Cell Injury and Adaptation and Cell Death pdf - د. محمود محمد

Cell Injury, Adaptation and

Cell Death

CELLULAR RESPONSES TO HARMFUL STIMULI

Each cell in the body is designed to carry a
specific function or functions, which is dependent
on its

machinery and metabolic pathways

These specificities are genetically determined.
Cells are continuously adjusting their structure
and function, within a narrow range, to deal with
the continually changing extra-cellular
environment. This ability on the part of the cell to
maintain a dynamically stable state is referred to as

homeostasis.

• They can modify the homeostatic state and

achieve a new steady state to counteract the
noxious effects of external stresses

• Excess

physiologic

pathologic

stress may

force the cell to a new steady state:
Adaptation

• The aim behind these adaptations is to avoid

cell injury & death.

• Too much stress exceeds the cell’s adaptive

capacity: Injury

• The morphological & functional changes

induced by the

injury

may be

• reversible

, i.e. the cells return to a normal

state on the removal of the offending agent,
or

irreversible

i.e. there is no possibility of

making a u-turn to normal.

• Irreversible changes ultimately eventuate in

cell death

• Reversibility depends on the

type

severity

and

duration

of injury

• Cell death

is the result of irreversible injury

The above mentioned possibilities can be exemplified
by the myocardium that is subjected to persistently
increased pressure load

(hypertension);

this adapts by

undergoing hypertrophy i.e. an increase in the size of
individual cells and ultimately the entire heart.

This generates the required higher contractile force to
counteract the effect of hypertension .

If the hypertension (an injurious external stress) is not
relieved, the muscle cells may undergo injury.

The injury may be

reversible, if the hypertension is

mild

; otherwise

irreversible injury (cell death)

occurs.

CELLULAR ADAPTATIONS

Adaptations are reversible changes and
are divided into physiologic & pathologic
adaptations.

Physiologic adaptations usually represent
responses of cells to normal stimulations
e.g., the hormone-induced enlargement of
the breast and uterus during pregnancy.

Pathologic adaptations, on the other
hand, can take several distinct forms

Slide

– Adaptation diagram

Hypertrophy:

this refers to an increase in the size

of cells that results in enlargement of their relevant
organ.

Hypertrophy can be

physiologic

pathologic

and is

caused either by

increased functional demand

or by

specific hormonal stimulation

Examples of physiologic hypertrophy include

that of

skeletal muscles in athletes and mechanical
workers & the massive physiologic enlargement of
the uterus during pregnancy due to estrogen-
stimulated smooth muscle hypertrophy (and
hyperplasia).

Pathologic hypertrophy

is exemplified by

cardiomegaly secondary to hypertension

  The stimuli of hypertrophy turn on signals that lead to the
induction of a number of genes, which in turn stimulate
synthesis of numerous contractile myofilaments  per cell.
This leads to improved performance to house the excessive
demand imposed by the external burden.

There is, however, a limit for the adaptation beyond which

injury occurs; as for e.g. in the heart, where several
degenerative changes occur in the myofilaments that
culminate in their loss. This limitation of cardiac hypertrophy
(an adaptation) may be related to the amount of available
blood to the enlarged fibers. The net result of these
regressive changes is ventricular dilation and ultimately
cardiac failure.

This means that an adaptation can progress to dysfunction

if the stress is not relieved.

Prostatic hyperplasia -- gross

Slide -- BPH

Atrophic testis -- gross

Hyperplasia

refers to an increase in the

number of cells. It takes place only if the
cells are capable of replication;

it may occur with hypertrophy and

often in response to the same stimuli.
Hyperplasia can be

physiologic

pathologic

Physiologic hyperplasia:

this is of two types

1. Hormonal hyperplasia

, exemplified by the proliferation

of the glandular epithelium of the female breast at puberty
and during pregnancy. The enlargement of the gravid
uterus is due to a combination of hypertrophy &
hyperplasia.

2. Compensatory hyperplasia

, which occurs when a

portion of the tissue is removed or diseased. For example,
when a liver is partially resected, mitotic activity in the
remaining cells begins that eventually restore the liver to
its normal weight. The stimuli for hyperplasia in this setting
are growth factors produced by remaining hepatocytes &
other cells within the organ. After restoration of the liver
mass, cell proliferation is "turned off" by various growth
inhibitors.

Pathologic hyperplasia:

is mostly caused by excessive

hormonal or growth factor stimulation. Examples include

1. Endometrial hyperplasia:

this results from persistent or

excessive estrogen stimulation of the endometrium. This
hyperplasia is a common cause of abnormal uterine bleeding.

2. Skin warts:

these are caused by Papillomaviruses, and are

composed of masses of hyperplastic epithelium. The growth
factors responsible may be produced by the

virus

or by the

infected cells

In all the above situations

, the hyperplastic

process remains controlled

; if hormonal or growth factors

stimulation subsides, the hyperplasia disappears.

It is this

response to normal regulatory control mechanisms that
distinguishes pathologic hyperplasias from cancer, in which
the growth control mechanisms become ineffective

However,

some types of pathologic hyperplasias may become a fertile
soil for the development of carcinoma

Atrophy:

this refers to shrinkage in the size of the cell

due to loss of its constituent substances.

This situation is

exactly opposite to hypertrophy.

When a sufficient number

of cells are involved, the entire tissue or organ diminishes
in size i.e. becomes atrophic .

Causes of atrophy include

1. A decreased workload

, which is the most common form

of atrophy; it follows reduced functional demand.
For example, after immobilization of a limb in a cast as
treatment for a bone fracture or after prolonged bed rest.
In these situations the limb's muscle cells atrophy and
muscular strength is reduced. When normal activity
resumes, the muscle's size and function return.

2. Denervation

of a limb as in poliomyelitis and traumatic

spinal cord injury

3. Diminished blood supply

e.g. decreased blood

supply to a limb or brain due to narrowing of the
lumina of the relevant artery (or arteries) by
atherosclerosis.

4. Inadequate nutrition

as in starvation and famines

5. Loss of endocrine stimulation

as in

*postmenopausal endometrial atrophy (due to
decrease in the levels of estrogen after menopause)
and *testicular atrophy (due to decrease in the
production of LH & FSH as in hypopituitarism .

6. Aging (senile atrophy).

Although some of these stimuli are

physiologic

(e.g., the loss of hormone stimulation in menopause)

and others

pathologic (e.g., denervation), the

fundamental cellular changes in atrophy are identical.
They represent a retreat by the cell to a smaller size
at which survival is still possible; a new equilibrium is
achieved between cell size and diminished blood
supply, nutrition, or trophic stimulation.

Atrophy results from decreased protein synthesis

together with increased protein degradation in the
affected cells. In many situations, atrophy is also
accompanied by increased autophagy ("self- eating"),
with resulting increases in the number of autophagic
vacuoles. The starved cell eats its own components
in an attempt to find nutrients and survive.

Metaplasia

refers to

a reversible change in which

there is “replacement of normal mature epithelium at
a given site by another mature benign epithelium
inappropriate

to that site.”

In this type of cellular

adaptation,

cells sensitive to a particular stress are

replaced by other cell types that are more capable of
resisting the adverse environment

Metaplasia is

thought to arise by genetic "reprogramming" of stem
cells. Epithelial metaplasia is exemplified by the
squamous change that occurs in the respiratory
epithelium in habitual cigarette smokers. The normal
ciliated columnar epithelial cells of the trachea and
bronchi are focally or extensively replaced by
stratified squamous epithelial cells.

Although the metaplastic squamous epithelium is
more resistant to the injurious environement, it has
its adverse effects that include

1.Loss of protective mechanisms

, such as mucus

secretion and ciliary clearance of particles.

2.Predisposition to malignancy

In fact,

squamous cell carcinoma of the bronchi

often coexists with squamous metaplasia.

Squamous

metaplasia is also seen in the urinary bladder harboring
Shistosomal ova.

When there persistent regurgitation of the

gastric contents in to the esophagus (chronic gastro-
esophageal reflux disease [GERD]), the normal stratified
squamous epithelium of the lower esophagus may be
replaced by a metaplastic intestinal-type columnar
epithelium.

The latter is more resistant to the highly acidic

regurgitating gastric contents

CELL INJURY AND CELL DEATH

Cell injury results when cells are exposed to

1. Persistent stress

so that the affected cells are no

longer able to adapt or

2. Inherently damaging agents.

Reversible cell injury occurs when the injurious
agent is mild but persistent or severe but short
lived. In this type of injury the functional and
morphologic changes are

reversible

. With

continuing damage, there

irreversible injury

which time the cell cannot recover even with the
removable of the injurious agent i.e. it dies.

MECHANISMS OF CELL INJURY

The outcomes of the interaction between
injurious agents & cells depend on

1. The injurious agent:

its

type

severity

, and

the

duration

of its application to the cells.

2. The cells exposed to the injury:

its

type

adaptability

, and their

genetic makeup.

The most important targets of injurious agnets are:

1. Mitochondria

(the sites of ATP generation)

2. Cell membranes

, which influence the ionic and

osmotic homeostasis of the cell

3. Protein synthesis

(ribosomes)

4. The cytoskeleton

(microtubules, and various

filaments)

5. The genetic apparatus of the cell

(nuclear DNA)

ATP Depletion

ATP, the energy fuel of cells, is produced mainly by

oxidative phosphorylation

of ADP within the

mitochondria. In addition, the

glycolytic pathway

can generate ATP in the absence of oxygen using
glucose derived either from the circulation or from
the hydrolysis of intracellular glycogen (anerobic
glycolysis).

The major causes of ATP depletion are

1. Reduced supply of oxygen and nutrients
2. Mitochondrial damage
3. The actions of some toxins (e.g., cyanide)

High-energy phosphate in the form of ATP is required
for virtually all synthetic and degradative processes
within the cell, including

membrane transport

protein

synthesis

phospholipid turnover

etc. Depletion of ATP

to less than 5% to 10% of normal levels has
widespread effects on many critical cellular systems.

a. The activity of the plasma membrane energy-
dependent sodium pump is reduced,

resulting in

intracellular accumulation of sodium and efflux of
potassium. The net gain of solute is accompanied
by iso-osmotic gain of water, causing cell swelling

b. There is a compensatory increase in anaerobic
glycolysis in an attempt to maintain the cell's energy
sources.

As a consequence, intracellular glycogen stores

are rapidly depleted, and lactic acid accumulates, leading to
decreased intracellular pH and decreased activity of many
cellular enzymes.

c. Failure of the Ca2+ pump leads to influx of Ca2+,
with damaging effects on numerous cellular
components .
d. Structural disruption of the protein synthetic
apparatus manifested as detachment of ribosomes
from the rough endoplastic reticulum (RER), with a
consequent reduction in protein synthesis.
e. Ultimately, there is irreversible damage to
mitochondrial and lysosomal membranes, and the
cell undergoes necrosis.

Mitochondrial Damage

Mitochondria can be damaged by increases of cytosolic
Ca2+, reactive oxygen species, and oxygen
deprivation, and so they are sensitive to virtually all
types of injurious stimuli, including hypoxia and toxins.

There are two major consequences of mitochondrial
damage:

Failure of oxidative phosphorylation with progressive
depletion of ATP, culminating in necrosis of the cell.
Leakage of cytochrome c that is capable of activating
apoptotic pathways.

Influx of Calcium

Cytoplasmic free calcium is normally maintained by
ATP-dependent calcium pump (transporter) at
concentrations that are10, 000 times lower than
the concentration of extra-cellular calcium or
intracellular mitochondrial and ER calcium.

Ischemia and certain toxins cause an increase in
cytoplasmic calcium concentration, initially
because of release of Ca2+ from the intracellular
stores, and later resulting from increased influx
across the plasma membrane.

Increased cytosolic Ca2+ leads to

1. Activates a number of enzymes including
phospholipases

(which cause membrane

damage),proteases (which break down both
membrane and cytoskeletal proteins),
endonucleases (which are responsible for DNA
and chromatin fragmentation), and ATPases
(worsen ATP depletion).

2. Induction of apoptosis

, by direct activation of

certain enzymes called caspases.

DEFECTS IN MEMBRANE PERMEABILITY

Early loss of selective membrane
permeability leading ultimately to overt
membrane damage is a consistent feature of
most forms of cell injury (except apoptosis).
The plasma membrane can be damaged by
ischemia, microbial toxins, complement
components-mediated lysis, etc.

Biochemical mechanisms contribute to membrane
damage include:

1. Decreased phospholipid synthesis due to a fall in ATP
levels.

This affects all cellular membranes including

mitochondrial, which worsen the loss of ATP.

2. Degradation of membrane phospholipids

due to

activation of intracellular phospholipases through
increased levels of intracellular Ca2+.

3. Injury to cell membranes by Oxygen free radicals (ROS)
4. Damage to the cytoskeleton

through activation of

proteases by increased cytoplasmic Ca2+

5. The detergent effect of free fatty acids on membranes.

These products result from phospholipid
degradation.

The most important sites of membrane
damage during cell injury

are the

mitochondrial membrane,

the plasma membrane ,
membranes of lysosomes.

Reperfusion Injury

If cells are reversibly injured, the restoration of blood flow
can result in cell recovery. However, under certain
circumstances, the restoration of blood flow to reversibly
ischemic tissues results in worsening the injury.

This

situation may contribute to tissue damage in myocardial and
cerebral infarctions.

The additional damage may be initiated during the blood re-
flow by

1. Increased generation of reactive oxygen species

from

native parenchymal and endothelial cells, as well as the
infiltrating inflammatory cells.

2. The cellular antioxidant defense mechanisms are already
interfered with by ischemia.
3. Ischemic injury is associated with inflammation, which
may increase with reperfusion

. The products of activated

leukocytes and activation of the complement system may
cause additional tissue injury.

Causes of Cell Injury include

1. Oxygen deprivation (Hypoxia)

insufficient supply of

oxygen interferes with aerobic oxidative respiration
and is a common cause of cell injury and death.
Causes of hypoxia include

a. Ischemia

i.e. loss of blood supply in a tissue due to

interference with arterial flow or reduced venous
drainage. This is the most common cause of hypoxia

b. Inadequate oxygenation of the blood

, as in

pneumonia or chronic bronchitis

c. Reduction in the oxygen-carrying capacity of the
blood

, as in anemia or carbon monoxide (CO)

poisoning.

2. Chemical agents:

various poisons cause damage by

affecting either membrane permeability, or the integrity of the
cellular enzymes. Environmental toxins as pollutants,
insecticides, CO, alcohol and drugs can cause cell injury.

3. Infectious agents

including viruses, bacteria, rickettsiae,

fungi and parasites.

4. Immunologic reactions

; these are primarily defensive in

nature but they can also result in cell and tissue injury. Examples
include autoimmune diseases & allergic reactions.

5. Genetic defects

including gross congenital malformations

(as in Down syndrome) or point mutations (as in sickle cell
anemia). Genetic defects may cause cell injury because of
deficiency of enzymes in inborn errors of metabolism.

6. Nutritional imbalances:

nutritional deficiencies are

still a major cause of cell injury. Protein-calorie & vitamins
insufficiencies are obvious example. Excesses of nutrition are
also important causes of morbidity and mortality; for example,
obesity markedly increases the risk for type 2 diabetes
mellitus. Moreover, diets rich in animal fat are strongly
implicated in the development of atherosclerosis as well as in
increased vulnerability to cancer e.g. that of the colon.

7. Physical agents:

trauma, extremes of temperatures,

radiation, electric shock, and sudden changes in atmospheric
pressure all are associated with cell injury.

8. Aging:

this leads to impairment of replicative and repair

abilities of individual cells that result in a diminished ability to
respond to damage and, eventually, the death of cells and of
the individual.

Morphologic features of cell and tissue injury

All harmful influences exert their effects first at the

molecular (subcellular) or biochemical level

Function may

be lost long before morphologic changes of cell injury
become obvious .

i.e, myocardial cells fail to contract after 1 to 2 minutes of
ischemia, although they do not die until after 20 to 30
minutes of ischemia. These myocytes do not appear
morphologically dead

by electron microscopy until after 3

hours

and

by light microscopy after 6 to 12 hours.

The

cellular changes associated with reversible injury can be
repaired once the injurious agent is removed.

Changes

associated with irreversible injury (as with persistent or
excessively severe injury) are irreversible even with the
removal of the injurious agent, i.e. their occurrence signals
the point of no retrun, and the cell inevitably dies.

Morphologic examples of

reversible

injury

1. Cellular swelling (hydropic change or vacuolar
degeneration):

this is due to paralysis of energy-

dependent ion pumps of the plasma membrane

This

leads to influx of sodium (with water) into the cell and
departure of potassium out. It is the first manifestation
of almost all forms of cell injury.

Microscopically, there

are clear vacuoles (of water) within the cytoplasm.

2. Fatty change:

this is manifested by the appearance

of lipid vacuoles in the cytoplasm

. It is principally

encountered in cells participating in fat metabolism
such as hepatocytes; as in

alcoholic liver disease,

malnutrition & total parenteral nutrition

There are two changes that characterize
irreversible injury (cell death)

1. Mitochondrial dysfunction

manifested as lack of

oxidative phosphorylation leading to ATP depletion

2. Membrane dysfunction

including not only the

outer cell membrane but also the membranes that
surround intracytoplasmic lysosomes. This results
in liberation of the harmful lysosomal enzymes into
the cytoplasm, which in turn leads to dissolution
of vital celluar structures

Irreversible cell injury

There are two morphological types of cell death

1. Apoptosis
2. Necrosis

Apoptosis

is an active, energy-dependent,

regulated type of cell death. It serves many
normal functions and is not necessarily
pathological is the mode of cell death when

a. The cell is deprived of its growth factors

b. The cell's DNA or proteins are damaged
beyond repair

Apoptosis Diagram

Events in apoptosis

Apoptosis

– Micro

Necrosis

is a reflection of the morphological

changes that accompany cell death due to the
digestion of cellular contents by the liberated
degradative lysosomal enzymes. It is associated
with an inflammatory response (unlike apoptosis),
due to leakage of the cellular contents through the
damaged plasma membrane.

The lysosomes of the inflammatory cells also
contribute to the digestion of the dying cells.

Necrosis is the major pathway of cell death in many
commonly encountered injuries, such as those
resulting from ischemia, exposure to toxins, &
various infections.

Morphologic features of necrosis:

these consists of cytoplasmic & nuclear changes.

Cytoplasmic changes:

the necrotic cells show

increased

cytoplasmic eosinophilia

i.e

. it appears deep pink in color

than normal cells

. This is attributable in part

to increased

binding of eosin to denatured cytoplasmic proteins

and in

part to loss of the basophilia

that is normally imparted by

the RNA in the cytoplasm (basophilia is the blue staining
from the hematoxylin dye). The cell may have a more
homogeneous appearance than viable cells, mostly because
of the loss of glycogen particles. The latter is responsible in
normal cells for the granularity of the cytoplasm.

Nuclear changes :

these assume one of three

patterns, all due to breakdown of DNA and
chromatin

a. Karyolysis

i.e. the basophilia of the chromatin

become pale secondary to deoxyribonuclease
(DNase) activity.

b. Pyknosis

characterized by nuclear shrinkage

and increased basophilia; the DNA condenses into
a solid shrunken mass.

c. Karyorrhexis

, the pyknotic nucleus undergoes

fragmentation.

Types of Necrosis --

• Coagulative (most common)
• Liquefactive
• Caseous
• Fat necrosis
• Gangrenous necrosis

Patterns of Tissue Necrosis

There are several morphologically patterns of tissue necrosis, which
may provide clues about the underlying cause.

1. Coagulative necrosis

is characterized

grossly by firmness

of the affected tissue due to denaturation of structural
proteins

and

microscopically by loss of the cellular fine

structural details but preservation of the basic tissue
architecture.

The necrotic cells show homogeneously

eosinophilic cytoplasm and are devoid of nuclei.

Ultimately

the necrotic cells are removed through the degradtative
enzymes released from both the dead cells themselves as
well as from the already present inflammatory cells. The
latter also contribute by phagocytosing the cellular debris.

Coagulative necrosis is characteristic of ischemic damage in
all solid organs except the brain.

Splenic infarcts -- gross

2. Liquefactive necrosis

characterized by complete

digestion of the dead cells, resulting in transformation
of the affected tissue into thick liquid mass (hence the
name liquefactive).

Eventually, the liquefied necrotic tissue

is enclosed within a cystic cavity. This type of necrosis is
seenin two situations

a. Focal pyogenic bacterial infections.

These bacteria

stimulate the the accumulation of inflammatory cells & the
enzymes of leukocytes digest ("liquefy") the tissue. This
process is associated acute suppurative inflammation
(abscess); the liquefied material is frequently creamy
yellow and is called pus.

b. Ischemic destruction of the brain tissue:

for unclear

reasons, hypoxic death of cells within the central nervous
system often induces liquefactive necrosis

3. Gangrenous necrosis (gangrene)

not a distinctive

pattern of cell death; however, the term is still commonly
used in clinical practice.

It is usually applied to a limb,

usually a leg that has lost its blood supply and has
undergone coagulative necrosis involving multiple tissue
layers (dry gangrene).

When bacterial infection is

superimposed, coagulative necrosis is modified by the
liquefactive action of the bacteria and the attracted
leukocytes (wet gangrene)

Intestinal gangrene (the

consequences of mesenteric vascular occlusion) and
gangrenous appendix are also commonly used terms; they
signify ischemic necrosis of these structures with
superimposed bacterial infection.

4. Caseous necrosis

unlike coagulative necrosis,

the tissue architecture is completely lost and
cellular outlines cannot be detected. It is
encountered most often in foci of tuberculous
infection.

The term

"caseous“ (cheese-like)

derived from the friable yellow-white appearance
of the area of necrosis .

Microscopically,

the necrotic focus appears as

pinkish, and granular in appearance. Caseous
necrosis is often bordered by a granulomatous
inflammation.

5. Fat necrosis

is typically seen in acute

pancreatitis and results from release of activated
pancreatic lipases into the pancreas and the
peritoneal cavity. Pancreatic enzymes that have
leaked out of acinar cells liquefy

the membranes of fat cells in and outside the
pancrease. Lipases split the liberated triglycerides
into fatty acids that combine with calcium to
produce grossly visible chalky white areas .

Microscopically,

the foci of necrosis contain vague outlines of

necrotic fat cells with bluish calcium deposits. The necrotic foci are
surrounded by an inflammatory reaction.

Another example of fat

necrosis is seen in female breasts; at least some of these cases are
preceded by a history of trauma (traumatic fat necrosis).

Fat necrosis -- gross

Fat necrosis -- micro

6. Fibrinoid necrosis

is typically seen in immune reactions

involving blood vessels. Deposits of immune complexes, together
with fibrin that has leaked out of vessels result in a homogeneous
bright pink appearance. This type is exemplified by the necrosis seen
in polyarteritis nodosa .

The leakage of intracellular proteins through the damaged cell
membrane and ultimately into the blood provides means of
detecting necrosis of specific tissues using blood or serum samples.
The measurement of the levels of these specific enzymes in the
serum is used clinically to assess damage to these tissues.

Cardiac

muscles contain a unique enzyme creatine kinase (CK) and the
contractile protein troponin. The serum levels of both are elevated
after acute myocardial infarction.

Hepatocytes contain transaminases

& these are elevated in the serum following an episode of hepatitis
(viral or otherwise).

Accumulation of Oxygen-Derived Free Radicals (Oxidative
Stress)

These are designated as

reactive oxygen species (ROS)

are units with a single unpaired electron in their outer
orbit. When generated in cells they enthusiastically attack
nucleic acids, cellular proteins and lipids

. ROS are

produced normally in cells during mitochondrial
respiration and energy generation, but they are degraded
and removed by cellular defense systems. When their
production increases or the defense systems are
ineffective, the result is an excess of these free radicals,
leading to a condition called oxidative stress.

Cell injury in

many circumstances involves damage by free radicals;
these Include

Reperfusion injury ,Chemical and radiation injury

Toxicity from oxygen and other gases ,Cellular aging , Inflammatory
cells mediated tissue injury

Free Radicals --

• Free radicals have an unpaired electron

in their outer orbit

• Free radicals cause chain reactions
• Generated by:

– Absorption of radiant energy
– Oxidation of endogenous constituents
– Oxidation of exogenous compounds

Examples of Free Radical Injury

• Chemical (e.g., CCl

, acetaminophen)

• Inflammation / Microbial killing
• Irradiation (e.g., UV rays  skin cancer)
• Oxygen (e.g., exposure to very high

oxygen tension on ventilator)

• Age-related changes

Reactive oxygen species

Mechanism of Free Radical Injury

• Lipid peroxidation  damage to cellular

and organellar membranes

• Protein cross-linking and fragmentation

due to oxidative modification of amino
acids and proteins

• DNA damage due to reactions of free

radicals with thymine

Intracellular Accumulations --

• Cells may acquire (either transiently or

permanently) various substances that arise
either from the cell itself or from nearby cells

– Normal cellular constituents accumulated in

excess (e.g., from increased production or
decreased/inadequate metabolism)

– e.g., lipid

accumulation in hepatocytes

– Abnormal substances due to defective metabolism

or excretion (e.g., storage diseases, alpha-1-AT
deficiency)

– Pigments due to inability of cell to metabolize or

transport them (e.g., carbon, silica/talc)

Intracellular accumulations

Lipids

• Steatosis (fatty change)

– Accumulation of lipids within hepatocytes

– Causes include drugs, toxins

– Accumulation can occur at any step in the

pathway

– from entrance of fatty acids into cell to

packaging and transport of triglycerides out of cell

• Cholesterol (usu. seen as needle-like clefts in

tissue; washes out with processing so looks
cleared out)

– E.g.,

– Atherosclerotic plaque in arteries

– Accumulation within macrophages (called “foamy”

macrophages)

– seen in xanthomas, areas of fat

necrosis, cholesterolosis in gall bladder

Steatosis

Slide

– Fatty liver

Proteins

• Accumulation may be due to inability of

cells to maintain proper rate of
metabolism

– Increased reabsorption of protein in renal

tubules  eosinophilic, glassy droplets in
cytoplasm

• Defective protein folding

– E.g., alpha-1-AT deficiency  intracellular

accumulation of partially folded intermediates

– May cause toxicity – e.g., some

neurodegenerative diseases

Alpha-1-antitrypsin

accumulation -- micro

Gaucher’s disease -- micro

Liver in EtOH -- micro

Mallory hyaline -- micro

Glycogen

• Intracellular accumulation of glycogen

can be normal (e.g., hepatocytes) or
pathologic (e.g., glycogen storage
diseases)

• Best seen with PAS stain – deep pink to

magenta color

Slide

– Liver – normal

glycogen

Liver

– Glycogen storage

disease

Pigments

• Exogenous pigments

– Anthracotic (carbon) pigment in the lungs
– Tattoos

Anthracotic pigment in lungs --

gross

Slide

– Anthracotic lymph

node

Anthracotic pigment in

macrophages -- micro

Pigments

• Endogenous pigments

– Lipofuscin (“wear-and-tear” pigment)
– Melanin
– Hemosiderin

Lipofuscin

• Results from free radical peroxidation of

membrane lipids

• Finely granular yellow-brown pigment
• Often seen in myocardial cells and

hepatocytes

Lipofuscin -- micro

Melanin

• The only endogenous brown-black

pigment

• Often (but not always) seen in

melanomas

Slide -- Melanoma

Hemosiderin --

• Derived from hemoglobin – represents

aggregates of ferritin micelles

• Granular or crystalline yellow-brown pigment
• Often seen in macrophages in bone marrow,

spleen and liver (lots of red cells and RBC
breakdown); also in macrophages in areas of
recent hemorrhage

• Best seen with iron stains (e.g., Prussian

blue), which makes the granular pigment
more visible

Hemosiderin -- micro

Hemosiderin

Hemosiderin in renal tubular

cells -- micro

Prussian Blue

– hemosiderin

in hepatocytes and Kupffer

cells -- micro

Dystrophic Calcification

• Occurs in areas of nonviable or dying

tissue in the setting of normal serum
calcium; also occurs in aging or
damaged heart valves and in
atherosclerotic plaques

• Gross: Hard, gritty, tan-white, lumpy

• Micro: Deeply basophilic on H&E stain;

glassy, amorphous appearance; may be
either crystalline or noncrystalline

Calcification

Slide

– Ganglioneuroblastoma

with calcification

Dystrophic calcification in wall

of stomach -- micro

Metastatic Calcification --

• May occur in normal, viable tissues in

the setting of hypercalcemia due to any
of a number of causes

– Calcification most often seen in kidney,

cardiac muscle and soft tissue

Metastatic calcification of lung

in pt with hypercalcemia --

micro