CELL INJURY

CELL INJURY
Dr IRA BHARADWAJ
MCI TEACHER ID: PAT 2300569
KUHS FACULTY ID: M21512

PA2.1
DEMONSTRATE KNOWLEDGE OF THE
CAUSES,MECHANISMS, TYPES and EFFECTS OF
CELL INJURY & THEIR CLINICAL SIGNIFICANCE
PA2.2
DESCRIBE THE ETIOLOGY OF CELL INJURY
DISTINGUISH BETWEEN REVERSIBLE & IRREVERSIBLE CELL
INJURY,MECHANISM OF CELL INJURY, MORPHOLOGY OF CELL
INJURY

TEXTBOOK REFRENCES
• ROBBINS BASIC PATHOLOGY
• HARSH MOHAN TEXTBOOK OF PATHOLOGY
• OTHER STANDARD REFRENCES

SLO
• DEFINTION OF CELL INJURY
• TYPES OF CELL INJURY
• ETIOLOGY [CAUSES] OF CELL INJURY

CELL INJURY
DEFINITION
CELL INJURY IS DEFINED AS
• A type of change which the cell undergoes due to external as
well as internal causes in it’s environment

CELL INJURY
DEFINITION
CELL INJURY OCCURS WHEN:
• Adaptive responses fail
• Injurious agent is inherently damaging
• Cell is already compromised due to some pre existing disease

TYPES OF CELL INJURY
There are two types of cell injury:
• Reversible cell injury
• Irreversible cell injury

REVERSIBLE CELL INJURY
Reversible cell injury is characterized by:
•Cell is damaged but viable [living]
•Withdrawal of cause is followed by return to normal
•However,continued injury leads to irreversible stage
•Two types of morphological changes are seen -
cellular swelling & fatty change

IRREVERSIBLE CELL INJURY
Irreversible cell injury is characterized by:
• Cell in nonviable [dead]
• Withdrawal of cause will not revive the cell
• It usually follows reversible cell injury
• Injurious agent can directly cause irreversible cell injury if it
is inherently very damaging
• Two types of morphological changes are seen necrosis &
apoptosis

Schematic representation of a normal cell and the
changes in reversible and irreversible cell injury

ETIOLOGY OF CELL INJURY
• HYPOXIA
• CHEMICAL AGENTS
• INFECTIOUS AGENTS
• NUTRITIONAL AGENTS
• PHYSICAL AGENTS
• GENETIC FACTORS
• IMMUNOLOGICAL
• AGING

HYPOXIA is decreased oxygen supply to cell, it may be due to
various causes like:
• Ischemia – decreased blood supply
• Anemia – decreased oxygen carrying capacity of blood
• Decreased oxygenation of blood eg pneumonia, high
altitude, CO poisoning
Hypoxia is usually the ultimate pathway of most cases of cell
injury

CHEMICAL AGENTS of various types, like:
• Poisons
• Toxins
• Social agents eg alcohol, tobacco
• Normal substances (water, salt, hormones) in abnormal
amount
• Normal substances (blood) in abnormal location (outside
blood vessel)

• INFECTIOUS AGENTS like bacteria, virus, fungus and many
more are one the commonest causes of cell injury
• NUTRITIONAL AGENTS – both over & under nutrition is
injurious to the cells
• PHYSICAL AGENTS – trauma due to heat, cold, mechanical
and other factors

• GENETIC FACTORS which may be inherited or acquired
• IMMUNOLOGICAL FACTORS like decrease in immunity,
autoimmunity, or excessive and inappropriate immune
response [hypersensitivity] may also damage the cell
• AGING: cumulative effect of various adaptations and
subclinical changes in the cell over a long period of time

SLO
PATHOGENESIS OF CELL INJURY [ PART 1]:
• GENERAL FEATURES
• ROLE OF INJURIOUS AGENT
• ROLE OF CELL
• ROLE OF VITAL CELLULAR METABOLIC FUNCTIONS
• ROLE OF MITOCHONDRIA
• DECREASE ATP PRODUCTION
• INCREASED ROS FORMATION

PATHOGENESIS OF CELL INJURY
GENERAL FEATURES
EXTENT OF INJURY DEPENDS ON
• Type of injurious agent, its duration & severity
• Type of cell, its adaptability, genetic makeup, presence of any pre
existing dysfunction
• One or more essential cellular components is affected leading to
biochemical & functional changes which injure the cell

ROLE OF INJURIOUS AGENT
TYPE OF INJURIOUS AGENT, ITS DURATION & SEVERITY Eg,
HEAT
• Type – dry heat, hot water, hot oil & other types of heat
• Duration – time factor, exposed for 1 sec or 1 hour
• Severity – temperature of hot object eg 50/75/100 degrees

ROLE OF CELL
TYPE OF CELL, ITS ADAPTABILITY, GENETIC MAKEUP, PRESENCE
OF PRE EXISTING CELLULAR DYSFUNCTION Eg oxygen
deficiency due to anemia
• Normal cardiac muscle can tolerate hypoxia for 20-30 mins
only, this duration is decreased in anemia
• Striated muscle can tolerate hypoxia for 2-3 hrs without
irreversible cell injury

ROLE OF VITAL BIOCHEMICAL PATHWAYS
ONE OR MORE ESSENTIAL CELLULAR COMPONENTS IS AFFECTED
LEADING TO BIOCHEMICAL CHANGES, FOLLOWED BY
FUNCTIONAL CHANGES:
• Damage to mitochondria
• Disturbance in calcium metabolism
• Damage to cellular membranes
• Damage to DNA & proteins

MITOCHONDRIAL DAMAGE & DYSFUNCTION
Mitochondria are the power house of the cell. They are
sensitive to:
•Hypoxia, toxins & radiation, leading to reversible cell
injury & type of cell death known as necrosis
•Decreased survival signals, damage to DNA &
proteins, resulting in type of cell death known as
apoptosis

HYPOXIA, TOXINS, RADIATION & OTHER CAUSES LEAD
TO:
•Decreased ATP (adenosine triphosphate) production
•Increased ROS (reactive oxygen species) formation
Leading Reversible & irreversible [necrosis] cell injury

DEPLETION OF ATP
• Hypoxia leads to decreased oxygen in the mitochondria
• This leads to decreased oxidative phosphorylation of ADP &
decrease in formation of ATP molecules
• In absence of oxygen , other pathway for generating ATP is
by using glucose, derived from circulation or stored as
glycogen eg, liver; hence hepatocytes can tolerate hypoxia
better than other cells like neurons

DEPLETION OF ATP
ATP is required for several functions in the cell, like
• Membrane transport, eg, sodium pump, calcium pump
• All synthetic functions like protein synthesis, lipogenesis
• Degradative processes like deacylation- reacylation reactions
necessary for phospholipid turnover

DEPLETION OF ATP: defective membrane transport
Dysfunction of ATP dependent Na pump in cell membrane,
leads to:
• Decreased efflux of Na causing sodium retention in the cell
• Increased efflux of potassium causing loss of cellular K
• This causes gain in cellular solute & water in the cell leading
to swelling of cellular organelles like ER & also, eventually
swelling of cell [reversible cell injury]
Similarly dysfunction of ca pump leads to influx of Calcium
• Calcium causes cell damage by various mechanisms [to be
discussed later]

DEPLETION OF ATP: defective cellular metabolism
• ATP decrease is also associated with decreased cellular
metabolic functions
• The most important cellular metabolism is protein synthesis
• There is decreased protein synthesis due to detachment of
ribosomes from the swollen endoplasmic reticulum

DEPLETION OF ATP: activation of compensatory
mechanisms
The cell tries to compensate for decrease in ATP by initiating
anaerobic glycolysis, this leads to:
• Decrease in cell glycogen &
• Increase in lactic acid, which causes
• Decreased pH in the cell, which leads to
• Decreased enzymatic activity [decrease in cellular
metabolism] &
• Clumping of chromatin in extreme cases [irreversible cell
injury]

INCREASED ROS
DEFINITON –ROS are oxygen derived free radicals
• Free radicals are chemicals with single unpaired electron in
outer orbital
• They are extremely unstable & react readily with organic &
inorganic chemicals
• In the cell they react with nucleic acids, proteins & lipids to
cause injury

INCREASED ROS
ROS – reactive oxygen species are oxygen derived free radicals
formed in cells due to normal redox reactions & in
inflammation (for killing microbes)
They are increased when mitochondria are damaged due to
chemicals, radiation, ischemia-reperfusion, aging & other
factors

INCREASED ROS: formation
ROS ARE FORMED IN ALL CELLS
• During redox reactions, when oxygen is converted to water,
very small amounts of short lived superoxide is formed
• This superoxide is converted to hydrogen peroxide by
superoxide dismutase (SOD)
• In presence of metals like Fe2+,hydrogen peroxide is
converted to hydroxyl radical (OH) by Fenton reaction

INCREASED ROS: formation
ROS FORMATION IN PHAGOCYTIC LEUKOCYTES
• In phagolysosomes superoxide & hydrogen peroxide are
formed by process of oxidative / respiratory burst
• These may be converted to hypochlorite(HOCl) by
myeloperoxidase [MPO].
• Nitric oxide (NO) which is also formed in cells, can react
with superoxide to form peroxynitrites (ONOO)

INCREASED ROS: degradation
ROS are unstable & decay spontaneous
• Superoxide dismutase [SOD] converts superoxide [O2*] to
hydrogen peroxide
• Glutathione (GSH) converts hydroxyl radical to hydrogen
peroxide
• Catalase converts hydrogen peroxide to water
• Antioxidants (vit A,C,E,B carotene) block the formation of
free radicals or/& destroys them.

INCREASED ROS: role in normal metabolism
ROS have important role in cellular metabolism:
•They function as chemical signals in all cells
•In leukocytic cells they inactivate the microbes &
eliminate them

INCREASED ROS: role in cell injury
CELL INJURY OCCURS WHEN FORMATION OF ROS
EXCEEDS DEGRADATION
Excess ROS lead to:
• Lipid peroxidation of membranes & malfunction of
organellar & cellular membranes
• Protein degradation with loss of important enzymatic
activity & abnormal folding
• DNA damage due breakage & mutations

SLO
PATHOGENESIS OF CELL INJURY [ PART 2]:
• REVIEW OF PART 1
• DISTURBANCE OF CALCIUM METABOLISM
• DAMAGE TO CELLULAR MEMBRANES
• DAMAGE TO DNA & PROTEINS
• CHANGE FORM REVERSIBLE TO IRREVERSIBLE CELL INJURY
• CELL INJURY DUE TO HYPOXIA [ISCHEMIA]
• CELL INJURY DUE TO CHEMICALS

REVIEW
ONE OR MORE ESSENTIAL CELLULAR COMPONENTS IS
AFFECTED LEADING TO BIOCHEMICAL CHANGES,
FOLLOWED BY FUNCTIONAL CHANGES:
•Damage to mitochondria
•Disturbance in calcium metabolism
•Damage to cellular membranes
•Damage to DNA & proteins

PATHOGENESIS OF CELL INJURY: REVIEW
Mitochondrial dysfunction leads to decreased ATP
(adenosine triphosphate) production
Decrease in ATP effects:
•Membrane transport, eg, sodium pump, calcium
pump
•All synthetic functions like protein synthesis,
lipogenesis
•Degradative processes like deacylation- reacylation
reactions necessary for phospholipid turnover

PATHOGENESIS OF CELL INJURY: REVIEW
Mitochondrial dysfunction leads to increased ROS
(reactive oxygen species) formation
Excess ROS lead to:
•Lipid peroxidation of membranes & malfunction of
organellar & cellular membranes
•Protein degradation with abnormal folding and loss
of important enzymatic activity
• DNA damage due breakage & mutations

CALCIUM METABOLISM: increase in calcium levels
INCREASED INTRA CELLULAR CALCIUM OCCURS DUE TO:
• Failure of ATP dependent Calcium pump, leading to
increased Calcium in the cytoplasm
• Release of Calcium from damaged mitochondria into the
cytoplasm
• Release of calcium from the damaged endoplasmic reticulum
in the cytoplasm

CALCIUM METABOLISM: activation of cellular enzymes
CALCIUM ACTIVATES VARIOUS ENZYMES LIKE:
• Phospholipase, which breakdown phospholipids in cellular
membranes leading to membrane damage
• Proteases which breakdown proteins in membranes,
cytoskeleton, and other cellular structures, causing extensive
cellular damage
• Endonuclease which cause breakdown of nuclear proteins
• ATPase which breakdown ATP, further exacerbating their
deficiency

DAMAGE TO CELLULAR MEMBRANES: mechanism
CELLULAR MEMBRANE DAMAGE OCCURS DUE TO:
•Increased phospholipid breakdown due to Calcium
activated enzymes & ROS
•Decreased protein synthesis due to decrease in
cellular ATP
•Cytoskeletal damage due to excessive activation of
enzymes by Calcium

• Lipid breakdown products (unesterified free fatty acids,
lysophospholipids, acyl carnitine) cause further increase of
membrane damage
• MEMBRANE DAMAGE LEADS TO INCREASED PERMEABILITY
OF CELLULAR & ORGANELLAR MEMBRANES
• Leading to leakage of organellar and cellular contents
outside the organelle as well as the cell respectively

DIRECT DAMAGE TO CELLULAR MEMBRANES IS
CAUSED BY VARIOUS FACTORS, INCLUDING:
•Microbial toxins
•Lytic agents,
•Physical & Chemical agents

DAMAGE TO CELLULAR MEMBRANES: effects
•Plasma membrane – loss of osmotic balance, cellular
contents leak out
•Mitochondria – decrease ATP production & increase
in ROS production
•Lysosomal membranes - activation of degradative
enzymes- proteases , etc
•ER – decrease protein synthesis

DAMAGE TO DNA & PROTEINS: mechanism
• Decrease in ATP contributes by decreasing, both, protein
synthesis & cellular pH [due to compensatory anerobic
glycolysis]
• Increase ROS can directly react with all types of proteins and
damage them
• Excess calcium activates various enzymes like protease,
endonuclease which degrade proteins in cell & nucleus
• Damage to nuclear membrane leads to loss of nuclear
integrity

DAMAGE TO DNA & PROTEINS: effects
• Mild DNA damage may be repaired & cell return to normal.
• DNA damage if severe causes cell death
• Persistence of DNA damage (mutation) may cause cancer.
• PROTEIN damage or misfolding also leads to cell injury &
death [apoptosis is more frequent as compared to necrosis]

WHEN REVERSIBLE INJURY BECOMES IRREVERSIBLE?

REVERSIBLE TO IRREVERSIBLE CELL INJURY:
ROLE OF VITAL CELLULAR METABOLIC FUNCTIONS
The biochemical changes which lead to irreversible cell injury are:
• Cessation of ATP production
• Lysis of cell membranes
• Absence of vital proteins
• Failure of vital metabolic functions

HYPOXIC CELL INJURY
INITIAL HYPOXIA CAUSES DECREASE IN ATP WHICH LEADS TO:
• Na & Ca pump dysfunction
• Decrease in cellular glycogen &
• Decrease in protein synthesis
• Characterized by morphological changes of reversible cell
injury known as cellular swelling, fatty change
• Correction of hypoxia leads to reversal of changes & return
to normal

HYPOXIC CELL INJURY
PERSISTENT HYPOXIA LEADS TO
• Increase in ROS [reactive oxygen species]
• Influx of more Ca &
• Cell membrane damage
• Characterized by morphological changes of cell death knows
as necrosis
• Correction of hypoxia does not have any effect

HYPOXIC REPERFUSION CELL INJURY
WHEN SOME CRITICAL METABOLIC FUNCTION IS DERANGED,
REPERFUSION OF TISSUES & INCREASE IN OXYGENATION CAUSES
FURTHER CELL INJURY BY
• Increasing Oxygen in cells leads to further increase in Reactive Oxygen
Species
• Increase in vascularity of tissues leads to more inflammation, which
causes further stasis if blood flow, and contributes by increasing ROS
• OVERALL MARKED INCREASE IN ROS LEADS TO NECROSIS DESPITE
REPERFUSION

CHEMICAL INJURY
• Some chemicals can act directly by combining with some
critical molecular component or cellular organelle.
• They are ka directly acting - maximum damage occurs to
cells that absorb, concentrate, metabolize or excrete the
chemical
For example:
• mercuric chloride poisoning,
• Cyanide poisoning
• Antineoplastic chemotherapeutic agents

CHEMICAL INJURY
• Most other chemicals are not biologically active but must be
converted to reactive toxic metabolites, which then act on
target cells.
• They are ka indirectly acting – maximum damage occurs to
cells which metabolize the chemical to its active compound
and cells which absorb & excrete the toxic metabolite
Example:
• carbon tetrachloride is an indirectly acting chemical which is
converted to carbon trichloride in liver and hence causes
maximum damage to liver

CHEMICAL INJURY
• Chemicals induce cell injury by one of two general
mechanisms:
• ATP inhibition
• Cell membrane damage
• Extent of damage depends on concentration of chemical in
the cell, genetics of the cell & presence of some pre-existing
condition
• Effects of CCl4 are depicted in the next slide, low levels cause
reversible cell injury [fatty change], higher levels lead to
necrosis

SLO
ETIO PATHOGENESIS WITH SPECIFIC EXAMPLES AND CLINICAL
SIGNIFICANCE OF:
• REVERSIBLE CELL INJURY – CELLULAR SWELLING KIDNEY
• REVERSIBLE CELL INJURY – FATTY CHANGE LIVER
• IRREVERSIBLE CELL INJURY – NECROSIS - INTRODUCTION
• COAGULATIVE NECROSIS eg, MYOCARDIUM
• LIQUIFACTIVE NECROSIS
• CASEOUS NECROSIS
• FAT NECROSIS IN ACUTE PANCREATITIS
• FIBRINOID NECROSIS IN IMMUNOLOGICAL LESIONS

CELLULAR SWELLING KIDNEY
ETIOPATHOGENESIS
Tubular epithelial cells are frequently exposed to & sensitive
to hypoxia as well as toxins, because of following reasons:
HYPOXIA
• Tubular blood supply is by efferent arterioles leaving the
glomerulus, therefore it is already low in oxygen content
• Further there is no anastomosis of vessels in tubules
TOXINS
• Many toxins are excreted via the kidneys, this exposes the
tubular epithelial cells to high luminal levels of toxins
• Tubular cells also reabsorb the toxins leading to increase in
intracellular levels

ETIOPATHOGENESIS
FOLLOWING FACTORS LEAD TO REVERSIBLE CELL INJURY:
• Decrease in ATP &
• Dysfunction of sodium pump & associated changes which
leads to absorption of water into the cell & it’s swelling
IN ADDITION
• Decreased reabsorption of Na in proximal tubules results in
• Increased Na in distal tubules which is associated with
preglomerular vasoconstriction & causes
• Further decrease in blood supply to glomeruli & tubules

CLINICAL SIGNIFICANCE
• Swelling of tubular cells is associated with narrowing of
tubular lumen & increased luminal pressure
• Due to decrease in ATP & increase in luminal pressure there
is dysfunction of these cells, resulting in some fluid &
electrolyte imbalance

• If the etiological agent is withdrawn eg, hypoxia is corrected,
regenerative changes of tubular epithelial cells begin & there
is complete recovery of structure & function
• However if the offending agent continues to effect the
tubular cells there is Irreversible cell injury [acute tubular
necrosis] which is associated with considerable morbidity &
mortality

FATTY CHANGE(DEGENERATION) / STEATOSIS
ETIOPATHOGENESIS
It is abnormal accumulation of triglycerides in parenchymal
cells, most frequently seen in the liver due to:
• Increase in fatty load associated with diet, malnutrition
[obesity] & Diabetes Mellitus
• Hepatocyte injury due to alcohol, malnutrition [Protein
Energy Malnutrition], hypoxia & toxins
• Fatty change should be differentiated from fatty infiltration
which is increased size of fat cells between parenchymal cells

FATTY CHANGE LIVER
ETIOPATHOGENESIS
• Increased fatty acids reaching the hepatocyte via blood lead
to increased formation of triglycerides in the cell
• If these triglycerides are not secreted out of the cell due to
deficiency of apoprotein or factors limiting secretion of
lipoproteins, they accumulate in the cell
• In the event of hepatocyte injury, the cellular metabolism is
deranged and fatty acids do not combine with acetate & are
not metabolized further
• Hence they accumulate in the cell

FATTY CHANGE LIVER
ETIOPATHOGENESIS

FATTY CHANGE LIVER
• In the early stage fatty change is asymptomatic, as liver has
large reserve capacity
• However there is some derangement of liver function, which
is reflected in abnormal LFT
• All changes are reversible with withdrawal of offending
etiology
• Continued exposure to injurious agents lead to
steatohepatitis [fat associated inflammation], cirrhosis [cell
death & repair by fibrosis] & rarely carcinoma

NECROSIS
INTRODUCTION
Definition of necrosis
SUM OF MORPHOLOGICAL CHANGES OCCURING
AFTER CELL DEATH due to damage of cellular
membranes & leakage of cell contents leading to
response known as inflammation

NECROSIS
INTRODUCTION
Sequence of changes
• FIRST BIOCHEMICAL CHANGES
• NEXT ULTRA STRUCTURAL CHANGES SEEN BY ELECTRON MICROSCOPE
• FOLLOWED BY CHANGES SEEN BY LIGHT MICROSCOPE
• LASTLY GROSS CHANGES

TYPES OF NECROSIS
(BASED ON LIGHT MICROSCOPIC HISTOLOGY)
• COAGULATIVE NECROSIS
• LIQUIFACTIVE NECROSIS
• CASEOUS NECROSIS
• FAT NECROSIS
• FIBRINOID NECROSIS
• GANGRENE

COAGULATIVE NECROSIS eg; MYOCARDIUM
ETIOPATHOGENESIS
ETIOLOGY
• Ischemia causes coagulative necrosis in all tissues except brain, where
it produces liquefactive necrosis
PATHOGENESIS
• Ischemia causes hypoxia and cardiac tissue has poor tolerance for
hypoxia due to its genetics & metabolism, this results in
• Decrease in ATP and cellular metabolism, leading to denaturation of
proteins & enzymes
• Preserving outline of cellular structure without any function, till
inflammatory cells remove the dead cells & repair takes place

COAGULATIVE NECROSIS eg; MYOCARDIUM
• Hypoxia in early stages causes reversible cell injury which
presents as pain known as angina pectoris
• If this is not corrected soon [10 mins], it results in irreversible
cell injury [coagulative necrosis]
• Necrosis of myocardial tissue ka myocardial infarction,
causes decreased functioning of the pump of circulatory
system
• Depending on the size of infarct this may cause shock
[decreased flow of blood to organs of the body] or may even
cause immediate death

LIQUIFACTIVE NECROSIS
ETIOPATHOGENESIS
ETIOLOGY
• Pyogenic bacterial infections eg Staphylococcus ,
Streptococcus & others; in all tissues & ischemia of brain
tissue
PATHOGENESIS
• Pyogenic infection leads to acute inflammation
• In acute inflammation phagocytic cells phagocytose the
organism with formation of phagolysosome, where the
bacteria is killed by formation of ROS & lysosomal enzymes

ETIOPATHOGENESIS
• At the end of this process the phagocytic cell [neutrophils
have short life span] dies & liberates all the cellular debris,
ROS & degradative enzymes in their microenvironment
• These ROS & degradative enzymes like proteases, lipases, act
on other cells at the site of & surrounding the inflammation;
to cause breakdown of cellular membranes & inactivate
various vital chemicals in the cell, this results in loss of
structure of the cell & conversion of cell contents into debris

• There is loss of cells due to necrosis
• Features of inflammation – redness, heat, swelling, pain & loss of
function are present at the site
• If infection & inflammation are severe systemic features like fever
& malaise are also seen
• Clinical features are variable, depending on the site & extent of
necrosis eg, in skin, infection of hair follicle may cause minor
discomfort, but
• In parenchymal tissues like brain , liver & kidney they may cause
considerable morbidity, untreated they may be fatal

CASEOUS NECROSIS
ETIOPATHOGENESIS
ETIOLOGY
• Infection by mycobacterium tuberculosis
PATHOPHSIOLOGY
• Combination of protein denaturation & limited enzymatic
action
• Factors which contribute to coagulative & liquefactive
necrosis

CASEOUS NECROSIS
• There is loss of tissue due to necrosis, hence cellular function
is compromised
• The infecting organism evokes a chronic inflammatory
response, which presents with local & systemic symptoms &
signs depending on site of infection, eg, lung infection is
associated with cough, low grade fever, anorexia, weight loss
• Infecting organism also evokes an immunological response
known as delayed type hypersensitivity reaction, this
contributes to granuloma formation [lesion rich in modified
macrophages] & necrosis

FAT NECROSIS IN ACUTE PANCREATITIS
ETIOPATHOGENESIS
• Occurs due to intra cellular activation of various proenzymes
including lipase, in the acinar cells of pancreas due to various
causes of acute inflammation
• These activated enzymes are also released outside the cell
into the surrounding tissues

ETIOPATHOGENESIS
• Lipase enzymatically breaks down the fat cells & triglycerides
to release fatty acids
• These FA combine with calcium to form chalky white areas
[fat saponification]
• Trauma directly causes fat necrosis in adipocyte rich tissues
like breast

• Depending on the intensity of inflammation acute
pancreatitis, clinical features range from being asymptomatic
to presenting as an acute emergency, which if untreated
leads to death in 20% cases
• Presence of calcium deposits can be seen radiologically and
are helpful in arriving at diagnosis of chronic pancreatitis [
repeated mild subclinical episodes of acute pancreatitis are
followed by progression to chronic pancreatitis]

FIBRINOID NECROSIS
ETIOPATHOGENESIS & CLINICAL SIGNIFICANCE
• This type of necrosis is most frequently associated with
immunological causes & is seen in blood vessels
• It occurs due to deposition of antigen antibody complexes,
which evoke an inflammatory response
• This leads to leakage of fibrin, which combines with the Ag-
Ab complexes & is seen as bright pink amorphous material in
H&E stain
• It can be seen only microscopically, not grossly

PART E
PA2.2
• DESCRIBE THE ETIOLOGY OF CELL INJURY
DISTINGUISH BETWEEN REVERSIBLE & IRREVERSIBLE CELL
INJURY,MECHANISM OF CELL INJURY, MORPHOLOGY OF CELL
INJURY
PA2.8, S,SH, Y
IDENTIFY & DESCRIBE VARIOUS FORMS OF CELL INJURIES,
THEIR MANIFESTATIONS AND CONSEQUENCES IN GROSS &
MICROSCOPIC SPECIMENS

REFRENCES
• PHOTOGRAPHS OF SPECIMEN
• MICROPHOTOGRAPHS OF SLIDES
• LINE DIAGRAMS
• TEXTBOOK PICTURES

SLO
• IDENTIFY & DESCRIBE REVERSIBLE CELL INJURY IN GROSS
SPECIMEN & MICROSCOPIC SLIDES
• IDENTIFY & DESCRIBE NECROSIS IN GROSS SPECIMEN &
MICROSCOPIC SLIDES

CELL INJURY
CELL INJURY:
The events occurring in a cell on exposure to stress and after
exhaustion of its adaptive responses are known as cell injury.
• REVESIBLE CELL INJURY
• CELLULAR SWELLING KIDNEY
• FATTY LIVER

(HYDROPIC/VACUOLAR DEGENERATION)
GROSS
•Kidney is increased in size & weight,
•It is pale & turgid
MICROSCOPY
•Tubular cells are swollen & pale in color
•Lumen of tubules is narrowed
•Cytoplasmic vacuoles may be seen in few cells

rt side shows tubular changes of cellular swelling, lt side
is normal histology for comparison

CELLULAR SWELLING
ELECTRON MICROSCOPY-
• Plasma membrane shows loosening of intercellular
attachments, blunting / loss of microvilli, blebbing;
• Mitochondria are swollen & phospholipid densities are seen;
• ER is dilated & smooth.

FATTY LIVER
Also know as fatty degeneration. It occurs as a result of
imbalance in production, utilization or mobilization of fat in
the cells. It is best seen in the liver.
GROSS:
• The liver is increased in size and weight; however its shape is
maintained, but it becomes rounded.
• It is yellow in color.
• It cuts soft, and is greasy.

INCREASED SIZE, ROUNDED EDGES, YELLOW
COLOR

FATTY LIVER
microscopy
• The normal liver, architecture is maintained.
• The hepatocytes are increased in size and become rounded. In very
early cases fat may be seen as small vesicles in the cytoplasm. Later
on, the nucleus and cytoplasm are pushed to the periphery and the
cell is occupied by a large fat vacuole. The fat vacuoles appear empty
in H&E sections as the fat is lost during tissue processing.
• The sinusoids are compressed and narrowed as a result of increased
size of hepatocytes
• Special stain to visualize fat is oil red o in frozen section

Scanner view showing portal triad on upper lt side,
some hepatocytes show clear cytoplasm [fatty
change], others are normal

Low power, many hepatocytes showing fatty
change, small & large fat vacuoles are seen

High power, hepatocytes with large vacuoles,
show nucleus pushed to one side

Hepatic steatosis in a an uncontrolled
diabetic. Frozen section, oil red O stain

NECROSIS
DEFINITION
SUM OF MORPHOLOGICAL CHANGES OCCURING
AFTER CELL DEATH due to damage of cellular
membranes & leakage of cell contents leading to
response known as inflammation

IRREVERSIBLE CELL INJURY / CELL DEATH
NECROSIS
• COAGULATIVE
• MYOCARDIAL INFARCTION
• LIQUEFACTIVE
• GROSS – ABCESS SUBCUTANEOUS TISSUE
• CASEOUS
• GROSS – TB LYMPH NODE

IRREVERSIBLE CELL INJURY / CELL DEATH
NECROSIS
• MICRO – TB LYMPH NODE [SHALL BE DISCUSSED WITH
INFLAMMATION]
• FAT NECROSIS
• INTRA ABDOMINAL FOLLOWING ACUTE PANCREATITIS
• FIBRINOID NECROSIS
• BLOOD VESSEL

NECROSIS [MI] – BIOCHEMICAL CHANGES
triphenyl tetrazolium chloride does not stain the dead tissue,
so it appears pale in color, normal viable tissue is reddish in
color

NECROSIS
ELECTRON MICROSCOPIC CHANGES
• Necrotic cells are characterized by overt discontinuities in
plasma and organelle membranes,
• Marked dilation of mitochondria with the appearance of
large amorphous densities,
• Intracytoplasmic myelin figures (phospholipids),
• Amorphous osmiophilic debris,
• Aggregates of fluffy material probably representing
denatured protein
• Necrotic cells are characterized by overt discontinuities

COAGULATIVE NECROSIS
MICROSCOPIC FEATURES
• Architecture of cells & organ is maintained
• Cell outlines are preserved
• Cytoplasm is eosinophilic (pink) due to denaturation of
proteins
• Nucleus shows pyknosis (small & dense), karyorrhexis (
fragmented), karyolysis (shadow/lost)
• Necrotic area is surrounded by inflammation

COAGULATIVE NECROSIS [MI] MICROSCOPIC FEATURES
LEFT SIDE SHOWS NORMAL MYOCARDIAL FIBRES, RIGHT SIDE SHOWS NECROTIC
MYOCARDIAL FIBRES [MORE EOSINOPHILIC CYTOPLASM, SPINDLE SHAPED NUCLEI
ARE ABSENT] SURROUNDED BY INFLAMMATORY CELLS [SMALL DARK NUCLEI]

COAGULATIVE NECROSIS [MYOCARDIAL INFARCTION]
GROSS FEATURES
Patterns depends on vessel involved & duration of ischemia, as
well as duration after which heart is examined ie, time elapsed
between ischemic episode & examination
Trans mural infarct
• Involving the entire thickness of the left ventricular wall from
endocardium to epicardium,
• Usually the anterior &/ posterior wall with septum
• Extension into the RV wall in 15-30%.
• Isolated infarcts of RV and right atrium are extremely rare.

TIME FROM
ONSET
GROSS MORPHOLOGIC FINDING
18 - 24 Hours Pallor of myocardium
24 - 72 Hours Pallor with some hyperemia
3 - 7 Days
Hyperemic border with central
yellowing
10 - 21 Days
Maximally yellow and soft with
vascular margins
7 weeks White fibrosis

GROSS
• Cell/ organ is liquefied & cannot be recognized (abscess)
MICROSCOPIC
• Cells are liquefied
• Cytoplasm & nucleus cannot be identified
• Surrounded by acute inflammation

LIQUIFACTIVE NECROSIS: SUBCUTANEOUS ABSCESS
ONE SMALL ABSCESS IS SEEN IN DEEPER TISSUE ALSO

LIQUIFACTIVE NECROSIS: SUBCUTANEOUS
ABSCESS CLOSE UP VIEW

CASEOUS NECROSIS :TUBERCULAR LYMPHADENITIS
GROSS:
• Lymph nodes are enlarged and matted together.
• It cuts soft, cut surface shows focal soft friable cheesy
creamish areas of caseation.

TUBERCULAR LYMPHADENITIS
CREAMISH AREAS CAN BE SEEN IN CENTER OF LN

TUBERCULAR LYMPHADENITIS
CLOSE UP VIEW

FAT NECROSIS
GROSS
• Chalky white firm to hard areas are seen
MICROSCOPIC
• Outlines of fat cells are seen,
• Along with dark blue amorphous material (Ca deposit),
• Surrounded by inflammation

FAT NECROSIS SECONDARY TO ACUTE
PANCREATITIS , NOTE THE CHALKY WHITE AREAS

Microscopic picture of Fat necrosis. Though
the cellular outlines vaguely remain, the fat
cells have lost their peripheral nuclei . Blue
deposits of amorphous calcium is evident

FIBRINOID NECROSIS
GROSS CHANGES USUALLY NOT EVIDENT
MICROSCOPIC
• Usually seen in wall of blood vessel as
• Bright pink amorphous material.
• It is deposit of antigen-antibody complex along with fibrin
surrounded by inflammatory reaction.

FIBRINOID NECROSIS
vessel wall shows bright pink amorphous deposits
some inflammation is also present

ESSAY
• Define reversible & irreversible cell injury. What is the
pathogenesis of irreversible cell injury. Define and describe
the type of necrosis & gangrene [gangrene to be studied
later]
• Define necrosis. Describe the various types of necrosis with
suitable examples. How does it differ from apoptosis
[apoptosis to be studied later]

SHORT ESSAY – CLINICAL CASE
A 35 yr old obese male found to have grade 3 fatty liver on abdominal
USG. Hb – 15gm/dl, total bilirubin – 1.1mg/dl, SGOT(AST) – 28 U/L,
SGPT ( ALT) – 32 U/L, alkaline phosphatase – 110 U/L. Liver biopsy
performed. Ans the following:
• Draw a labeled diagram of the expected microscopic findings
• What is the etiopathogenesis of this condition
• What is the prognosis

MCQ
The Fenton reaction leads to free radical generation when
a) Radiant energy is absorbed by water b) Hydrogen peroxide is formed
by myeloperoxidase
c) Ferrous ions are converted to ferric ions d) Nitric oxide is converted
to peroxynitrites anion
Necrosis of cell is due to
a) Ca2+ influx in cytoplasm b) Fat deposition in cells
c) Water imbibition in cells d) deficiency of lysosomal
enzymes

MCQ
Caseous necrosis is seen in
a)Tuberculosis b) Fungal infection c) Sarcoidosis
d) Wet gangrene
Trauma to breast causes which type of necrosis
a)Coagulative necrosis b) Liquefactive necrosis c)
Caseous necrosis d) Fat necrosis

MCQ
Steatosis means
a) Fatty change b) Accumulation of cholestrol
c) Accumulation of glycogen d) Accumulation of pigment
Most common type of cell death due to sudden occlusion of blood
supply
a) Coagulation necrosis b) Caseation necrosis
c) Liquefactive necrosis d) Gangrene

MCQ
Cloudy swelling is due to
a)Accumulation of water intracellularly b) Fat Accumulation
intracellularly
c) Lysozyme degeneration d) Glycogen Accumulation
intracellularly
Pyogenic infection and brain infarction are associated with
a)Coagulation necrosis b) Liquefactive necrosis
c) Caseous necrosis d) Fat necrosis

MCQ
CELL INJURY OCCURS WHEN:
• INJURIOUS AGENT IS VERY DAMAGING
• CELL HAS ALREADY UNDERGONE ADAPTATION
• BOTH OF THE ABOVE
• NONE OF THE ABOVE
OVER NUTRITION CAN ALSO CAUSE CELL INJURY
• TRUE
• FALSE

MCQ
ALL EXCEPT THIS CAN CAUSE HYPOXIA:
• STARVATION
• HIGH ALTITUDE
• ANEMIA
• PNEUMONIA

MCQ
REVERSIBLE CELL INJURY IS CHARACTERIZED BY ALL FEATURES, EXCEPT:
• IT IS NOT FOLLOWED BY CELL DEATH
• CELL IS VIABLE
• OCCURS IN RESPONSE TO EXTERNAL AS WELL AS INTERNAL CHANGE
IN IT’S ENVIORNMENT
• WITHDRAWAL OF CAUSE IS FOLLOWED BY COMPLETE RETURN TO
NORMAL

MCQ
CAUSES OF CELL INJURY ARE:
• BACTERIAL INFECTIONS
• IMMUNE REACTIONS
• ALCOHOL
• ALL OF ABOVE

MCQ
EXTENT OF CELL INJURY DEPENDS ON:
• DURATION OF EXPOSURE TO INJURIOUS AGENT
• CELL GENETICS
• PRESENCE OF PRE EXISTING DISEASE
• ALL OF ABOVE

MCQ
ATP PRODUCTION IS DECREASED DUE TO:
• DECREASE IN OXYGEN
• PRESENCE OF TOXINS
• RADIATION TO CELL
• ALL OF ABOVE

MCQ
DECREASE IN ATP CAUSES CELL INJURY BY:
• MALFUNCTION OF SODIUM POTASSIUM PUMP
• DECREASE IN GLUTATHIONE
• DECREASE IN GLUCOSE
• MALFUNCTION OF PROTEINS

MCQ
FOLLOWING IS NOT A ROS:
• HYDROGEN PEROXIDE
• HYDROXYL RADICAL
• NITROGEN OXIDE
• SUPEROXIDE

MCQ
FOLLOWING IS NOT AN ANTIOXIDANT:
• CATALASE
• VITAMIN C
• GLUTAMINE
• VITAMIN E

MCQ
ROS DAMAGE:
• PHOSPHOLIPIDS IN CELL MEMBRANES
• SODIUM PUMP IN CELL MEMBRANES
• OXYGEN IN CELL MEMBRANES
• CALCIUM PUMP IN CELL MEMBRANES

MCQ
ROS IN LEUKOCYTES:
• DAMAGE THE MICROBES IN PHAGOLYSOSOMES
• DAMAGE THE NUCLEUS
• DAMAGE THE PHAGOLYSOSOME
• DAMAGE THE CELL MEMBRANE

MCQ
SUPEROXIDE DISMUTASE PREVENTS CELL INJURY BY:
• INACTIVATING ATPase
• INACTIVATING PHOSPHOLIPASE
• INACTIVATING ROS
• INACTIVATING VITAMIN C

NEET preparation
• https://youtu.be/iWqsg6_iH64
• https://youtu.be/ijENMdG5nUw

CELL INJURY

More Related Content

What's hot

Similar to CELL INJURY

More from Ira Bharadwaj

Recently uploaded

In this document

CELL INJURY