is actively maintained.
• Cell death is accompanied by an
accumulation of Ca2+ within the cell.
• Calcium ions have a wide range of
biological functions and their
accumulation may account for many of
the features of coagulative necrosis.
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Pathogenesis of Necrosis
• The sequence of events leading to CN
may be:
– Irreversible cell injury and death
– loss of membrane’s ability to maintain
the calcium gradients.
– Influx and accumulation of Ca2+
– Morphologic appearance of Coagulative
Necrosis.
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Morphology of Necrosis
• Several different
patterns of necrosis
are described.
• These largely reflect
various macroscopic
appearances of the
dead tissues.
• These include:-
•
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•
•
Coagulative
Liquefactive
Fat necrosis
Gummatous
Haemorrhagic
Fibrinoid
Caseous
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Coagulative Necrosis
• This describes dead tissue which
appears pale and firm - giving the
appearance almost of cooked meat!
• Even though the cells are dead, much
of the cellular outline and tissue
architecture can still be recognised
• Tissues with relatively low levels of
lysosomes exhibit this form.
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Coagulative Necrosis
• The most common cause of CN is
ischaemia due to the occlusion of the
arterial blood supply to a tissue.
• In some cases of CN, the proteins and
enzymes which are released from dead
cells can be used as a diagnostic
indicator or marker of specific disease.
• Their presence in blood indicating
specific cellular damage.
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Coagulative Necrosis
• In order for a particular protein or
enzyme assay to be of use as a
diagnostic aid, the substance must
satisfy two major criteria:
– It must have a restricted cellular
distribution
– It must be normally present in blood in only
low concentrations, making an elevation in
concentration significant.
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Diagnostic Assays
• A number of fairly routine diagnostic
clinical chemistry assays for the
following, rely on this process:–
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Myocardial infarct
Liver damage
Striated muscle
Exocrine pancreas
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Coagulative Necrosis
• In coagulative necrosis the dead cells
remain in situ long enough to be
recognised and identified.
• In most cases the necrotic debris is
eventually removed as a consequence
of the inflammatory reaction.
• In cases where the are large areas of
coagulative necrosis the necrotic
tissue may remain in place for years.
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Coagulative Necrosis
• Examples would include occlusion of a
coronary artery and the resultant
infarction of a large area of the
myocardium.
• The central area of necrosis may be
inaccessible to the inflammatory
reaction and the necrotic debris
remains in situ.
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Coagulative Necrosis
• This explains how, on post mortem
studies, previous infarcts are evident
as fibrous scars.
• In most cases regeneration and repair
mechanisms are responsible for the
active removal of necrotic tissue.
• Unfortunately, the heart is composed
of a permanent tissue - cardiac muscle.
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Coagulative Necrosis
• Coagulative necrosis
in area of the kidney
• Ischaemia has led to
an infarction
• Tissue architecture
is maintained despite
all of the cells in the
area being dead
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Normal v Coagulative
Necrosis
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Liquefactive Necrosis
• This pattern of necrosis describes tissue
which appears semi-liquid.
• The appearance is due to the dissolution
of the necrotic tissue under the influence
of powerful hydrolytic enzymes.
• Two main instances:
– Necrosis in the brain
– Necrosis due to bacterial infection.
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Liquefactive Necrosis
• Liquefactive necrosis in a
cerebral infarct
• No residual tissue
architecture is retained.
• The area of the brain is
transformed into a semiliquid mass of protein
with numerous
macrophages
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Fat Necrosis
• This affects adipose tissue and is most
commonly the result of either:
– Physical trauma to adipose tissue e.g.
breast
– Pancreatitis.
• Unique feature in this form of necrosis
is the presence of triglycerides
released from damaged fat cells.
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Fat Necrosis - Pancreas
• The process begins with the inappropriate
release of digestive enzymes.
• These are normally restricted to:
– pancreatic acinar cells
– pancreatic ducts
– small intestine.
• They are released inappropriately from
damaged pancreatic acinar cells.
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Fat Necrosis
• The enzymes gain access to the
extracellular compartment.
• They commence to digest the tissue of
the pancreas itself as well as the
surrounding tissue, especially adipose
cells.
• Phospholipases and proteases released
attack the plasma membranes of the fat
cells. Stored triglycerides are released.
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Fat Necrosis
• The pancreatic enzymes then digest
the triglycerides in to free fatty
acids.
• These precipitate in the form of
‘calcium soaps’.
• These accumulate as amorphous,
basophilic deposits at the edge of
irregular islands of necrotic adipose
cells.
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Fat Necrosis
• On macrosciopic examination (left) fat necrosis appears as
chalky-white areas, embedded in otherwise normal tissue.
Histologically these areas of fat necrosis are composed of
large areas of necrotic fat, usually around 5 mm diameter,
with surrounding areas of reactive inflammation (right)
Necrotic Fat
Foci of fat necrosis
Inflammation
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Caseous Necrosis
• This form of necrosis is highly
characteristic of Tuberculosis.
• The lesions associated with TB are
tuberculous granulomas or tubercles.
• In the centre of the granulomas the
chronic inflammatory cells (mononuclear
cells) which are mediating the response
against the infection are killed along with
the tissue cells.
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Caseous Necrosis
• In caseous necrosis the necrotic cells don’t
retain their cellular outlines nor are they
completely lysed as in liquefactive necrosis.
• The dead cells persist as amorphous,
coarsely granular eosinophilic debris.
• Macroscopically the debris appears greyish
white and crumbly.
• It has an appearance resembling crumbly
cheese - hence ‘caseous’ necrosis.
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Caseous Necrosis
• This form of necrosis is not seen at the
centre of granulomas caused by other
agents.
• This highly characteristic pattern of
necrosis is thought to be due to the toxic
effects of the unusual cell wall of the
mycobacterium, which contains complex
waxes, known as peptidoglycolipids.
• Viable mycobacteria are present within the
necrotic debris.
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Caseous Necrosis Tuberculosis
AM
GC
CN
L
A tuberculous granuloma with central caseous necrosis
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Gummatous Necrosis
• This describes dead
tissue that is firm and
rubbery.
• None of the original
tissue architecture
can be seen
histologically.
• The dead cells form an
amorphous mass.
• Seen in syphillis due to
spirochaete T.pallidum
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N
Haemorrhagic Necrosis
• This describes necrotic tissues which are
engorged or suffused with extravascular red
blood cells.
• This pattern of necrosis is seen particularly
when cell death is due to a blockage of the
venous drainage from the tissue e.g. torsion
of the testis.
• Congestion of the tissue by blood with a
result of failure in arterial perfusion 
ischaemia.
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Haemorrhagic Necrosis Testicular torsion
• Torsion of the testis, due
to torsion or twisting of
the spermatic cord.
• Venous return is blocked
• Blood cannot escape the
tissue which becomes
engorged.
• Arterial perfusion fails
as tissue is full of venous
blood  ischaemia.
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Fibrinoid Necrosis Vasculitis
• Term used to describe
the appearance of
arteries in cases of
vasculitis or in severe
hypertension.
• Plasma proteins, and in
particular fibrin,
become deposited in
the damaged necrotic
vessel wall producing
marked eosionophilia
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FN