KELAINAN SEL

Kelainan Retrogresif, Progresif, Degenerasi,

Nekrosis, Apoptosis, dan Onkogenesis
Bagian Patologi Anatomi
Fakultas Kedokteran Universitas Islam Sumatera Utara
2010 /2011
Dr. H. Soekimin, SpPA
Dr. T. Ibnu Alferraly, SpPA

CELL INJURY, DEATH, AND ADAPTATIO

Definitons
Pathology is a dicipline bridging clinical practice
and basic sience
To render diagnosis and guide therapy
- Identity changes in gross
- Morphology ( microscopy ) appearan
of cell tissues
The scientific focus of pathology is :
Etiology : on the cause of disease
Pathogenesis : mechanisme of its developmen
and the pathways by which morphologic chan
occur

Normal homeostasis if cell adjusting structure a

function to accommodate changing demands an
extracellular stresses

Stresses or pathologic stimuli the cell ca

- undergo adaptation
eg.: atrophy, hypertrophy, hyperplasi
metaplasia
- irreversible injury and ultimately dies

Two principal pattern of cell

death :
1.NECROSIS,
commonly
coagulative necrosis
- cellular swelling
- protein denaturation
2. APOPTOSIS,
- regulated event
- organellar breakdown
- programmed death

CAUSES OF CELL INJURY

1. Hypoxia :-Anemia-Ischemia-Intoxication CO2
-Aerobic oxidative respiration
2. Physical Agent :
- mechanical trauma
- extreme temprature
- radiation
- electric shock
- athmosphere pressure

3. Chemical and drugs :

- sufficiently concentrated glucose, salt, O2

air pollutants
insecticides
asbestosis
ethanol

4. Microbilogy Agents
- tape worms
- rickettsia
- virus
- bacteria
- fungi
5. Immunologic Reaction
- anaphylactic reaction
- autoimmune diseases

6. Genetic Defects
- congenital Malformation
- sicle cell anemia
7. Nutritional Inbalance
- protein calori insufficiency
- vitamins defficiency
- diabetes
8. Aging

Mechanism of Cell Injury

Cellular response to injurious stimuli

depens on the : - injury type
- duration
- severity
Current Status : ~ nutrional
~ hormonal
~ adaptibility of the cell

Intercellular systems
>
>
>
>

cell membrane integrity

aerobic respiration
protein synthesis
integrity genetic apparatus

Oxygen and oxygen derived free radicals

: ischemic and hypoxic injury

Reversible Injury

Rediced oxidative phosphorylation in mitoc

Activity Natrium Pump is reduced
Producing cellular swelling. Loss of microvil
Glycogen depleted
Reduction in protein synthesis
Formation of cell surface blebs

Irreversible Injury
Severe vacuolization of the mitochondria
Demage of the mitochondrial matrix
Demage of plasma membrane
Swelling of lysosomes
Accumulation of amorphous calcium
Rich dentities in mitochondrial matrix

Forms and Morphology of Cell Injury

1. Reversible acute cell injury
2. Necrosis ( Cell death after irreversible injury )
3. Cell death by suicide = Apoptosis
4. Subcellular alteration as a respond to chronic or
persistent injury stimuli

5. Intracellular accumulations of a number of substances : lipid, carbohidrat, protein, as a result of de

in cell metabolism or excessive storage.

Sublethal Damage
1. Recoverable necrosis is not
2. Ultrastructural damage to mitochondria

3. Swelling of cellular organelles ( hydrophic d

4. Fatty change is impairment of metabolism

NECROSIS
Refers to a sequence of morphologic changes
that follow cell death in living tissue

1. Intense eosinophilia of the dead cell is due t

loss of RNA and coagulation of protein.

2. Nuclei undergo phase of pyknosis, karyorhex

and karyolysis
leaving a shrunken cell devoid of nucleus
3. Protein may be liberated from the dead cell

The morphologic appearance of necrosis is

the result of two essentially processes :
1. Ensymic digestion of the cell
2. Denaturation of protein
Autolysis is a dead cell themselves by
hydrolitic enzymes
Heterolysis from the lysosomes of
invading
inflammatory cells

Morphologic Evidence of
Necrosis
A Early Change
1 3 hour before changes of necrosis are
recognizable on electron microscopy
6 8 hour on light microscopy organelle
degeneration
B. Nuclear Change
Pyknosis : The chromatine clumps into
coare strands
The nucleus becomes a shrunken
dense, basophilic mass

Karyorrhexis : The pyknotic nucleus

break up
into numerous small
basophilic
mass
Karyolysis : The nucleus lysis as a result
of
the action of lysosome deoxy

ribonucleases
C. Cytoplasmic Change
About 6 hour after cell necrosis
Cytoplasma becomes homogenous and
deeply
`
acidophilic. Enzymatic digestion

Tipes of Necrosis
Depends on :
1. Cells compotitions
2. Speed of necrosis
3. Type of injuries
> Coagulative Necrosis
Implies preservation of basic structural outline of
the coagulated
cell or tissue
for a span of days.
The structural protein and the enzymatic protein
thus blocking
cellular
proteolysis
Coagulation necrosis is cahareteristic of hypoxic
death of cells in
all tissue except
the brain
eq. Myocardial Infarction

Liquefactive or Colliquativa Necrosis

Dead tissue that appears semi liquid as a result of
dissolution of
tissue by the action of hydrolytic
enzymes
eq.: - cerebral infarction
- necrosis caused by bacterial inf.
Caseous Necrosis
Dead cell form an amorphous proteinaceaus mass,
no original
architecture can be seen
histologically ( soft and white
resembling cream
cheese )
Most often in fact of tuberculous infection with
central necrosis

> Gumatous Necrosis

describes dead tissue when it is firm and
rubbery
like caseous necrosis in the spirochetal infection
syphilis.
> Hemorrhagic Necrosis
describes dead tissue that are suffused with
extravasated red cell, when cell death is due to
blockage
> Fat Necrosis
does not really necrosis.
It describes focal areas of fat destruction
tipically occuring following pancreatic injury.
Or after trauma to fat for example in the breast

Describes foci of hard yellow material seen in

dead adipose tissue
> Fibrinoid Necrosis
when fibrin is deposited in damage necrotic
vessel walls in hypertension and vasculitis
> Gangrene
extensive tissue necrosis ; is complicated to a
variable degree by secondary bacterial
infection

APOPTOSIS

is responsible for the programmed cell deat

several important physiology processes

including :
The programmed destruction of cells during em
genesis as in implantation, organogenesis, and
developmental involution

Hormon dependent physiologic involution such

the endometrium, lactating, as in the prostate

castration

 Cell deletion in proliferating population such

intestinal crypt epithelium or cell dead in tum

Deletion of autoreactive T cell in the thymus,

cell death of cytokine starved lymphocytes

CELL DEATH
APOPTOSIS
What

vs. NECROSIS

is DEATH? (What is LIFE?)

DEATH is IRREVERSIBLE

So the question is.

NOT what is life or
death, but what is
REVERSIBLE or
IRREVERSIBLE injury

REVERSIBLE CHANGES
REDUCED

oxidative
phosphorylation

ATP

depletion

Cellular

SWELLING

IRREVERSIBLE
CHANGES
MITOCHONDRIAL

IRREVERSIBILITY
IRREVERSIBLE
MEMBRANE DEFECTS
LYSOSOMAL DIGESTION

REVERSIBLE = INJURY
IRREVERSIBLE = DEATH
SOME INJURIES CAN LEAD
TO DEATH IF PROLONGED
and/or SEVERE enough

INJURY CAUSES (REVERSIBLE)

THE
USUAL
SUSPECTS
But
WHO are
the
THREE

INJURY CAUSES (REVERSIBLE)

Hypoxia, (decreased O2)

PHYSICAL Agents
CHEMICAL Agents
INFECTIOUS Agents
Immunologic
Genetic
Nutritional

INJURY MECHANISMS (REVERSIBLE)

DECREASED ATP
MITOCHONDRIAL DAMAGE
INCREASED INTRACELLULAR CALCIUM
INCREASED FREE RADICALS
INCREASED CELL MEMBRANE
PERMEABILITY

What is Death?
What is Life?
DEATH is
IRREVERSIBLE MITOCHONDRIAL
DYSFUNCTION
PROFOUND MEMBRANE DISTURBANCES

LIFE

is..???

 REVERSIBLE

IRREVERSIBLE
DEATH
EM
LIGHT MICROSCOPY
GROSS APPEARANCES

DEATH:
ELECTRON MICROSCOPY

DEATH:
LIGHT MICROSCOPY

NECROSIS BROTHERS:

Liquefactive (Brain)

Gangrenous (Extremities, Bowel, non-specific)

WET
DRY

Fibrinoid (Rheumatoid, non-specific)

Caseous (cheese) (Tuberculosis)

Fat (Breast, any fat)

Ischemic (non-specific)

Avascular (aseptic), radiation, organ specific,

papillary

LIQUEFACTIVE NECROSIS,
BRAIN

MORE LIQUID MORE WATER

MORE PROTONS

CASEOUS NECROSIS, TB

FIBRINOID NECROSIS

WET GANGRENE

DRY GANGRENE

EXAMPLES of Cell
INJURY/NECROSIS
Ischemic (Hypoxic)

Ischemia/Reperfusion
Chemical

ISCHEMIC INJURY
REVERSIBLE

IRREVERSIBLE
DEATH

(INFARCT)

ISCHEMIA/REPERFUSION INJURY

NEW Damage
Theory

CHEMICAL INJURY
Toxic Chemicals,

Drugs, e.g tylenol

Dose
Free

e.g CCl4

Relationship

radicals, organelle, DNA

damage

APOPTOSIS
NORMAL

(preprogrammed)

PATHOLOGIC

(associated with
Necrosis)

NORMAL APOPTOSIS
Embryogenesis
Hormonal
Cell

Involution

population control, e.g., crypts

Post

Inflammatory Clean-up

Elimination
Cytotoxic

of HARMFUL cells

T-Cells cleaning up

PATHOLOGIC APOPTOSIS
Toxic

effect on cells, e.g.,

chemicals, pathogens

Duct

obstruction

Tumor

cells

Apoptosis/Necrosis

spectrum

APOPTOSIS MORPHOLOGY
DE-crease

in cell size, i.e., shrinkage

IN-crease

in chromatin
concentration, i.e., hyperchromasia,
pyknosis karyorhexis karyolysis

IN-crease

in membrane blebs

Phagocytosis

SHRINKAGE/HYPERCHROMASIA

PHAGOCYTOSIS

APOPTOSIS BIOCHEMISTRY
Protein
DNA

Digestion (Caspases)

breakdown

Phagocytic

Recognition

SUB-Cellular Responses to Injury

(APOPTOSIS/NECROSIS)
Lysosomal

Auto-Digestion
Smooth Endoplasmic Reticulum
(SER) activation
Mitochondrial
Cytoskeleton
Thin

SWELLING

Breakdown

Filaments (actin, myosin)

Microtubules
Intermediate Filaments (keratin, desmin,
vimentin, neurofilaments, glial filaments)

INTRAcellular
ACCUMULATIONS
Lipids
Neutral

Fat
Cholesterol
Hyaline

= any proteinaceous
pink glassy substance
Glycogen
Pigments (EX-ogenous, ENDogenous)
Calcium

LIPID LAW
ALL

Lipids are
YELLOW grossly and
WASHED out
(CLEAR)
microscopically

FATTY LIVER

FATTY LIVER

PIGMENTS
EX-ogenous--- (tattoo,
Anthracosis)
END-ogenous--- they all look the
same, (e.g., hemosiderin,
melanin, lipofucsin, bile), in
that hey are all golden
yellowish brown on routine
Hematoxylin & Eosin (H&E)
stains

Hemosiderin/Melanin/etc.

CLINICAL EFFECTS OF NECROSIS

Abnormal function
Kidney
Cortex in brain
Heart
Lung
Bacterial infection

:
:
:
:

renal failure
muscle paralysis
heart failure
hemoptysis
: gangrene

Realease of contens of necrotic cells

Liver
: elevation SGOT
Heart
: creatine kinase

Systemic effects
Fever
Inflamatoir Reaction

Local effects
Hemorrhage
Ulceration

CELLULAR ADAPTATIONS OF GROWTH AND

DIFFENTIATION
Environment adaptation of the cell
1. Physiologic Adaptation
- Hormones
- Endogenous chemical mediators
2. Pathologic Adaptation
- Induction of new protein synthesis by target
cell
Cell Injury :
Death of cells ( permanent organ injury )
Sublethal injury ( adaptation )

Perubahan sel dan jaringan

1. Agenesis
2. Aplasia
3. Hypoplasia
4. Atrophy
5. Hypertrophy
6. Hyperplasia
7. Metaplasia
8. Dysplasia
9. Anaplasia
10.Granuloma

The

plasia brothers

HYPERHYPO- (A-)
NORMOMETA-

DYS ANA Frank ANA

Agenesis

Complet absen of an organ

Exc : - renal agenesis
- ovarial agenesis
- tubal agenesis, etc

Aplasia

Anlarge is present but never develops

Exc : lung aplasia with tissue containing
rudimentary duct and connective tissue

HYPO-PLASIA
DE-CREASE IN NUMBER OF CELLS

Hypoplasia

Anlarge develoved incompletly but the

tissue histhologicaly normal
Exc : microcephaly

The

trophy brothers

HYPERHYPO- (A-)

DYS-

A-TROPHY
DE-CREASE IN SIZE OF CELLS? YES

IN CELL SIZE DUE

TO LOSS OF CELL
SUBSTANCE

SHRINKAGE

ATROPHY
DECREASED

WORKLOAD
DENERVATION
DECREASED BLOOD FLOW
DECREASED NUTRITION
AGING (involution)
PRESSURE

A t r o p h y

is the decrease in the size and a

function of a cell but are not dead

Causes of atrophy :

1. Reduced functional deman

Immobilitation in fracture
Prolonged bed rest
2. Inadequate supply of oxygen
Ischemia
3. Insufficient nutrients
Starvation
Inadequate nutritions
Chronic disease
4. Interrruption of trophic signals
The functions of many cells depend on signal
transmitted by chemical mediators

-Endocrin system
-Neuromucculator transmission
eq. Thyroid
Adrenal cortex
Ovarium
Testis
5. Persistant cell injury
Caused by chrinic inflamation
eq. - chronic gastritis
- prolonged pressure

6. Aging
Particularly in non replacating cells such bra
heart.
> Senile Atrophy

The mechanism of atrophy :

decreased synthesis
increased catabolism
influenced by a number of hormones
eq. Insulin, tyroid stimulating hormon,
glucocorticoids

HYPER-TROPHY
IN-CREASE IN SIZE OF CELLS

Is an increase in the size of cell accompanied

ybyp e r t r o p h y

Augmented functional capacity

Hypertrophy is a response to trophic signals

and

Commonly a normal procesess

I.

Physiological ( Hormonal ) hypertrophy

- in puberty an icreased production of sex h
mon
- hypertrophy breast tissue
- abnormal hormon production in cancer

II. Increased functional demands

- exercise
- pathological conditions
eq. Myocardial cell
- kidney hypertrophy on surgical removed

HYPER-PLASIA
IN-CREASE IN NUMBER OF CELLS

HYPERPLASIA
is an increase in the number of cells in an
or tissue
Hyperplasia can be :
I . Physiologic hyperplasia
- hormonal hyperplasia
- compensatory hyperplasia

II. Pathologic hyperplasia

excessive hormonal or growth factor s
lation
eq. Endometrial hyperplasia

1. Hormonal stimulation
- estrogen increased endometrium ( hyperp
- gynecomastia
2. Increased functional demand
- secondary polycytemia
- lymphocyte hyperplasia

3. Persistent Cell Injury

- chronic inflammation in the skin and the e
thelium of viscera
- hyperplasia of the bladder epithelium

METAPLASIA
A

SUBSTITUTION of one NORMAL

CELL or TISSUE type, for
ANOTHER
COLUMNAR SQUAMOUS (Cervix)
SQUAMOUS COLUMNAR (Glandular)
(Stomach)
FIBROUS BONE

WHY?

METAPLASIA
is a reversible change in which one adult ce
type is replace by another adult cell type
( Metaplasia is the convertion of one differen
ted cell type of another )
It is almost invariably a response to persistent inj
and can be thought of as an adaptive mechanism
Most common is the replacment of a glandular ep
um by a squamous cell.
- Squamous metaplasia of the bronchial epit
to tobacco
- lower oesophagus by reflux acidic gastric
- endocervical metaplasia
Metaplasia is usually reversible if the stimulus is
removed

DYSPLASIA
cellular dysplasia refers to an alteration in the
size, shape and organization of the cellular com
ponent of a tissue
The cells an epithelium exhibit uniformity of size,
And nucleus.

Dysplasia mean is disturbed by

1. Variation in the size and shape of cells
2. Enlargment, irregularity and hyperchromatism
the nuclei.
3. Disorderly arrangement of the cells within the e
thelium

The most common in the cervix and bronchus

It is established that dysplasia is a preneopla

lession in the sense that it is a necessary sta
in the multistep cellular evolution to cancer.

Dysplasia included in the morphological classificat

Of the stage if intraepithelial neoplasia

Anaplasia

normal cell
primitive cell
Exc : malignan cell (carcinoma,
sarcoma, adenocarcinoma,
lymphoma, etc)

Granuloma

specialized type of chronic inflamation in

tissue reaction
Cause : - infection : tbc, fungal,
siphylis, etc
- non-infection : sarcoidosis,
Crohns disease, etc

C E L L U L A R
A G I N G
Alterations in structure and fuction that may
to cell death, or at least diminished capacity
the cell to respond an injury
Reduced cell in :
- pleomorphic vacuolated mitochondria
- repair of chromosomal damage
Morphologic alteration in :
pleomorphic vacuolated mitochondria
decreased endoplasmic reticulum
disorted Golgi Apparatus
accumutaion of lipofuscin pigment

Cellular senescence is multifactorial :

1. The cumulative effects of extrinsic influences

: free radical damage
2. Intrinsic molecular program of cellular aging
cell have a finite life span
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