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Introduction to Pathology

Divisions of pathology:
General pathology reactions of cells and tissues to abnormal stimuli and to
inherited defects
Systemic pathology alterations in specialized organs and tissues that are
responsible for disorders involving the organ
Four Aspects of a disease
1. Etiology
a. Genetic
b. Acquired
c. Idiopathic
d. Iatrogenic unintended or unwanted medical treatment
2. Pathogenesis
3. Molecular and morphological changes
4. Clinical manifestations
a. Signs observed manifestations
b. Symptoms subjective feelings of abnormality
c. Sequelae disease produces a subsequent pathologic condition
d. Complication new or separate process that may arise
History
Hippocrates father of medicine; first to deal with the anatomy and
pathology of the human spine
Benivieni pioneered autopsy
Leeuwenhoek father of microscopy
Virchow father of modern pathology

Cellular Injury, Adaptations, and Death


CELL INJURY set of biochemical and/or morphologic changes that occur when the
state of homeostasis is perturbed by adverse influences. It may be reversible or
irreversible.
Occurs due to:
o Excessive or overly prolonged normal stimuli
o Action of toxins and other adverse influences
o Deficiency of oxygen and/or essential nutrients and metabolites
How does hypoxia cause cell injury?
Prevents normal oxidative phosphorylation low ATP
Na/K ATPase cell swell (HYDROPIC or VACUOLAR
change, typically reversible) H2O accumulates in
cytoplasm, mitochondria, RER mito produces less
energy, RER dilates and ribosomes detach reducing
protein synthesis
Caused by:
o Exogenous
Physical, chemical, and biological factors
Ex. Heat and cold, toxins and drugs, viruses and bacteria
o Endogenous
Genetic defects, metabolites, hormones, cytokines, other
bioactive substances
What is the role of calcium in acute cell injury?
o Calcium derived from ECF, mitochondrial compartment, and cisterns of
RER activates several enzymes:
Lytic ATPase reduce energy stores
Phospholipases remove phospholipids from plasma or
mitochondrial membrane
Proteases degrade cell membrane or cytoskeletal proteins
Endonucleases nuclear chromatin damage
What does the cell do to compensate for the loss of aerobic respiration?
o Shift to anaerobic metabolism depletion of glycogen lactic acid
acidic milieu inhibits most enzymes except those in lysosomes cell
injury
C ELLULAR ADAPTATIONS describe changes that occur in response to prolonged
stimulation, lack of oxygen, or chronic injury. Usually reversible but may become
irreversible.
Five main types:

o
o

o
o

ADAPTATIO

Atrophy
Ubiquitin-proteosome pathway
Hypertrophy
Myocardial hypertrophy
Athletes heart mechanical stimuli IGF-1 (IGF1R)
PI3K hypertrophy
Diseased myocardium wall stress Ang II, ET-1
transcription of hypertrophic gene
Hyperplasia
Precursor for malignancies
Metaplasia
Reprogramming of stem cells or of undifferentiated
mesenchymal stem cells
Precursor for malignancies
Intracellular accumulation of various substances
Normal cellular constituents fat, water, protein
Abnormal substances exogenous or endogenous by-products

DESCRIPTION

PHYSIOLOGIC

PATHOLOGIC

Atrophy

Reduction of cell
size and number

Involution
related
irreversible

Hypertrophy

Increase in cell size

Hyperplasia

Increase
number

Heart and skeletal


muscles
uterus
Uterus, erythroid bone
marrow
in
high
altitudes, BPH

Metaplasia

Replacement of one
cell type by another

INTRACELLUL

DESCRIPTION

IDENTIFICATION

Disuse, denervation,
lack
of
trophic
hormones, ischemia,
malnutrition
Cardiac
hypertrophy
(box-shaped nucleus),
chronic alcoholism
endometrial
hyperplasia,
HPVinduced
lesions,
adenomatous
hyperplasia
in
pulmonary epithelium
Squamous metaplasia

Respiratory
epithelium, cervix
Barretts metaplasia
squamous
to
columnar w/ goblet
cells
SEEN IN

Accumulation of

Oil-Red O or Sudan IV

Liver and heart

in

cell

ageand

AR
ACCUMULATI
ONS

Steatosis

Cholesterol
and
cholesterol
esters
Proteins

Keratin
(Mallory
body)
Neurofilame
nts

Hyaline
change

Glycogen
Exogenous
pigments

Endogenous
pigments

triglycerides
Accumulation of
cholesterol laden
macrophages

(orange red)
Foam cells

Defect in protein
folding or transport

Eosinophilic
vacuoles,
aggregates

Accumulation of
keratin inside
hepatocytes
Thickened coarse
filaments
resembling braids
which is a sign of
cytoskeletal lesion
Intracellular:
Russel bodies in
plasma cells
indicative of
myeloma or chronic
inflammatory state
Extracellular
Diabetic
glomerulosclerosis
Lack of enzyme
Tattoo
Coal dust/carbon
anthracosis
Dental amalgam
Hematogenous
Hemosiderin
Hematoma
Tyrosine derived
melanin
Lipofuscin - Cells
undergoing slow,
regressive changes

droplets,
or

Cholesterolosis,
chronic cholecystitis,
skin xanthoma,
atherosclerosis
Severe proteinuria,
emphysema
Alcoholic liver disease

H&E:
homogenous
glassy pink

Plasma cells

Kidney

Clear cells containing


collagen; PAS

Liver and kidney

Hemosiderin pigment
iron-rich brown

Liver, patients with


multiple transfusions

Lipid-rich
pigment

Liver and heart

IRREVERSIBLE CELL INJURY


Signs:
o Plasma membrane ruptures

brown

Nuclear changes
Pyknosis condensation of chromatin
Karyolysis lysis of chromatin
Karyorrhexis fragmentation of nuclear material
o Mitochondria
rupture of double membrane
fragmentation
myelin figures concentric whorls of membranes derived from
damaged cytoplasmic organelles. Prominent in Tay-Sachs and
other inborn errors of metabolism damaging the cytoplasmic
membranes
calcifications
Dx signs
o Release of cytoplasmic enzymes into the blood
CK cardiac or skeletal muscle injury
AST and ALT liver cells
LDH ruptured RBC and other cells
o

Irreversibly damaged cells cannot be revived by oxygen. Reversibly injured


cells can be reoxygenated. However, note for reperfusion injury. caused
by oxygen-derived free radicals
o O2 O2- (superoxide) H2O2 (hydrogen peroxide) OH- (hydroxyl
radical)
o Superoxide SOD
o Hydrogen peroxide Catalase and glutathione peroxidase

Cell death

Necrosis localized death manifesting signs similar to irreversible cell injury


o Six main forms:
Coagulative necrosis
Most common
Usually happens to solid organs which underwent sudden
cessation of cell function no hydrolytic enzymes
therefore no dissolution of tissue
Infarct: localized area of coagulative necrosis
Wedge-shaped
Liquefactive necrosis
Aka colliquative necrosis
Digestion of dead cell
Seen in focal bacterial or occasionally fungal infections
Occurs due to action of hydrolytic enzymes released from
dead cells as in brain infarct or from lysosomes of
inflammatory cells as in abscess

Wet gangrene of extremities coagulative necrosis with


superimposed bacterial infection causing liquefactive
necrosis
Gangrenous necrosis
Coagulative necrosis on multiple tissue planes
Caseous necrosis
Cottage-cheese in appearance within a distinct
inflammatory border
Typical for tuberculosis and fungal granulomas
Fat necrosis
Occurs when fat cells are permeated by lipase and other
lytic enzymes released from damaged pancreatic cells
(acute pancreatitis)
Soft and gelatinous at first chalky white patches
composed of calcium soaps which gives it a bluish tinge
Fibrinoid necrosis
Limited to small blood vessels, typically small arteries,
arterioles and glomeruli affected by autoimmune disease
(ex. Systemic lupus erythematosus) or malignant
hypertension
Walls impregnated with fibrin and appear homogenously
red in routine H&E slides
Have no distinct macroscopic features
Pathologic calcification
Dystrophic calcification
o Deposition occurs locally in dying (necrotic) tissues
o Occurs despite normal serum levels of calcium
Metastatic calcification
o Deposition of calcium salts in normal tissues due to hypercalcemia
secondary to some disturbance in calcium metabolism
What is the outcome of necrosis?
o Complete restitution
aka regeneration
dead cells are replaced by almost parenchymal cell
occurs mostly in organs with facultative mitotic cells (kidney or
liver)
o Repair
Dead cells replaced by fibrogenous tissue causing fibrous scars
o Calcification
Necrotic tissue is impregnated with calcium salts (dystrophic
calcification)
o Resorption of necrotic tissue
In the brain, necrotic tissue is removed by macrophages and the
infarct is transformed into a fluid filled pseudocyst

Apoptosis
Cell death based on sequential activation of death genes and suicide pathway
enzymes
Aka programmed cell death
How is it initiated?
o Extrinsic pathway
Via death receptors such as TNF or Fas ligand
o Intrinsic mitochondrial pathway
Initiated by an increased permeability of mitochondria release
proaptotic molecules such as cytochrome act on initiator
caspases
o Initial signal from membrane or mitochondria initiator caspases
activated execution caspase activated act on enzymes leading to
fragmentation into membrane bound apoptotic bodies phagocytized
by neighboring cells or macrophages
Morphologic and biochemical changes
o Cell shrinkage (vs swelling in necrosis)
o Does not illicit inflammatory reaction
Example:
o Parkinsons disease
o Apoptosis of limb bud to form hands
Cellular aging
Progressive decline in cellular function and viability caused by genetic
abnormalities and accumulation of cellular and molecular damage due to the
effects of exposure to exogenous influences
Mechanisms of cell aging
o Telomere shortening
o Environmental insults
o DNA repair defects
o Abnormal growth

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