Cell Injury

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Cell Injury and Cell Death
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Cell Injury
If a cell is stressed or exposed to a damaging
stimulus it may adapt or become injured
If a cell is injured, the injury might be
reversible or irreversible
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Cell Injury
The line between reversible and irreversible is
not clear
Nor is the line between irreversible injury and
cell death
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Cell Injury
Cell responses to injurious stimuli depend
upon Type of injury Duration Severity
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Cell Injury
Consequences of injurious stimulus depend
upon Type of cell
Cell status
Cell adaptability
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Cell Injury
4 interdependent cell components are principal
targets for damaging stimuli
Cell Membrane Mitochondria Cytoskeleton Cellular
DNA
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Cell Injury
Because of the interdependence , damage to one
leads to secondary damage to others and
ultimately cell death
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Mechanisms of Cell Injury
Ischemia-Hypoxia-Anoxia
Free Radicals
Viruses
Chemicals
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Ischemic and Hypoxic Injury
Ischemia is a reduced blood supply or delivery to
a cell or tissue
Hypoxia is an oxygen deficiency
The two are not the the same, but are often used
interchangeably
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Ischemia
Hypoxia
Decreased oxidatative phosphorlation In
mitochondria, fall in ATP production
Depletion of Cellular ATP
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Depletion of Cellular ATP
Failure of membrane Na/K pump
Failure of membrane Ca pump
K leaves the cell Na water inter the cell
Ca inters the cell
Cell Swelling Loss of microvilli Blebs Endoplasmic
reticulum swelling Myelin figures
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Increased Cytosolic Calcium
Activation of Protein Kinases
Phosphorylation of proteins
Activation of ATPase
Decrease ATP
Activation of Phospolipases
Membrane damage
Activation of Endonuclease
Nuclear chromatin damage
Activation of Proteases
Cytoskeleton/membrane damage
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Depletion of Cellular ATP
Stimulate phospofructokinase
Increase glycolysis
Increase lactic acid Decrease pH
Clumping of nuclear chromatin Activation/release
of lysosomal enzymes
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Activation / release of Lysosomal enzymes
Detachment of ribosomes from RER
Decreased protein synthesis
Lysosomal enzymes degrade cytoplasmic and nuclear
components
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Hypoxic Injury
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Hypoxic Injury
ATP generation drops rapidly after loss of
oxygen Mitochondria function declines, Ca
released Loss of membrane pumps Na Ca inter
the cell, Water enters Ca activates
enzymes Lysosomes release enzymes Membranes
further damaged Cell death
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Injury By Oxygen Radicals
Free radicals are chemical species with an
un-paired electron in the outer orbital
They are very unstable and react with everything
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Free Radicals
They are formed in cells by
Absorption of radiant energy (ionizing radiation)
ReDox reactions during respiration(mitochondria)
Metabolism of drugs exogenous chemicals
Intracellular oxidase reactions (xanthine)
Oxygen therapy
Neutrophils
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Free Radicals
Most important are the reactive oxygen species
Superoxide anion ( O.2 ) Hydroxyl radical ( OH.
) Hydrogen peroxide ( H2O2 )
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Free Radicals
Because they are potentially damaging to cells,
there are inherent (innate) mechanisms to protect
from free radicals
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Free Radicals
Superoxidase dismutase Glutathione
peroxidase Catalses Antioxidants (Vit E)
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Free Radicals
Damaging effects
Membrane Damage
Peroxidation of lipids
Thiol-containing protein damage
Ion Pump Damage
Impaired Protein Synthesis
DNA damage
Ca Influx Into cell
Mitochondrial damage
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Re-Perfusion Necrosis
Following ischemia, cells become depleted of
energy (ATP), but reactive oxygen species do not
develop because there is no oxygen in the tissue
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Re-Perfusion Necrosis
If blood supply is re-established Tissues are
re-perfused, and huge amounts of reactive oxygen
species are generated from mitochondria and
xanthine oxidase.
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Xanthine Oxidase.
In hypoxic tissues, xanthine, a metabolite of
ATP, accumulates
Xanthine oxidase, oxidixes xanthine, to generate
reactive oxygen species
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Role of Iron
Free Ferric iron (Fe3)appears to participate in
the injury of cells by reduced oxygen species
Fe3 is reduced by superoxide anions ( O.2 )to
ferrous iron (Fe2)
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Role of Iron
Hydrogen peroxide ( H2O2 ) then reacts with the
Fe2 to produce hydroxyl radicals ( OH. )
This is the Fenton reaction
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Re-Perfusion Necrosis
The innate protective mechanisms are over
whelmed, and extensive cell damage and cell death
ensue
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Reactive Oxygen
Cell injury by these species occurs by
Lipid peroxidation of membranes Damaging
DNA Damaging protein structure via cross-linking
of sulfhydryl groups
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Mechanism of Viral Injury
Virus injure kill cells in one of two general
mechanisms
Directly Cytopathic Indirectly Cytopathic
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Directly Cytopathic
Polio Virus (ss RNA) produces pores or channels
in the host cell membrane, which allow
equilibration of ionic gradients potassium
leaves, sodium and calcium enter and the cell is
dead
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Membrane receptors
HOST CELL
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Direct Membrane Injury
Inside Cell
Cell Membrane
Viral Protein
Outside Cell
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Indirectly Cytopathic
Unlike the polio virus, Hepatitis B Virus
(dsDNA),can not have its genome directly
translated into protein.
Rather, its DNA is first transcribed into mRNA,
then into protein by the hosts DNA-dependent RNA
polymerase
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Membrane receptors
HOST CELL
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Indirect Membrane Injury
Inside Cell
Cell Membrane
Outside Cell
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HBV infection
The T-cell, recognizing the membrane-imbedded
viral protein as foreign, releases a protein that
disrupts the membranes integrity and cell death
occurs
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HBV infection
Individual hepatocytes are affected by viral
hepatitis.
A large pink cell undergoing "ballooning
degeneration" is seen below the right arrow,a
dying hepatocyte is seen shrinking down to form
an eosinophilic "councilman body" below the arrow
on the left. Other hepatocytes are swollen and
have granular pink cytoplasm.
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Chemical Induced Cell injury
Toxicology attempts to define the mechanisms that
determine both the target cell specificity and
the mechanisms of actions of chemicals
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Chemical Induced Cell injury
In general, toxic chemical are divided into two
classes
Directly cytopathic Indirectly cytopathic
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Directly CytopathicChemicals
Some chemicals act directly with a cell component
or organelle to bring about injury or cell death
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Directly CytopathicChemicals
Heavy metals lead and mercury
Mercury binds to sulfhydryl groups of the
membrane proteins,causing an inhibition of
ATP-ase dependent transport, resulting in
increased membrane permeability
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Indirectly CytopathicChemicals
These types of chemicals are themselves not
toxic, but rather are metabolized to yield a form
or metabolite that is toxic
Also, the target cell of the toxin need not be
the cell that metabolizes the chemical
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Indirectly CytopathicChemicals
Two examples of this type are the hepatotoxins
CCL4 and acetaminophen
Both of these are metabolized by the mixed
function(P450) oxidase system of the endoplasmic
reticulum of the liver
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Indirectly CytopathicChemicals
Both of these cause membrane damage as a result
of the peroxidation of membrane phospholipids
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Indirectly CytopathicChemicals
This is the result of the formation of free
radicals during the metabolism of the chemicals
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Acetaminophen
Extensive hepatocyte necrosis seen here in a case
of acetaminophen overdose. The hepatocytes at the
right are dead, and those at the left are dying.
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Cell Injury Summary
The main targets for cell injury are
Cell membranes Mitochondria Cytoskeleton DNA
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Cell Injury Summary
Damage to one cellular component or system often
leads to damage to others
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Cell Injury
When cells or tissues are injured they under go
morphological changes
There are patterns of change, each associated
with the type or extent of cell damage
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Cell Injury
Patterns of reversible or sublethal
injury Patterns of irreversible or lethal
injury A pattern of cell suicideApotosis Subcellu
lar alterations Intracellular accumulations
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Reversible injury
The two most common morphological changes are
Cellular swelling Fatty change
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Cellular swelling
Cellular swelling is the first change to be
recoganized in almost all types of cell injury
Cellular swelling occurs when there is membrane
damage and a loss of ability to maintain ionic
and fluid homeostasis
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Cellular swelling
Cellular swelling is also referred to as hydropic
change, cloudy swelling, or vacuoluar degeneration
Vacuoluar degeneration is from the development of
small intracellular vacuoles
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Cellular swelling
Swollen Liver cells
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Cellular swelling
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Fatty Change
This is a result of metabolic derangement of
injured cells which have a high thoughput of
lipid as part of their normal metabolic
requirements
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Fatty Change
Such change is usually seen in the liver , but
occurs less commonly in the myocardium and kidney
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Fatty Change
Fatty Liver
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Fatty Change
There are 4 main mechanisms for the accumulation
of fat (triglyceride) in cells
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Fat Accumulation
1
Increased peripheral mobilization of free fatty
acids and uptake into cells
Diabetes Mellitus
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Fat Accumulation
2
Increased conversion of fatty acids to
triglycerides
Alcohol
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Fat Accumulation
3
Reduced oxidation of triglycerides to acetyl-CoA
Hypoxia Alcohol
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Fat Accumulation
4
Deficiency of lipid acceptor proteins
(apoproteins), preventing export of formed
triglycerides
Genetic disease Protein malnutrition
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Fat Accumulation
The most common cause of fatty change (in the
liver) is alcohol abuse
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Fatty Change
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Lethal injury
Necrosis is the gross and histologic correlate of
cell death
Necrosis is the result of two concurrent processes
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Necrosis
Enzymatic digestion of the cell Denaturation of
proteins
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Necrosis
The digestion or dissolution of cells through the
activity of intrinsic enzymes is termed
autolysis, dissolution from enzymes from other
cells is termed heterolysis
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Necrosis
Autolysis brings about changes in both the
cytoplasm and nucleus during the evolution of a
necrotic cell
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Necrosis
Normal cell has an intact nucleus with visible
nucleolus
Cytoplasm is pale pink,with purple from RNA of
the rER
Sublethal damage may produce cytoplasmic
vaculation
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Necrosis
Early necrotic cell shows increased cytoplasmic
eosinophilia due to loss of cytoplasmic RNA
Nucleus becomes small,basophilic termed pyknosis,
indication cessation of DNA transcription
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Pyknosis
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Necrosis
Process continues with releases of nucleases
causing fragmentation of the nucleus in to
pieces, termed karyorrhexis
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Karyorrhexis
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Necrosis
Process continues with complete dissolution of
the nucleus termed karyolysis
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Karyolysis
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Necrosis
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Necrosis
Pyknosis nuclear shrinkage,increased
basophilia,DNA condenses into a shrunken mass
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Necrosis
karyorrhexis Pyknotic nucleus fragments
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Necrosis
karyolysis Dissolution of nucleus and fragments
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Necrosis
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Necrosis
Once these dead cells have undergone these early
changes,the mass of dead (necrotic) tissue may
exhibit distinct morphologic patterns, depending
on whether enzymatic catabolism or protein
denaturation predominates
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Necrosis
Although the terms for these patterns are
somewhat outmoded,they are used and understood by
pathologists and clinicians AND
They appear on Part I National Boards and the
first path exam
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Patterns of Cell Necrosis
Or everything you wanted to know about dead cells
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Patterns of Tissue Necrosis
Coagulation Liquefactive Gangrenous Caseous Fat
Fibrinoid Hemmorrhagic Gummatous
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Coagulative necrosis
Coagulative necrosis describes dead tissue that
appears firm and pale
Coagulative necrosis implies preservation of the
structural outline of the coagulated cells
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Coagulative necrosis
Preservation of general structure occurs because
the injury or subsequent acidosis denatures not
only the structural proteins but also enzymatic
proteins, preventing protolysis
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Coagulative necrosis
This pattern, with preservation of the general
tissue architecture, is characteristic of
hypoxic cell death of all tissues, except the
brain
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Coagulative necrosis
Ischemic injury to the kidney
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Liquefactive necrosis
Liquefactive or colliquative necrosis describes
dead tissue that appears semiliquid as a result
of dissolution of tissue by the action of
hydrolytic enzymes.
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Liquefactive necrosis
The most common types of damage leading to the
liquefactive pattern are necrosis in the brain
owing to arterial occlusion (cerebral infarction
and necrosis caused by bacterial infections).
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Liquefactive necrosis
With this pattern there is no preservation of
cellular structure or morphology
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Liquefactive necrosis
Liquefaction necrosis of a cerebral infarct
Semi-fluid mass of protein and no cellular
structure
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Gangrenousnecrosis
Is not a distinct pattern, but a combination
It refers to coagulative necrosis with a
superimposed infection with a liquefactive
component, the lesion is called
wet gangrene
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Gangrenousnecrosis
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Caseous Necrosis
Describes dead tissue that is soft and white,
resembling cream cheese
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Caseous Necrosis
With this type of necrosis, dead cells form an
amorphous proteinaceous mass but, in contrast to
coagulative necrosis, no original architecture
can be seen histologically
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Caseous Necrosis
This pattern is invariably associated with
tuberculosis
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Caseous Necrosis
Caseous necrosis of a kidney infected with
Mycobacterium tubelculosis
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Gummatous Necrosis
Describes dead tissue when it is firm and rubbery
As in caseous necrosis the dead cells form an
amorphous proteinaceous mass in which no
original architecture can be seen histologically
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Gummatous Necrosis
However, the gummatous pattern is restricted to
describing necrosis in the spirochaetal infection
syphilis
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Gummatous Necrosis
Gummatous necrosis of the liver with infection of
Treponema pallidum
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Hemmorrhagic necrosis
Describes dead tissues that are suffused with
extravasated red cells
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Hemmorrhagic necrosis
This pattern is seen particularly when cell death
is due to blockage of the venous drainage of a
tissue, leading to massive congestion by blood
and to subsequent arterial failure of perfusion
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Hemmorrhagic necrosis
An area of testicular hemmorrhagic necrosis
Caused by twisting of the testis on the end of
the spermatic chord,cutting of venus return,
leading to ischemia massively infused with RBC
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Fat Necrosis
Not a specific pattern, but rather a description
of fat destruction
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Fat Necrosis
Fat necrosis most often is associated with the
release of activated pancreatic enzymes into the
adjacent parenchyma or peritoneal cavity during
acute pancreatitis
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Fat Necrosis
Activated pancreatic enzymes liquefy fat cell
membranes and hydrolyze the triglyceride esters
contained within them
The released fatty acids combine with calcium to
produce chalky white areas
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Fat Necrosis
Fat necrosis may also be seen after trauma to
fat, for example in the breast
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Fat Necrosis
Gross appearance of acute pancreatitis
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Fat Necrosis
Microscopic appearance of acute pancreatitis
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Fat Necrosis
Fat necrosis of the breast follows trauma and can
clinically mimic neoplastic disease
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Fibrinoid necrosis
Describes the appearance of arteries in cases of
vasculitis and hypertension, when fibrin is
deposited in the damaged necrotic vessel wall
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Fibrinoid necrosis
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Patterns of necrosis
Gummatous necrosis seen in Syhpilis
Most common pattern is coagulative necrosis
caused by ischemia
Liquefactive necrosis is seen in brain and
infections
Caseous necrosis is seen in tuberculosis
Fibrinoid necrosis seen in blood vessel walls
Fat necrosis seen in Pancreatitis and Breast
trauma
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Programmed Cell Death Non-Pathological Cell
Death Normal Cell Death Innate Cell Death
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Apoptosis
A programmed and energy -dependent process
designed specifically to switch-off cells and
eliminate them
This controlled pattern of cell death is very
different than that which occurs as a result of a
damaging stimuli
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Apoptosis
Destruction of cells during embryogensis
implantation organogenesis developmental
involution
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Involution
A reduction in the number of cells in the form of
physiological organ atrophy, through programmed
cell death (apotosis)
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Apoptosis
Hormonal-dependent physiological involution
Endometrium during the menstrual cycle Lactating
breast after weaning Prostrate after castration
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Apoptosis
Cell depletion in proliferating populations
Intestional crypt epithelium Cell death in tumors
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Apoptosis
Depletion of immune-cell populations
T-cell in the thymus Cytokine deprived
T-cells Cytotoxic T-cell induced death
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Apoptosis
Apoptosis is brought about by the synthesis and
or activation of a number of cytosolic proteases
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Apoptosis
In development cells are primed for apoptosis and
survive only if rescued by a specific trophic
factor ie bcl-2 gene product
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Apoptosis
In development cells are primed for apoptosis and
survive only if rescued by a specific trophic
factor ie bcl-2 gene product
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Apoptosis
The apoptotic cells lose surface
specializations and junctions, shrinking in size.
The nuclear chromatin condenses beneth the
nuclear membrane. In contrast to necrosis,cell
organells remain normal
Endonuclease enzyme cleave chromosomes into
individual necleosome fragments
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Apoptosis
The apoptotic cells lose surface
specializations and junctions, shrinking in size.
The nuclear chromatin condenses beneth the
nuclear membrane. In contrast to necrosis,cell
organells remain normal
Endonuclease enzyme cleave chromosomes into
individual necleosome fragments
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Apoptosis
There is splitting of the cell into several
fragments, apoptotic bodies. Nuclear
fragmentation also occurs,with each fragment
containig viable mitochondria and organells
This process takes only a few minutes
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Apoptosis
There is splitting of the cell into several
fragments, apoptotic bodies. Nuclear
fragmentation also occurs,with each fragment
containig viable mitochondria and organells
This process takes only a few minutes
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Apoptosis
Apoptotic fragements are recognized by adjacent
cells, which ingest them by phagocytosis for
destruction. Some fragments degenerate
extracellulary , while others are ingested by
local phagocytic cells
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Apoptosis
Apoptotic fragements are recognized by adjacent
cells, which ingest them by phagocytosis for
destruction. Some fragments degenerate
extracellulary , while others are ingested by
local phagocytic cells
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Dont Forget
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Subcellular Responses to Injury
Or Sometimes you seem and Sometimes you dont
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Subcellular Responses
Distinctive alteration of cells involving
organelles
These occur in more chronic forms of cell injury
and sometimes represent adaptive responses
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Subcellular Responses
Cytoskeletal Abnormalities Lysosomal Catabolism
Mitochondrial Alterations SER Induction
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Cytoskeletal Abnormalities
The cytoskeleton consists of microtubules, thin
actin filaments thick myosin filaments, and
various classes of intermediate filaments
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Cytoskeletal Abnormalities
May be reflected by defects in cell function,
such as cell locomotion and intracellular
organelle movements in some instances by
intracellular accumulations of fibrillar material
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Cytoskeletal Abnormalities
Functioning myofilaments and microtubules are
essential for various stages of leukocyte
migration and phagocytosis
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Cytoskeletal Abnormalities
Deficiencies of the cytoskeleton appear to
underlie certain defects in leukocyte movement
toward an injurious stimulus (chemotaxis)or the
ability of such cells to perform phagocytosis
adequately.
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Cytoskeletal Abnormalities
A defect of microtubule polymerization in the
Chédiak-Higashi syndrome causes delayed or
decreased fusion of lysosomes with phagosomes in
leukocytes and thus impairs phagocytosis of
bacteria.
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Cytoskeletal Abnormalities
Defects in the organization of microtubules can
inhibit sperm motility, causing male sterility
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Cytoskeletal Abnormalities
Microtubules defects can immobilize the cilia of
respiratory epithelium, causing interference with
the ability of this epithelium to clear inhaled
bacteria, leading to bronchiectasis (the
immotile cilia syndrome).
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Cytoskeletal Abnormalities
Accumulations of intermediate filaments may be
seen in certain types of cell injury. For
example, the Mallory body, or alcoholic hyalin,
is an eosinophilic intracytoplasmic inclusion in
liver cells that is characteristic of alcoholic
liver disease but seen in many other conditions
as well.
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Lysosomal Catabolism
Lysosomes contain a variety of hydrolytic
enzymes, including acid phosphatase,
glucuronidase, sulfatase, ribonuclease,
collagenase
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Lysosomal Catabolism
These enzymes are synthesized in the RER and then
packaged into vesicles in the Golgi apparatus and
are called primary lysosomes
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Lysosomal Catabolism
Primary lysosomes fuse with membrane-bound
vacuoles that contain material to be digested
(the latter called phagosomes), forming secondary
lysosomes or phagolysosomes
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Lysosomal Catabolism
Lysosomes are involved in the breakdown of
phagocytosed material in one of two ways
Heterophagy Autophagy
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Heterophagy
Materials from the external environment are taken
up through the process of endocytosis
Uptake of particulate matter is known as
phagocytosis
Uptake of soluble smaller macromolecules is
pinocytosis
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Heterophagy
Heterophagy is most common in the professional
phagocytes, such as neutrophils and macrophages
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Heterophagy
Examples of heterophagocytosis include the uptake
and digestion of bacteria by neutrophilic
leukocytes and the removal of apoptotic cells and
bodies by macrophages
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Heterophagy
Fusion of the phagocytic vacuole with a lysosome
then occurs, with eventual digestion of the
engulfed material.
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Autophagy
In this process, intracellular organelles and
portions of cytosol are first sequestered from
the cytoplasm in an autophagic vacuole
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Autophagy
An autophagic vacuole is formed from
ribosome-free regions of the RER, which then
fuses with pre-existing primary lysosomes or
Golgi elements
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Autophagy
Autophagy is a common phenomenon involved in the
removal of damaged organelles during cell injury
and the cellular remodeling of differentiation
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Autophagy
Itis particularly pronounced in cells undergoing
atrophy induced by nutrient deprivation or
hormonal involution.
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Autophagy
The enzymes in the lysosomes are capable of
breaking down most proteins and carbohydrates,
but some lipids remain undigested.
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Autophagy
Lysosomes are also wastebaskets in which cells
sequester abnormal substances when these cannot
be adequately metabolized
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Autophagy
Hereditary lysosomal storage disorders, marked by
deficiencies of enzymes that degrade various
macromolecules, cause abnormal amounts of these
compounds to be sequestered in the lysosomes of
cells all over the body, particularly neurons,
leading to severe abnormalities
160
Autophagy
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Mitochondrial Alterations
In cell hypertrophy and atrophy, there is an
increase and a decrease, respectively, in the
number of mitochondria in cells
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Mitochondrial Hyperplasia
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Mitochondrial Alterations
Mitochondria may assume extremely large and
abnormal shapes (megamitochondria). These can be
seen in the liver in alcoholic liver disease and
in certain nutritional deficiencies
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Megamitochondria
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Mitochondrial Alterations
In certain inherited metabolic diseases of
skeletal muscle, the mitochondrial myopathies,
defects in mitochondrial metabolism are
associated with increased numbers of mitochondria
that often are unusually large, have abnormal
cristae, and contain crystalloids
166
Mitochondrial Alterations
In certain tumors of the salivary glands,
thyroid, parathyroids, and kidneys called
oncocytomas consist of cells with abundant
enlarged mitochondria, giving the cell a
distinctly eosinophilic appearance.
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SER Induction
Hypertrophy of Smooth Endoplasmic Reticulum
168
SER Induction
Classic example is chronic barbiturate use
Protracted human(but not dogs) use of
barbiturates leads to a state of increased
tolerance, so repeated doses lead to
progressively shorter time spans of sleep.
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SER Induction
The patients have thus adapted to the
medication. due to induction of an increased
volume (hypertrophy) of the SER of hepatocytes
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SER Induction
Barbiturates are detoxified in the liver by the
P-450centered, mixed-function oxidase system
found in the SER The barbiturates stimulate
(induce) the synthesis of more enzymes as well as
more SER.
171
SER Induction
Thus,the cell is better able to detoxify the
drugs and so adapt to its altered environment
The mixed-function oxidase system of the SER is
also involved in the metabolism of other
exogenous compound such as alcohol
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SER Induction
Cells adapted to one drug have increased capacity
to detoxify other drugs handled by the system
SO WHAT?
173
A patient of yours, who suffers from seizure
disorders, begins to drink alcohol. The alcohol
is detoxed by the P-450 mixed oxidase system,
the SER becomes hypertrophic, the detox enzymes
are increased, the anti-seizure meds are
metabolized faster/more efficient. The patient is
effectively taking a sub-therapeutic dose
174
As the patient pulls into to park in front of
your office for his weekly visit, he has a
seizure, steps on the gas rather than the brake,
drives the car through your office
And kills you and the 22 patients you have
scheduled that hour THATS WHAT
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(No Transcript)
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Intracellular Accumulatuions
Lipids Proteins Glycogen Pigments Calcium
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Intracellular Accumulatuions
One of the cellular manifestations of metabolic
derangements in pathology is the accumulation of
abnormal amounts of various substances
178
Intracellular Accumulatuions
These may be
a normal cellular constituent accumulated in
excess, such as water, lipid, protein, and
carbohydrates
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Intracellular Accumulatuions
These may be
an abnormal substance, either exogenous, such as
a mineral, or a product of abnormal metabolism
180
Intracellular Accumulatuions
These may be
a pigment or an infectious product
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Intracellular Accumulatuions
These substances may accumulate either
transiently or permanently, and they may be
harmless to the cells, but on occasion they are
severely toxic.
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AccumulatuionProcess
A normal endogenous substance is produced at a
normal or increased rate, but the rate of
metabolism is inadequate to remove it
Fatty change in the liver due to intracellular
accumulation of triglycerides.
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AccumulatuionProcess
A normal or abnormal endogenous substance
accumulates because it cannot be metabolized or
is deposited intracellularly in an amorphous or
filamentous form
Storage diseases
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AccumulatuionProcess
An abnormal exogenous substance is deposited and
accumulates because the cell has neither the
enzymic machinery to degrade the substance nor
the ability to transport it to other sites
carbon particles
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Lipids
Steatosis (Fatty Change)
An abnormal accumulations of triglycerides within
parenchymal cells
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Lipids
Fatty change is often seen in the liver because
it is the major organ involved in fat metabolism,
but it also occurs in heart, muscle, and kidney
187
Lipids
The causes of steatosis include toxins, protein
malnutrition, diabetes mellitus, obesity, and
anoxia. In industrialized nations, by far the
most common cause of significant fatty change in
the liver (fatty liver) is alcohol abuse
188
Lipids
The significance of fatty change depends on the
cause and severity of the accumulation. When
mild, it may have no effect on cellular function.
189
Lipids
More severe fatty change may impair cellular
function, but unless some vital intracellular
process is irreversibly impaired fatty change per
se is reversible
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Fatty Change
Alcoholic Liver
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Foam Cells
Macrophages become filled with lipids from
phagocytosis of necrotic debris or abnormal lipids
192
Foam Cells
Macrophages filled with lipids
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Atherosclerosis
In atherosclerotic plaques, smooth muscle cells
and macrophages within the intimal layer of the
aorta and large arteries are filled with lipid
vacuoles, most of which are made up of
cholesterol and cholesterol esters.
194
Atherosclerosis
Such cells appear foamy, and aggregates of them
in the intima produce the yellow
cholesterol-laden atheromas characteristic of the
disorder
195
Xanthomas
Intracellular accumulation of cholesterol within
macrophages is also characteristic of acquired
and hereditary hyperlipidemic states.
196
Xanthomas
Clusters of foamy cells are found in the
subepithelial connective tissue of the skin and
in tendons producing tumorous masses known as
xanthomas
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Cholesterolosis
Focal accumulations of cholesterol-laden
macrophages in the lamina propria of the
gallbladder
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Proteins
Excesses of proteins within the cells sufficient
to cause morphologically visible accumulation are
less common than accumulation of lipids
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Russell bodies
The endoplasmic reticulum of plasma cells engaged
in active synthesis of immunoglobulins may become
hugely distended, producing large, homogeneous
eosinophilic inclusions
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Alpha1-antitrypsin
In AAT deficiency, the enzyme accumulates in the
endoplasmic reticulum of the liver in the form of
globular eosinophilic inclusions
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Alpha1-antitrypsin
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Glycogen
Excessive intracellular deposits of glycogen are
seen in patients with an abnormality in either
glucose or glycogen metabolism
203
Glycogen
Diabetes mellitus is the prime example of a
disorder of glucose metabolism
Glycogen is found in the renal epithelial cells,
within liver cells, beta cells of the islets of
Langerhans, and heart muscle cells.
204
Glycogen
205
Pigments
Pigments are colored substances, some of which
are normal constituents of cells whereas others
are abnormal and collect in cells only under
special circumstances Pigments can be either
exogenous or endogenous
206
Carbon
The most common exogenous
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
207
Carbon
Accumulations of this pigment blacken the tissues
of the lungs (anthracosis) and the involved lymph
nodes.
208
Anthracosis
Lymph node of the lung showing carbon deposition
209
Anthracosis
lung showing carbon deposition
210
Lipofuscin
Also known as lipochrome and wear-and-tear or
aging pigment
It is derived through lipid peroxidation of
polyunsaturated lipids of subcellular membranes
211
Lipofuscin
Lipofuscin is not injurious to the cell or its
functions. Its importance lies in its being a
sign of free radical injury and lipid peroxidation
212
Lipofuscin
It is particularly prominent in the liver and
heart of aging patients or patients with severe
malnutrition and cancer cachexia. It is usually
accompanied by organ shrinkage (brown atrophy).
213
Lipofuscin
Liver
214
Hemosiderin
A hemoglobin-derived, golden-yellow to brown,
pigment in which form iron is stored in cells
Excesses of iron cause hemosiderin to accumulate
within cells
215
Hemosiderin
Hemosiderin Deposition In renal tubules
216
Hemosiderin
Iron is normally carried by transport proteins,
transferrins In cells, it is normally stored in
association with a protein, apoferritin, to form
ferritin micelles
217
Hemosiderin
When there is a local or systemic excess of iron,
ferritin forms hemosiderin granules, which are
easily seen with the light microscope.
218
Hemosiderosis
Wide spread deposition of hemosiderin,usually
following a systemic iron overload
219
Hemosiderin in lung
Hemosiderin in liver
220
Hemosiderosis
An example of localized hemosiderosis is the
common bruise
Following local hemorrhage, the area is at first
red-blue.
With lysis of the erythrocytes, the hemoglobin
eventually undergoes transformation to hemosiderin
221
Hemosiderosis
Macrophages take part in this process by
phagocytizing the red cell debris, and then
lysosomal enzymes eventually convert the
hemoglobin, through a sequence of pigments, into
hemosiderin
222
Hemosiderosis
The original red-blue color of hemoglobin is
transformed to varying shades of green-blue,
comprising the local formation of biliverdin,then
bilirubin and thereafter the iron moiety of
hemoglobin is deposited as golden-yellow
hemosiderin
223
Hemosiderosis
In most instances of systemic hemosiderosis, the
pigment does not damage the parenchymal cells or
impair organ function
224
Hemochromatosis
The more extreme accumulation of iron, however,
in a disease called hemochromatosis is associated
with liver and pancreatic damage, resulting in
liver fibrosis, heart failure, and diabetes
mellitus
225
Bilirubin
The normal major pigment found in bile. It is
derived from hemoglobin but contains no iron.
Jaundice is a common clinical disorder due to
excesses of this pigment within cells and tissues
226
Jaundice
227
Bilirubin
Bilirubin pigment within cells and tissues is
visible morphologically only when the patient is
rather severely jaundiced for some period of time
228
Bilirubin pigment
229
Calcification
Pathologic calcification implies the abnormal
deposition of calcium salts, together with
smaller amounts of iron, magnesium, and other
mineral salts
two forms of pathologic calcification
230
Dystrophic calcification
Occurs in nonviable or dying tissues, It occurs
despite normal serum levels of calcium and in the
absence of derangements in calcium metabolism
231
Dystrophic calcification
Although dystrophic calcification may be simply a
sign of previous cell injury, it is often a cause
of organ dysfunction. Such is the case in
calcific valvular disease and atherosclerosis
232
Metastatic Calcification
This may occur in normal tissues whenever there
is hypercalcemia
Hypercalcemia gt11.0mg/dl
233
Metastatic Calcification
In general, calcium causes no clinical
dysfunction, but, on occasion, massive
involvement of the lungs produces remarkable
x-ray films and respiratory deficits. Massive
deposits in the kidney (nephrocalcinosis) may in
time cause renal damage
234
Calcification
Metastatic calcification Lung
Dystrophic calcification Stomach