DEGENERATION,

NECROSIS AND
GANGRENE
PRESENTED BY-MADHULIKA K
CONTENTS
• INTRODUCTION
• CELL INJURY
• CELLULAR RESPONSE TO INJURY
• MECHANISM OF CELL INJURY
• MORPHOLOGICAL CHANGES IN VARIOUS FORMS OF CELL INJURY
• REVERSIBLE INJURY: DEGENERATION
• IRREVERSIBLE INJURY: - NECROSIS
- APOPTOSIS
- GANGRENE
• CONCLUSION
• REFERENCES
 INTRODUCTION
• The normal cells are usually confined to a fairly narrow range of functions and
structure by its state of metabolism, differentiation and specialization

• It is basically capable of handling the physiologic demands by maintaining a

steady state

HOMEOSTASIS
• Cells actively interact with their environment, constantly adjusting their
structure and function to accommodate changing demands and extracellular
stresses.
CELL INJURY
• Cell injury results when the
adaptive capability of the cell to
external stress becomes harmful
or excessive.
 CELLULAR RESPONSE TO CELL INJURY
Nature and Severity of Injurious Stimulus Cellular Response
Altered physiologic stimuli: Cellular adaptations:
•Increased demand, increased trophic •Hyperplasia, hypertrophy
stimulation (e.g. growth factors, hormones)
•Decreased nutrients, lack of stimulation •Atrophy
•Chronic irritation (chemical or physical) •Metaplasia
Reduced oxygen supply; chemical injury; Cell injury:
microbial infection
•Acute and self-limited •Acute reversible injury
•Progressive and severe (including DNA •Irreversible injury ----- cell death
damage) Necrosis
•Mild chronic injury Apoptosis

•Subcellular alterations in various organelles

Metabolic alterations, genetic or acquired Intracellular accumulations; calcifications
Cumulative sublethal injury over long life span Cellular aging
 CELL ADAPTATION
• Adaptations are reversible functional and structural responses to changes in
physiologic states (e.g. pregnancy) and some pathologic stimuli.

• During this pathologic stimuli----new altered steady states are achieved------This

allows the cells to survive and continue to function.

• For example, chronic exposure to sunlight causes melanocytes in the skin to

synthesize more melanin to protect cells from potentially injurious UV radiation.
 HYPERTROPHY HYPERPLASIA

RESPONSE TO
CELLULAR
ADAPTATION
ATROPHY METAPLASIA
HYPERTROPHY HYPERPLASIA ATROPHY METAPLASIA
Increase in the size Increase in the Reduction in the size Reversible change in which
of the cells that number of cells in an of an organ or tissue one differentiated cell type is
result in an organ or tissue due to a decrease in replaced by another
increase in size of response to a cell size and number
the cell stimulus
Occurs in cells Takes place only in Decreased metabolic It occurs as a result of a
which undergo cells which are activity--- reprogramming of stem cells
division and non- capable of dividing Decreased protein that are known to exist in
dividing cells synthesis and normal tissues or of
increased protein undifferentiated mesenchymal
degeneration--- cells present in connective
ATROPHY tissue
E.g. Muscles in E.g. Compensatory E.g. Skeletal muscle E.g. In chronic smokers, The
body builders hyperplasia --- liver atrophy in fractured normal ciliated columnar
regeneration bone due to epithelial cells of trachea and
immobilization. bronchi--- replaced by
 CELL INJURY
• Sequence of events that occurs when the stresses exceed the ability to adapt or
are exposed to inherently damaging agents or suffer from intrinsic
abnormalities.

• For example, acute severe exposure of the skin to solar UV radiation may lead to
"sunburn" - an epidermal injury.
If the injury is severe enough,
If injured cells recover their
however, a “point of no return” is
normal functions when the stress
reached and the cell suffers
is removed, the injury is said to
irreversible injury and dies. Two
be reversible.
patterns of cell death are observed:
necrosis and apoptosis.
CAUSES OF CELL INJURY
• Hypoxia and ischemia
• Toxins
• Infectious agents
• Immunologic reactions
• Genetic abnormalities
• Nutritional imbalances
• Physical agents
• Aging
MECHANISM
OF CELL
INJURY
 Consequences of cell injury

• ATP depletion
• Mitochondrial damage
• Membrane damage (Defects in Membrane Permeability)
• Influx of Intracellular Calcium and Loss of Calcium Homeostasis
• Increased ROS production
• DNA damage
Depletion of
ATP
Mitochondrial
Damage
Influx of
Intracellular
Calcium and
Loss of Calcium
Homeostasis
Accumulation of
Oxygen-Derived
Free Radicals
(Oxidative Stress)
Defects in
Membrane
Permeability
MORPHOLOGIC CHANGES IN VARIOUS FORMS OF CELL
INJURY
 REVERSIBLE CELL INJURY
• Reversible injury is the stage of cell injury at which the deranged function and
morphology of the injured cells can return to normal if the damaging stimulus is
removed.

• In reversible injury, cells and intracellular organelles typically become swollen

because they take in water as a result of the failure of energy-dependent ion pumps
in the plasma membrane, leading to an inability to maintain ionic and fluid
homeostasis
 CELL DEGENERATION
• Defined as visible, retrogressive changes in the living cells, apart from those of
atrophy, indicative of cellular damage just short of death.

• Retrogressive changes are the direct result of an injury.

• It is the commonest and earliest form of cell injury from almost all the causes .

• The manifested changes consists of excess accumulation of normal substances in

cytoplasm or appearance of abnormal substances in intercellular space.

• Occurs in cells having high metabolic activity and rich in mitochondrial enzymes
such as liver cells, kidney tubules and cardiac muscles.
 CAUSES OF DEGENERATION

External Internal:
Dietary,
• Physical: heat, cold, vitamins
radiations. Genetic
deficiency
defects
• Toxic chemicals
Hypoxia: deficiency in Increase in
• Infective agents
the amount of oxygen endogenous
reaching the tissues. toxins e.g.,
e.g., anemia, cholesterol or uric
respiratory failure, or acid.
ischemia.
 TYPES OF DEGENERATION

• DEPENDING UPON • DEPENDING UPON THE

THE NATURE OF THE NATURE OF THE
METABOLITE THAT METABOLITE THAT
ACCUMULATES ACCUMULATES OUTSIDE
WITHIN THE CELL THE CELL
 DEPENDING UPON THE NATURE OF THE METABOLITE
THAT ACCUMULATES WITHIN THE CELL
Common in
Type Characteristics

ACCUMULATION OF WATER INSIDE CELL:

1.Cell Due to failure of energy dependent ion pumps in
swelling plasma membrane resulting in inability to
maintain ionic and fluid homeostasis. Kidney, liver & heart muscles.
Swelling of cells seen with clear vacuoles within the
cytoplasm.

ACCUMULATION OF PROTEIN INSIDE CELL :

Non- specific degeneration.
2. Hyaline Affects the collagenous connective tissue and fibrous
Droplet tissue. Proximal tubular epithelial cells, liver
Appearance is Hyaline, glassy , homogenous
appearance.
 Common in
Type Characteristics

3. Waxy / Form of severe hyaline degeneration in skeletal Infections like Typhoid & Diphtheria
Zenkers muscle. The muscles become waxy, homogenous
degeneration and structureless. Muscle appear pale friable due to
coagulation of sarcoplasm proteins.

ACCUMULATION OF LIPID INSIDE THE CELL

Fatty change Accumulation of neutral fats within parenchymal

(steatosis) cells. Due to excessive accumulation of free fatty Mostly Liver, occasionally kidney and
acids in hepatocytes or due to increase heart
accumulation of lipoproteins. Grossly, it is enlarged
with glossy round margins.
 Mechanisms of
intracellular
accumulations
(1) abnormal metabolism
(2) alterations in protein folding and transport
(3) deficiency of critical enzymes
(4) inability to degrade phagocytosed particles
Hydropic Degeneration
Fatty change
• Mechanism of development of fatty change: 3 forms of biochemical injury:-

1. Excessive formation of triglycerides

2. Depletion of micelle (Triglyceride molecular aggregates)

– phospholipid depletion – (natural emulsifying agent)
- impaired apolipoprotein synthesis – in protein- malnutrition
- inhibition of protein- synthesis by -tetracycline

3. Excessive cytoplasmic cholesterol – inhibits emulsification ; Diabetes

mellitus, Atheroma
DEGENERATION BASED ON ACCUMULATION
OF METABOLITES OUTSIDE THE CELL
1. METABOLITES THAT ARE PROTEIN IN NATURE:
HYALINE - HYALINIZATION
FIBRINOID - FIBRINOID DEGENERATION AMYLOIDOSIS
AMYLOID - AMYLOIDOSIS
URIC ACID - GOUT

2. METABOLITES THAT ARE LIPID IN NATURE:

CHOLESTROL - ATHEROSCLEROSIS GOUT
ATHEROSCLEROSIS OF AORTA

3. METABOLITE THAT IS MINERAL IN NATURE:

CALCIUM - METASTATIC CALCIFICATION
 Irreversible cell injury
Inability of the cell to reverse mitochondrial NECROSIS
dysfunction on reperfusion.
APOPTOSIS AND
GANGRENE
Disturbance in cell membrane function could be
due to:

• Continued protein depletion

• Leakage of lysosomal enzymes.
• Further reduction in ATP CELL
• Intracellular pH DEATH
 Necrosis
▪ Defined as focal death along with degradation of
tissue by hydrolytic enzymes liberated by cells
accompanied by inflammatory reaction.

▪ The morphologic appearance of necrosis is the result

of two essentially concurrent processes:
(1) denaturation of proteins and
(2) enzymatic digestion of the cell

▪ Following cell death both cytoplasmic and nuclear

changes occur but the autolytic changes of nucleus
(1. Pyknosis, 2. karyorrhexis, 3. karyolysis) are
regarded as pathognomic of necrosis.
MORPHOLOGICAL
CHANGES IN
NECROSIS
Nuclear changes In necrosis

Chromatin dissolution due DNA condenses into Pyknotic nuclear membrane ruptures
to action of DNAse and shrunken basophilic mass and nucleus undergoes fragmentation
RNAse
 HISTOPATHOLOGIC FEATURES
• Cytoplasmic changes.
- Necrotic cells show increased eosinophilia.
- these cell may have a glassy, homogeneous appearance,
mostly due to loss of lighter staining glycogen particles.
- Myelin figures are more prominent.
- When enzymes have digested cytoplasmic organelles, the
cytoplasm becomes vacuolated and appears “moth-eaten.”
- By electron microscopy, necrotic cells are characterized by
discontinuities in plasma and organelle membranes, marked
dilation of mitochondria associated with the appearance of
large amorphous intramitochondrial densities, disruption of
lysosomes, and intracytoplasmic myelin figures.
• Nuclear changes.
- Nuclear changes assume one of three patterns, all resulting
from a breakdown of DNA and chromatin.
- Pyknosis is characterized by nuclear shrinkage and increased
basophilia; the DNA condenses into a dark shrunken mass.
- The pyknotic nucleus can undergo fragmentation; this
change is called karyorrhexis.
- Ultimately, the nucleus may undergo karyolysis, in which the
basophilia fades because of digestion of DNA by
deoxyribonuclease (DNase) activity.
- In 1 to 2 days, the nucleus in a dead cell may completely
disappear.
• FATE OF NECROTIC CELLS:

- Necrotic cells may persist for some time or may be digested by enzymes
and disappear.
- Dead cells may be replaced by myelin figures, which are either
phagocytosed by other cells or further degraded into fatty acids.
- These fatty acids bind calcium salts, which may result in the dead cells
ultimately becoming calcified.
 TYPES OF NECROSIS
Coagulative Liquefactive
• Depending on whether necrosis – necrosis –
denaturation of dominant
enzymatic catabolism; or protein protein, primary enzymatic
denaturation predominates: pattern digestion

Caseous necrosis Fat necrosis

 Coagulative Necrosis
• It is a form of necrosis in which the underlying tissue architecture is preserved for
at least several days after death of cells in the tissue.

• The affected tissues take on a firm texture.

injury denatures structural proteins and enzymes

blocking the proteolysis of the dead cells

eosinophilic, anucleate cells may persist for days or weeks.

• Leukocytes are recruited to the site of necrosis,
and the dead cells are ultimately digested by the
action of lysosomal enzymes of the leukocytes.

• The cellular debris is then removed by

phagocytosis mediated primarily by infiltrating
neutrophils and macrophages.

• Coagulative necrosis is characteristic of infarcts

(areas of necrosis caused by ischemia) in all solid
organs except the brain.
 LIQUEFACTIVE NECROSIS
• It is seen in focal bacterial and, occasionally,
fungal infections because microbes stimulate
rapid accumulation of inflammatory cells, and
the enzymes of leukocytes digest (“liquefy”) the
tissue.

• the dead cells are completely digested,

transforming the tissue into a viscous liquid that
is eventually removed by phagocytes.

• If the process is initiated by acute inflammation,

as in a bacterial infection, the material is
frequently creamy yellow and is called pus.
 CASEOUS NECROSIS
• It is most often seen in foci of tuberculous
infection.
• Caseous means “cheeselike,” referring to the
friable yellow-white appearance of the area of
necrosis on gross examination.

• On microscopic examination, the necrotic

focus appears as a collection of fragmented or
lysed cells with an amorphous granular pink
appearance in H&E stained tissue sections.
• Unlike coagulative necrosis, the tissue
architecture is completely obliterated, and
cellular outlines cannot be discerned.

• Caseous necrosis is often surrounded by a

collection of macrophages and other
inflammatory cells; this appearance is
characteristic of a nodular inflammatory lesion
called a granuloma.
 FAT NECROSIS
In this disorder,
pancreatic enzymes
• Refers to focal areas of fat
destruction, typically resulting that have leaked out of acinar cells and ducts
from the release of activated
pancreatic lipases into the liquefy the membranes of fat cells in the peritoneum,
substance of the pancreas and
the peritoneal cavity. and lipases split the triglyceride esters contained
within fat cells.

• This occurs in the calamitous The released fatty acids combine with calcium to
abdominal emergency known
as acute pancreatitis. produce grossly visible chalky white areas (fat
saponification)
• On histologic examination, the foci of necrosis contain shadowy
outlines of necrotic fat cells surrounded by basophilic calcium deposits
and an inflammatory reaction.
Necrosis in special sites
Necrosis of the muscle :striated muscle during acute fevers, typhoid and small pox.

• Muscle fibers loose their striations, nuclei disappear, eosinophilic hyaline mass.
• Usually, rectus abdominis muscle or the diaphragm, may rupture – hemorrhage and pain,
‘Zenker’s degeneration’, is in fact a true necrosis.

Necrosis Of Collagen :
Whether it is permissible to describe the degenerative changes seen in collagen as necrosis is
debatable.
The associated fibrocytes undergo destruction.
But it is difficult to define necrosis in an exracellular substance like collagen
Necrosis In Oral Cavity

Agranulocytosis-Mucosa exhibit isolated patches that are black & grey

and are sharply demarcated from the adjacent uninvolved area.

Acute gingival necrosis-seen in leukemia and ANUG.

Pulpal necrosis

Necrotic cementum
• Osteonecrosis

oNecrosis of the bone affects the medullary bone (medullary cavity or its
trabecular bone) or may affect both cortical and medullary bone

oCauses :

a. Due to infection or radiation damage

b. Due to ischemic necrosis – vascular interruption following trauma,
vasculitis, sickle cell anaemia, thrombosis, thromboembolism or nitrogen
embolism
c. Due to corticosteroid administration, alcoholism, or pregnancy
d. Idiopathic
Diagnosis of necrosis

BY BIOCHEMICAL MEANS
• Serum glutamate oxaloacetate transaminase – infarcted heart muscle

• Serum glutamate pyruvate transaminase– liver necrosis

• Creatinine phosphokinase– skeletal muscle damage ;

o polymyositis,
o alcoholic myopathy,
o malignant hyperpyrexia,
o after strenuous exercise,
o even following intramuscular injections
o highest levels in muscular dystrophies
TREATMENT OF NECROSIS
• Treatment of necrosis typically involves two distinct processes.
Usually, the underlying cause of the necrosis must be treated.
oFor example, a snake or spider bite victim will receive anti-venom to
halt the spread of the toxins, while an infected patient will receive
antibiotics.

• Even after the initial cause of the necrosis has been halted, the necrotic
tissue will remain in the body. The body's immune response to
apoptosis, is not triggered by necrotic cell death.
• The standard therapy of necrosis (wounds, bedsores, burns etc.) is
surgical removal of necrotic tissue.

• Depending on the severity of the necrosis, this may range from

removal of small patches of skin, to complete amputation of affected
limbs or organs.

• Chemical removal, via an enzymatic debriding agent.

• In selected cases, special maggot therapy has been utilized.

• Maggot therapy (also known as maggot debridement therapy (MDT))
is a type of biotherapy involving the intentional introduction of live,
disinfected maggots (fly larvae) into the non-healing skin and soft tissue
wound(s) of a human or animal for the purposes of selectively cleaning
out only the necrotic tissue within a wound (debridement), disinfection,
and promotion of wound healing.
 Apoptosis
Greek means ‘falling away from’
• Apoptosis is a process of
programmed cell death.

• It is a pathway of cell death induced

by a tightly regulated suicidal
programme in which cells activate
enzymes that degrade the cells’ own
nuclear DNA and nuclear and
cytoplasmic proteins.
MORPHOLOGIC
FEATURES OF
APOPTOSIS
 Morphologic features
• Apoptosis usually involves single cells.
• Cell shrinkage, chromatin condensation,
formation of cytoplasmic blebs and
apoptotic bodies.
• The apoptotic cell appears as a round or
oval mass of intensely eosinophilic
cytoplasm with dense nuclear chromatin
fragments.
• Plasma membrane appear to remain
intact during apoptosis.
• Phagocytosis of apoptotic cells by
neighbouring cells.
Biochemical changes
• Proteolysis of cytoskeleton proteins.
• Protein-protein cross linking
• Fragmentation of nuclear chromatin by
activation of nuclease.
• Appearance of phosphatidylserine and
thrombospondin on the outer surface of
apoptotic cell facilitates early
recognition by macrophages for
phagocytosis prior to appearance of
inflammatory cells.
MECHANISM OF APOPTOSIS
 AFTER-EFFECTS OF NECROSIS
GANGRENE
• A form of necrosis of the tissue with superadded
putrefaction.
• All types of gangrene undergoes liquefaction by the
action of putrefactive bacteria.
• It may be cause due to inflammation or ischemia
- Due to ischemia: Gangrene of bowel
Gangrene of limb
- Due to gangrenous or necrotising inflammation:
Primarily thee inflammation provoked by virulent
bacteria resulting in massive tissue necrosis.
> Gangrenous appendicitis
> Gangrenous stomatitis (NOMA, Cancrum oris)
Types of gangrene
1. Secondary to arterial obstruction from disease

• Thrombosis of an atherosclerotic artery

• Embolus from the heart in Artial fibrillation,

• Coronary thrombosis

• Arteritis with neuropathy in diabetes

• Arterial injection (thiopentone)

2. Infective

• Abscesses
• Carbuncles
• Boils
• Gas gangrene
3. TRAUMATIC

• Direct including bed sores

• Indirect
1. Pressure
2. Thrombosis
3. Ligation
4. Poor digital LA technique
5. Putrefied lung abscess following tooth extraction done under GA
4. PHYSICAL AND CHEMICAL CAUSE :

Ainhum
& Ergot

Physical and
Drug
chemical Trench
abuse causes of foot
gangrene

Frost
bite
 CLINICAL TYPES
Feature Dry gangrene Wet gangrene

1. Site Commonly limbs More common in bowel

2. Mechanism Arterial occlusion Venous obstruction, less commonly arterial

occlusion

3. Macroscopy Organ, dry, shrunken and black Moist, soft, swollen, rotten and dark
Marked due to stuffing of organ with blood
4. Putrefaction Limited due to very little blood supply
No clear line of demarcation
At the junction between healthy and gangrenous
5. Line of part-clear
demarcation Numerous present
Bacteria fail to survive
6. Bacteria Poor, profound toxemia
Better, little septicemia
7. Prognosis
 GAS GANGRENE
• Special form of wet gangrene caused by gas forming clostridia
(gram +ve anaerobic bacteria).
• Gains entry into tissues through open contaminated wounds.
• Especially seen in muscles, or as a complication of operation on
colon which normally contains clostridia.
• It produces various toxins which produce necrosis and oedema
locally.
• It could also be absorbed producing profound systemic
manifestations.
• MORPHOLOGICAL FEATURES:
- Affected area becomes swollen, oedematous, painful and crepitant due to
accumulation of gas bubbles within the tissues.
- Subsequently the affected tissue becomes dark black and foul smelling.

• MICROSCOPICALLY:
- The muscle fibres undergo coagulative necrosis with liquefaction.
- Large number of gram +ve bacilli identified.
- At the periphery, a zone of leukocytic infilteration, oedema and congestion are
found.
- Capillary and venous thrombi are common.
DIABETIC GANGRENE
• People with diabetes may unknowingly develop wet
gangrene after experiencing a minor toe or foot injury.
• Blood flow to the extremities is generally diminished in
people with diabetes.
• This means that the tissue in these areas is unable to heal
as quickly. As a result, infection can develop more easily.

• Due to 3 factors:

1. Trophic changes – peripheral neuritis

2. Atheroma – ischemia
3. Excess blood and tissue sugar level – decreased
resistance to infection
 treatment
• Improved blood supply- percutaneous transluminal angioplasty or
direct arterial surgery
• Local treatment – care of the affected part
• Gas gangrene:
- Inj. Benzyl penicillin 20 lac IU 4hrly + Metronidazole
- Blood transfusion
- Excision and debridedment
- Rehydration and Electrolytic management
- Amputation
 Conclusion
• Normal cells are able to alter their function in response to modest stress and
maintain homeostatic control.

• As cells encounter physiologic stresses (such as increased workload in the heart)

or potentially injurious conditions (such as nutrient deprivation), they can undergo
adaptation, achieving a new steady state and preserving viability and function.
• If the adaptive capability is exceeded, cell injury develops.
• Within limits, injury is reversible, cells return to baseline.
• Severe or persistent stress, results in irreversible injury, and the affected cells die.
 REFERENCES
• Cell Injury, Cell Death, and Adaptations . Kumar, Vinay, Abul K.
Abbas, and Jon C. Aster. Robbins Basic Pathology. 10th ed.
Philadelphia, PA: Elsevier - Health Sciences Division.2017; 31-56

• Etiology, Pathogenesis and Morphology of Cell Injury. Harsh Mohan,

Sugandha Mohan. Essential Pathology for Dental students. 4th
edition.editors.2011; 27-47