This document discusses cell injury, adaptations, and degenerations in pathology. It begins by defining key terms like etiology, pathogenesis, and morphology. It then explains the causes of cell injury including hypoxia, physical agents, chemicals, microbes, and immune reactions. The document delves into the pathogenesis of cell injury, noting factors like the type, duration, and severity of the injurious agent and target cell characteristics. It also describes the mechanisms of cell injury such as ATP depletion, mitochondrial damage, calcium influx, oxidative stress, and membrane permeability defects. Finally, it distinguishes between reversible and irreversible cell injury.

1. CELL INJURY, ADAPTATIONS AND
DEGENERATIONS
Dr Neha Mahajan
MD Pathology

2. PATHOLOGY
Pathos (suffering)
Logos

3. PATHOLOGY
ETIOLOGY (“Cause”)
PATHOGENESIS (“Insidious
development”)
MORPHOLOGY (ABNORMAL
ANATOMY)
CLINICAL EXPRESSION

4. ETIOLOGY
Cause
vs.
Risk Factors

5. PATHOGENESIS
“sequence of
events from the
initial stimulus to
the ultimate
expression of the
disease”

6. MORPHOLOGY
Abnormal Anatomy
Gross
Microscopic
Radiologic
Molecular

7. Most long term students of pathology, like myself,
will strongly agree that the very best way for most
minds to remember, or identify, or understand a
disease is to associate it with a morphologic
IMAGE.
This can be gross, electron microscopic, light
microscopic, radiologic, or molecular.
In MOST cases it is at the LIGHT
MICROSCOPIC LEVEL.

8. CELL INJURY, DEFINITIONS
 When the cell is exposed to an injurious agent or
stress, a sequence of events follows that is loosely
termed cell injury.
 Cell injury is reversible up to a certain point
 If the stimulus persists or is severe enough from
the beginning, the cell reaches a point of no return
and suffers irreversible cell injury and ultimately
cell death.
 Cell death, is the ultimate result of cell injury

9. NORMAL CELL
ADAPTATIONS
REVERSIBLE
CELL INJURY
IRREVERSIBLE
CELL INJURY
Severe,persistent stressMild to moderate
stress
Altered
functional demand
Atrophy,Hypertrophy
Hyperplasia,Metaplasia,
Dysplasia
Degenerations,
Subcellular alterations,
Intracellular accumulations
NORMAL CELL
RESTORED
REPAIR
AND HEALING
IRREVERSIBLE
CELL INJURY

10. CAUSES OF CELL INJURY
 Hypoxia
 Direct physical action
 Ionizing radiation
 Toxic molecular injury
 Microbes
 Inflammatory & immune reactions

11. CAUSES OF CELL INJURY
1) Oxygen Deprivation (Hypoxia). It is a common
cause of cell injury and cell death.
-Hypoxia can be due to :
A- inadequate oxygenation of the blood due to
Cardiorespiratory failure
B- loss of the oxygen-carrying capacity of the blood,
as in anemia or carbon monoxide poisoning, heart
diseases, lung diseases
Depending on the severity of the hypoxic state, cells
may adapt, undergo injury, or die.

12. CAUSES OF CELL INJURY CONT.
2) Physical Agents :
- Mechanical trauma,
- Burns,
- Deep cold
- Sudden changes in atmospheric pressure,
- radiation, and electric shock

13. CAUSES OF CELL INJURY CONT.
3) Chemical Agents and Drugs
- oxygen, in high concentrations
- poisons, such as arsenic, cyanide, or mercuric
salts
- environmental and air pollutants
- insecticides, herbicides, industrial and occupational
hazards
- alcohol and narcotic drugs and therapeutic drugs

14. CAUSES OF CELL INJURY CONT.
4) Infectious Agents e.g. bacteria, fungi, viruses
and parasites.
5) Immunologic Reactions.
Hypersensitivity reactions,
Anaphylactic reactions
Autoimmune diseases
6) Genetic Derangements.
7)Aging
8) Nutritional Imbalances

15. PATHOGENESIS OF CELL INJURY
 The following principles apply in pathogenesis of
most forms of cell injury by various agents:
1.Type,duration & severity of injurious agent
2.Type,status & adaptability of target cell
3.Underlying intracellular phenomenom
4.Morphologic consequences

16. MECHANISM OF CELL INJURY
 1.DEPLETION OF ATP
 2.MITOCHONDRIAL DAMAGE
 3.INFLUX OF INTRACELLULAR CALCIUM &
LOSS OF CALCIUM HOMEOSTASIS
 4.ACCUMULATION OF OXYGEN-DERIVED
FREE RADICALS (OXIDATIVE STRESS)
 5. DEFECTS IN MEMBRANE PERMEABILITY

17. MECHANISM OF CELL INJURY
1.DEPLETION OF ATP:
. ATP depletion and decreased ATP synthesis are
associated with both hypoxic and chemical
(toxic) injury.
. ATP is required for many synthetic and degradative
processes within the cell.

18. MECHANISM OF CELL INJURY CONT.
 ATP is produced in two ways.
A- The major pathway is oxidative phosphorylation of
adenosine diphosphate.
B-The second is the glycolytic pathway, which
generate ATP in absence of oxygen using glucose
derived from body fluids or from glycogen
Myocardium, neurons of CNS, proximal tubules of
kidney- Aerobic respiration

19. MECHANISM OF CELL INJURY CONT.
Effects of depleted ATP
a) The activity of the plasma membrane energy-
dependent sodium pump is reduced. It causes
sodium to accumulate intracellularly and potassium
to diffuse out of the cell causing cell swelling, and
dilation of the endoplasmic reticulum.

20. MECHANISM OF CELL INJURY CONT.
b) If oxygen supply to cells is reduced, as in ischemia,
oxidative phosphorylation ceases and cells rely on
glycolysis for energy production (anaerobic
metabolism) resulting in depletion of glycogen
stores.
Glycolysis results in the accumulation of lactic acid
which reduces the intracellular pH, resulting in
decreased activity of many cellular enzymes.

21. MECHANISM OF CELL INJURY CONT.
c) Failure of the Ca2+ pump leads to influx of Ca2+,
with damaging effects on numerous cellular
components
d) Ribosomes detach from the RER and polysomes
breakdown into monosomes, leading to reduction in
protein synthesis. Ultimately, irreversible damage to
mitochondrial and lysosomal membranes occurs,
and cell undergoes necrosis

22. MECHANISM OF CELL INJURY CONT.
e) In cells deprived of oxygen or glucose, proteins
may become misfolded, and trigger the unfolded
protein response leading to cell injury and even
death.

23. MECHANISM OF CELL INJURY CONT.
2- Mitochondrial Damage:
 Mitochondria are important targets for all types of
injury, including hypoxia and toxins.
 Mitochondrial changes are seen as vacuoles in the
mitochondria and deposit of amorphous calcium
salts in mitochondrial matrix

24. MECHANISM OF CELL INJURY CONT.
Mitochondria can be damaged by :
A- Increases of cytosolic Ca2+
B- Oxidative stress
C- Breakdown of phospholipids, and by
D- Lipid breakdown products.

25. MECHANISM OF CELL INJURY CONT.
. Mitochondrial damage results in the formation of a
high-conductance channel, called mitochondrial
permeability transition, present in the inner
mitochondrial membrane. In the initial phase it is
reversible but once mitochondrial permeability
transition is irreversble it becomes a deathblow to
the cell.
 Mitochondrial damage can also be associated with
leakage of cytochrome c into the cytosol.

27. MECHANISM OF CELL INJURY CONT.
3.INFLUX OF INTRACELLULAR CALCIUM & LOSS OF
CALCIUM HOMEOSTASIS.
. Ischemia causes an increase in cytosolic calcium
concentration. Increased Ca2+ in turn activates a
number of enzymes, e.g.
- ATPases (thereby hastening ATP depletion),
-Phospholipases (which cause membrane damage),
- Proteases (which break down both membrane and
cytoskeletal proteins), and
-Endonucleases (which are responsible for DNA and
chromatin fragmentation).

29. MECHANISM OF CELL INJURY CONT.
4. ACCUMULATION OF OXYGEN-DERIVED FREE
RADICALS (OXIDATIVE STRESS)
- Small amounts of partially reduced reactive oxygen
forms are produced as a byproduct of mitochondrial
respiration.
- Some of these free radicals can damage lipids,
proteins, and nucleic acids.
- They are referred to as reactive oxygen species.

30. MECHANISM OF CELL INJURY CONT.
- Cells have defense systems to prevent injury
caused by these products.
- An imbalance between free radical-generating and
radical-scavenging systems results in oxidative
stress causing cell injury.

31. MECHANISM OF CELL INJURY CONT.
Free radical-mediated damage are seen in
1. chemical and radiation injury
2. ischemia-reperfusion injury
3. cellular aging, and
4. microbial killing by phagocytes.

32. MECHANISM OF CELL INJURY CONT.
- Free radicals are chemical species that have single
unpaired electron in an outer orbit.
- They are initiated within cells in several ways:
a) Absorption of radiant energy (e.g., ultraviolet light,
x-rays).
b) Enzymatic metabolism of exogenous chemicals or
drugs .

33. MECHANISM OF CELL INJURY CONT.
c) The reduction-oxidation reactions that occur during
normal metabolic processes. During normal
respiration, small amounts of toxic intermediates
are produced; these include superoxide anion
radical (O2-), hydrogen peroxide (H2O2), and
hydroxyl ions (OH).
d) Transition metals such as iron and copper
e) Nitric Oxide (NO), an important chemical
mediator generated by various cells, can act as a
free radical.

34. MECHANISM OF CELL INJURY CONT.
-The main effects of these reactive species are
 Lipid peroxidation of membranes: result in
extensive membrane, organellar, and cellular
damage.
 Oxidative modification of proteins. resulting in
protein fragmentation.
 Lesions in DNA. This DNA damage has been
implicated in cell aging and malignant
transformation of cells

35. MECHANISM OF CELL INJURY CONT.
-Cells have developed multiple mechanisms to
remove free radicals and thereby minimize injury.
1- Antioxidants. Examples vitamins E and A and
ascorbic acid.
2- Enzymes which break down hydrogen peroxide
and superoxide anion e.g. Catalase, Superoxide
dismutases,and Glutathione peroxidase.

36. MECHANISM OF CELL INJURY CONT.
5. Defects In Membrane
Permeability:
- In ischemic cells, membrane damage may be the
result of ATP depletion and calcium-modulated
activation of phospholipases.
- It can also be damaged directly by certain bacterial
toxins, viral proteins etc.

37. MECHANISM OF CELL INJURY CONT.
The biochemical mechanisms which contribute to
membrane damage are:
 Accelerated degradation of membrane phosholipid
 Mitochondrial dysfunction
 Cytoskeletal abnormalities
 Reactive oxygen species
 Lipid breakdown products

39. Cellular and biochemical sites of damage in cell injury.

40. Functional and morphologic consequences of decreased intracellular ATP during cell injury.

41. REVERSIBLE AND IRREVERSIBLE CELL INJURY
 Within limits, the cell can compensate for these
derangements and,
 If the injurious stimulus is removed the damage can
be reversed.
 Persistent or excessive injury, however, causes
cells to pass the threshold into irreversible injury.

42. REVERSIBLE AND IRREVERSIBLE CELL INJURY
Irreversble injury is marked by :
- severe mitochondrial vacuolization,
- extensive damage to plasma membranes,
- swelling of lysosomes and
- the appearance large, amorphous densities in
mitochondria..

43. REVERSIBLE AND IRREVERSIBLE CELL INJURY
Two phenomena consistently characterize
irreversibility.
1) The inability to reverse mitochondrial
dysfunction (lack of oxidative phosphorylation and
ATP generation) even after removal of the original
injury.
2) Profound loss in membrane function

44. PATHOGENESIS OF ISCHAEMIC & HYPOXIC
INJURY
Hypoxia/Ishaemia
ATP loss
Decresed PH
( cytosol)
Damaged sodium pump
(membrane)
Decreased Protein synthesis
(RER)
Ultastuctural/functional changes
Reversible cell injury

45. Reversible cell injury
 1.Decresed generation of cellular ATP
 2Reduced intracellular PH
 3.Damage to plasma membrane sodium pump
 4.Reduced protein synthesis
 5.Functional consequences
 6.Ultrastructural changes

46. Reversible
Ireversible
Ultrastructural changes

47. IRREVERSIBLE CELL INJURY
 1.Mitochondrial dysfunction
 2.Membrane damage
 3.Hydrolytic enzymes
 Serum estimation of liberated enzymes

48. ISCHEMIA-REPERFUSION INJURY
 Restoration of blood flow to ischemic tissues can result in
recovery of cells if they are reversibly injured.
 Ischemia-reperfusion injury is a clinically important
process in such conditions as myocardial infarction and
stroke.

49. ISCHEMIA-REPERFUSION INJURY
 New damaging processes are set in motion during
reperfusion, causing the death of cells that might
have recovered otherwise New damage may be
initiated during reoxygenation by increased
generation of oxygen free radicals from
parenchymal and endothelial cells and from
infiltrating leukocytes
 Reactive oxygen species can further promote the
mitochondrial permeability transition,

50. ISCHEMIA-REPERFUSION INJURY
 Ischemic injury is associated with inflammation as a
result of the production of cytokines and increased
expression of adhesion molecules by hypoxic
parenchymal and endothelial cells.
 These agents recruit circulating polymorphonuclear
leukocytes to reperfused tissue; the ensuing
inflammation causes additional injury.
 Activation of the complement pathway may
contribute to ischemia-reperfusion injury.

51. FREE RADICAL MEDIATED INJURY
Role of free radical injury:
1.Ischaemia reperfusion injury
2.Ionisation radiation by causing radiolysis of water
3.Chemical toxicity
4.Hyperoxia
5.Cellular ageing
6.Killing of exogenous biologic agents
7.Inflammatory damage
8.Destruction of tumor cells
9.Chemical carcinogenesis

53. CHEMICAL /TOXIC INJURY
 Chemicals cause cell injury
 Mechanism- free radical mediated injury
 Examples:
Eg: Mercuric chloride
Cyanide poisoning
Acetaminophen
CCL4

54. PHYSICAL INJURY
Ionising Radiation
H20
0H
Proliferating cells
(epithelial cells)
Non proliferating
cells(neurons)
DNA damage Lipid peroxidation
Cell membrane damage
NECROSIS
Genetic damage
Inhibition of DNA
replication
MUTATIONS
APOPTOSIS

55. CLASSIFICATION OF MORPHOLOGIC FORMS
OF CELL INJURY
Mechanism of cell injury Nomenclature
Reversible cell injury Retrogressive changes
Irreversible cell injury Cell death-necrosis
Programmed cell death Apoptosis
Residual effect of cell injury Subcellular alterations
Deranged cell metabolism Intracellular accumulation of
lipd,protein,carbohydrates
Altered effects of necrosis Gangrene,pathologic
Calcification

56. MORPHOLOGY OF REVERSIBLE CELL INJURY
DEGENERATION
RETROGRESSIVE CHANGES
 1.Cellular Swelling/Cloudy change/ Hydropic
degeneration
 2.Hyaline change
 3.Mucoid change
 4.Fatty change

57. 1.Cellular Swelling/Cloudy change/ Hydropic
degeneration
 Commonest & earliest form of cell injury from
almost all causes
 Causes: Bacterial toxins, chemicals, poisons, burns
 Impaired regulation of cellular volume esp sodium

58. GROSS FINDINGS
 Affected organ (Kidney, Liver or heart) enlarged due
to swelling
 Cut surface- bulges outwards and is slightly opaque
MICROSCOPIC FINDINGS：
 1. Cell swelling, cytoplasm contains coarse
granules, microvasculature compressed
 2.Small clear vacuoles seen in cells(VACUOLAR
DEGENERTION)

59. Cloudy Kidney (Microscopic examination)

60. HYALINE CHANGE
 Glassy, eosinophilic, homogenous in H & E
 Hyaline change : Intracellular & Extracellular
INTRACELLULAR HYALINE: ( epithelial cells)
Hyaline droplets in proximal tubular epithelium
Zenkers degeneration
Mallory hyaline
Russels bodies
Nuclear cytoplasmic hyaline inclusions

61. EXTRACELLULAR HYALINE (connective tissue)
Hyaline degeneration of uterus (Leiomyoma)
Hyalinised old scar of fibrocollagenous tissue
Hyaline arteriosclerosis in renal vessels in HT& DM
Hyalines glomeruli in CGN
Corpora amylacea seen in elderly, in brain spinal cord
of old age, old infarcts in lung

62. Hyaline degeneration

63. MUCOID CHANGE
 Mucin- mucus glands,
 Epithelial and connective tissue
 Epithelial mucin PAS +
 Connective tissue mucin PAS-
Epithelial mucin:
Catarrhal inflammation of mucus membranes( resp
tract,GIT,Uterus)
Obstruction of duct leading to mucocoele in oral
cavity and gall bladder
Cystic fibrosis of pancreas
Mucin secreting tumors

64. Connective tissue mucin
Mucoid or myxoid degeneration in some tumors eg
myxomas,neurofibromas
Dissecting aneurysms of aorta
Myxomatous change of dermis in myxedema
Myxoid change in synovium in ganglion on the wrist

65. INTRACELLULAR ACCUMULATIONS
 Abnormal intracellular accumulations can be
divided in to 3 groups
1.Accumulation of constituents of normal cell
metabolite produced in excess:
Accumulation of lipid(fatty change,cholestrol deposits)
proteins and carbohydrates,amyloid
2.Accumulation of abnormal substances due to
abnormal metabolism/lack of enzymes:
Storage disorders or inborn errors of metabolism
3.Accumulation of pigments

66. FATTY CHANGE/STEATOSIS
 Intracellular accumulation of neutral fat within
parenchymal cells
 Commonest- liver, others- heart, skeletal
muscle,kidney
FATTY LIVER
Liver- commonest site of accumulation of fat
Etiology:
Alcohol, Starvation,malnutrition,obesity,diabetes
mellitus, chronic illnesses, drugs,reyes syndrome

67. Diet Adipose tissue
Free Fatty acids
Fatty acids
Triglyceride
Lipoproteins
Plasma Lipoprotein
Cholestrol esters
Phospholipids
Ketone bodies
Acetate
1
2
3
4
5
6
Pathogenesis

68. GROSS- enlarged, with tense glistening capsule
and rounded margins.Cut surface-bulges slightly,pale
yellow, greasy

69. Microscopy showing numerous lipid vacuoles in hepatocytes

70. SUMMARY
 Cell Injury
Types
Mechanism
Reversible & Irreversible Injury
Hypoxic injury
Free radical Injury
Chemical & Physical Injury
 Degenerations
Cloudy
Fatty
Hyaline
Mucoid