Cellular Injury

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Reversible cellular changes

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1- Physiological- uterine enlargement

2- Pathological- Myocardial hypertrophy 2 to systemic HTN

3- If stress become persistent or excessive adaptation lead to

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Hypertrophy

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1- Increase in cell size

2- Increase structural proteins and organelles

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Hyperplasia

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1- Increase in number of cell

2- Controlled proliferation of stem cells and differentiated cells

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Atrophy

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1- Decrease in cell size and number

2- Apoptosis, disuse, denervation, loss of blood supply, loss of hormonal stimulation, poor nutrition

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Metaplasia

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1- Change from one cell type to another

2- Reprogramming of stem cells

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Dysplasia

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Disordered cell growth

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Why 2 pathologic processes usually precede dysplasia

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Persistent metaplasia

Pathological hyperplasia

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What is the major difference between metaplasia and dysplasia

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Metaplasia- Change in cell type

Dysplasia - Change in cell structure

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What type of metaplasia that can occur after trauma

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Myositis ossificans (formation of bone within muscle after trauma)

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Reversible cell injury

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1- Decrease ATP- Decrease Ca and Na/k pump- Cellular swelling and mitochondrial swelling

2- Ribosomal/Lysosomal detachment- Decrease protein synthesis

3- Plasma membrane changes- blending

4- Nuclear changes

5- Rapid loss of function

6- Myelin figures

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Irreversible cell injury

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1- Breakdown of plasma membrane - Cytosolic enzyme leak outside of cell, influx of Ca- activation of degradative enzyme be

2- Mitochondria damage/dysfunction- loss of electrons transport chain- Decrease ATP

3- Cytoplasmic vacuolization and programmed cell death

4- Rupture of lysosomes

5- Nuclear degradation

6- Amphoteric inclusions in mitochondria

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Pyknosis vs karyothexis vs karyolysis

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Pyknosis- nuclear condensation

Karyorrhexis- nuclear fragmentation

Karyolysis- nuclear dissolution

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What is the earliest morphologic manifestation of reversible cell injury

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Cellular swelling

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Apoptosis

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1- ATP dependent programmed cell death

2- Two pathways intrinsic and extrinsic both involve the release of caspases(cytosolic protease) cellular breakdown include cell shrinkage, chromatin condensation, plasma membrane blending and formation of apoptotic bodies that are phagocytosed

3- Characterized by deeply eosinophilia cytoplasm, basophils nucleus, pyknosis, karyorrhexis. Cell membrane remain intact without significant inflammation

4- DNA laddering (fragments in multiples of 180) significant indicator of apoptosis

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Intrinsic pathway of apoptosis

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1- Occurs in tissue remodeling in embryogenesis

Occurs when a regulator factor is withdrawn from a proliferative effector cell or exposure to injurious stimuli

2- Regulated by Bcl-2 family BAX and BAK are proapoptotic and Bcl-2 and Bcl-xl are antiapoptotic

3- BAX and BAK for pores in mitochondrial membrane causing the release of cytochrome C from mitochondrial membrane into cytosplam causing activation of caspases

4- Bcl- 2 keep mitochondrial membrane impermeable preventing cytochrome C release

Bcl-2 over expression - decrease caspases activation- tumerogenesis

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Extrinsic pathway of apoptosis

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1- Ligand receptor interaction (FASL binding to FAS(CD59) or TNF-alph)

2- Immune complex (T-cell release from progeria of granozymes B)

3- FAS-FASL interaction is necessary for Thymic medullary negative selection

4- FAS mutation increase number of circulation self reaction lymphocytes due to failure of clinic deletion

5- Defects in FAS-FASL interaction cause autoimmune lymphoproliferative syndrome

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Chromosome location of Bcl -2

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Chromosome 18 on heavy chain of antibody

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Types of necrosis

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1- Coagulative

2- Liquefactive

3- Caseous

4- Fat

5- Fibrinoid

6- Gangrene

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Necrosis

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1- Exogenous injury

2- Plasma membrane damage

3- Enzyme degradation and Protein denaturing

4- Intracellular cell leakage

5- Local inflammatory reaction

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Coagulative necrosis

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1- Seen in ischemic/infarcts of most tissues (except brain)

2- Due to ischemia or infarction of tissues- enzyme degradation proteolysis blockage

3- Histology 1- Preserve cellular architects

2- Nuclear disappear

3- Increase cytoplasmic binding

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Liquefactive necrosis

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1- Seen in Bacterial abscess and Brain in fact

2- Due to neutrophils reals lysosomal enzymes that digest tissue

3- Histology early 1- Cellular debris and macrophages

Late cystic space and cavitation (brain)

Neutrophils and cellular debris (bacterial)

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Caseous necrosis

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1- Seen in TB and systemic fungal infection

2- Due to macrophages wall of infectious microorganisms- granular debris

3- Histology Fragmented cells and debris surrounded by lymphocytes and macrophages

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Fat necrosis

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1- Seen in enzymatic- acute pancreatitis (soaponification of peripancreatic fat)

Non-enzymatic Trauma (injury to breast tissue)

2- Due to damaged pancreatic cells release lipase that break down triglycerides to fatty acids that bind to calcium (soaponification)

3- Histology Dead fat cell without peripheral nucleus dark blue on H&E stain

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Fibrinoid necrosis

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1- Seen in immune- vascular reaction (PAN)

non-immune - vascular reaction (hypertensive emergency and Pre-eclampsia)

2- Due to immune mediated deposition type 3 hypersensitivity and/or plasma protein leakage from damaged vessels

3- Histology - Vascular wall thick and pink

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Gangrene necrosis

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1- Seen in distal digits and GI tract due to chronic ischemia

2- Due to Dry- ischemia

Wet- superinfection

3- Histology- Dry- Coagulative necrosis

Wet- Liquefactive necrosis with superimposed Coagulative

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Ischemia

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1- Inadequate blood supply to meet demand

2- Decrease arterial perfusion (artherioschlorosis, vasospasm and decrease cardiac output)

3- Decrease venous drainage( testicular and ovarian torsion, bud chiarri syndrome)

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Areas most vulnerable to hypoxia/ischemia and subsequent infarction

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Brain- ACA, MCA, PCA boundary area

Heart- Subendicardium of LV

Kidney- Straight segment of proximal tube (medulla) and thick ascending limb of medulla

Liver- Area around central vein zone 3

Colon- splenic flexure (Griffith’s point)

Rectosigmoid junction (Sudeck point)

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Watershed areas border areas

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Recurve blood supple from the most distal branched of 2 arteries with limited collateral vascularity

These area are susceptible to ischemia from hypo-perfusion

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Nerves vulnerable to hypoxia/ischemic insults

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Purkinje cell of cerebellum

Pyramidal cells of the hippocampus and neocortex (zone 3,5,6)

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Types of infarcts

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Red infarct

Pale infarct

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Red infarct

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1- Occurs in 1- venous occlusion

2- Tissue with multiple blood supple

3- Reperfusion- after angioplasty

2- Reperfusion injury due to damage by free radicals

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Pale infarct

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1- Occur in solid organs with single blood supple (Heart and kidney)

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Free radicals

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1- Damage cells via membrane lipid perioxidation, protein modification and DNA breakage

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Initiation of free radicals

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1- Radiation (cancer therapy)

2- Redox reaction

3- Transitional metals

4- Metabolism of drugs - phase 1

5- Nitric oxide (inflammation)

6- WBC

7- Oxidative burst

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Elimination of free radicals

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1- Scavenger enzymes (catalase, superoxide dismutase and Gluthione perioxidase

2- Spontaneous decay

3- Antioxidant ( vitamin A,C and E)

4- Curtain metal carting protein- transferin, ceruloplasmin)

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Examples of free radical oxygen toxicity

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1- Retinopathy of prematurity (abnormal vascularization)

2- Bronchopulmonary dysplasia

3- Reperfusion injury after thrombotic therapy

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Examples of free radical Drug/chemical toxicity

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1- Acetaminophen overdose (hepatotoxicity)

2- Carbon tetrachloride (convert cytochrome P 450 to CCl free radical- Fatty liver (cell injury - Decrease apolipoprotein synthesis- Fatty changes) Centri-lobular necrosis

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Example of free radical metal storage disease

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Hemochromatosis (iron)

Wilson disease (copper)

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Types of calcification

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Dystrophic

Metastatic

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Dystrophic calcification

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1- Seen in abnormal tissue (disease tissues

2- Extent- localized

3- Associated condition 1- TB and other granulomatous disease

2- Liquefactive necrosis of chronic abscess

3- Fat necrosis

4- Infarct

5- Thrombosis

6- Schistosomiasis

7- Congenital CMV

8- Toxoplasmosis

9- Rubella

10- Psammoma bodies

11- CREST

12- Atherosclerotic plaque

4- Etiology- 2 to injury or necrosis

5- Serum Ca- normal

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Metastatic calcification

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1- Seen in normal tissue

2- Extent- widespread

3- Associated conditions- Predominantly in intestinal tissue in lung, kidney or Gut ( decrease acid secretion which increase pH favor Ca deposition)

2- Nephrocalcinosis of collecting tubules leading to nephrogenic diabetes insipidus and renal failure

4- Etiology- 1- 2nd Hypercalcemia (1 hyperparathyroidism, sarcoidosis and hypervitaminosis D) 2- high calcium phosphate product level ( chronic renal failure from 2nd hyperparathyroidism, long term dialysis, calciphylasxis and multiple myeloma)

4- Serum calcium- Abnormal

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Lipofuscin

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1- A yellow brown wear and tear pigment associated with normal aging

2- Composed of polymers of lipid and phospholipid complexed with protein

3- May be derived through lipid perioxidation of polyunsaturated lipid of subcellular membrane

4- Autopsy of elder revelease deposition in eyes, heart, liver, kidney colon and other organs

5- Lipid containing residues of lysosomal degradation

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Too much lipofuscin

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Macular degeneration

Neurodegeneration

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Ionizing radiation

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1- Induced cellular and DNA damage

2- Affects rapidly regenerating tissues

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Acute radiation full exposure on the skin

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1- Hair loss

2- Erythema

3- Desquamation

4- Ulcer/necrosis

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Acute radiation full exposure on neurovascular

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1- Ataxia

2- Cognitive impairment

3- Impaired reflex

4- Seizure

5- Papiloedema

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Acute radiation full exposure on gastrointestinal

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1- Stomatitis

2- Abdominal pain

3- Nausea

4- Vomiting

5- Diarrhea

6- GI bleeding

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Acute radiation full exposure on hemotopoetic cells

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Myelosuppression

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Acute radiation partial exposure on skin gonads eyes

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Skin- blister

Gonads- 1- Sterility

2- Decrease spermatozoa

Eyes- cataract

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Radiation induced fibrosis head and neck

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1- Truisms

2- Mucosal fibrosis

3- Ulceration

4- Fistula

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Radiation induced fibrosis Lungs

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Pulmonary fibrosis

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Radiation induced fibrosis GI

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1- Ulceration

2- Fistula

3- Obstruction

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Radiation induced fibrosis GU

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1- Uretral and ureteric stenosis

2- Fibrotic bladder construction 1- azospermia

2- Fistual of ovaries, Vulva and vagina

3- Obstructive uropathy

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Radiation induced fibrosis GU

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1- Uretral and ureteric stenosis

2- Fibrotic bladder construction 1- azospermia

2- Fistual of ovaries, Vulva and vagina

3- Obstructive uropathy

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Radiation fibrosis of the skin

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1- Induration

2- Thickness

3- Shrinkage

4- Loss of elasticity

5- Lymphodemia

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Radiation related malignancy thyroid

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Papillary thyroid carcinoma

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Radiation related malignancy hematopoietic

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1- Myelodisplastic syndrome

2- Lymphomas and leukemia (CML, AML, ALL)

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Radiation related malignancy skin bone and others

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Skin- angiosarcoma

Bone- osteosarcoma

Others- solid tumor (breast, ovaries and lungs)

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How does ionizing radiation induce cellular and DNA damage directly

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Via particles or photons

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How does ionizing radiation induce cellular and DNA damage indirectly

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Via release of reactive oxygen species

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How does ionizing radiation lead to tissue damage

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Progressive inflammation

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Amyloidosis

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1- Abnormal aggregation of protein in beta platted linear sheets- Insoluble fibrils- Cellular damage and apoptosis

2- Amyloid deposits visualize with Congo red stain (red/orange with non-polarized light) apple green with polarized light

3- Tubular basement membrane enlarged under light microscope

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Primary amyloidosis

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1- AL (from Ig light chain)

2- Seen in Plasma cell disorders ( multiple myeloma)

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Primary amyloidosis

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1- AL (from Ig light chain)

2- Seen in Plasma cell disorders ( multiple myeloma)

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Secondary amyloidosis

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1- Serum Amylod A (AA)

2- Seen in chronic inflammatory conditions

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Primary amyloidosis

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1- AL (from Ig light chain)

2- Seen in Plasma cell disorders ( multiple myeloma)

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Secondary amyloidosis

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1- Serum Amylod A (AA)

2- Seen in chronic inflammatory conditions

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Dialysis related amyloidosis

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1- Beta 2 microglobulin

2- Seen in patients with ESRD and/or on longer term dialysis

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Manifestation of amyloidosis

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1- Nuerological- neuropathy

2- Cardiac- restrictive cardiomyopathy

3- GI- macroglosia and Hepatomegaly

4- Kidney- nephrotic syndrome

5- Hematological - easily brushing and splenomegaly

6- MSK- carpal tunnel syndrome

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Localized amyloidosis

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1- Alzheimer’s disease

2- Type 2 diabetes Mellitus

3- Medullary thyroid cancer

4- Isolated atrial amyloidosis

5- Systemic denial (age related) amyloidosis

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Localized amyloidosis

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1- Alzheimer’s disease

2- Type 2 diabetes Mellitus

3- Medullary thyroid cancer

4- Isolated atrial amyloidosis

5- Systemic denial (age related) amyloidosis

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Alzheimer’s disease and amyloidosis

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1- Beta amyloid plaque

2- Cleave from amyloid precursor protein (APP)on chromosome 21

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Type 2 diabetes Mellitus and amyloidosis

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1- Islet amyloid polypeptide (IAPP)

2- Deposition of amylin in pancreatic islet

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Medullary thyroid cancer and amyloidosis

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Calcitonin

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Isolated atrial amyloidosis

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1- ANP

2- Normal in aging increase risk of atrial fibrillation

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Systemic senile (age related) amyloidosis

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1- Normal with aging Tranthyretin (TTR)

2- Seen predominately in cardiac ventricle

3- Cardiac dysfunction more insidious than in AL amyloidosis

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Hereditary amyloidosis

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Familial amyloid cardiomyopathy

Familial amyloid neuropathy

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Hereditary amyloidosis

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Familial amyloid cardiomyopathy

Familial amyloid neuropathy

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Familial amyloid cardiomyopathy

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1- Mutated Tranthretin (ATTH)

2- Ventricular endomyocardium deposition- Restrictive cardiomyopathy and arrhythmia

3- 5% of African American are carriers of muted alleles

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Familial amyloid polyneuropathy

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1- Mutated Transthyretin (ATTR)

2- Due to transthyretin gene mutation

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Familial Mediterranean fever

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1- Dysfunction of neutrophils AR Occurs in persons of meditation origin

2- Frequent episodes of fever and serous inflammation

3- Serum amyloid A deposit as AA amyloid