General Pathology

PETER S. AZNAR, MD, FPSP

Pathology
The study of suffering (from the Greek pathos),
or the study of functional changes in cells,
tissues, and organs that underlie disease

Homeostasis
State of internal equilibrium at which normal
physiologic demands of a cell are met;
pathophysiology results when stimuli (ie, cell
injury) sufficiently disrupt homeostasis.

Cellular Adaptation to Stress:

Hyperplasia
Hypertrophy
Atrophy
Metaplasia
Dysplasia

Hyperplasia
An increase in number of cells as an adaptive
response to stress, usually resulting in
increased volume of an organ or tissue. Cells
must be capable of mitotic division (eg,
prostate).

Hypertrophy
An increase in cell size due to synthesis of
cellular structural components as an adaptive
response to stress, usually resulting in
increased size of an organ or tissue.

Atrophy
reduction of cell size due to loss of structural
components of the cell. An attempt by the cell
to reduce demand to match reduced supply.
The entire tissue/organ diminishes in size
when enough cells are involved.

Metaplasia
is the process of reversible change that
occurs when one adult cell type is
replaced by another adult cell type.

Dysplasia
is the process of disordered cell growth
harbinger to cancer

Cell Injury
Reversible

Irreversible

ATP depletion
Cellular/mitochondrial swelling

Nuclear pyknosis, karyorrhexis,

karyolysis

Nuclear chromatin clumping

Plasma membrane damage

Fatty change
Ribosomal/polysomal detachment
Membrane blebbing
Water influx
Ion efflux
Reduced oxidative phosphorylation

Lysosomal rupture
Mitochondrial
permeability/vacuolization
Phospholipid-containing amorphous
densities within mitochondria

Hallmarks of Irreversible Cell Injury

Karyolysis
Karyorrhexis
Pyknosis

Karyolysis
Dissolution of the nucleus (karyo- = nucleus,
-lysis = to break apart)

Karyorrhexis
Nuclear fragmentation (karyo- = nucleus,
-rrhexis = rupture)

Neutrophilic karyorrhexis in patient with MI

Pyknosis
Nuclear shrinkage and condensation

Main types of Cell Death:

Apoptosis
Necrosis

Apoptosis
A process of cell death by which a cell
activates enzymes (caspases) that degrade
the cells own DNA and proteins (ie,
programmed cell death) while maintaining

Steps of Apoptosis:

Cell shrinkage
Chromatin condensation and fragmentation
Formation of apoptotic bodies
Phagocytosis by macrophages

Three Pathways that Initiates Apoptosis

Intrinsic (mitochondrial) pathway

Extrinsic (death receptor-initiated) pathway
Cytotoxic T-lymphocyte mediated pathway;
all three converge on executioner caspases
to initiate the execution phase of apoptosis

Simplified schematic of apoptosis. TNF, Tumor necrosis

factor; TNFR, tumor necrosis factor receptor.

Death Receptor Pathway Activation

AKA Extrinsic pathway
Death receptors (TNFR1)are cell surface receptors
that transmit signals for apoptosis when they are
bound by specific ligands
TNFR1 is activated by TNF
TNF is an important cytokine produced by
macrophages

Death Receptor Pathway Activation

TNFR1 activation by TNF leads to activation of
initiator caspases (8 & 10) in the cytosol
Initiator caspases activate effector caspases
(proteases and endonucleases)
Proteases destroy cytoskeleton
Endonucleases causes pyknosis and karyorrhexis

Mitochondrial Pathway Activation

AKA Intrinsic pathway
Involves the release of sensors that lead to
leakage of mitochondrial proteins (cytochrome c)
resulting in activation of caspases.
Associated with the BCL gene family
(mitochondrial) pathway activation

Mitochondrial Pathway Activation

BCL gene family

BCL-2 (antiapoptotic)
BAX (apoptotic)
BAK (apoptotic)

Mitochondrial Pathway Activation

BCL-2

Located in chromosome 18
Maintains mitochondrial membrane integrity
Prevents leakage of mitochondrial proteins
that can trigger apoptosis

Mitochondrial Pathway Activation

BAK and BAX
Produced by DNA damage, misfolded proteins, FR
damage, viral infections
Forms mitochondrial membrane channels causing leakage
of cytochrome c to the cytosol
Cytochrome c complexes with another protein leading to
the activation of an initiator caspase (caspase-9)
Caspase-9 will activate proteases and endonucleases

Execution Phase of Apoptosis

Proteases and Endonucleases do their work
Cytoplasmic buds begin the form in cell membrane
Cytoplasmic buds break off and form apoptotic
bodies
Apoptotic bodies are phagocytosed by
macrophages

Microscopic Appearance of Apoptosis

a. Cell detaches from neighboring cells
b. Apoptotic cells have deeply eosinophilic-staining
cytoplasm with the H&E stain
c.

Nucleus is pyknotic, fragmented, or absent

d. Inflammatory infiltrate is absent or minimal

Necrosis
A process of cell death by lysosomal enzymatic
digestion and loss of plasma membrane
integrity

Coagulative Necrosis
heart, liver, kidney
occurs in tissues supplied by end-arteries
increase cytoplasmic binding of acidophilic dye
proteins denature first, followed by enzymatic
degradation

Coagulative Necrosis

Liquefactive Necrosis
Brain, bacterial abscess
Occurs in CNS due to high fat content
Enzymatic degradation due to the release of
lysosomal enzymes occurs first

Liquefactive Necrosis

Liquefactive Necrosis

Liquefactive Necrosis

Coagulative Necrosis

Caseous Necrosis

TB
Systemic fungi
Nocardia

Caseous Necrosis Gross

Langhan Giant Cell

Foreign Body Giant Cell

Fatty Necrosis
Enzymatic (pancreatitis [saponification])
Nonenzymatic (e.g., breast trauma)
Calcium deposits appear dark blue on staining.

Acute Pancreatitis with Enzymatic Fat Necrosis

Fibrinoid Necrosis
Vasculitides (e.g., Henoch-Schnlein purpura,
Churg-Strauss syndrome)
Malignant hypertension

Henoch-Schnlein purpura

Gangrenous Necrosis
Dry (ischemic coagulative) and wet (infection)
Common in limbs and GI tract

Gangrenous Necrosis

Areas susceptible to hypoxia/ischemia and

infarction:
Organ

Location

Brain

ACA/MCA/PCA boundary areas

Heart

Subendocardium (LV)

Kidney

Straight segment of proximal tubule (medulla)

Thick ascending limb (medulla)

Liver

Area around central vein (zone III)

Colon

Splenic flexure, Rectum

Infarcts
Red

Pale

(hemorrhagic) infarcts occur in

infarcts occur in solid
loose tissues with multiple tissues with a single blood
blood supplies, such as liver, supply, such as heart, kidney,
lungs, and intestine.
and spleen.

Infarct
Red

Pale

Etiology

Apoptosis

Necrosis

Physiologic or Pathologic

Pathologic

Initiated by
Caspases
Digestion

Lysosomal Enzymatic

Cell Apoptosis Compared with Necrosis

Features

Apoptosis

Cell Necrosis

General

Programmed, enzyme-mediated
individual cell death without a
prominent inflammatory infiltrate

Death of groups of cells usually

accompanied by an inflammatory
infiltrate

Size of cell

Shrunken cell due to loss of

cytoplasm from cytoplasmic buds
that pinch off and become
apoptotic bodies

Intracellular swelling due to

sodium-containing water entering
the cell (dysfunctional Na+/K+
ATPase pump)

Enzymes involved

Initiator caspases, executioner

caspases (protease,
endonuclease)

Phospholipase, protease,
endonuclease

Genes involved

BCL-2 (anti-apoptosis), BAX

(proapoptotic), BAK (proapoptotic)

None

Role

Physiologic functions (e.g.,

embryology, thymus involution);
pathologic function (e.g., removal
misfolded proteins, removal of
neutrophils in acute inflammation)

Usually associated with a

pathologic process

Characteristics of Inflammation

Rubor (redness)
Dolor (pain)
Calor (heat)
Tumor (swelling)
Functio laesa (loss of function)

Inflammation
Acute

Chronic

Cells

Neutrophil
Eosinophil

Mononuclear cells
Fibroblast

Hallmarks

None

Blood vessel proliferation

Fibrosis
Granuloma

Course

Resolution
Abscess formation

Scarring
Amyloidosis

Histamine-mediated

Rubor
Calor
Tumor

Mediated by ProstaglandinE2 and Bradykinin

Dolor

Sequential Vascular Events in AI

Vasoconstriction of arterioles
Vasodilation of arterioles
Increased permeability of venules
Swelling of tissue
Reduced blood flow

Vasodilation of Arterioles
Histamine and other vasodilators relax vascular
smooth muscle, causing increased blood flow.
Increased blood flow due to vasodilation of arterioles
increases hydrostatic pressure (HP) in venule
lumens.

Vasoconstriction of Arterioles
Due to a neurogenic reflex that lasts only a few seconds

Increased Permeability of Venules

a. Histamine and other mediators contract
endothelial cells in venules, producing
endothelial gaps exposing bare basement
membrane.
b. Transudates (fluid low in proteins and cells)
move through the intact venular basement
membrane into interstitial tissue because of the
increased HP.

Swelling of tissue (tumor, edema)

Net outflow of fluid from venules surpasses the
capacity of lymphatics to remove fluid; hence,
there is swelling of tissue.

Reduced Blood Flow

Reduced blood flow eventually occurs because of
outflow of fluid into the interstitial tissue and
increased uptake of fluid by lymphatics.

Types of Calcification
Dystrophic calcification
Metastatic calcification

Dystrophic Calcification
Calcium deposition in tissues 2 to necrosis.
Tends to be localized (e.g., on heart valves).
Seen in TB (lungs and pericardium), liquefactive necrosis of
chronic abscesses, fat necrosis,
infarcts, thrombi, schistosomiasis, Mnckeberg
arteriolosclerosis, congenital CMV
+ toxoplasmosis, psammoma bodies.
Is not directly associated with hypercalcemia (i.e., patients are
usually normocalcemic).

Metastatic Calcification
Widespread (i.e., diffuse, metastatic) deposition of
calcium in normal tissue 2 to hypercalcemia
1 hyperparathyroidism, sarcoidosis, hypervitaminosis
D) or high calcium-phosphate product (e.g., chronic
renal failure + 2 hyperparathyroidism, long-term
dialysis, calciphylaxis, warfarin).
Calcium deposits predominantly in interstitial tissues of
kidney, lungs, and gastric mucosa
Patients are usually not normocalcemic.

Chemical Mediators in AI
Mediator

Sources

Functions

Prostaglandins

Macrophages, endothelial cells

platelets
PGH2: major precursor of PGs and
thromboxanes

PGE2: vasodilation, pain, fever,

PGE1: vasodilation, inhibition of
platelet aggregation

Thromboxane A2

Platelets converted from PHG2 by

thromboxane synthase

Vasoconstriction, platelet
aggregation

Leukotienes (LIs)

Leukocytes
Converted from arachidonic acid by
lipoxygenase-mediated hydroxylation

LTB4: chemotaxis and activation of

neutrophil adhesion molecules
LTC4, LTD4, LTE4:
vasoconstriction, increase venular
permeability, bronchoconstriction
Zeleuton inhibits 5- lipoxygenase:
decrease synthesis LTB4, LTC4,
LTD4, LTE4

Arachidonic Acid
Metabolites

Chemical Mediators in AI
Mediator

Sources

Functions

Bradykinin

Product of kinin system

activation by activated
factor XII

Vasodilation, increased venular

permeability, pain

Chemokines

Leukocytes, endothelial
cells

Activate neutrophils and stimulate their

migration through the endothelium to the
site of infection (Chemotaxis, see figure
3-5)

Complement

Synthesized in liver
(acute phase reactant)

C3a, C5a (anaphylatoxins): stimulate

mast cell release of histamine
C3b: Opsonization
C5a: activation of neutrophil adhesion
molecules, chemotaxis
CS-C9 (membrane attack complex): cell
lysis

Arachidonic Acid Metabolites

Chemical Mediators in AI
Mediator

Sources

Functions

Arachidonic Acid Metabolites

IL-1, TNF

Macrophages (main source),

monocytes, dendritic cells,
endothelial cells

Initiate PGE2 synthesis in the anterior

hypothalamus, leading to production of fever
Activate endothelial cell adhesion molecules
TNF is a promoter of apoptosis

IL-6

Primary cytokine responsible for increased liver

synthesis of acute phase reactants (APRs),such
as ferritin, coagulation factors, (e.g., fibrinogen),
and C-reactive protein

IL-8

Chemotaxis

Histamine

Mast cells (primary cell),

platelets, enterochromaffin
cells

Vasodilation, increased venular permeability

Nitric Oxide (NO)

Macrophages, endothelial cells

free radical gas released
during conversion of arginine
to citrulline by NO synthase

Vasolidation, bactericidal

Factors Involved in Tissue Repair

FACTOR

FUNCTIONS

Growth Factors
Vascular endothelial cell
growth factor (VEGF)

Stimulates angiogenesis
Stimulation factors: TNF released by macrophages,
hypoxia via hypoxia-inducible factor released by cells

Fibroblast growth factor

(FGF)

Chemotactic for fibroblasts; stimulates keratinocyte

migration, angiogenesis, wound contraction

Epidermal growth factor

(EGF)

Stimulates keratinocyte migration, granulation tissue

formation

Platelet-derived growth
factor (PDGF)

Chemotactic for neutrophils, macrophages, fibroblasts,

endothelial cells, smooth muscle cells

Factors Involved in Tissue Repair (contd)

FACTOR

FUNCTIONS

Growth Factors

Transforming growth factor-

(TGF-)

Chemotactic for macrophages, lymphocytes,

fibroblasts, smooth muscle cells

Interleukins (IL), Cytokines

IL-1

Stimulates synthesis of metalloproteinases

Stimulates synthesis and release of acute phase
reactants from the liver
.

Tumor necrosis factor (TNF)

Activates macrophages; stimulates release of acute

phase reactants

Comparison of Chronic Granulomatous

Disease and Myeloperoxides Deficiency
CHRONIC
GRANULOMATOUS
DISEASE

MYELOPEROXIDASE
DEFICIENCY

Inheritance pattern

X-linked recessive

Autosomal recessive

NADPH oxidase

Absent

Present

Myeloperoxidase

Present

Absent

Respiratory burst

Absent

Present

Peroxide (H2O2)

Absent

Present

Bleach (HOCl)

Absent

Absent

Cell Cycle

Stages of the Cell Cycle

G0 phase: resting phase of stable cells
G1 phase: most variable phase
synthesis of DNA, RNA and protein
S (synthesis) phase
synthesis of DNA, RNA and protein

Stages of the Cell Cycle

G2 Phase
synthesis of tubulin for mitotic spindle
M (mitotic) phase
two daughter cells are produced

Stages of the Cell Cycle

Regulation of the G1 checkpoint (G 1 to S phase)
Most critical phase
Control proteins include:
Cyclin-dependent kinase 4 (Cdk4) and cyclin D
Cdk4 phosphorylates the RB1 protein, causing
the cell to enter S phase

Genes controlling G1 to S phase

RB1
p53 suppressor genes

Note: Inhibition of Cdk4, prevents RB1 protein phosphorylation, which

provides time for repair of damaged DNA in the cell

p53 Suppressor Gene

Inhibit the translation of the BCL-2 antiapoptosis
genes, which leads to apoptosis of the cell
Inhibit the translation of growth-promoting genes
leading to growth arrest
Absence of the p53 gene product allows the cell to
enter the S phase of the cell cycle

Types of Wound Healing

Primary
Secondary
Tertiary

Types of Wound Healing

Primary
clean wound approximated by suturing

Types of Wound Healing

Primary (Day 1)
Fibrin clot (hematoma) develops
PDGF attracts neutrophils
Increase mitotic activity of basal cells squamous
epithelium in the apposing wound margins
FGF, EGF involved in keratinocyte migration

Types of Wound Healing

Primary (Day 2)
Squamous cells from apposing basal cell
layers migrate under the fibrin clot and seal off
the wound after 48 hours.
Macrophages emigrate into the wound (PDGF,
TGF- chemotactic to macrophages).

Types of Wound Healing

Primary (Day 3)
Granulation tissue begins to form (FGF, EGF, PDGF,
TGF- all involved in angiogenesis).
Initial deposition of type III collagen by fibroblasts
begins but does not bridge the incision site (FGF,
PDGF, TGF- chemotactic to fibroblasts).
Macrophages replace neutrophils.

Types of Wound Healing

Primary (Day 4-6)

Granulation tissue formation peaks, and

collagen bridges the incision site.

Types of Wound Healing

Primary (Week 2)

Collagen compresses blood vessels in fibrous

tissue, resulting in reduced blood flow. Tensile
strength is ~ 10%.

Types of Wound Healing

Primary (Month 1-3)
Collagenase remodeling of the wound occurs with
degradation of type III collagen and replacement by type I
collagen
Tensile strength increases, reaching ~ 80% within 3 months
Scar tissue is devoid of adnexal structures and
inflammatory cells.

Types of Wound Healing

Secondary
contaminated wound left open for reepithelialization
reserved for highly contaminated wounds

Types of Wound Healing

Secondary Intention
More intense inflammatory reaction than primary
healing
Increased amount of granulation tissue formation
than in primary healing
Wound contraction caused by increased numbers
of myofibroblasts

Types of Wound Healing

Tertiary Intention

contaminated wound dbrided and treated

with antibiotics
wound is surgically closed

Factors Affecting Wound Healing

A.

Persistent infection

Most common etiology

S. aureus is the most common pathogen

Nosocomial and community-acquired

methicillin-resistant S. aureus (MRSA)
wound infections are increasing

Factors Affecting Wound Healing

A2. Disruption of skin and malnutrition

A3. Improper hand washing

20% 40% people carry MRSA in anterior

nares

Factors Affecting Wound Healing

A4.Majority of community-acquired MRSA (CA-MRSA) infections
produce the Panton-Valentine leukocidin

Accelerates apoptosis of neutrophils; hence not many

neutrophils are present in the wounds to phagocytose
and destroy the bacteria

Causes the infection to progress to necrotizing fasciitis

Trimethoprim-sulfamethoxazole-DS (primary)
IV vancomycin (alternative) are frequently used in
treating these infections.

Factors Affecting Wound Healing

B. Diabetes Mellitus
Increase susceptibility to infection by:
Decrease Blood Flow
Increase Tissue Glucose Levels

Factors Affecting Wound Healing

C. Nutritional Deficiencies
Decreased protein
Vitamin C deficiency
Trace metal deficiency
Copper deficiency leads to decreased cross-linking in
collagen
Zinc deficiency leads to defects in removal of type III
collagen in wound remodeling.

Factors Affecting Wound Healing

D. Glucocorticoids
Prevents scar formation
Interfere with collagen formation and decrease tensile strength
Useful clinically in preventing excessive scar formation
Dexamethasone is used along with antibiotics to prevent scar
formation in bacterial meningitis.
Plastic surgeons inject high potency steroids into wounds to
prevent excessive scar tissue formation.

Keloids and Hypertrophic Scars

Genetic Predisposition

Keloid

Hypertrophic Scar

Grow beyond the border of

the original wound

Raised scar remaining

in confines of original
wound

Develop in 15% to 20% of

African-Americans, Asians
and Hispanics

None

Refractory to medical and

surgical intervention

Frequently regress
spontaneously

Keloid

Hypertrophic scar

Thank You!