01 studyguide celladaptandnec latham 0820-22
DESCRIPTION
cell pathology. science.TRANSCRIPT
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