Pathology: Cell Injury

August 5 | Dr. DeRisio

FOUR PILLARS: Injury pathogenesis morphology clinical
CHANGES IN HOMEOSTASIS
First order response: Body adapts to internal/external stresses
Second order response: If adaptation fails, injury results
Third order response: Body tries to reverse injury
Fourth order response: Irreversible injury, results in cell death
Sample Case: 62yo comes into ER with chest pain
Atherosclerosis coronary artery blockage
Treatment:
o Options:
Break down barrier (lysis)
Place a stent
o Time frame:
Within 30 minutes or less: injury reversible
After 60 minutes: injury irreversible, try to
minimize injury

CELLULAR ADAPTIONS
1. ALTERED PHYSIOLOGICAL STIMULI/NONLETHAL INJURIOUS STIMULI:
Increased demand or stimulation (e.g. by growth factors, hormones)
Decreased nutrients or stimulation
Chronic irritation (chemical or physical)
RESPONSES:
Hypertrophy: increase in cell size and functional ability with increased synthesis of intracellular components
REVERSIBLE
Mechanism:
o Increase in cytoskeletal growth via protein
synthesis (most common)
Induction of genes causes:
Cytokine growth factors
Increased nuclear transcription
Increased contractile proteins
o Increase in organelles, i.e. mitochondria +
ribosomes (less common)
Photo: Hypertrophic + hyperplastic uterus on left.
Locations:
Left slide: normal uterine cells
o Cardiac skeletal muscle + nerves
Right slide: hypertrophy and hyperplasia of uterine cells
Causes:
o Increased demand
Note:
Weight lifting
Cardiac and skeletal muscle will NOT
Hypertension
have hyperplasia, only hypertrophy
o Increased endocrine stimulation
because their cells cannot divide
Puberty
Estrogen
Prolactin + estrogen
Hyperplasia: increase in cell number
REVERSIBLE
Mechanism:
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Pathology: Cell Injury

August 5 | Dr. DeRisio

o Mitosis of pluripotent stem cells

o Remember, cannot occur in cardiac cells and neurons
Causes:
o Hormonal
Ex. Glandular epithelium in female breast at puberty
o Compensatory
Ex. Liver regeneration
o Pathologic excess of hormones or growth factors, such as:
Endometrial hyperplasia: prognostic of cancer
Prostatic: benign, normal part of aging
Symptoms: peeing in the middle of the night
Ductal hyperplasia of the breast: prognostic of cancer, often benign
Viral infections: warts from papillomavirus

Prostatic hyperplasia

Metaplasia: replacement of one mature cell type by another (usually in surface epithelium)
REVERSIBLE
Note: Breast aprocrine metaplasia is NORMAL
o May be marker for progression to cancer
o Generally occurs under conditions of stress
Mechanism:
o Reserve cells induced to differentiate by growth factors, cytokines & mediators
Types of replacement:
o Glandular to squamous
Lung
Endocervix: columnar surface becomes squamous when exposed to acid environment after menarche
o Squamous to glandular
Distal esophagus (Barretts change)
o Glandular to different glandular
Intestinal metaplasia in stomach due to Helicobacter pylori
o Transitional to squamous
Mc in bladder secondary to schistosoma hematoblum
Dysplasia: disordered cell growth that results in increase nuclear to cytoplasm ratio
REVERSIBLE, pre-cancerous
Dysplasia vs. metaplasia
o Metaplasia does not have disordered cell growth nor increased nuclear to cytoplasm ratio
o For now, think of metaplasia as a precursor to dysplasia
o Dysplasia can progress to carcinoma
Carcinoma includes dysplasia on the other side of the basement membrane
Risk factors:
o Infection with HPV in cervix
o Smoking
o Sunlight
o Hormonal exposure, esp. uterus
o Prior metaplasia
Atrophy: degradation of cells, decrease in size, number, weight and functionality of
organ
IRREVERSIBLE
Mechanism:
o Tagging of cytoskeletal proteins with ubiquitin proteasome
degrades tagged protein

Left: Normal brain

Right: Atrophic brain

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Pathology: Cell Injury

August 5 | Dr. DeRisio
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o
Causes:
o
o
o
o

Autophagia of organelles
Decreased workload (ex. paralysis)
Loss of innervation (ex. ALS)
Ischemia (decrease oxygen)
Senile atrophy of brain secondary to atherosclerosis
Lack of hormonal or neural stimulation
Post-menopausal uterus
Thyroid atrophy after hypopituitarism
Malnutrition
Marasmus: protein deficiency with muscle wasting (cachexia)
Increase in tumor necrosis factor can suppress appetite
Cause lipid depletion also resulting in cachexia
Ex. Chronic inflammatory diseases
Pressure
Mass expansion with atrophy of surrounding tissue
Probably secondary to ischemia

2. REDUCED OXYGEN SUPPLY/CHEMICAL INJURY/MICROBIAL INFECTION:

Acute and transient OR
Progressive and severe
RESPONSES:
Acute reversible injury
Cellular swelling
Fatty change
Irreversible injury
Necrosis
Apoptosis
3. METABOLIC ALTERATIONS: GENETIC OR ACQUIRED/CHRONIC INJURY
Responses:
Intracellular accumulations
Calcification
4. CUMULATIVE SUBLETHAL INJURY OVER LONG LIFE SPAN
Response: Cellular aging

CELLULAR INJURY
Major Pathogenic Mechanisms:
ATP DEPLETION
FREE RADICAL INJURY
ATP DEPLETION:
ATP is normally produced by:
o Oxidative phosphorylation of ADP
o Via glycolytic pathway (in absence of O2)
When there is a lack of ATP:
o Anaerobic glycolysis
Decreased cellular pH due to formation of lactate
o Detachment of ribosomes decreased protein synthesis
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Pathology: Cell Injury

August 5 | Dr. DeRisio
o

o
o

Ca2+ pump altered and Ca2+ enters cell

Mitochondrial Effects
Mitochondrial membrane becomes more permeable
o More Ca2+ leaks out enzyme activator
o Release of cytochrome C into cytosol activates caspases apoptosis
Cytosolic Effects
Enzyme activation Phospholipases
Permeability
o Proteases damage cytoskeleton
o Endonucleases cause nuclear disruption
Reversible damage: cellular swelling + fatty change
Irreversible damage: denaturation of intracellular proteins and enzyme digestion of injured cells

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Pathology: Cell Injury

August 5 | Dr. DeRisio
Major cause of ATP Depletion: OXYGEN DEPRIVATION
No O2 means no final electron acceptor for production of ATP in oxidative phosphorylation
Plasma membrane, mitochondrial membrane and lysosomal membrane integrity lost
Hypoxia: tissue deprived of oxygen and thus ATP deprivation
Types:
Ischemia: decrease in blood flow that serves an organ
o Obstructive ischemia: blockage, constriction, or outflow obstruction
o Non-obstructive ischemia: trauma, blood loss, global ischemia/shock
Hypoxemia: Decreasing partial pressure of oxygen (such as would occur at a high altitude)
o Ex. ventilation problems- hypoventilation from COPD causing buildup of CO2 in alveoli
Hemoglobin abnormalities: hemoglobin fails to adequately deliver oxygen to tissues, partial pressure of O2 NOT decreased
o Ex. Anemia
o Ex. carbon monoxide poisoning (competitive inhibition)
cherry red: venous blood cannot be desaturated so it appears red just like arterial blood
o Ex. methemoglobinemia: Fe3+ instead of Fe2+, caused by sulfa drugs
Left shift of oxygen binding curve
o Decreased 2, 3 bisphosphoglycerate
o Carbon monoxide, alkalosis, methemoglobin, fetal Hb, hypothermia
Tissues prone to hypoxia:
Watersheds: areas of tissue between terminal branches of arteries (such as ACA and MCA)
Superior and inferior mesenteric arteries
Subendocardial tissue
Renal cortex and medulla
Neurons in CNS
Hepatocytes around the central vein of the liver
Reversible Injury: Cellular swelling and fatty change
Swelling: decreased ATP causes decreased efficacy of
Na+/K+ and Ca2+ pumps
o In heart can cause arrhythmia
Normal kidney tubules
Blebbing of cell surface
rER swelling loss of ribosomes, decreased protein production
Red cell appearance: loss of RNA

Reversible Injury

Irreversible Injury

Irreversible Injury: denaturing of intracellular proteins and enzyme digestion of injured cells
Loss of nuclei
Dissolution of membranes (plasma, mitochondrial, lysosome): enzymes leak and destroy cell
o Myelin figures: fat rich, derived from destroyed membranes
Lysis of ER

CELL DEATH
Morphologic expressions of cell death:
Cytoplasmic changes:
o Eosinophilic homogeneity red appearance
Loss of RNA
Denatured cytoplasmic proteins
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Pathology: Cell Injury

August 5 | Dr. DeRisio

Loss of glycogen
o Myelin figures: phospholipid blobs derived from destroyed membranes
o Calcification
Nuclear changes
Pyknosis

Karyohexis

Karyolysis
Necrosis: large scale cell death, induces inflammation
Apoptosis: Death of a single cell, induces macrophage influx WITHOUT inflammation
NECROSIS
Large scale cell death, induces inflammation
Types of necrosis:
Coagulative necrosis: proteins still present architecture preserved for a few days
Commonly seen in ischemic etiology
Inactivated enzyme block dissolution of the cell
Infarct: gross appearance of coagulative necrosis
May be pale (white) or hemorrhagic
Influencing factors:
o Size of occluded vessel
o Collateral circulation
o Dual blood supply (lung)
o Pre-existing disease
Necrotic kidney: white infarction
*Wedge shaped area due to branching blood supply

Myocardial infarction: coagulative necrosis

Gangrenous necrosis: coagulative necrosis in a limb

Due to loss of blood supply
Can turn to liquefactive wet gangrene
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Left: Necrotic pink, loss of nuclei

Right: Normal healthy tissue blue

Liquefactive necrosis: dead cells are digested liquefying of tissue

Loss of architecture
Commonly seen in infective processes pus
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Pathology: Cell Injury

August 5 | Dr. DeRisio
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o Exception: in the brain it is associated with ischemia

Hydrolytic enzymes from cells such as neutrophils liquefy tissue
Autolysis: result of catalytic enzymes derived from lysosomes of dead cells themselves
Heterolysis: result of catalytic enzymes derived from lysosomes of immigrant leukocytes

Caseous necrosis: combines coagulative and liquefactive necrosis

Cheese like
Characteristic of tuberculosis
Partially preserved cells in a necrotic center surrounded by a
granulomatous inflammatory wall

Fibrinoid necrosis: occurs in blood vessels

Can only see it microscopically
Associated with vasculitis
o Potentially due to autoimmune disease
Circle: occluded blood vessel becomes fibrinoid
o Disruption of endothelium
o Protein leaked
o Antigen-antibody complex forms fibrinoid
May lead to other types of necrosis
Example: fibrinous necrosis of coronary artery with ischemic hypoxia coagulative necrosis

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Pathology: Cell Injury

August 5 | Dr. DeRisio
Fat necrosis: destruction of fat
due to leakage of activated
pancreatic lipases into the
pancreas
Can be seen both
microscopically and
macroscopically
Not a specific pattern
Can lead to pancreatic necrosis
Saponification: fatty acids (from triglyceride esters split by lipases) combine
with calcium and look chalky white
Visible on x-ray/ultrasound
Prognostic for worsening acute pancreatitis and eventual death
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Pathologic calcification: abnormal deposition of calcium phosphate
Dystrophic: deposition of calcium in necrotic tissue
o Normal serum Ca2+ and phosphate
o No derangement in metabolism
o Calcium binds phospholipids of damaged membrane
microcrystal formation
self propagating
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Metastatic: deposition of calcium phosphate in NORMAL tissue

o Increased serum Ca2+ and/or phosphate
o Related diseases:
Destruction of bone
Endocrine mechanisms
Hyperparathyroidism
Renal failure
Decreased parathyroid hormone
Vitamin D disorders

Dystrophic calcification of leaflets of tricuspid

LABORATORY FINDINGS IN CELL DEATH:

Leakage of cytoplasmic enzymes into circulation
o Evidence of plasma membrane damage and cell death
Measurement of certain enzymes and isoenzymes provides clues as to cell death location
o Some enzymes present in many cells
ex. LDH
o Some enzymes only present in limited organs
ex. AST in hepatocytes, myocardium and skeletal muscle
o Some enzymes are organ specific
Ex. serum troponin I and T in heart
APOPTOSIS:
Death of a single cell, induces macrophage influx WITHOUT inflammation
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Eliminates unwanted cells through activation of coordinated, programmed

series of events
o Effected by dedicated set of gene products
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Pathology: Cell Injury

August 5 | Dr. DeRisio
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o May be normal or pathologic

Two major mechanisms:
o Intrinsic (mitochondrial) pathway
Decreased hormonal stimulation
Irreversible damage to DNA
o Extrinsic (death receptor initiated) pathway
T-cell management
Prevents wide-spread hyperactive T-cell response
FAS recognizes receptor adaptor proteins
Both mechanisms result in initiation of executioner caspases
o Activate endonucleases and proteases to breakdown DNA + cytoskeleton
o Package pieces
o Release for phagocytosis by macrophages

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