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Introduction to pathology
Literal translation of the word pathology is the study (logos) of suffering (Pathos).
It is a discipline that bridges clinical practice and basic sciences.
Pathology is concerned with the study of diseases in a scientific way.
It comprises a wide base of scientific data and investigative techniques that are essential practice of modern medicine.
Pathology in essence consists of two sets of related changes that are seen in various diseases:
1. Structural
2. Functional
The range of these changes is from those affecting sub-cellular organelles (molecular pathology) up to the alterations seen by the naked eye (gross pathology).
Pathology is a dynamic science in that its contents are continuously subjected to changes, revisions and expansions.
This is because there are always new scientific methods and findings that in turn shed more light on, add or modify an already established knowledge of various diseases.
The ultimate goal of pathology is the identification of the cause or causes of disease (etiology) as well as the mechanisms (pathogenesis) that can eventuate in;
1. Disease prevention &/or
2. Successful therapy
Cellular Injury and Adaptation
Each cell in the body is devoted to carry
specific functions, which are dependent on the
machinery and metabolic pathways present
within the cell.
This functional specificity is genetically determined.
Normally the cells of the body are in equilibrium with
the external environment.
They maintain their internal machinery in a
dynamically stable and steady state; this is called
homeostasis i.e. the supply of raw material
(substrates) and O2 are well coordinated with the
production of the materials or jobs required.
In the presence of external disturbances that lend to upset the fine equilibrium, changes within the cells occur through internal regulatory mechanisms that counteract the external changes.
In other words the cells are able to handle normal (physiological) and sometimes, abnormal (pathological) demands without get injured; to achieve this, a number of changes inside the cells occur that eventually lead to a new but altered steady state. These induced changes are referred to as adaptations.
The aim of adaptations is to preserve cell viability
i.e. prevent cell injury.
The increase in muscle mass (as in athletes or
heavy mechanical workers) is a reflection of an
increase in the size of individual muscle fibers so
that when the muscle is subjected to excess
workload, this will be shared by the thick and
strong muscle fibers and thus each fiber is spared
excess work and thus escapes injury.
This protective adaptation is referred to as
hypertrophy.
Hypertrophy may be physiological as that of
the uterus in pregnancy or pathological as that of
the left ventricle in systemic hypertension.
Opposite to the above is the adaptive response
atrophy in which there is a decrease in the size
and function of cells and consequently the size of
the organ or tissue containing them.
If the limits of adaptive capability of the cells
are exceeded (persistence of the injurious agent),
or when no adaptive response is possible
(sudden severe injurious agent that leaves no
time for adaptive responses to take place),
a sequence of events follows that are collectively
known as cell injury
Cell injury is divided into
1. Reversible cell injury
2. Irreversible cell injury
• Reversible cell injury indicates that the
changes will regress and disappear when the
injurious agent is removed; the cells will return
to normal, morphologically and functionally.
• Irreversible cell injury occurs when the
injury persists or when it is severe from the
outset.
• Here the cell alterations reach the point of no
return and progression to cell death is
inevitable.
Take an example:
• If the blood supply to a portion of the heart
musculature is cut off for few minutes and then
restored; the muscle cells will sustain
reversible injury i.e. after restoration of the
blood it will recover and function normally (as in
angina pectoris).
• But if cessation of blood continues for 60
minutes and then restored the myocardial cells in
this instance sustain irreversible injury that
terminates invariably to death.
• So there is a spectrum cellular changes in
response to injurious agent ranging from
adaptation to cell death .
• Classification (categorization) of injurious
agents
• Injurious agents can be categorized as follows:
• 1. Oxygen deprivation (hypoxia)
• 2. Physical agents
• 3. Chemical agents
• 4. Infectious agents
• 5. Immunological reactions
• 6. Genetic derangement
• 7. Nutritional imbalances
• Hypoxia
This refers to a decrease in oxygen supply to the
cells. It acts through interference with oxidative
respiration of the cells.
• Hypoxia results from:
A. Loss of blood supply (ischemia), which is the most
common cause and occurs when arterial flow is
interfered with by e.g. narrowing of the lumen of an
artery by atherosclerosis, thrombi or emboli.
B. Inadequate blood oxygenation due to for e.g. cardiac
failure and/or respiratory failure.
C. Decrease in the oxygen-carrying capacity of the
blood e.g. anemia and carbon mono-oxide poisoning.
Depending on the severity & duration of hypoxia, the
cells may show one of the following changes:
1. Adaptive atrophy
2. Injury( reversible or irreversible)
For e.g. if the femoral artery is narrowed, the muscles
of the leg shrink in size (atrophy).
This adaptive response continues till there is a
balance between the metabolic needs of the cells
(low in this instance) and the available oxygen
supply.
More severe hypoxia (for e.g. when there is more
severe narrowing or complete occlusion of the
artery) will induce injury (reversible then irreversible
that progresses to cell death).
Physical agents: that include
• -Mechanical trauma
• -Thermal injury;
a. hyperthermia (extreme heat)
b. hypothermia (deep cold)
• -Electrical injury;
a. burn
b. ventricular fibrillation
• -Radiation;
a. direct effect
b. indirect effect (free-radical formation)
• Chemical agents: that include
- Simple chemicals such as glucose and
salts in hypertonic concentrations
- Oxygen in high concentration
- Poisons such as arsenic or cyanide
- Air pollutants
- Insecticides
- Occupational exposure e.g. to asbestos.
- Social poisons such as alcohol and
narcotic
- drugs.
Infectious agents:
these include viruses, bacteria, fungi and
parasites.
Immunological reactions;
these are primarily protective defense
mechanisms against for e.g. infectious agents.
However, sometimes they are harmful and
injurious; this occurs in two situations:
A. Hypersensitivity reactions (triggered for e.g.
by drugs).
B. Directed to self-antigens (autoimmune
diseases).
• Genetic derangement:
exemplified by the wide range of
hereditary diseases
that range from those that are the result of
gross chromosomal defects leading to
severe congenital malformations
e.g.Down's syndrome
,to those that are caused by a single amino
acid substitution in the structure of
hemoglobin that leading to the synthesis
of abnormal Hb e.g. HbS in sickle cell
anemia.
• Nutritional imbalances
- Deficiency: as of proteins-
caloric malnutrition or vitamins
deficiency etc.
- Excess: as of lipids that leads to
obesity with all its consequences
including fatty change in cells and
predisposition to atherosclerosis.
Mechanisms of Cell InjuryThe biochemical mechanisms responsible for cell injury
are complex.
There are however, a number of principles that are
relevant to most forms of cell injury:
1-The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity. Thus, small doses of a chemical toxin or brief periods
of ischemia may induce reversible injury, whereas
large doses of the same toxin or more prolonged
ischemia might result either in instantaneous cell
death or in slow, irreversible injury leading in time to
cell death.
.
2. The consequences of cell injury depend on the type, state, and adaptability of the injured cell. The
cell’s nutritional and hormonal status
and its metabolic needs are important
in its response to injury
3- Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components
The most important targets of injurious stimuli are:(1) aerobic respiration involving mitochondrial
oxidative phosphorylation and production of
ATP;
(2)the integrity of cell membranes, on which the
ionic and osmotic homeostasis of the cell and
its organelles depends;
(3) protein synthesis;
(4) The cytoskeleton; and
(5) The integrity of the genetic apparatus of the
cell
A. DEPLETION OF ATPATP depletion and decreased ATP synthesis are frequently
associated with both hypoxic and chemical (toxic) injury .
High-energy phosphate in the form of ATP is required
for many synthetic and degradative processes within the cell.
These include membrane transport, protein synthesis,
lipogenesis, and the deacylation – reacylation reactions
necessary for phospholipid turnover. *ATP is produced in two ways; The major pathway in
mammalian cells is oxidative phosphorylation of adenosine
diphosphate.
The second is the glycolytic pathway, which can generate
ATP in the absence of oxygen using glucose derived either
from body fluids or from the hydrolysis of glycogen.
1-The activity of the plasma membrane energy-dependent sodium pump is reduced.
Failure of this active transport system, due to
diminished ATP concentration and enhanced
ATPase activity, causes sodium to accumulate
intracellularly and potassium to diffuse out of the
cell.
The net gain of solute is accompanied by isosmotic gain of water, causing cell swelling, and dilation of
the endoplasmic reticulum .
2-Cellular energy metabolism is altered.
3-Failure of the Ca2+ pump leads to influx of
Ca2+, with damaging effects on numerous
cellular components.
4 -Structural disruption of the protein synthetic apparatus
With prolonged or worsening ATP depletion, reduction in protein synthesis occurs due to;
a. Detachment of ribosomes from the rough endoplasmic reticulum
b. Dissociation of polysomes into monosomes.
5 -In cells deprived of oxygen or glucose, proteins may
become misfolded, and misfolded proteins trigger a cellular
reaction called the unfolded protein response that may
lead to cell injury and even death.
Protein misfolding is also seen in cells exposed to stress,
such as heat, and when proteins are damaged by enzymes
(such as Ca2+-responsive enzymes) and free radicals.
B. mitochondrial damage:Mitochondria are important targets for
virtually all types of injurious agent, including hypoxia & toxins. Mitochondria can be damage by:
1. Increase in cytoplasmic Ca++
2. Oxidative stress
3. Breakdown of phospholipids by activated phospholipase.
Injury to mitochondria leads to increased permeability of its membrane that result in leakage from the mitochondria of H+ and cytochrome C.
The former leads to loss of mitochondrial membrane potential, which is critical for mitochondrial oxidative phosphorylation thus leading to ATP depletion.
Leakage of cytochrome C can trigger apoptotic cell death
C. INFLUX OF INTRACELLULAR CALCIUM
AND LOSS OF CALCIUM HOMEOSTASIS
Calcium ions are important mediators of cell injury.
Cytosolic free calcium is maintained at extremely low
concentrations(<0.1 μmol) compared with extracellular
levels of 1.3 mmol, and most intracellular calcium is
sequestered in mitochondria and endoplasmic
reticulum.
Such gradients are modulated by membrane-associated,
energy-dependent Ca2+, Mg2+-ATPases.
Ischemia and certain toxins cause an early increase in
cytosolic calcium concentration, owing to the net influx
of Ca2+ across the plasma membrane and the release
of Ca2+ from mitochondria and endoplasmic reticulum .
Sustained rises in intracellular Ca2+ subsequently result
from nonspecific increases in membrane permeability.
Increased Ca2+ in turn activates a number of enzymes,
with potential deleterious cellular effects.
The enzymes known to be activated by calcium include
ATPases , phospholipases , proteases and
endonucleases .
Increased intracellular Ca2+ levels also result in increased
mitochondrial permeability and the induction of
apoptosis.
* Although cell injury often results in increased intracellular
calcium and this in turn mediates a variety of deleterious
effects, including cell death, loss of calcium
homeostasis is not always a proximal event in
irreversible cell injury
D-ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS
(OXIDATIVE STRESS)
Cells generate energy by reducing molecular oxygen to water.
During this process, small amounts of partially reduced reactive
oxygen forms are produced as an unavoidable byproduct of
mitochondrial respiration.
Some of these forms are free radicals that can damage lipids,
proteins, and nucleic acids. They are referred to as reactive oxygen species. Cells have defense systems to prevent injury caused by these
products.
An imbalance between free radical-generating and radical scavenging
systems results in oxidative stress, a condition that has been
associated with the cell injury seen in many pathologic conditions.
Free radical–mediated damage contributes to such varied processes
as chemical and radiation injury, ischemia-reperfusion injury (induced
by restoration of blood flow in ischemic tissue), cellular aging, and
microbial killing by phagocytes.
Free radicals may be initiated within cells in several ways:a-Absorption of radiant energy (e.g., ultraviolet light, x-rays). For example, ionizing
radiation can hydrolyze water into hydroxyl (OH) and hydrogen (H) free radicals.
b-Enzymatic metabolism of exogenous chemicals or drugs
(e.g., carbon tetrachloride [CCl4] can generate CCl3).
c-The reduction-oxidation reactions that occur during normal metabolic processes.
d-Transition metals such as iron and copper donate or accept free electrons during
intracellular reactions and catalyze free radical formation, as in the Fenton (H2O2
+ Fe2+ <---- Fe3+ + OH + OH-).
e-Nitric oxide (NO), an important chemical mediator generated by endothelial cells,
macrophages, neurons, and other cell types can act as a free radical and can
also be converted to highly reactive peroxynitrite anion (ONOO-) as well as NO2 and
NO3-.
The effects of these reactive species are wide-ranging , but three reactions are
particularly relevant to cell injury:
1-Lipid peroxidation of membranes. 2-Oxidative modification of proteins. 3-Lesions in DNA.
*In many pathologic processes, the final effects induced by free radicals depend on
the net balance between free radical formation and termination
E. 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.
Membrane damage may affect the mitochondria, the
plasma membrane, and other cellular membranes.
In ischemic cells, membrane defects may be the result
of a series of events involving ATP depletion and
calcium-modulated activation of phospholipases.
The plasma membrane, however, can also be
damaged directly by certain bacterial toxins, viral
proteins, lytic complement components, and a
variety of physical and chemical agents.
:Several biochemical mechanisms may contribute to membrane
:damage
2-Loss of membrane phospholipids 1- Mitochondrial dysfunction
3- Cytoskeletal abnormalities. 4- Reactive oxygen species.
5- Lipid breakdown products
Reperfusion injury
It has been noted that many of the effects of ischemic
injury seem to occur not during the ischemic episode
itself but when perfusion (blood flow) is reestablished
to an area of tissue that has been ischemic.
The re-flowed blood encounters cells with already
disrupted membrane from the initial ischemia.
Among other consequences of this membrane
dysfunction that is particularly important in this context
is impairment of calcium transport out of the cell and
from organelles (such as mitochondria). The rise of
intracellular Ca ++ causes activation of oxygen-
dependent free radicals that lead eventually to cell
damage. The necrosis of reperfusion injury appears to
be of the apoptotic rather than of the conventional type
Factors influencing the severity of the cell injury:
Types, duration & severity of the injurious agent.
Types of the affected cells: cells differ in their susceptibility to the effects of the
injurious agent; for e.g.
Reversible cell injuryIschemia is one of the commonest causes of the cell injury.
- Ischemia leads to hypoxia. This in turn result in reduction of the
available ATP.
-The cell, as a result of hypoxia, switches over to anaerobic
glycolysis (in an attempt to maintain energy supply).
-The glycogen stores get depleted with an increase in the
concentration of intracellular lactic acid(a byproduct of anaerobic
glycolysis).
-Lack of` ATP results in failure of sodium-potassium pump with
resultant influx of sodium into the cell & this is accompanied by
water (to insure isotonicity).
The result is swelling of the cell.
Additionally the lowering of intracellular pH (by lactic acid)
interferes with the proper functions of enzymes
Examples of reversible cell injury
1. Acute cellular swelling (hydropic change,
hydropic degeneration)
This is an early change in many examples of
reversible cell injury. The extra-fluid may be
seen by light microscopy as in increase in size
of the cell with pallor of the cytoplasm (cloudy
swelling). With further water accumulation
clear vacuoles are created within the cytoplasm
(vacuolar degeneration)
2. Fatty change
Irreversible cell injuryMitochondrial damage is one of the most reliable early
features of this type of injury.
In irreversible injury the damage to cell membrane is
most severe than in reversible injury, resulting in
leakage of the cellular constitutes outside their
normal confines.
This also results in liberation and activation of
lysosomal enzymes (proteinases, nucleases etc.),
which are also normally bounded by membranes.
These liberated and activated enzymes digest both
cytoplasmic and nuclear components (autolysis). The
end result is total cell necrosis, which is the
morphological expression of cell death.
Cell Death
There are two modes of cell death
1. Necrosis
2. Apoptosis
Necrosis
Necrosis is defined as the morphological changes that follow cell death in a living tissue or organ.
Necrosis results from the degrading action of enzymes on irreversibly damaged cells with denaturation of cellular proteins.
In necrosis, there are cytoplasmic as well as nuclear changes.
Cytoplasmic changesIn the hematoxylin-eosin stain (H&C), the hematoxylin
bluestains acidic materials (including the nucleus) where as eosin stains alkaline materials (including the
.pinkcytoplasm)
The necrotic cell is more eosinophilic than viable cells :(i.e. more intensely pinkish) this is due to
1. Loss of cytoplasmic RNA (RNA is acidic so stains with hematoxylin bluish) i.e. loss of basophilia.
2. Increase binding of eosin (which is responsible for the pinkish color of the cytoplasm) to the denaturated proteins.
The cell may have more glassy homogeneous appearance than normal cells; this is due to loss of the glycogen particles (which normally gives a granular appearance to cytoplasm)
Nuclear changes
The earliest change is chromatin clumping, which
is followed by one of two changes;
1. The nucleus may shrinks & transformed into
small wrinkled basophilic mass (pyknosis), with
time there is progressive disintegration of the
chromatin with subsequent disappearance of
the nucleus altogether (karylysis) or
2. The nucleus may break into many; clumps
(karyorrhexis).
In 1 to 2 days, the nucleus in a dead cell
completely disappears
Types of cell necrosis1. Coagulation (coagulative) necrosis.
2. Liquefaction (liquefactive) necrosis.
3. Fat necrosis
4. Caseous necrosis.
5. Gangrenous necrosis.
6. Fibrinoid necrosis.
1. Coagulation necrosisResults from sudden sever ischemia in such organs as the heart ,kidney etc.
Microscopically; the fine structural details of the affected tissue (and cells) are lost but their outlines are maintained.
-The nucleus is lost
-The cytoplasm is converted into homogeneous deeply eosinophilic and structureless material.
-- The basic tissue architecture is preserved for at least several -days
2. Liquefaction necrosis
Seen in two situations
1. Brain infarcts i.e. ischemic destruction of brain
tissue.
2. Abscesses i.e. suppurative bacterial infection
Liquefaction necrosis is characterized by
complete digestion of dead cells by enzymes
and thus the necrotic area is eventually
liquefied i.e. converted into a cyst filled with
debris and fluid
3. Fat necrosis
This is a specific pattern of cell death seen in
adipose tissue due to action of lipases.
It is most commonly seen in acute pancreatitis.
The released fatty acids from necrotic cells,
complex with calcium to create calcium soaps.
These are seen grossly as chalky white
deposits.
Fat necrosis can also be induced by mechanical
trauma as in female breast (traumatic fat
necrosis)
4. Caseous necrosis (caseation)
This combines the features of coagulative & liquefactive necrosis.
It is encountered principally in the center of tuberculous granuloma.
The body is response to tuberculous infection is a specific form of chronic inflammation referred to as granulomatous inflammation.
The morphological unit of this called granuloma.
the caseous material is soft , friable, Grossly; whitish- gray cheesy material
the area is surrounded by Microscopically;granulomatous inflammation. It has distinctive amorphous granular pinkish debris
5. Fibrinoid necrosis
Is a special form of necrosis usually seen in
immune reactions involving blood vessels.
This pattern of necrosis is prominent when
complexes of Ag & Ab are deposited in the
walls of arteries.
Deposit of these ―immune complexes ― together
with fibrin that has leaked out of vessel, result
in a bright pink and amorphous appearance in
H & E stain , called ―fibrinoid‖ (fibrin-like ) by
pathologist
6. Gangrenous necrosis
is not a distinctive pattern of cell death, the term is
still commonly used in surgical clinical practice.
It is usually applied to a limb, generally the lower leg,
that has lost its blood supply and has undergone
coagulation necrosis.
When bacterial infection is superimposed,
coagulative necrosis is modified by the liquefactive
action of the bacteria and the attracted leukocytes
(so-called wet gangrene; this term is used when the
dominant is the liquefactive action,
but when the dominant action is coagulative; the term
is dry gangrene.
ApoptosisNecrosis may be regarded as a morphological
expression of cellular ―cellular homicide‖
where as apoptosis mean ― a cellular suicide‖.
It is an energy dependent process for deletion of
unwanted individual cells.
CAUSES OF APOPTOSIS ;
Apoptosis occurs normally both during development and
throughout adulthood, and serves to eliminate
unwanted, aged or potentially harmful cells.
It is also a pathologic event when diseased cells
become damaged beyond repair and are eliminated.
Apoptosis in Physiologic Situations:
Death by apoptosis is a normal phenomenon that serves to eliminate cells that are no longer needed, and to maintain a steady number of various cell populations in tissues. It is important in the following physiologic
situations:
1- The programmed destruction of cells during embryogenesis;
including implantation, organogenesis, developmental
involution, and metamorphosis.
2- Involution of hormone-dependent tissues upon hormone
withdrawal; such as endometrial cell breakdown during the
menstrual cycle, ovarian follicular atresia in menopause, the
regression of the lactating breast after weaning, and prostatic
atrophy after castration.
3-Cell loss in proliferating cell populations ; epithelial
cells in intestinal crypts, so as to maintain a constant
number (homeostasis) .
4- Elimination of potentially harmful self-reactive lymphocytes, either before or after they have
completed their maturation, so as to prevent reactions
against one's own tissues.
5- Death of host cells that have served their useful
purpose, such as neutrophils in an acute inflammatory response, and lymphocytes at the end of an immune response.
In these situations cells undergo apoptosis because they
are deprived of necessary survival signals, such as
growth factors.
*Apoptosis in Pathologic ConditionsApoptosis eliminates cells that are injured beyond repair without eliciting a host reaction, thus limiting collateral tissue damage.
Death by apoptosis is responsible for loss of cells in a variety of
pathologic states:
1- DNA damage. Radiation, cytotoxic anticancer drugs, and
hypoxia can damage DNA, either directly or via production
of free radicals.
If repair mechanisms cannot cope with the injury, the cell
triggers intrinsic mechanisms that induce apoptosis. In
these situations elimination of the cell may be a better
alternative than risking mutations in the damaged DNA,
which may result in malignant transformation.
These injurious stimuli can cause apoptosis if the insult is
mild, but larger doses of the same stimuli may result in
necrotic cell death.
2- Accumulation of misfolded proteins; Improperly folded
proteins may arise because of mutations in the genes
encoding these proteins or because of extrinsic
factors, such as damage caused by free radicals.
3- Cell death in certain infections; particularly viral
infections, in which loss of infected cells is largely due
to apoptosis that may be induced by the virus (as in
adenovirus and HIV infections) or by the host immune
response (as in viral hepatitis).
4- Pathologic atrophy in parenchymal organs after duct obstruction; such as occurs in the pancreas, parotid
gland, and kidney
Morphology.
The following morphologic features, some best seen with
the electron microscope, characterize cells undergoing
apoptosis:
1. Cell shrinkage. The cell is smaller in size; the cytoplasm is
dense; and the organelles, though relatively normal, are
more tightly packed.
2. Chromatin condensation. This is the most characteristic
feature of apoptosis. The chromatin aggregates
peripherally, under the nuclear membrane, into dense
masses of various shapes and sizes .
3. Formation of cytoplasmic blebs and apoptotic bodies. The
apoptotic cell first shows extensive surface blebbing, then
undergoes fragmentation into membrane-bound apoptotic
bodies composed of cytoplasm and tightly packed
organelles, with or without nuclear fragments
4. Phagocytosis of apoptotic cells or cell bodies, usually
by macrophages. The apoptotic bodies are rapidly
ingested by phagocytes and degraded by the
phagocyte's lysosomal enzymes.
On histologic examination, in tissues stained with
hematoxylin and eosin, the apoptotic cell appears as a
round or oval mass of intensely eosinophilic cytoplasm
with fragments of dense nuclear chromatin.
Because the cell shrinkage and formation of apoptotic
bodies are rapid and the pieces are quickly
phagocytosed, considerable apoptosis may occur in
tissues before it becomes apparent in histologic
sections.
In addition, apoptosis—in contrast to necrosis—does not elicit
inflammation, making it more difficult to detect histologically.
Intracellular accumulations
Under certain situations, cells may accumulate abnormal
amount of various substances.
The accumulated substance fails into one of three
categories:
1. A normal cellular constituent accumulated in excess e.g.
lipid, protein and CHO
2. An abnormal substance that is a product of abnormal
metabolic pathway.
3. A pigment i.e. a colored substance.
The accumulated substance may be harmless or severely
toxic to the cell. The site of accumulation is either nuclear
or cytoplasmic. Within the cytoplasm ,the accumulated
substance is most frequently within the lysosomes
The mechanisms of abnormal intracellular
accumulation are many but can be divided
into four general types :
1. Abnormal metabolism: a normal substance is
produced at a normal rate but the rate of its removal is
inadequate e.g. fatty change of the liver.
2. Genetic mutations producing changes in
protein folding and transport.
A protein is composed of amino acids linked in specific
sequences by peptide bonds and coiled and folded
into complex globular or fibrous structures. A change
in this configuration may result in interference with its
transport so that it gets accumulated at the site of
production.
3. A normal or abnormal substance is produced but
cannot be metabolized.
This is most commonly due to lack of an enzyme,
which is genetically determined (inborn error of
metabolism).
Such a deficiency of enzymes blocks a specific
metabolic pathway resulting in the accumulation
unused metabolite (s) proximal to the block. The
resulting diseases are, referred to as storage
diseases.
4. An abnormally exogenous substance is
deposited and accumulates because the cell is
incapable to get rid of it (through enzymatic
degradation or to transport it to the outside)e.g. carbon
particles in anthracosis and silica particles in silicosis.
Accumulation of lipid
Fatty changes
This refer to abnormal accumulation of fat of
within parenchymal cells. triglyceride type
It is an example of reversible (non- lethal) cell injury and
is often seen in the liver because of the central role of
this organ in fat metabolism.
Free fatty acids are transported to the liver from two
sources
1. adipose tissue
2. ingested food
In the liver these fatty acids are esterified to
triglycerides. Release of triglycerides from the liver
required their association with carrier proteins
(apoproteins) . Such complexes circulate in the blood
as lipoproteins .
Excess accumulation of triglycerides within the
liver (fatty change) may result from defects in
any one of the above steps from entry to, till
their exit from the hepatocytes.
1. Alcohol may induce a number of such defects
through alterations in mitochondrial and
microsomal function.
2. CCl4 and protein malnutrition act by
decreasing apoproteins synthesis.
3. Anoxia (hypoxia) inhibits fatty acid oxidation.
4. Starvation increases fatty acid mobilization
from peripheral stores.
Gross features
In the liver mild fatty changes shows no gross changes,
but with progressive accumulation, the organ enlarges
and become increasingly yellow, soft & greasy to touch.
Microscopic features
In the early stages there are small fat vacuoles around the
nucleus. With progression the vacuoles fuse together
creating large clear space that displaces the nucleus to
the periphery.
myocardial cells Fatty change may also be seen within *
e.g. in ischemia and myocarditis. The latter may be seen
as a complication of diphtheria.
The above examples refer to accumulations of triglycerides
Accumulations may involve cholesterol and its
esters within
1. Smooth muscle cells and macrophages that
are located within the intima of arteries in
atherosclerosis.
2. Macrophages in the acquired and hereditary
hyperlipidemias; in such cases the
accumulations are usually seen within the
subcutaneous connective tissues of the skin
and in tendons producing masses known as
xanthomas.
Protein accumulation
This occurs principally in the;
1.Epithelial cells of proximal convoluted
renal tubules.e.g.in cases of
proteinuria.
2. plasma cells, these cells are actively
engaged in immunoglobulin synthesis
(antibody-forming ) and may become
overloaded with its own products.
GLYCOGEN
Glycogen is a readily available energy source
stored in the cytoplasm of healthy cells.
Excessive intracellular deposits of glycogen are
seen in patients with an abnormality in either
glucose or glycogen metabolism.
Whatever the clinical setting, the glycogen masses
appear as clear vacuoles within the cytoplasm.
Diabetes mellitus is the prime example of a
disorder of glucose metabolism. In this disease
glycogen is found in renal tubular epithelial cells,
as well as within liver cells, β cells of the islets of
Langerhans, and heart muscle cells.
Glycogen accumulates within the cells in a group of
related genetic disorders that are collectively
or , glycogen storage diseasesreferred to as the
glycogenoses . In these diseases enzymatic
defects in the synthesis or breakdown of glycogen
result in massive accumulation, causing cell injury
and cell death.
PIGMENTSPigments are colored substances, some of which are
normal constituents of cells (e.g., melanin),
whereas others are abnormal and accumulate in
cells only under special circumstances. Pigments
can be exogenous, coming from outside the body,
or endogenous, synthesized within the body itself
Exogenous Pigments
The most common exogenous pigment is carbon
(coal dust) . When inhaled it is picked up by
macrophages within the alveoli and is then
transported through lymphatic channels to the
regional lymph nodes in the tracheobronchial
region.
Accumulations of this pigment blacken the tissues of
the lungs (anthracosis) and the involved lymph
nodes.
In coal miners the aggregates of carbon dust may
induce a fibroblastic reaction or even emphysema
and thus cause a serious lung disease known as
coal worker's pneumoconiosis .
Tattooing is a form of localized, exogenous
pigmentation of the skin.
The pigments inoculated are phagocytosed
by dermal macrophages, in which they
reside for the remainder of the life of the
embellished (sometimes with
embarrassing consequences for the
bearer of the tattoo!). The pigments do not
usually evoke any inflammatory response.
Endogenous Pigments A- Lipofuscin is an insoluble pigment, also
known as lipochrome or wear-and-tear pigment.
Lipofuscin is composed of polymers of lipids and
phospholipids in complex with protein,
suggesting that it is derived through lipid
peroxidation of polyunsaturated lipids of
subcellular membranes.
Lipofuscin is not injurious to the cell or its
functions. Its importance lies in its being a
telltale sign of free radical injury and lipid
peroxidation.
The term is derived from the Latin (fuscus,
brown), referring to brown lipid.
In tissue sections it appears as a yellow-
brown, finely granular cytoplasmic, often
perinuclear, pigment .
It is seen in cells undergoing slow,
regressive changes and is particularly
prominent in the liver and heart of aging
patients or patients with severe
malnutrition and cancer cachexia.
B- Melanin,
derived from the Greek (melas, black), is
an endogenous, non-hemoglobin-derived,
brown-black pigment .
It formed when the enzyme tyrosinase
catalyzes the oxidation of tyrosine to
dihydroxyphenylalanine in melanocytes.
For practical purposes melanin is the only endogenous brown-black pigment.
The only other that could be considered in
this category is homogentisic acid, a black
pigment that occurs in patients with
alkaptonuria, a rare metabolic disease.
Here the pigment is deposited in the skin,
connective tissue, and cartilage, and the
pigmentation is known as ochronosis
3-Hemosiderin is a hemoglobin-derived,
golden yellow-to-brown, granular or crystalline
pigment that serves as one of the major storage
forms 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, which are easily seen with the light
microscope.
Hemosiderin pigment represents aggregates of
ferritin micelles.
Under normal conditions small amounts of
hemosiderin can be seen in the mononuclear
phagocytes of the bone marrow, spleen, and
liver, which are actively engaged in red cell
breakdown.
Local or systemic excesses of iron cause
hemosiderin to accumulate within cells.
result from hemorrhages in Local excessestissues.
The best example of localized hemosiderosis is
the common bruise.
Extravasated red blood cells at the site of injury
are phagocytosed over several days by
macrophages, which break down the
hemoglobin and recover the iron.
After removal of iron, the heme moiety is
converted first to biliverdin (―green bile‖) and
then to bilirubin (―red bile‖). In parallel, the iron
released from heme is incorporated into ferritin
and eventually hemosiderin.
These conversions account for the often dramatic
play of colors seen in a healing bruise, which
typically changes from red-blue to green-blue to
golden-yellow before it is resolved.
systemic overload of ironWhen there is
hemosiderin may be deposited in many
organs and tissues, a condition called
hemosiderosis.
The main causes of hemosiderosis are
(1) increased absorption of dietary iron,
(2) hemolytic anemias, in which abnormal
quantities of iron are released from
erythrocytes, and
(3) repeated blood transfusions because the
transfused red cells constitute an exogenous
load of iron.
Morphology
Iron pigment appears as a coarse, golden,
granular pigment lying within the cell's
cytoplasm .
localizedWhen the underlying cause is the
breakdown of red cells, the hemosiderin is
found initially in the phagocytes in the area.
hemosiderosis it is found at first in the systemicIn
mononuclear phagocytes of the liver, bone
marrow, spleen, and lymph nodes and in
scattered macrophages throughout other
organs such as the skin, pancreas, and kidneys
With progressive accumulation, parenchymal
cells throughout the body (principally in the
liver, pancreas, heart, and endocrine organs)
become pigmented.
In most instances of systemic hemosiderosis the
pigment does not damage the parenchymal
cells or impair organ function.
The more extreme accumulation of iron, however,
in an inherited disease called hemochromatosisis associated with liver, heart, and pancreatic
damage, resulting in liver fibrosis, heart failure,
and diabetes mellitus.
4- Bilirubin is the normal major pigment found
in bile. It is derived from hemoglobin but
contains no iron.
Its normal formation and excretion are vital to
health, and jaundice is a common clinical
disorder caused by excesses of this pigment
within cells and tissues.
Degenerative changesPathological calcification
Calcification is refers to abnormal deposition of calcium
salts.
There are two forms of calcification:
1. Dystrophic calcification; refers to calcium deposition
in nonviable or dying tissue that occurs despite occurs
normal calcium levels and the absence of any the
absence of any derangement of calcium metabolism.
2. Metastatic calcification ;signifies deposition of
calcium in viable tissue, almost always a reflection of
some derangement of Calcium metabolism that leads
to hypercalcemia.
Dystrophic calcification is noted in
1. Areas of necrosis (whether coagulative,
caseous, liquefactive, or fat necrosis
2. Advanced atherosclerosis.
3. Damaged or- aging heart valves.
The calcification is seen grossly as fine,
white granules or clumps giving gritty
feeling.
Microscopically (with H & E stains) it appears
as basophilic (bluish), amorphous granules
that may coalesce to form larger clumps.
Sometimes calcium deposition occurs in a
round lamellar fashion at a nidus of
necrotic cells.
These structures are called psammoma
bodies. This is seen in some tumors such
as carcinomas of the thyroid & ovary as
well as in some meningioma.
Metastatic calcificationis seen in cases of hypercalcemia of any cause.
It principally affects blood vessels, kidney, lungs
and gastric mucosa
The four major cause of hypercalcemia are;
a. Increased secretions of parathyroid hormone.
b. Destruction of bone due to the effects of
accelerated turnover. (e.g. Paget
disease),immobilization , or tumors (increase
bone metabolism associated with multiple
myeloma , leukemia ,or diffuse skeletal
metastases ).
c. Vitamin D-related disorders including vitamin D
intoxication & sarcoidosis (in which
macrophages activate a vitamin D precursor).
d. Renal failure; in which phosphate retention
leads to secondary hyperparathyroidism.
Hyaline change:This refers to intra- or extra-cellular homogeneous, pinkish
alteration in sections stained with H & E.
Examples of intracellular hyaline change include:
1. Hyaline droplets within renal tubular epithelium in cases of
protein urea.
2. Russell bodies in plasma cells
3. Viral inclusions (nuclear or cytoplasmic)
4. Alcoholic hyaline in liver cells (Mallory bodies).
Extracellular hyalinization may be encountered in
1. Collagen in old scar.
2. Hyalinization of arteriolar walls associated with
hypertension and diabetes.
3. Amyloid deposition.
CELLULAR AGINGCellular aging is the result of a progressive decline
in the proliferative capacity and life span of cells and
the effects of continuous exposure to exogenous
factors that cause accumulation of cellular and
molecular damage.
Several mechanisms are known or suspected to be
responsible for cellular aging:
1-DNA damage. Cellular aging is associated with
increasing DNA damage, which may happen during
normal DNA replication and can be enhanced by free
radicals. Although most DNA damage is repaired by
DNA repair enzymes, some persists and
accumulates as cells age.
2-Decreased cellular replication.
All normal cells have a limited capacity for replication,
and after a fixed number of divisions cells become
arrested in a terminally non dividing state, known as
replicative senescence (Replicative senescence:reduced capacity of cells to divide because of
decreasing amounts of telomerase and progressive
shortening of chromosomal ends (telomeres)).
Aging is associated with progressive replicative
senescence of cells. Cells from children have the
capacity to undergo more rounds of replication than do
cells from older people.
In contrast, cells from patients with Werner syndrome,a rare disease characterized by premature aging,
have a markedly reduced in vitro life span.
Note; Telomeres are short repeated sequences of
DNA present at the linear ends of chromosomes
that are important for ensuring the complete
replication of chromosome ends and for protecting
the ends from fusion and degradation.
3-Accumulation of metabolic damage. Cellular
life span is also determined by a balance between
damage resulting from metabolic events occurring
within the cell and counteracting molecular
responses that can repair the damage.