Cell Injury, Cell Adaptation and Cell Death
Cell
Injury, Cell Death, and Adaptations
CELLULAR ADAPTATIONS TO STRESS
Adaptations are reversible changes in the number,
size, phenotype, metabolic activity, or functions of cells in response to
changes in their environment.
1. Physiologic adaptations usually represent responses of cells to normal stimulation by hormones or
endogenous chemical mediators (e.g., the hormone-induced enlargement of the
breast and uterus during pregnancy).
2. Pathologic adaptations are responses to stress that allow cells to modulate their structure and
function and thus escape injury.
Cellular Adaptations
4 types of cellular adaptations are seen :
1. Hypertrophy
2. Hyperplasia
3. Atrophy
4. Metaplasia
Hypertrophy
Definition :
Hypertrophy is an increase in the size of cells resulting in increase in
the size of the organ.
There are no new cells, just bigger cells, enlarged
by an increased amount of structural proteins and organelles.
Hypertrophy occurs when cells are incapable of
dividing.
Hypertrophy can be physiologic or pathologic
and is caused either by increased functional demand or by specific hormonal
stimulation.
Hypertrophy and
hyperplasia can also occur together, and obviously both result in an enlarged (hypertrophic)
organ.
Example of physiologic hypertrophy :
1. The massive physiologic enlargement of the uterus
during pregnancy occurs as a consequence of estrogen-stimulated smooth muscle
hypertrophy and smooth muscle hyperplasia .
2. The striated muscle cells eg. skeletal
muscle e.g weightlifter .
Examples of pathologic cellular hypertrophy
1. Cardiac enlargement that occurs with hypertension or
aortic valve disease.
Hyperplasia
Hyperplasia takes place if the cell population is
capable of replication.
It may occur with hypertrophy and often in response
to the same stimuli.
1. Physiologic
2. Pathologic
A. Physiologic hyperplasia :
(1)
Hormonal hyperplasia, eg. proliferation of the glandular epithelium of the female breast at
puberty and during pregnancy
(2)Compensatory hyperplasia, eg. hyperplasia that occurs when a portion of the tissue is removed or
diseased. Eg. liver
B. Pathologic
hyperplasia - caused by excessive hormonal or growth factor
stimulation.
Eg 1. After a normal menstrual period there is a
burst of uterine epithelial proliferation that is normally tightly regulated by
stimulation through pituitary hormones and ovarian estrogen and by inhibition
through progesterone.
If the balance between estrogen and progesterone is
disturbed, endometrial hyperplasia -abnormal menstrual bleeding.
Eg. 2. Hyperplasia that is associated with certain
viral infections; for example, papillomaviruses cause skin warts .
The hyperplastic process remains controlled.
It is this sensitivity to normal regulatory control
mechanisms that distinguishes benign pathologic hyperplasias from cancer, in
which the growth control mechanisms become dysregulated or ineffective .
Atrophy
Definition : Shrinkage
in the size of the cell by the loss of cell substance is known as atrophy.
Although atrophic cells may have diminished
function, they are not dead.
Causes of atrophy
1. Decreased workload (e.g., immobilization of a limb to permit healing of a
fracture),
2. Loss of innervation,
3. Diminished blood supply,
4. Inadequate nutrition,
5. Loss of endocrine stimulation,
6. Aging (senile atrophy).
Atrophy results from
1. Decreased protein synthesis
2. Increased protein degradation in cells.
Protein synthesis decreases because of reduced
metabolic activity.
The degradation of cellular proteins occurs mainly
by the ubiquitin-proteasome pathway.
Nutrient
deficiency and disuse may activate ubiquitin ligases, which attach multiple
copies of the small peptide ubiquitin to cellular proteins and target these
proteins for degradation in proteasomes.
Metaplasia
Definition : Metaplasia is a reversible change in which
one adult cell type (epithelial or mesenchymal) is replaced by another adult
cell type.
In this type of cellular adaptation, cells sensitive
to a particular stress are replaced by other cell types better able to withstand
the adverse environment.
Eg. Squamous change that occurs in the respiratory
epithelium in habitual cigarette smokers , Vit A deficiency
Although the metaplastic squamous epithelium has
survival advantages, important protective mechanisms are lost
Eg. mucus
secretion and ciliary clearance of particulate matter.
The influences that induce metaplastic
transformation, if persistent, may predispose to malignant transformation of
the epithelium.
Summary - Cellular Adaptations to Stress
1. Hypertrophy: increased
cell and organ size, often in response to increased workload; induced by
mechanical stress and by growth factors; occurs in tissues incapable of cell
division.
2. Hyperplasia: increased
cell numbers in response to hormones and other growth factors; occurs in
tissues whose cells are able to divide.
3. Atrophy: decreased
cell and organ size, as a result of decreased nutrient supply or disuse;
associated with decreased synthesis and increased proteolytic breakdown of
cellular organelles.
4. Metaplasia: change in
phenotype of differentiated cells, often a response to chronic irritation that
makes cells better able to withstand the stress; usually induced by altered
differentiation pathway of tissue stem cells; may result in reduced functions
or increased propensity for malignant transformation.
CELL INJURY AND CELL DEATH
CAUSES OF CELL INJURY
1. Oxygen Deprivation : Hypoxia , Ischemia
2. Chemical Agents : Glucose , salt , oxygen , insecticides, CO, asbestos
etc.
3. Infectious Agents : Viruses , rickettsiae, bacteria, fungi, protozoans
and worms.
4. Immunologic Reactions : autoimmune reactions , allergic reactions etc.
5. Genetic Defects : deficiency of functional proteins , accumulation of
damaged DNA or misfolded proteins.
6. Nutritional Imbalances : Protein-calorie
insufficiency , excesses of nutrition , vit defeciency etc.
7. Physical Agents
: Temperatures, radiation, electric shock etc.
8. Aging : Diminished ability to respond to damage,
eventually, the death of cells .
CELL INJURY AND CELL DEATH
Reversible cell injury : In early stages or mild forms of injury the functional and morphologic changes
are reversible if the damaging stimulus is removed.
Cell death : With continuing
damage, the injury becomes irreversible, at which time the cell cannot recover and
it dies.
There are two types of cell death-
1. Necrosis
2. Apoptosis
Differ in their morphology, mechanisms, and roles in
disease and physiology.
The relationship between cellular function, cell
death, and the morphologic changes of cell injury.
THE MORPHOLOGY OF CELL AND TISSUE INJURY
Reversible Injury :
1. Cellular swelling : Cellular swelling is the result
of failure of energy-dependent ion pumps in the plasma membrane, leading to an
inability to maintain ionic and fluid homeostasis.
2. Fatty change. Fatty
change occurs in hypoxic injury and various forms of toxic or metabolic injury,
and is manifested by the appearance of small or large lipid vacuoles in the
cytoplasm.
Eg. hepatocytes and myocardial cells.
Reversible cell injury - Morphology
Cellular swelling - the first manifestation .
Microscopic examination - small, clear vacuoles within the cytoplasm -
distended and pinched-off segments of the ER.
This pattern of nonlethal injury is sometimes called
hydropic change or vacuolar degeneration.
Swelling of cells is reversible.
Fatty change is manifested by the appearance of lipid
vacuoles in the cytoplasm.
It is principally encountered in cells participating
in fat metabolism (e.g., hepatocytes and myocardial cells) .
Reversible.
Ultrastructural changes of reversible cell injury
(1)
plasma membrane alterations -
blebbing, blunting or distortion of microvilli, and loosening of intercellular
attachments;
(2)
Mitochondrial changes such as
swelling and the appearance of phospholipid-rich amorphous densities;
(3)
Dilation of the ER with detachment
of ribosomes and dissociation of polysomes;
(4)
Nuclear alterations, clumping of
chromatin.
Necrosis
Definition :
Necrosis is a series of changes that accompany cell death, largely resulting
from the degradative action of enzymes on lethally injured cells.
The enzymes responsible for digestion of the cell
are derived either from the lysosomes of the dying cells themselves or from the
lysosomes of leukocytes that are recruited as part of the inflammatory reaction
to the dead cells.
Necrosis - Morphology
The necrotic cells show increased eosinophilia .
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 ribonucleic acid (RNA) in the cytoplasm .
The cell may have a more glassy homogeneous appearance
than viable cells, mostly because of the loss of glycogen particles.
Dead cells may be replaced by large, whorled
phospholipid masses, called myelin figures, that are derived from damaged
cellular membranes.
They are thought to result from dissociation of
lipoproteins with unmasking of phosphatide groups, promoting the uptake and
intercalation of water between the lamellar stacks of membranes.
These phospholipid precipitates are then either
phagocytosed by other cells or further degraded into fatty acids; calcification
of such fatty acid residues results in the generation of calcium soaps.
Thus, the dead cells may ultimately become calcified.
Nuclear changes in Necrosis
1. Karyolysis -The basophilia of the chromatin may fade presumably secondary
to deoxyribonuclease (DNase) activity.
2. Pyknosis - characterized by nuclear shrinkage and increased basophilia;
the DNA condenses into a solid shrunken mass.
3. Karyorrhexis - the pyknotic nucleus undergoes fragmentation.
SUMMARY - Morphologic Alterations in Injured Cells
Reversible cell injury:
1. Cell swelling,
2. Fatty change,
3. Plasma membrane blebbing and loss of micro-villi,
4. Mitochondrial swelling,
5. Dilation of the ER,
6. Eosinophilia (decreased cytoplasmic RNA)
Necrosis:
1. Increased eosinophilia;
2. Nuclear shrinkage, fragmentation, and dissolution;
3. Breakdown of plasma membrane and organellar membranes;
4. Myelin figures;
5. Leakage and enzymatic digestion of cellular contents.
Patterns of Tissue Necrosis
1. Coagulative necrosis
2. Liquefactive necrosis
3. Caseous necrosis
4. Fat necrosis
5. Fibrinoid necrosis
Coagulative necrosis is a form of tissue necrosis in
which the component cells are dead but the basic tissue architecture is
preserved .
Presumably the injury denatures not only structural
proteins but also enzymes and so blocks the proteolysis of the dead cells .
Ultimately, the necrotic cells are removed by
phagocytosis .
Coagulative necrosis is characteristic of infarcts
(areas of ischemic necrosis) in all solid organs except the brain.
Liquefactive necrosis is seen in focal bacterial or,
occasionally, fungal infections, because microbes stimulate the accumulation of
inflammatory cells and the enzymes of leukocytes digest ("liquefy")
the tissue.
For obscure
reasons, hypoxic death of cells within the central nervous system often evokes
liquefactive necrosis .
Whatever the pathogenesis, liquefaction completely
digests the dead cells, resulting in transformation of the tissue into a liquid
viscous mass.
If the
process was initiated by acute inflammation, the material is frequently creamy
yellow and is called pus .
Liquefactive necrosis
Caseous necrosis is encountered most often in foci
of tuberculous infection.
The term "caseous" (cheese-like) is
derived from the friable yellow-white appearance of the area of necrosis .
On microscopic examination, the necrotic focus
appears as a collection of fragmented
cells with an amorphous granular appearance.
Obliterated architecture / Granuloma .
Caseous necrosis
Fat necrosis, a term that is well fixed in medical
parlance, refers to focal areas of fat destruction, typically resulting from
release of activated pancreatic lipases into the substance of the pancreas and
the peritoneal cavity.
Eg. Acute pancreatitis.
Pancreatic enzymes that have leaked out of acinar
cells and ducts liquefy the membranes of fat cells in the peritoneum, and
lipases split the triglyceride esters contained within fat cells.
Fat necrosis
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 antigens and antibodies are deposited in the walls of arteries.
Deposits of these "immune complexes,"
together with fibrin that has leaked out of vessels, result in a bright pink
and amorphous appearance in H&E stains, called "fibrinoid“ .
Fibrinoid necrosis
Mechanism of Cell Injury
Principles of cell injury :
1. The cellular response to injurious stimuli depends on type of injury,
its duration and its severity –
Small
dose / less duration : Reversible . Large dose / long duration – irreversible .
2. The
consequences of cell injury depend on type , state and adaptability of the
injured cell eg. Striated muscle of the thigh / cardiac muscles.
Mechanism of cell injury contd.
3. Cell injury results from functional and biochemical
abnormalities in one or more cellular components :
a) Aerobic respiration involving mitochondrial oxidative phosphorylation and
production of ATP.
b) The integrity of cell membrane depends on – ionic and osmotic
homeostasis.
c) Protein synthesis
d) The cytoskeleton
e) The integrity of the genetic apparatus of the cell .
MECHANISMS OF CELL INJURY
1. Depletion of ATP
ATP depletion + decreased synthesis – associated
with both hypoxic and chemical injury .
ATP production – 1. Oxidative Phosphorylation
2. Glycolytic
pathway.
Depletion of ATP <5% - 10% - has widespread
effect.
Depletion of ATP
2. Mitochondrial Damage
Mitochondria is damaged in both hypoxic injury and
toxic injury .
Damaged by –a) Increased cytosolic Ca++
b) Oxidative
stress
c) Breakdown of
phospholipids through phospholipaseA2 etc .
Result in – High conductance channel (Membrane
Damage ) – Mitochondrial permiability transition (MPT) – ions leak out .
Mitochondrial dysfunction
3.Influx of intracellular calcium and loss of
calcium homeostasis
Intracellular Ca++ is at very low level
(<0.1micromol) compared to extracellular Ca++ (1.3mmol). Mostly in
mitochondria and endoplasmic reticulum .
Level is maintained by Energy dependent Ca2+-Mg2+-
ATPase.
Injury – Increased influx of Ca2+ across the plasma
membrane and release from mitochon and ER.
Sources and consequences of increased cytosolic
calcium in cell injury
4.Accumulation of Oxygen derived free radical
In cells, energy is generated by reducing molecular
oxygen to water .
During this process small amount of partially
reduced reactive oxygen forms are produced – as unavoidable byproducts of
mitochondrial respiration.
This free radical can damage lipids, proteins and
nucleic acids.
These are referred to as “ REACTIVE OXYGEN
SPECIES “
Cells have a defence system to prevent injury caused
by these reactive oxygen species.
But imbalance between free radical generating and
radical scavenging system – results in oxidative stress .
Free radical associated damage is seen in –
1. Chemical and radiation injury
2. Ischemia – reperfusion injury
3. Cellular aging
4. Microbial killing by phagocytes.
Free radical are chemical species that have a single
unpaired electron in an outer orbit .
Energy is released through reaction with adjacent
molecules eg lipid , protein etc . Or by reacting with themselves – propagating
a chain of damage.
Free radical are generated by various ways –
1. Absorption of radiant energy : UV light
, X-Ray. Eg. Water is hydrolysed to OH ion and H free radical .
2. Enzymatic metabolism of exogenous chemicals/drugs .
3. The reduction – oxidation reaction that occurs in normal metabolic
process
4. Transition metals : Iron and copper.
5. Nitric oxide : produced by macrophages, endothelial cells and neurons .
5.Defect in Membrane Permiability
Early loss of selective membrane permiability leads
to membrane damage.
Membrane damage – due to – ATP depletion , Ca++
modulated activation of phospholipases or directly by bacterial toxins, viral
proteins etc.
Defects in Membrane Permeability
SUMMARY - Mechanisms of Cell Injury
ATP depletion: failure
of energy-dependent functions → reversible injury → necrosis
Mitochondrial damage: ATP depletion → failure of energy-dependent cellular functions →
ultimately, necrosis; under some conditions, leakage of proteins that cause
apoptosis
Influx of calcium:
activation of enzymes that damage cellular components and may also trigger
apoptosis
Accumulation of reactive oxygen species: covalent modification of cellular proteins, lipids, nucleic acids
Increased permeability of cellular membranes: may affect plasma membrane, lysosomal membranes, mitochondrial
membranes; typically culminates in necrosis.
Accumulation of damaged DNA and misfolded proteins: triggers apoptosis.
APOPTOSIS
("falling off").
Apoptosis is a
pathway of cell death that is induced by a tightly regulated suicide program in
which cells destined to die activate enzymes capable of degrading the cells'
own nuclear DNA and nuclear and cytoplasmic proteins.
Apoptosis is an active enzymatic process in which
nucleoproteins are broken down and then the cell is fragmented.
Causes of Apoptosis
Serves to eliminate potentially harmful cells .
Cells that have outlived their usefulness.
It is also a pathologic event when cells are damaged
beyond repair, especially when the damage affects the cell's DNA or proteins;
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. Embryogenesis
2. Involution of hormone-dependent tissues upon hormone deprivation eg.
endometrium
3. Cell loss in proliferating cell populations eg. intestinal crypt epithelia
4. Elimination of potentially harmful
self-reactive lymphocytes.
5. Cell death induced by cytotoxic T lymphocytes.
Apoptosis in Pathologic Conditions
1. DNA damage : Radiation, cytotoxic anticancer
drugs, extremes of temperature, and even hypoxia can damage DNA, either
directly or via production of free radicals.
2. Accumulation of misfolded proteins : mutations
in the genes encoding .
3. Cell injury in certain infections : virus
4. Pathologic atrophy in parenchymal organs after duct obstruction : pancreas, parotid gland, and kidney
Apoptosis – Morphology
Cell Shrinkage : Smaller size, dense cytoplasm ,
Organelles are tightly packed.
Chromatin condensation : Most characteristic feature
. Chromatin condenses peripherally . Nucleus may break down into 2 – 3 bits.
Formation of cyoplasmic blebs and apoptotic bodies:
First show extensive blebbing – then fragments into membrane bound apoptotic
bodies – composed of tightly packed organelles with or without nuclear
fragments .
Phagocytosis of apoptotic cells or cell bodies by
macrophages.
PLASMA MEMBRANE REMAINS INTACT – UNTIL LAST STAGE
Mechanism of Apoptosis
The fundamental event in apoptosis is the activation
of enzymes called caspases .
Activated caspases cleave numerous targets,
culminating in activation of nucleases that degrade DNA and other enzymes that
presumably destroy nucleoproteins and cytokeletal proteins.
The activation of caspases depends on a finely tuned
balance between pro- and anti-apoptotic molecular pathways.
Mechanism of Apoptosis
Two distinct pathways converge on caspase activation
–
1. Mitochondrial pathway
2. Death receptor pathway.
Mechanisms of Apoptosis
Clearance of Apoptotic Cells
In apoptotic cells - phospholipid "flips"
out and is expressed on the outer layer of the membrane - is recognized by macrophages.
Cells that are dying by apoptosis also secrete
soluble factors that recruit phagocytes.
Some apoptotic bodies express adhesive glycoproteins
that are recognized by phagocytes.
Macrophages themselves may produce proteins that bind
to apoptotic cells (but not to live cells) and target the dead cells for
engulfment.
This process of phagocytosis of apoptotic cells is
so efficient that dead cells disappear without leaving a trace, and
inflammation is virtually absent.
SUMMARY
Regulated mechanism of cell death that serves to
eliminate unwanted and irreparably damaged cells, with the least possible host
reaction.
Characterized by: enzymatic degradation of proteins
and DNA, initiated by caspases; and recognition and removal of dead cells by
phagocytes.
Initiated by two major pathways:
1. Mitochondrial (intrinsic) pathway
2. Death receptor (extrinsic) pathway
INTRACELLULAR ACCUMULATIONS
Under some circumstances cells may accumulate
abnormal amounts of various substances, which may be harmless or associated
with varying degrees of injury.
The substance may be located in the cytoplasm,
within organelles (typically lysosomes), or in the nucleus.
It may be synthesized by the affected cells or may
be produced elsewhere.
There are three main pathways of abnormal
intracellular accumulations
A normal substance is produced at a normal or an increased
rate, but the metabolic rate is inadequate to remove it. Eg. fatty change in the liver.
Fatty Change (Steatosis)
Fatty change refers to
any abnormal accumulation of triglycerides within parenchymal cells.
It is most often seen in the liver, since this is
the major organ involved in fat metabolism, but it may also occur in heart, skeletal
muscle, kidney, and other organs.
Steatosis may be caused by toxins, protein
malnutrition, diabetes mellitus, obesity, and anoxia.
Alcohol abuse and diabetes associated with obesity
are the most common causes of fatty change in the liver (fatty liver) in industrialized nations.
Free fatty acids from adipose tissue or ingested
food are normally transported into hepatocytes, where they are esterified to
triglycerides, converted into cholesterol or phospholipids, or oxidized to
ketone bodies .
The triglycerides from the hepatocytes requires the
formation of complexes with apoproteins to form lipoproteins, which are able to
enter the circulation.
Excess accumulation of triglycerides may result from
defects at any step from fatty acid entry to lipoprotein exit,
Hepatotoxins (e.g., alcohol) alter mitochondrial and
SER function and thus inhibit fatty acid oxidation;
CCl4 and protein malnutrition decrease
the synthesis of apoproteins;
Anoxia inhibits fatty acid oxidation;
Starvation increases fatty acid mobilization from
peripheral stores.
The significance of fatty change depends on the
cause and severity of the accumulation.
When mild it
may have no effect on cellular function.
More severe fatty change may transiently impair
cellular function, but unless some vital intracellular process is irreversibly
impaired (e.g., in CCl4 poisoning), fatty change is reversible.
In the severe form, fatty change may precede cell
death, and may be an early lesion in a serious liver disease called
nonalcoholic steatohepatitis .
Morphology – Steatosis
In any site, fatty accumulation appears as clear
vacuoles within parenchymal cells.
Special staining techniques – Sudan IV or oil red O
(these stain fat orange-red).
Fatty change is most commonly seen in the liver and
the heart.
Mild fatty change in the liver may not affect the
gross appearance.
With increasing accumulation, the organ enlarges and
becomes progressively yellow until, in extreme cases, it may weigh 3 to 6 kg
(1.5-3 times the normal weight) and appear bright yellow, soft, and greasy.
Early fatty change is seen by light microscopy as
small fat vacuoles in the cytoplasm around the nucleus.
In later stages, the vacuoles coalesce to create
cleared spaces that displace the nucleus to the cell periphery .
In the heart, lipid is found in the form of small
droplets, occurring in one of two patterns.
Prolonged moderate hypoxia (as in profound anemia)
results in focal intracellular fat deposits, creating grossly apparent bands of
yellowed myocardium alternating with bands of darker, red-brown, uninvolved
heart ("tigered effect").
Cholesterol and Cholesteryl Esters
Macrophages in contact with the lipid debris of
necrotic cells or abnormal (e.g., oxidized) forms of lipoproteins may become
stuffed with phagocytosed lipid.
These macrophages may be filled with minute,
membrane-bound vacuoles of lipid, imparting a foamy appearance to their
cytoplasm (foam cells).
In atherosclerosis, smooth muscle cells and
macrophages are filled with lipid vacuoles composed of cholesterol and
cholesteryl esters; these give atherosclerotic plaques their characteristic
yellow color .
In hereditary and acquired hyperlipidemic syndromes,
macrophages accumulate intracellular cholesterol; when present in the
subepithelial connective tissue of skin or in tendons, clusters of these foamy
macrophages form masses called xanthomas.
Proteins – Intracellular accumulation
Much less common
Occur - excesses are presented to the cells or
because the cells synthesize excessive amounts.
Accumulation of immunoglobulins in plasma cells,
form rounded, eosinophilic Russell bodies.
Mallory body, or "alcoholic hyalin," is an
eosinophilic cytoplasmic inclusion in liver cells - alcoholic liver disease.
Glycogen
In poorly controlled diabetes mellitus, the prime
example of abnormal glucose metabolism, glycogen accumulates in renal tubular
epithelium, cardiac myocytes, and β cells of the islets of Langerhans.
Glycogen also accumulates within cells in a group of
closely related genetic disorders collectively referred to as glycogen
storage diseases, or glycogenoses
Pigments
Pigments are colored substances that are either exogenous,
coming from outside the body, or endogenous, synthesized within the body
itself.
1. Carbon (anthracosis).
2. Lipofuscin, or
"wear-and-tear pigment," is an insoluble brownish-yellow granular
intracellular material (particularly the heart, liver, and brain) as a function
of age or atrophy ( brown atrophy).
Pigments contd.
3. Melanin is an
endogenous, brown-black pigment produced in melanocytes following the
tyrosinase-catalyzed oxidation of tyrosine to dihydroxyphenylalanine.
4. Hemosiderin is a hemoglobin-derived
granular pigment that is golden yellow to brown and accumulates in tissues when
there is a local or systemic excess of iron. Hemosiderosis .
Hereditary
hemochromatosis
Class 6
2010/1/29
PATHOLOGIC CALCIFICATION
Pathologic calcification is a common process in a
wide variety of disease states; it implies the abnormal deposition of calcium
salts, together with smaller amounts of iron, magnesium, and other minerals.
When the deposition occurs in dead or dying tissues,
it is called dystrophic calcification; it occurs in the absence of calcium
metabolic derangements (i.e., with normal serum levels of calcium).
In contrast, the deposition of calcium salts in
normal tissues is known as metastatic calcification and almost always
reflects some derangement in calcium metabolism (hypercalcemia). It should
be noted that while hypercalcemia is not a prerequisite for dystrophic
calcification, it can exacerbate it.
Dystrophic Calcification
Regardless of the site, calcium salts are grossly
seen as fine white granules or clumps, often felt as gritty deposits.
Sometimes a tuberculous lymph node is essentially
converted to radio-opaque stone.
Histologically, calcification appears as
intracellular and/or extracellular basophilic deposits.
In time, heterotopic bone may be formed in the focus
of calcification.
The pathogenesis of dystrophic calcification
involves initiation (or nucleation) and propagation, both of
which may be either intracellular or extracellular;
the ultimate end product is the formation of
crystalline calcium phosphate.
Initiation in extracellular sites occurs in
membrane-bound vesicles about 200 nm in diameter; in normal cartilage and bone
they are known as matrix vesicles, and in pathologic calcification they
derive from degenerating cells.
It is thought that calcium is initially concentrated
in these vesicles by its affinity for membrane phospholipids, while phosphates
accumulate as a result of the action of membrane-bound phosphatases.
Initiation of intracellular calcification occurs in
the mitochondria of dead or dying cells that have lost their ability to
regulate intracellular calcium.
After initiation in either location, propagation of
crystal formation occurs. This is dependent on the concentration of Ca2+
and PO4- in the extracellular spaces, the presence of
mineral inhibitors, and the degree of collagenization, which enhances the rate
of crystal growth.
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