Path 1: Cell Adaptation and Necrosis

Aug 20 and Aug 22, 2012, Professor Latham

Accommodations: Hypertrophy, Atrophy, and Metaplasia

Hypertrophy: Increase

o Rule: Hyperplasia happens in mitotically active cells Cellular Hypertrophy only happens in post-mitotic cells - cardiac and skeletal muscle

HYPERTROPHY: Increase in Organ Size Example Phys or Path Process Gross Micro

Cellular Hypertrophy

(SIZE)

LVH: Left Ventricular

Hypertrophy

Pathologic: HTN Æ increase resistance Æ LV

grows to compensate

1) growth factors and vasoc-onstrictive agents Æ contractile

proteins Æ cells get bigger 2) genetic changes Æ fetal

isoforms efficient Æ chromatin duplicates but doesn’t divide Æ 4N

Normal: 1.5 cm thick LV

Path: super thick LV!

-Box car nuclei: large blueish rectangles filled

with chromatin

-Large myocytes

Hyperplasia (NUMBER)

Lactating Breast

Physiologic: normal response when breastfeeding

prolactin Æ Proliferation of glandular epithelium acinar cells

Æ increase cell # Breasts enlarge More epithelial acinar cells

BPH: Benign Prostate

Hypertrophy

Pathologic: adeno-fibromatous hyperplasia

5-a-reductase increases Æ increase metabolism of

testosterone to DHT ÆIncrease in glandular tissue

and stroma

-Nodules -Compressed urethra,

so Bladder hypertrophies to

push urine

-Infolded

-Increase in cell number

Atrophy: Decrease 1. Lack of nutrients 2. Ubiquitin-proteosome degradation - ubiquitin tags a cell for degradation by ligase 3. Autophagy: cell reduces its size Æ reduces the nutrients it demands Æ reduces the nutrients it receives

� bud off vesicles of ER Æcollect cellular proteins Æ brings it to the lysosome Æ 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

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) Æ Smoking Æ 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

ATROPHY: Decrease in Organ Size Example Process Gross Micro Pic

Cellular Atrophy

(SIZE)

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

Cell Death (NUMBER)

Cerebral Atrophy

Alzheimer’s and dementia Æ decrease in number of neurons and supporting

tissue

-Deep sulci, narrow gyri

-ventricles expand Æ hydrocephalus ex

vacuo

Both (SIZE AND NUMBER)

Atrophy of the Heart

Autophagy (see above) Æ Decrease in both myocyte

size and cell number

-Deep brown color due to accumulation of lipofuscin in cardiac

myocytes

-Reduced epicardial fat

See golden brown

lipofuscin granules

Example What is it Process Pathology

LIPOFUSCIN

Residual bodies

resulting from Autophagy

Lipid-protein complex bound to

ceroid

Autophagy Æ un-digestible proteins form in cytoplasm Æ sign of wear and tear and metabolic stress Gold-brown deposits

FAT

Hepatic Steatosis

Reversible

Fat accumulation in a non-adipocyte

no membrane around the fat

Deranged fatty acid metabolism Æ increase triglyceride stores Æ fat accumulation

(1) Alcohol, Diabetes, and Starvation Æ

increase Free FAs (2) Alcohol Æ increase esterification of FA to TG

(3) Alcohol, Hypoxia, and Toxins Æ decrease oxidation of FAs

(4) Alcohol, Toxins, Protein Malnutrition Ædecrease 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

Macrophage Fat

Accumulation

Fat accumulation in a non-adipocyte

Macrophages phagocytize necrotic cell membrane debris that contain lots of phospholipidsÆ foamy lipid-filled macrophages accumulate Æ Crystals of cholesterol

accumulate in plaque in thickened intima of arteries

Foamy macrophages

Cholesterol Crystals

Fatty Infiltration of

Heart

ADIPOCYTE sticks between cells in normally fat free organs (DIFFERENT than other two)

aging and atrophy Æ lipocytes between myocytes from epicardium to endocardium

See adipocyte fat cells between myocytes, normally in R atrium

IRON Hemosiderin Ferric Oxide

Iron normally stored in hepatocyte

(ferritin) and marrow (macrophages)

Primary: genetic mutation increases iron absorption from gut Secondary: (1) Other causes of increased iron absorption (2) hemorrhage Æ hemoglobin catabolism Æ RBBCs release iron Æ hemosiderin accumulate in macrophages

granular gold-brown deposit

Accumulations – Cellular and Tissue

PROTEIN

Hyaline Arterio-sclerosis

Hyalinization of arterioles due to

protein accumulation

HTN Æ endothelial damage Æ protein leaks from circulation to vessel walls Æ protein accumulation in AFF ONLY

Diabetes Æ proteins glycosylate Æ proteins get trapped in

BOTH AFF AND EFF arterioles and glomeruli of kidney

Amorphous, homogenous, glassy, pink appearance

Thick walls

Can be nodular

DM in Kidney HTN in Artery

Hyaline Change due to Amyloid

small 80-100 A filamentous

degraded protein w Ig light chains

Chronic injury Æ degenerated proteins to beta-sheets Æ accumulate in heart and vessel wall

Diabetes Æ amyloid or collagen in pancreas

islets of Langerhans

Amorphous, homogenous, glassy, pink appearance

Hyaline Scar

Collagen Scar in Myocardium Healed myocardial Infarct

Amorphous, homogenous, glassy, pink appearance

Myocytes drop out

Intracellular Hyaline Change

Mallory Bodies Obesity and alcohol Æ hyaline change in hepatocytes Dense red within a hepatocyte

Russell Bodies Chronic Infection Æ Immunoglobulins accumulate Æhyaline droplets in plasma cells Glassy pink hyaline in plasma cell

Mallory Russell

CALCIUM

Metastatic Calcification

Excess Calcium in circulation Messed up calcium metabolism

Micro: Deep purple, dense, slightly fragmented deposits

Gross: Firm, gritty, sandpaper

Renal Lung

Dystrophic Calcification

Calcium deposits at injured cell sites

activated phosphatases bind Ca ions to phospholipid membrane of injured cells

Deep purple, dense, slightly fragmented, grainy deposits in

damaged tissue Gross: aorta cracks like an egg

Gross: Coronary Artery: Aorta:

Reversible Cell Injury

10-15 mins: Ischemia (lack of oxygen) Æ ↓ Ox Phosph in Mitoch Æ ↓ ATP Energy Prod --> 3 paths 1. ↓ Na-K-ATPase Æ Na + water + Ca enter the cell Æ

(Cloudy) Swelling Ca precip in mitochondria Myelin figures Blebs 2. ↑ Glycolysis anaerobic support Æ ↓ Glycogen, ↑lactic acid Æ ↓ pH Æ chromatin clumping 3. Detachment of ribosomes from RER Æ ↓ protein synth and ↑ fat deposits

15-60 mins: If oxygen not returned, lose plasma membrane integrity: 1. Lose phospholipids Æ membrane holes Æ enzymes leak into circulation Æ CPK and LDH mark cell 2. Cytoskeleton breaks down Æ cell loses shape and breaks down 3. Free radicals generated Æ lipid peroxidation breakdown 4. Mitochondria Ca deposits Æ internal membrane integrity destroyed Æ ox phosph can no longer take place 5. Release of lysosomal enzymes Æ protein degradation Æ 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 Necrosis Apoptosis

Death by… Injury Suicide Cause Disruption of homeostasis Death by Design, programmed

Energy Depleted Dependent, requires new RNA and protein synth

Cell membrane

Dissolves, releasing proteases and inflammatory substances,

damaging neighboring tissues

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) Induction and Signaling

-One cell labeled for death

-Enzyme

activation and synthesis

(1) Extrinsic Pathway: signaling by death ligands TNF and FAS Æ activate initiator caspases

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

Growth factor Æ mitochondria permeable Æ DNA damage Æ p53 tries to repair damage but it’s too

overwhelmed Æ cytochrome C Æ apoptosis

(3) Cytotoxic T cells: virally infected cells Æ directly activate execution caspases

(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:

Nuc Arch Look Cause Effect Mechanism Example

Coagulative

No Yes 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

Liquifactive

No No Debris, fluid, no parenchyma

Abcess: InfectionÆneutrophi

l influx Brain: Hypoxia

Abscess: pus Brain: Cyst Complete lysis of cell

Abscess: Neutrophil enzymes digest

Brain: Mech unknown

Enzymatic / Fat

No? No?

-no membrane on fat cells

-dark dystrophic calcification

(white on gross exam)

Alcohol, Gallstones

Acute Pancreatitis

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

Acute Pancreatitis

Nuclear change What’s happening? What does it look like? Picture

Pyknosis Balling up of chromatin opaque round basophilic density in

cloudy swelling cells

Karyorrhexis fragmentation of nucleus into debris

Small, dense basophilic fragments (dust) in cells that have begun to lose

architecture

Karyolysis Dissolution of nuclear fragments by DNAse

Caseous

No 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 Æapoptosis Æ necrosis of

macrophages at center Æ TNF and CD8 activation of

Fas Fas

Mycobacteria Tuberculosis

see margin of macrophage

Fibrinoid

-Eosinophilic (red) amorphous fibrin

strands in vessel walls -varying Sm Musc

Fragmentation -neutrophils (inflamm)

Injury to Arterial Walls:

(1) Injury to vascular walls (immune complex)

(2) Hypertension endothelium damage

Vessel wall injury Æ leak protein and

fibrin from circ Æ entrapped in wall

Vascularitis: entrapped immune complexes activate

complement Æ vascular injury