Path 1: Cell Adaptation and Necrosis

Aug 20 and Aug 22, 2012, Professor Latham

Accommodations: Hypertrophy, Atrophy, and Metaplasia
Hypertrophy: Increase

HYPERTROPHY: Increase in Organ Size

Example

Cellular
Hypertrophy
(SIZE)

Phys or Path

Process

Pathologic: HTN
increase resistance LV
grows to compensate

1) growth factors and vasoconstrictive agents contractile

proteins cells get bigger
2) genetic changes fetal
isoforms efficient chromatin
duplicates but doesnt divide 4N

Gross

Micro

Normal: 1.5 cm thick

LV

-Box car nuclei: large

blueish rectangles filled
with chromatin

Path: super thick LV!

-Large myocytes

LVH:
Left Ventricular
Hypertrophy

Physiologic: normal
response when
breastfeeding

prolactin Proliferation of
glandular epithelium acinar cells
increase cell #

Breasts enlarge

More epithelial acinar cells

Lactating Breast

Hyperplasia
(NUMBER)

Pathologic: adenofibromatous hyperplasia

5-a-reductase increases
increase metabolism of
testosterone to DHT
Increase in glandular tissue
and stroma

-Nodules
-Compressed urethra,
so Bladder
hypertrophies to
push urine

-Infolded
-Increase in cell number

BPH:
Benign Prostate
Hypertrophy

Rule:

Hyperplasia happens in mitotically active cells

Cellular Hypertrophy only happens in post-mitotic cells - cardiac and skeletal muscle

Atrophy: Decrease
1. Lack of nutrients
2. Ubiquitin-proteosome degradation - ubiquitin tags a cell for degradation by ligase
3. Autophagy: cell reduces its size reduces the nutrients it demands reduces the nutrients it receives
bud off vesicles of ER collect cellular proteins brings it to the lysosome degradation
Residual bodies: un-digestible proteins that form in the cytoplasm due to lipofuscin granules
Lipofuscin: insoluble gold-brown deposit made of oxidized lipid-protein complex bound to
ceroid; wear and tear pigment because it shows the cell has undergone metabolic stress

ATROPHY: Decrease in Organ Size

Cellular
Atrophy
(SIZE)

Cell Death
(NUMBER)

Both
(SIZE AND
NUMBER)

Example

Process

Gross

Micro

Skeletal
Muscle
Atrophy

1)Disuse
2)Denervation
3)Decrease in functional
need
4)Decrease in resources
to support it

Lose bulk

Smaller size
of skeletal
myocytes

Cerebral
Atrophy

Alzheimers and dementia

decrease in number of
neurons and supporting
tissue

Atrophy
of the
Heart

Autophagy (see above)

Decrease in both myocyte
size and cell number

-Deep sulci, narrow gyri

-ventricles expand
hydrocephalus ex
vacuo
-Deep brown color due
to accumulation of
lipofuscin in cardiac
myocytes

See golden
brown
lipofuscin
granules

-Reduced epicardial fat

Metaplasia: Change
o One adult differentiated cell type is replaced by another
o Occurs through local effects, usually chronic injury
o Change is potentially reversible if the stress is removed
and it is pre-cancerous
o increases risk of cancer
o Ex: bronchial mucosa (pseudostrat ciliated columnar w
goblet) Smoking squamous cell metaplasia
Question: Kidneys from a 65 y.o. man with HTN.
o R kidney hypertrophied, L kidney atrophied
o Hyperplasia and Cell Death most likely change in NUMBER, not CELL SIZE
Why hyperplasia? Kidneys are mitotically active!
Why Cell Death? Decreased blood and nutrients will kill the cells
o L kidney atrophies due to a pathology (deficient blood supply), so the R
hypertrophies as a compensatory means to meet demands of the renal system

Pic

Accumulations Cellular and Tissue

Example

LIPOFUSCIN

Residual
bodies
resulting from
Autophagy

What is it

Process

Pathology

Lipid-protein
complex bound to
ceroid

Autophagy un-digestible proteins form in cytoplasm

sign of wear and tear and metabolic stress

Gold-brown deposits

Reversible
Fat accumulation in a
non-adipocyte
no membrane
around the fat
Hepatic
Steatosis

Fat accumulation in a
non-adipocyte

FAT

Deranged fatty acid metabolism increase

triglyceride stores fat accumulation
(1) Alcohol, Diabetes, and Starvation
increase Free FAs
(2) Alcohol increase esterification of FA to TG
(3) Alcohol, Hypoxia, and Toxins
decrease oxidation of FAs
(4) Alcohol, Toxins, Protein Malnutrition decrease
apoprotein synthes

Gross:
-Yellow
-Greasy
-3x Weight -Round Edges
Micro:
Microvesicular central nucleus,
many small globs of fat
Macrovesicular: displaced nucleus,
one large glob of fat

Macrophages phagocytize necrotic cell membrane debris

that contain lots of phospholipids foamy lipid-filled
macrophages accumulate Crystals of cholesterol
accumulate in plaque in thickened intima of arteries

Foamy macrophages
Cholesterol Crystals

Macrophage
Fat
Accumulation

ADIPOCYTE sticks between cells

in normally fat free organs
(DIFFERENT than other two)

aging and atrophy lipocytes between

myocytes from epicardium to endocardium

See adipocyte fat cells between

myocytes, normally in R atrium

Fatty
Infiltration of
Heart

Iron normally stored

in hepatocyte
(ferritin) and marrow
(macrophages)
IRON

Hemosiderin
Ferric Oxide

Primary: genetic mutation increases iron absorption from gut

Secondary: (1) Other causes of increased iron absorption
(2) hemorrhage hemoglobin catabolism
RBBCs release iron hemosiderin accumulate
in macrophages

granular gold-brown
deposit

Hyalinization of
arterioles due to
protein
accumulation
Hyaline
Arteriosclerosis

HTN

endothelial damage protein leaks from circulation

to vessel walls
protein accumulation in AFF ONLY

Diabetes proteins glycosylate proteins get trapped in

BOTH AFF AND EFF arterioles and glomeruli of kidney

DM in Kidney
small 80-100 A
filamentous
degraded protein w
Ig light chains

Amorphous, homogenous,
glassy, pink appearance
Thick walls
Can be nodular

HTN in Artery
Chronic injury degenerated proteins to betasheets accumulate in heart and vessel wall
Diabetes

Hyaline
Change due
to Amyloid

amyloid or collagen in pancreas

islets of Langerhans

Amorphous, homogenous, glassy, pink

appearance

PROTEIN

Collagen Scar in
Myocardium

Amorphous, homogenous, glassy, pink

appearance
Myocytes drop out

Healed myocardial Infarct

Hyaline Scar

Mallory Bodies
Intracellular
Hyaline
Change

Russell Bodies

Obesity and alcohol hyaline change in

hepatocytes
Chronic Infection Immunoglobulins
accumulate hyaline droplets in plasma cells

Mallory
Excess Calcium in
circulation

Dense red within a hepatocyte

Glassy pink hyaline in plasma cell

Russell
Micro: Deep purple, dense, slightly
fragmented deposits
Gross: Firm, gritty, sandpaper

Messed up calcium metabolism

Metastatic
Calcification

Renal

CALCIUM
Calcium deposits at
injured cell sites

Lung
Deep purple, dense, slightly
fragmented, grainy deposits in
damaged tissue
Gross: aorta cracks like an egg

activated phosphatases bind Ca ions to

phospholipid membrane of injured cells

Dystrophic
Calcification

Gross:

Coronary Artery:

Aorta:

Reversible Cell Injury

10-15 mins: Ischemia (lack of oxygen) Ox Phosph in Mitoch ATP Energy Prod --> 3 paths
1. Na-K-ATPase Na + water + Ca enter the cell
(Cloudy) Swelling
Ca precip in mitochondria
Myelin figures
Blebs
2. Glycolysis anaerobic support Glycogen, lactic acid pH chromatin clumping
3. Detachment of ribosomes from RER protein synth and fat deposits
15-60 mins: If oxygen not returned, lose plasma membrane integrity:
1. Lose phospholipids membrane holes enzymes leak into circulation CPK and LDH mark cell
2. Cytoskeleton breaks down cell loses shape and breaks down
3. Free radicals generated lipid peroxidation breakdown
4. Mitochondria Ca deposits internal membrane integrity destroyed ox phosph can no longer take place
5. Release of lysosomal enzymes protein degradation cell and nucleus fall apart
4-8 hours: cell death

Cloudy Swelling: Early Reversible Cell Injury

o Kidney: PCT cells more vulnerable to oxygen
Micro: Swelling, pallor of cytoplasm, chromatin clumping
Gross:swollen, pale, parboiled, bulging cortex
o Hydropic degeneration: vacuoles of water within the injured cell
sign of more severe cloudy swelling on its way to irreversible
Differentiate from fat vacuoles:
Small vacuoles that look empty
around central vein of liver (end of Ox supply)

Irreversible Cell Injury and Death: Necrosis and Apoptosis

Apoptosis vs. Necrosis
Death by
Cause

Necrosis
Injury
Disruption of homeostasis

Energy

Depleted

Cell
membrane

Dissolves, releasing proteases and

inflammatory substances,
damaging neighboring tissues

Apoptosis
Suicide
Death by Design, programmed
Dependent, requires new RNA and
protein synth
Intact. Phagocytosis of sub-cell
fragments removes cell without
exposing neighboring tissues

Cell
physically

Explodes

Shrinks

Distribution

large area of tissue induced by

injury

one cell or small cluster of cells

induced by signaling

Apoptosis
Step

What Happens

Notes

Picture

(1) Extrinsic Pathway: signaling by death ligands TNF

and FAS activate initiator caspases
-One cell labeled
for death
(1) Induction
and Signaling

-Enzyme
activation and
synthesis

(2)Intrinsic Pathway: radiation, toxins, radicals,

Growth factor
mitochondria permeable DNA
damage p53 tries to repair damage but its too
overwhelmed cytochrome C apoptosis
(3) Cytotoxic T cells: virally infected cells
activate execution caspases

directly

(2)
Execution

Executioner
Caspases activate
proteases and
endonucleases

-Caspases: family of proteases with cysteine at active

cite that cleave proteins at aspartic acid sites
- executioner caspases 3, 6 activated = point of no
return
-Eosinophilic cell condenses, dark nucleus fragments

(3)
Degeneration

Formation of
Apoptotic bodies

Small membrane bound subunits of cytosol with a bit

of nuclear content

(4)
Phagocytosis

Apoptotic bodies
cleared by
Macrophages

Apoptotic bodies have ligands for macrophage binding

and uptake

Above: Characteristic of an apoptotic cell in

a man with chronic Hep C viral infection
(1) Densely Eosinophilic
(2) Isolated cells are affected, not
everything around it
(3) Viral

Necrosis Irreversible Change Indicators:

o Mitochondrial Changes: severe swelling, cristae gone, Ca precipitate, electron-densities appear
o Nuclear Changes indicating irreversible cell death:
Nuclear change

Whats happening?

What does it look like?

Pyknosis

Balling up of chromatin

opaque round basophilic density in

cloudy swelling cells

Karyorrhexis

fragmentation of nucleus
into debris

Karyolysis

Picture

Small, dense basophilic fragments (dust)

in cells that have begun to lose
architecture

Dissolution of nuclear fragments by DNAse

Nuc

No

Arch

Look

Cause

Effect

Mechanism

Example

Uniform flat
pink quality

Sudden Ischemia
(NOT gradual no
time to adapt)

Infarct

so sudden that
proteolytic enzymes
that normally
dissolve the tissue
are denatured

Gangrene: extremity
infarction, many tissue planes
Dry: No infection
Wet: Infection, superimposed
liquifactive necrosis

Yes

No

Debris, fluid, no
parenchyma

Abcess:
Infection neutrophi
l influx
Brain: Hypoxia

Abscess: pus
Brain: Cyst

Complete lysis of cell

Abscess: Neutrophil enzymes

digest
Brain: Mech unknown

No?

-no membrane
on fat cells
-dark dystrophic
calcification
(white on gross
exam)

Acute
Pancreatitis

Injured acinars Panc

lipase leaks
digest
lipocyte membrane
TG to FA precip Ca
fat saponification

Acute Pancreatitis

Coagulative

No

Liquifactive

No?

Enzymatic /
Fat

Alcohol,
Gallstones

No

Caseous

No

-Gross: cottage
cheese debris
-Micro: pink
amorphous
granular debris
-macrophages
and/or fibrosis

Mycobacteria
Tuberculosis

Not empty, but

no arch. Between
Coag and Liqu

Granuloma apoptosis
necrosis of
macrophages at center
TNF and CD8 activation of
Fas Fas

Mycobacteria Tuberculosis

see margin of macrophage

-Eosinophilic (red)
amorphous fibrin
strands in vessel walls
-varying Sm Musc
Fragmentation
-neutrophils (inflamm)
Fibrinoid

Injury to Arterial Walls:

(1) Injury to vascular
walls (immune complex)
(2) Hypertension
endothelium damage

Vessel wall injury

leak protein and
fibrin from circ
entrapped in wall

Vascularitis:
entrapped immune
complexes activate
complement
vascular injury