UNIT 2 –

INTRODUCTION
TO PATHOLOGY
Sarah Tan de Luna, MD, MPH
End of Unit Quiz
WEDNESDAY, AUG 31,
2022 – 8116, 8123,
8130, 8144
End of Unit Quiz
SATURDAY, SEPT 27,
2022 – 8151, 8158,
8165
◼UNIT2, PART 1
◼VOCABULARY 2
YOU:
PART 2
Cell Injury, Death,
and Adaptation
Sarah Tan de Luna, MD, MPH
CELL ADAPTATION
Pathology: the Study of Disease
◼ Etiology or cause: infection, genetic etc. and
often mutifactoral

◼ Pathogenesis: progression of the disease

◼ (Molecular and Morphologic Changes)

◼ Clinical Manifestations: signs and symptoms

Overview
 Overview
◼ Cells are the structural and functional units
of tissues and organs. They are capable of
adjusting their structure and functions in
response to various physiological and
pathological conditions. This capability is
called cellular adaptation.
◼ Adaptation results in a NEW STEADY
STATE and PRESERVING VIABILITY
Adapted-Normal-Injured Cells
 Overview
◼ Whether a specific form of stress induces
adaptation or causes reversible or
irreversible injury depends not only on the
nature and severity of the stress, but also
on several other cell-specific variables,
including vulnerability, differentiation, blood
supply, nutrition, and the previous state of
the cell
Cell Proliferation Varies
◼ Labile cells – continuously dividing
(epithelium, bone marrow, hematopoietic
cells)
◼ Stable cells – quiescent (in G0 stage;
hepatocytes, smooth muscle,
lymphocytes, fibroblasts, endothelial cells)
◼ Permanent cells – nondividing (neurons,
skeletal and cardiac muscle)
Various Types of Adaptations

◼ Cells may undergo various adaptations in

physiological and pathological conditions.
These are controlled by complex
molecular mechanisms.
 Cellular Adaptations
◼ Hypertrophy
◼ Hyperplasia
◼ Atrophy
◼ Metaplasia
◼ Dysplasia*
 Cellular Adaptations
◼ Physiologic – occurs due to a normal
stressor/stimuli; results in enhanced
function
◼ Pathologic – occurs due to an abnormal
stressor/stimuli; results in dysfunction and
mortality
◼ Compensatory – adaptation to positively
counteract reduction in function
Hypertrophy-
◼ Increase in the size of cells which results
in enlargement of the organs.
◼ There are no new cells, just bigger cells,
enlarged by an increased amount of
structural proteins and organelles
(increase in mRNA and proteins)
Hypertrophy-
◼ Occurs in response to increased demands
◼ It is mostly seen in cells that cannot divide,
such as:
 skeletal muscle (pumping iron),
 cardiac muscle (hypertension).
◼ These changes usually revert to normal if
the cause is removed.
Physiologic Hypertrophy
Pathologic Hypertrophy
◼ Cross-section of the
heart of a patient with
long-standing
hypertension shows
pronounced,
concentric left
ventricular
hypertrophy
Hyperplasia-
◼ Increased number of cells in an organ or
tissue. Hyperplasia may sometimes co-
exist with hypertrophy.
◼ Takes place if the cell is capable of
replication
Physiologic Hyperplasia
Pathologic Hyperplasia
Hypertrophy and Hyperplasia
Atrophy
◼ Shrinkage in the size of the cell by loss of
substance
◼ When a sufficient number of cells is
involved, the entire tissue or organ
diminishes in size
◼ Although atrophic cells may have
diminished function, they are not dead
Atrophy results from both…

◼ Decreased protein synthesis

◼ Increased protein degradation
-Lysosomes with hydrolytic enzymes
-The ubiquitin-proteasome pathway
Physiologic Atrophy
Pathologic Atrophy
Metaplasia
◼ A reversible change in which one ADULT
cell type is replaced by another ADULT cell
type that is able to withstand the adverse
environment
◼ Reversible change in which one
differentiated cell type (epithelial or
mesenchymal) is replaced by another cell
type.
◼ Usually occurs in response to stress or
chronic irritation.
Mechanisms of Metaplasia
◼ Re-programing of stem cells that exist in
normal tissue.
◼ Induced by cytokines, growth factors and
other environmental signals
◼ Retinoic acid may play a role.
◼ Exact mechanism is unknown.
Squamous cells replace columnar cells
Metaplasia
◼ Squamous metaplasia
◼ Osseous metaplasia
◼ Myeloid metaplasia
Squamous Metaplasia
Squamous Metaplasia
Esophagus: glandular epithelium (R) is metaplastic
Bronchus with Columnar to
Squamous Metaplasia
Esophagus with Squamous to
Columnar metaplasia
Endometrial Osseous
Metaplasia
Myeloid Metaplasia
◼ Atrophy, Hypertrophy, Hyperplasia and
Metaplasia are reversible changes!
◼ Hyperplasia and Metaplasia are not
premalignant changes, however they are
“fertile fields” for Dysplasia which is a
premalignant change
Dysplasia
◼ Atypical proliferative changes due to
chronic irritation or inflammation;
◼ Cells vary in size and shape, large nuclei
are frequently present, and rate of mitosis
is increased
◼ Premalignant change
DYSPLASIA IN THE CERVIX

Mild dysplasia Moderate Marked

dysplasia dysplasia
Anaplasia
◼ Cells are undifferentiated with variable
nuclear and cell structures and numerous
mitotic figures
◼ Characteristic of cancer and tumor and is
the basis for grading the aggressiveness
of a tumor
Neoplasia
◼ “New growth”
◼ A tumor
◼ Benign – considered less serious because
they do not spread and are not life
threatening (except in the brain)
◼ Malignant - cancer
Aplasia
◼ Failure of cell production. During fetal
development, aplasia results in agenesis,
or absence of an organ due to failure of
production.

Hypoplasia
Incomplete development of an organ so
that it fails to reach adult size; decrease in
cell production that is less extreme than in
aplasia.
Examples of Hypoplasia

Hypoplastic Left Ventricle

Hypoplastic Kidney
CELL INJURY
Cell Injury
Overview of Cell Injury
◼ Cells actively control the composition of
their immediate environment and
intracellular milieu within a narrow range of
physiological parameters
(“homeostasis”)
◼ Under physiological stresses or
pathological stimuli (“injury”), cells can
undergo adaptation to achieve a new
steady state that would be compatible with
their viability in the new environment.
Overview of Cell Injury
◼ Reversible cell injury – denotes
pathologic changes that can be reversed
when the stimulus is removed, or if the
cause of injury is mild
◼ Irreversible injury – denotes pathologic
changes that are permanent and cause
cell death
Causes of Cellular Injury
1. Hypoxic Cell injury – oxygen deprivation
a) Ischemia – loss of blood supply(oxygen
and nutrients); more rapidly and
severely injures tissues than does
hypoxia alone
b) Inadequate oxygenation –
cardiorespiratory failure
c) Loss of oxygen carrying capacity of blood
– anemia, carbon monoxide poisoning
Cell Proliferation Varies
◼ Labile cells – continuously dividing
(epithelium, bone marrow, hematopoietic
cells)
◼ Stable cells – quiescent (in G0 stage;
hepatocytes, smooth muscle,
lymphocytes, fibroblasts, endothelial cells)
◼ Permanent cells – nondividing (neurons,
skeletal and cardiac muscle)
Susceptibility of Cells to
Hypoxic Injury
High Neurons (3-4 min)

Intermediate Myocardium, hepatocytes,

renal epithelium (30 min-2hr)

Low Fibroblasts, epidermis, skeletal

muscle (many hours)
Causes of Cellular Injury
2. Free Radical Injury
◼ ROS – Hydroxyl, Hydrogen, Superoxide
◼ Chemical species with a single unpaired
electron in an outer orbital
◼ Chemically unstable and therefore react with
other molecules, resulting in chemical damage
◼ Initiate autocatalytic reactions; molecules that
react with free radicals are in turn converted to
free radicals
Free-Radical Induced Injury
◼ If not adequately neutralized, free radicals
can damage cells by
1. Lipid peroxidation of membranes –
double bonds in polyunsaturated
membrane lipids are vulnerable to attack
by oxygen free radicals
Free-Radical Induced Injury
2. DNA fragmentation – Free radicals react
with thymine in nuclear and mitochondrial
DNA to produce single strands breaks
3. Protein cross-linking – Free radicals
promote sulfhydryl-mediated protein cross
linking, resulting in increased degradation
and loss of activity
Neutralization of Free Radicals
1. Spontaneous decay
2. Superoxide dismutase
3. Glutathione (GSH)
4. Catalase
5. Endogenous and exogenous antioxidants
(Vitamins E, A, C and β carotene)
Causes of Cellular Injury
3. Physical Agents – trauma, heat, cold,
radiation, electric shock
4. Chemical Agents -
a) Therapeutic drugs - paracetamol
b) Nontherapeutic agents – lead, alcohol
c) Binding of mercuric chloride to sulfhydryl
groups of proteins
d) Generation of toxic metabolites such as
conversion of CCl4 to CCL3* free radicals in
the SER of the liver
Causes of Cellular Injury
5. Infectious Agents -
a) Viruses
b) Bacteria
c) Fungi
d) Rickettsiae
e) Bacteria
f) Fungi
g) Parasites
Infectious agents
◼ Infectious agents - direct effects of
bacterial toxins; cytopathic effects of
viruses and other actions such as:
 interfering with DNA,RNA, proteins, cell
membranes or
 inducing apoptosis.
 -indirect effects via the host immune reaction.
Causes of Cellular Injury
6. Immune System - anaphylaxis, loss of
immune tolerance leading to autoimmunity
7. Genetic Abnormalities - sickle cell
disease, inborn errors of metabolism
Causes of Cellular Injury
8. Nutritional imbalances – vitamin
deficiencies, obesity leading to type II DM,
fat leading to atherosclerosis
9. Aging – degeneration as a result of
trauma, intrinsic cellular senesence
CELL DEATH
Cell Death

◼ Death of cells occurs in two ways:

 Necrosis--(irreversible injury) changes
produced by enzymatic digestion of dead
cellular elements
 Apoptosis--vital process that helps eliminate
unwanted cells--an internally programmed
series of events effected by dedicated gene
products
Necrosis
◼ Morphologic expression of cell death
◼ Progressive disintegration of cell
structure
◼ Initiated by overwhelming stress
◼ Usually elicits an acute inflammatory cell
response (neutrophils may be present).
Types of Necrosis
Patterns of Necrosis In Tissues or
Organs – Macroscopic Changes
Coagulative necrosis:
◼ typically seen in hypoxic environments
◼ the outline of the dead cells are
maintained and the tissue is
somewhat firm.
◼ Example: myocardial infarction
Coagulative Necrosis
◼ When there is marked cellular
injury, there is cell death. This
microscopic appearance of
myocardium is a mess
because so many cells have
died that the tissue is not
recognizable. Many nuclei
have become pyknotic
(shrunken and dark) and have
then undergone karorrhexis
(fragmentation) and karyolysis
(dissolution). The cytoplasm
and cell borders are not
recognizable.
Patterns of Necrosis In Tissues or
Organs – Macroscopic Changes
 Liquefactive necrosis: the dead cells
undergo disintegration and affected tissue is
liquified.
◼ Example: cerebral infarction.
◼ usually associated with cellular destruction
and pus formation (e.g. pneumonia).
◼ ischemia (restriction of blood supply) in the
brain produces liquefactive rather than
coagulative necrosis.
Brain Abscess with
Liquefactive Necrosis
Abscess/Liquefactive Necrosis
Liquefactive necrosis
◼ This is liquefactive
necrosis in the brain in a
patient who suffered a
"stroke" with focal loss of
blood supply to a portion
of cerebrum. This type of
infarction is marked by
loss of neurons and
neuroglial cells and the
formation of a clear space
at the centre left.
Patterns of Necrosis In Tissues or
Organs – Macroscopic Changes
◼ Caseous necrosis:
 specific form of coagulation necrosis typically
caused by mycobacteria (e.g. tuberculosis).
 a form of coagulative necrosis (cheese-like).
 Example: tuberculosis lesions.
◼ Caseous necrosis hilar
lymph node lung
Caseous Necrosis of
Lung
Granulomatous Inflammation with Central Necrosis
Patterns of Necrosis In Tissues or
Organs – Macroscopic Changes

◼ Gangrenous necrosis:
 Necrosis (secondary to ischemia)
 usually with superimposed infection.
 Example: necrosis of distal limbs, usually foot
and toes in diabetes.
Gangrenous Necrosis
Gangrenous Necrosis
◼ In this case, the toes
were involved in a
frostbite injury. This is
an example of "dry"
gangrene in which
there is mainly
coagulative necrosis
from the anoxic injury.
Patterns of Necrosis In Tissues or
Organs – Macroscopic Changes
 Fibrinoid necrosis is caused by immune-mediated
vascular damage. It is marked by deposition of fibrin-
like proteinaceous material in arterial walls, which
appears smudgy and eosinophilic on light microscopy.
Patterns of Necrosis In Tissues or
Organs – Macroscopic Changes

◼ Fatnecrosis:
Traumatic fat necrosis
Enzymatic fat necrosis - necrosis of
fat by pancreatic enzymes.
Fat Necrosis
◼ This is fat necrosis of the
pancreas. Cellular injury
to the pancreatic acini
leads to release of
powerful enzymes which
damage fat by the
production of soaps, and
these appear grossly as
the soft, chalky white
areas seen here on the
cut surfaces.
Fat Necrosis
Fat Necrosis (L) and Normal Pancreas (R)
Patterns of Necrosis In Tissues or
Organs – Macroscopic Changes
 Gummatous necrosis is restricted to necrosis
involving spirochaetal infections (e.g. syphilis).
Patterns of Necrosis In Tissues or
Organs – Macroscopic Changes
 Haemorrhagic necrosis is due to blockage of the
venous drainage of an organ or tissue (e.g. in
testicular torsion).
Apoptosis
◼ Pathway of cell death induced by a
tightly regulated suicide program.
◼ Controlled by specific genes.
◼ Fragmentation of nucleus, DNA
◼ Blebs form and apoptotic bodies are
released.
◼ Apoptotic bodies are phagocytized.
◼ No neutrophils.
Apoptosis
◼ In the human body ~ 100,000 cells are
produced every second by mitosis and a
similar number die by apoptosis.
◼ Development and morphogenesis
 During limb formation separate digits evolve
 Ablation of cells no longer needed (tadpole)
◼ Homeostasis
 Immune system
 >95% T and B cells die during maturation
(negative selection)
◼ Deletion of damaged/ dangerous cells
Actual Examples of Apoptosis
◼ During development for removal of excess
cells during embryogenesis
◼ To maintain cell population in tissues with
high turnover of cells, such as skin,
bowels.
◼ To eliminate immune cells after cytokine
depletion, and autoreactive T-cells in
developing thymus.
Actual Examples of Apoptosis
◼ To remove damaged cells by virus
◼ To eliminate cells with DNA damage by
radiation, cytotoxic agents etc.
◼ Hormone-dependent involution -
Endometrium, ovary, breasts etc.
◼ Cell death in tumours.
Causes of Apoptosis
◼ Physiologic
◼ Pathologic
Physiologic Apoptosis
◼ Embryogenesis and fetal development
◼ Hormone dependent involution - Prostate
glandular epithelium after castration;
Regression of lactating breast after
weaning, endometrium in menstrual cycle,
mammary gland in menopause
◼ Cell loss in proliferating cell populations –
Immature lymphocytes, Epithelial cells in
the GI tract
Physiologic Apoptosis
◼ Elimination of self-reactive lymphocytes
◼ Death of cells that have served their
function
◼ In developing tissues
◼ programmed cell destruction in
embryogenesis, for example formation of
digits
Apoptosis (Cell Death)
Apoptosis (Cell Death)
Apoptosis (Cell Death)
Pathologic Apoptosis
◼ DNA damage due to radiation, chemotherapy
◼ Accumulation of misfolded proteins leads to ER stress
which ends with apoptosis
◼ Cell death in viral infections that induce apoptosis such
as HIV and Adenovirus or by the host immune response
such as hepatitis
◼ Organ atrophy after duct obstruction
◼ Viral infection – e.g. councilman bodies in liver during
hepatitis
Necrosis vs Apoptosis