Cell injury
By
Dr. Abdelaty Shawky Dr. Gehan Mohamed
Fatty Change
* Definition: abnormal accumulation of triglycerides
within parenchymal cells.
* Site:
 liver, most common site which has a central role in
fat metabolism.
 it may also occur in heart as in anaemia or
starvation (anorexia nervosa)
 Other sites: skeletal muscle, kidney and other
organs.
* Causes:
1.
2.
3.
4.
5.
Toxins (most importantly: Alcohol abuse)
Diabetes mellitus
Protein malnutrition (starvation)
Obesity
Anoxia
* The significance of fatty change:
 Depends on the severity of the accumulation.
 Mild: it may have no effect .
 Severe: form, fatty change may precede cell
death, and may be an early lesion in a serious
liver disease called nonalcoholic steatohepatitis
* Is Fatty liver reversible?
• Fatty change is reversible except if some vital
intracellular process is irreversibly impaired .
* Prognosis of Fatty liver:
• In Mild cases: 3% will develop cirrhosis
• Moderate to sever: inflammation,
degeneration in hepatocytes, fibrosis (30%
develop cirrhosis).
Other form of accumulation
• Cholesteryl esters:
• These give atherosclerotic
plaques with their characteristic
yellow color and contribute to
the pathogenesis of narrowing of
the blood vessels.
• This is called atherosclerosis
Accumlation of Exogenous pigment
• Tattooing: Indian ink pigments produce effective
tattoos because they are engulfed by dermal
macrophages which become immobilized and
permanently deposited.
• Anthracosis: inhalation of carbon dust particles.
When inhaled, it is phagocytosed by alveolar
macrophages and transported through lymphatic
channels to the regional tracheobronchial lymph
nodes.
Anthracosis
Accumulation of Endogenous pigments
Hemosiderin ( iron)
 is a hemoglobin-derived granular pigment that is
golden yellow to brown and accumulates in tissues
when there is a local or systemic excess of iron.
 Iron is normally carried by specific transport proteins,
transferrins. In cells, it is stored in association with a
protein, apoferritin, to form ferritin micelles. Ferritin
is a constituent of most cell types. When there is a
local or systemic excess of iron, ferritin forms
hemosiderin granules.
Hemosiderosis
* Causes of Hemosiderosis:
1. Increased absorption of dietary iron
2. Impaired utilization of iron
3. Hemolytic anemias
4. Repeated blood transfusions (the transfused red cells
constitute an exogenous load of iron).
5. Hereditary hemochromatosis with tissue injury including liver
fibrosis, heart failure, and diabetes mellitus
.
 Although hemosiderin accumulation is usually
pathologic, small amounts of this pigment are
normal.
 Where?
 in the mononuclear phagocytes of the bone
marrow, spleen, and liver.
 Why?
 there is extensive red cell breakdown.
Hemosiderosis
(systemic overload of iron)
 It is found at first in the mononuclear phagocytes
of the liver, bone marrow, spleen, and lymph
nodes and in scattered macrophages throughout
other organs.
 With progressive accumulation, parenchymal cells
throughout the body (principally the liver,
pancreas, heart, and endocrine organs) will be
affected
Hemosiderin
H&E: golden brown pigment
Prussian blue stain: blue
Lipofuscin
• “Wear-and-tear pigment" is a brownish-yellow granular
intracellular material that seen normally in a variety of tissues
(the heart, liver, and brain) as a function of age or atrophy.
• Consists of complexes of lipid and protein that derive from the
free radical-catalyzed peroxidation of lipids of subcellular
membranes.
• It is not injurious to the cell but is important as a marker of past
free-radical injury.
• The brown pigment when present in large amounts, imparts an
appearance to the tissue that is called brown atrophy.
Pathological calcification
• It implies the abnormal deposition of calcium
salts in tissues rather than bone and teeth.
• It has 2 types:
 Dystrophic calcification:
 When the deposition occurs in dead or dying
tissues e.g. areas of necrosis or atherosclerotic
patches.
 it occurs with normal serum levels of calcium
 Metastatic calcification:
 The deposition of calcium salts in normal tissues
 It almost always reflects hypercalcemia.
Irreversible cell injury
* Mechanism:
•
•
•
Persistent or severe injury (hypoxia) takes the cell to
the "point of no return" where the injury becomes
irreversible.
At this point no intervention can save the cell.
Two phenomenon characterize irreversible injury:
1. Mitochondrial damage.
2. Damage to the structural integrity of
plasma membrane.
•
Calcium plays a major role in irreversible injury.
1. Mitochondrial damage:
• Marked reduction in ATP production leads to
mitochondrial damage results in formation of high
conductance channels (Mitochondrial Permeability Transition
(MPT) channels) which Release cytochrome c into cytosol
which is a trigger for apoptosis.
MITOCHONDRIAL DYSFUNCTION or INJURY
↓ATP production
H+
Mitochondrial
Permeability
Transition (MPT)
Cytochrome C
Apoptosis
2. Damage to plasma membrane:
• Due to:
– Decreased production of membrane
phospholipids: due to mitochondrial dysfunction
and decreased ATP production.
– Loss of membrane phospholipids: due to the
action of phospholipases.
– Damage to cytoskeleton due to the action of
proteases.
* Consequences of membrane damage:
• Mitochondrial membrane:
– Formation of MPT (mitochondrial permeability transition
channels).
– Release of cytochrome c  activates apoptosis.
• Plasma membrane:
– Loss of osmotic balance.
– Influx of fluids and ions.
– Loss of proteins, enzymes, RNA.
• Lysosomal membrane:
– Leakage of lysosomal enzymes and their activation
• RNases, DNases, proteases, phosphatases,
glucosidases.
– Enzymatic digestion of cell components
– Cell death by necrosis.
* Role of calcium in irreversible cell injury:
• Increased cytosolic calcium: Leads to :
1. Enzyme activation:
 ATPases: Hasten ATP depletion
 Phospholipases : cause membrane damage 
increased permeability.
 Proteases  damages membrane and structural
proteins
 Endonucleases  damages nuclear chromatin
and DNA, causing fragmentation (karyorrhexis).
2. Increased mitochondrial permeability :
release of cytochrome c (activates apoptosis)
INJURIOUS AGENT
Ca
2+
Ca
2+
Ca
2+
Increased Cytosolic Ca2+
ATPase
ATP
Phospholipase
 Phospholipids
Protease
Disruption
of membrane
& cytoskeletal
Proteins
Endonuclease
Nuclear
Chromatin
damage
Morphology of irreversible cell
injury
Light microscopy of irreversible cell
injury
• Pyknosis = Shrinkage and darkening of the
nucleus.
• Karyorrhexis = fragmentation and breakdown
of the nucleus, (into "nuclear dust").
• Karyolysis = dissolution of the nucleus.
Karyorrhexis
Nuclear pyknosis
Karyolysis
* Types of cell death:
• Necrosis: local death of a group of cells within
the living body.
• Apoptosis: genetically controlled programmed
single cell death.
Some important terms!
• Autolysis: degradation of cell and its
constituents caused by its own enzymes.
• Heterolysis: degradation of cell and its
constituents by enzymes derived from sources
extrinsic to the cell (e.g. neutrophils, bacteria).
• Putrefaction: lysis of dead tissue by bacterial
enzymes.
Morphological types of necrosis:
1.
2.
3.
4.
Coagulation necrosis.
Liquefactive necrosis.
Caseation necrosis.
Fat necrosis.
A. Traumatic.
B. Enzymatic .
5. Fibrinoid necrosis.
6. Gangrenous necrosis.
7. Gummatous necrosis.
Coagulative necrosis
* Mechanism:
– Denaturation and coagulation of structural
and enzymatic proteins due to intracellular
acidosis.
• Denaturation of lysosomal enzymes by
intracellular acidosis prevents autolysis.
• Preserving cell outlines and tissue
architecture.
* Etiology:
a. ischemia (secondary to atherosclerosis 
thrombus formation). The most common cause.
b. Heavy metal poisoning (lead).
c. Irradiation.
* Organs affected: Commonly seen in solid organs
like Heart, kidney, spleen
Infarction
– Refers to a localized area of tissue necrosis resulting
from loss or reduction in blood supply (= ischemic
necrosis).
– The dead tissue is called an infarct.
• Coagulative necrosis is the type of necrosis associated
with infarction except in infarction of brain.
• In Brain:
– Lack of good structural support.
– Cells rich in lysosomal enzymes result in liquefactive
necrosis.
Infarction of the spleen (ischemic
coagulative necrosis)
* Morphology of Coagulation necrosis:
* GROSS APPEARANCE:
– The necrotic tissue appears firm and dry.
– Cut surface: grey white.
* MICROSCOPY:
– Loss of the nucleus but preservation of cellular
shape.
– Increased cytoplasmic eosinophilia.
Area of necrosis
Area of
Necrosis
Preservation
of cellular
shape.
Increased
cytoplasmic
eosinophilia
Good luck