Lecture 4
Morphological Alterations in Cell
Injury and Necrosis
Associate Professor
Dr. Alexey Podcheko
Spring 2015
A routine H&E histologic section from an
irregular white area within the anterior wall of the
heart of a 54-year-old female who died secondary
to ischemic heart disease reveals the myocytes
to be replaced by diffuse red material. This
material stains blue with a trichrome stain. Which
one of the listed statements correctly describes
this material?
It is secreted by fibroblasts and has a high content of glycine
and hydroxyproline
It is secreted by endothelial cells and links macromolecules to
integrins
It is secreted by hepatocytes and is mainly responsible for
intravascular oncotic pressure
It is secreted by monocytes and contains a core protein that is
linked to mucopolysaccharides
INTENDED LEARNING
OUTCOMES
1. To know at least 4 morphological signs
of reversible injury
2. To know 3 morphological features of
necrosis
3. List 6 morphologic patterns of necrosis
with clinical examples
Stages of the cellular response to stress
and injurious stimuli
Common Mechanisms Leading
to Cell Injury and Death
1
2
3
4
5
What are the signs of REVERSIBLE
and IRREVERSIBLE injury?
Sequential development of biochemical and
morphologic changes in cell injury
•There is a time lag between the stress and the morphologic changes of cell injury
or death
•Light microscopy changes of cell death visible only 4-12 hours after total
ischemia
List of Reversible Injury
Associated Morphologic Changes
1. Acute swelling of the cell and cellular
organelles (mitochondria, nucleus)
a. Formation of membrane blebs
b. Detachment of polyribosomes from dilated
ER
c. Clumping of nuclear chromatin
(desegregation)
2. Fatty changes (lipid vacuoles)
3. Loss of Glycogen
Acute swelling of the cell
Acute swelling is the result of failure of energy-dependent ion
pumps in the plasma membrane
Gross View of Cellular Swelling (Edema) at
the level of whole organ
Pallor, turgor and increased weight
Microscopic changes induced by cellular
edema (swelling)
1. Appearance of clear
vacuoles (distended
ER)- vacuolar
degeneration
2. Increased eosinophilic
staining
Ultrastructural
(EM) changes
shown on this
slide:
1. Plasma
membrane
alterations
2. Mitochondrial
changes
3. Dilation of ER
4. Nuclear
alterations
5. Myelin figures
6. Loss of
microvilli
Mitochondrial
changes, including
swelling , ER
swelling
Plasma membrane
alterations, such as
blebbing, blunting,
and loss of microvilli
Nuclear alterations, with disaggregation
of granular and fibrillar elements,
clumping of nuclear content
Ultrastructural
changes
(shown on this
slide):
1. Plasma
membrane
alterations
2. Mitochondrial
changes
3. Dilation of ER
4. Nuclear
alterations
5. Myelin figures
6. Loss of
microvilli
Myelin Figures
Ultrastructural
changes
(shown on this
slide):
1. Plasma
membrane
alterations
2. Mitochondrial
changes
3. Dilation of ER
4. Nuclear
alterations
5. Myelin figures
6. Loss of
microvilli
normal
swelling
Fatty Changes (Steatosis)
Definition: abnormal accumulation of triglycerides within cells
Normal Liver
Liver Steatosis (Fatty Liver)
Mechanisms of hepatic steatosis
Etiology of Hepatic Steatosis:
1. Obesity
2. Diabetes Mellitus
3. Toxins (CCl4)
4. Protein Malnutrition
5. Hypoxia
NAFLD (non-alcoholic fatty liver
disease) represents a spectrum
of fatty liver diseases:
1. simple steatosis
2. steatosis with
inflammation NASH : nonalcoholic steatohepatitis
3. fatty liver disease with
inflammation and fibrosis
(severe NASH)
4. cirrhosis.
Signs of reversible damage on
cardiomyocytes
Myofibril relaxation is an
early sign of reversible injury
in cardiac myocytes, which
occurs within the first 30
minutes of severe ischemia.
Myofibril relaxation
corresponds with intracellular
ATP depletion and lactate
accumulation due to
anaerobic glycolysis during
this period.
Approximate Time of Onset of
Key Events in Ischemic Cardiac
Myocytes
Irreversible Morphologic Changes
Stages of the cellular response to stress and injurious stimuli
List of Irreversible Morphologic
Changes
1. Rapture of lysosomal membranes (autolysis)
2. Rapture of cell membranes
3. Mitochondria: The appearance of vacuoles and
phospholipid-containing amorphous densities,
aggregates of fluffy material probably due to
denaturation of proteins
4. Nuclear changes:
a. Piknosis – degeneration of nuclear chromatin
b. Karyorrexis – nuclear fragmentation
c. Karyolysis – dissolution of the nucleus
Morphologic changes of cells in reversible and
irreversible cell injury
Normal kidney
tubules with viable
epithelial cells
Early (reversible)
ischemic injury
showing surface
blebs, increased
eosinophilia of
cytoplasm, and
swelling of
occasional cells
Irreversible injury
of epithelial cells,
with loss of nuclei,
fragmentation of
cells, and leakage
of contents
Q3: A 35-year-old man infected with hepatitis B
experiences mild nausea for about 1 week and
develops very mild scleral icterus. On physical
examination, he has minimal right upper quadrant
tenderness. Laboratory findings include a serum
AST of 68 U/L, ALT of 75 U/L, and total bilirubin of 5.1
mg/dL. The increase in this patient's serum enzyme
levels most likely results from which of the following
changes in the hepatocytes?
(A) Autophagy by lysosomes
(B) Clumping of nuclear chromatin
(C) Swelling of the mitochondria
(D) Dispersion of ribosomes
(E) Defects in the cell membrane
Dead cells show typical nuclear changes
• Pyknosis (pyknos, dense) - condensation of chromatin,
shrunken dark nuclei
• Karyorrhexis - (rhexis, tearing apart) - fragmentation of
nuclear material
• Karyolysis - lysis of chromatin due to the action of
endonucleases (loss of nuclear staining, DNA breaking
down and disappearing)
Nuclear changes during irreversible cell injury
Pyknosis – degeneration of nuclear
chromatin
Karyorrhexis – nuclear fragmentation
Karyolysis – dissolution of the nucleus
Three types of IRREVERSIBLE INJURY
Necrosis
Apoptosis
Autophagy
Q1: It is important to be able to distinguish
reversible from irreversible injury. Which one
of the following morphologic changes is
irreversible:
A. Ischemic induced glycogen depletion
B. Acute cellular swelling
C. Formation of membrane blebs
D. Karyolysis
E. Clumping of nuclear chromatin
Q2: A 54-year-old Caucasian male comes to the
emergency room with retrosternal chest pain of 30
minutes duration. The patient also complains of
sweating and mild dyspnea. A single tablet of
nitroglycerin is delivered sublingually, and the patient’s
pain decreases significantly. The patient has
experienced several similar episodes of pain over the
last 12 hours, all of which resolved spontaneously.
Which of the following ultra structural changes would
most likely indicate irreversible myocardial cell injury in
this patient?
A. Myofibril relaxation
B. Disaggregation of polysomes
C. Mitochondrial vacuolization
D. Disaggregation of nuclear granules
E. Triglyceride droplet accumulation
Necrosis
• Necrosis=Denaturation of intracellular proteins +
enzymatic digestion of cell components/cell
•Occur in living cells
•Autolysis vs. Heterolysis
•Cytoplasmic Eosinophilia
• Nuclear Pyknosis, Karyolysis and Karyorrhexis
Distinctive Morphologic Patterns
of Necrosis
1.Coagulative
2.Liquefactive
3.Caseous
4.Fat
5.Fibrinoid
6.Gangrenous
Coagulative Necrosis
1. It is the most common form of necrosis (affect
all organs except brain)
2. Characteristic of ischemia
3. Infarct is a localized area of coagulative
necrosis
Coagulative Necrosis, Main Features
A. Architecture of dead tissues is preserved
for at least several days due to the
denaturing and coagulation of proteins
within cytoplasm
B. Ghost outlines of cells but loss of nucleus
C. Firm texture of affected tissues
D. Necrotic cells eventually are removed by
phagocytosis by infiltrating leukocytes
Miocardial Infarction
anterior wall
Transmural MI
1 day
3-4 days
7 days
MI: pale myocardial infarction
MI morphology
-The infracted myocardial fibers are eosinophilic
-there is no nuclear staining;
-neutrophilic granulocytes accumulated at
the margins of infarction (vital sign)
Coagulative Necrosis
Spleen Infarct
Coagulative Necrosis
Spleen Infarct
Examples of Coagulative Necrosis
MI
Spleen Infarct
Kidney Infarct
Liquefactive Necrosis
1.Characteristic of bacterially induced
necrosis
2.Presence of large numbers of inflammatory
cells with complete digestion of cells
3.Cellular destruction by hydrolytic enzymes
4.Examples: abscesses in various organs and
tissues, brain and pancreas infarcts
Liquefactive Necrosis - Gross
MORE LIQUID  MORE
WATER  MORE PROTONS
T2 weighted MRI images emphasize water density but some anatomic resolution is lost
Liquefactive Necrosis
Liver
Puss
Abscessing bronchopneumonia
Q4: A 68-year-old woman suddenly lost
consciousness; on awakening 1 hour later, she
could not speak or move her right arm and leg.
Two months later, a head CT scan showed a
large cystic area in the left parietal lobe. Which
of the following pathologic processes has most
likely occurred in the brain?
(A) Fat necrosis
(B) Coagulative necrosis
(C) Apoptosis
(D) Liquefactive necrosis
(E) Karyolysis
Caseous Necrosis
1.Combination of coagulation and liquefaction
necrosis
2.Gross:
soft
and
“cottage-cheese-like”
appearance
3.Characteristic of Lung Tuberculosis
Caseous Necrosis=TB
Caseous Necrosis
Q5: A chest radiograph of a 26-year-old man showed a
4-cm nodule in the upper lobe of the left lung. The
nodule was excised with a pulmonary wedge
resection, and sectioning showed the nodule to be
sharply circumscribed with a soft, white center.
Culture of tissue from the nodule grew
Mycobacterium tuberculosis. Which of the following
pathologic processes has most likely occurred in this
nodule?
(A) Apoptosis
(B) Caseous necrosis
(C) Coagulative necrosis
(D) Fat necrosis
(E) Fatty change
Fat Necrosis
• Distinct morphologic appearance and
occurs in a distinct set of clinical
circumstances – chalky white appearance
• Action of pancreatic lipases on surrounding
fatty tissues
•Examples:
1. Acute pancreatitis
2. Trauma of fat tissue (breast)
Fat Necrosis
The areas of white chalky deposits represent foci of fat necrosis with
calcium soap formation - saponification
Enzymatic Fat Necrosis
Damage to cells releases tryglycerides . The triglycerides are broken down by action of
lipases to fatty acids. Fatty acids associate with calcium and then form calcium soaps
(saponification)
Breast Fat Necrosis
Calcification on mammography mimic
breast cancer
Fibrinoid Necrosis
Necrotic tissue that histologically resembles fibrin
Micro: has an eosinophilic pink homogenous
appearance
Fibrinoid necrosis in an artery (AI Vasculitis)
Gangrenous Necrosis
Gross term used to describe dead tissue
Common sites: lower limbs, gallbladder,
GI tract, testes
Two types:
-Wet gangrene resembles liquefactive
necrosis;
-Dry gangrene resembles coagulative
necrosis
Gangrene = ischemic necrosis with
bacterial superinfection
Wet Gangrene (Diabetic angiopathy)
DRY GANGRENE
Objectives Review:
1. To know at least 4 morphological signs of
reversible injury
1. Acute swelling of the cell and mitochondria
2. Loss of microvilli
3. Formation of membrane blebs, myelin figures
4. Detachment of ribosomes from dilated ER
5. Clumping of nuclear chromatin (desegregation)
6. Fatty changes (lipid vacuoles)
7. Loss of glycogen
Objectives Review:
2. To know 4 morphological features of
necrosis
1. Rapture of lysosomal membranes (autolysis)
2. Rapture of cell membranes
3. Mitochondria: The appearance of vacuoles and
phospholipid-containing amorphous densities,
aggregates of fluffy material probably due to
denaturation of proteins
4. Nuclear changes:
a. Piknosis – degeneration of nuclear chromatin
b. Karyorrexis – nuclear fragmentation
c. Karyolysis – dissolution of the nucleus
Objectives Review:
3. List 6 morphologic patterns of necrosis
with clinical examples
Necrosis Pattern
Example
1
Coagulative
Myocardial Infarction (MI)
2
Liquefactive
Brain Abscess
3
Caseous
Lung Tuberculosis
4
Fat
Acute Pancreatitis
5
Fibrinoid
Autoimmune Vasculitis
6
Gangrenous
Diabetic angiopathy