General pathology

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

Cellular and biochemical sites of damage in cell injury

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.

Functional and morphologic consequences of decreased intracellular ATP during cell injury :

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

Mitochondrial dysfunction in cell injury.

.

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

Sources and consequences of increased cytosolic calcium in 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.