Cell Injury review

[Anonymous]

Found this very interesting, it is from doctor G-Papi.

CELL INJURY

Note: MC= most common; MCC= most common cause;
S/S= signs & symptoms; N=normal; I=increase; D= decrease

Oxygen (O2) Related Terms

1. O2 Content

A. Definition: Total amount of Oxygen O2 carried in Blood.
B. Formula:

O2 Content = 1.34 (Hb) x SatO2 + PaO2

Hb= Hemoglobin; SaO2= O2 Saturation; and PaO2= amount of O2 dissolved in plasma

C. Amount of Hb in RBCs is the most important factor for carrying O2 in the blood.


2. PaO2

A. Def: Amount of O2 dissolved in the plasma of arterial blood; a=arterial
• It is not the O2 attached to Hb in RBCs (SaO2)
• Decrease in PaO2 is called Hypoxemia (normal: 75-105mmHg)

B. PaO2 depends on:
• O2% in inspired air (21%)
• Atmospheric Pressure:  with high elevation while O2% is still 21%
• Matched Ventilation/Perfusion in the lungs
• Normal diffusion of O2 through the Alveolar-Capillary interface.

C. Decreased Alveolar PO2 (PAO2) always leads to Hypoxemia
D. Hypoxemia always leads to less O2 carried by the Hb in RBCs (SaO2)
E. PO2 at the tissue level:
• PO2 is the driving force for diffusion of O2 from capillaries into the tissue
• Capillary PO2 must be higher than tissue PO2 for diffusion to occur
• In hypoxemia, the amount of Oxygen diffused into tissue is decreased


3. SaO2
A. Def: %O2 attached to the 4 Heme groups in Hb within RBCs (N: 94-96%)


B. SaO2 is dependent on:
- PaO2
- Valence of Heme Iron: Must be Ferrous (+2) to bind O2
- If oxidized to ferric (+3), it cannot bind O2: +3 Iron is called Methemoglobin

C. Measurement of SaO2:
- Measured non-invasively with a pulse oximeter
- In Arterial Blood Gases (ABG), it is usually calculated from the measured PaO2

D. Decreased  SaO2 correlates with cyanosis of Skin/Mucous membranes: SaO2<80% produces visible CYANOSIS.

4. ALVEOLAR – ARTERIAL (A-a) Gradient-difference between calculated PAO2 and measured PaO2.

A. Normally, the (A-a) is less than < 10mmHg; > 30mmHg is medically significant

B. Problems with lung ventilation, perfusion, diffusion, and right to left shunting in the hearts always increase the gradient.



IMPORTANCE OF OXYGEN:

1. Oxygen is an electron acceptor in the oxidative pathway
A. If Oxygenation is inadequate; then the oxidative pathway cannot pump protons into the intermembranous space in the mitochondria.

B. No protons in the intermembranous space means that none can reenter proton pores in the inner mitochondrial membrane for the synthesis of ATP.

2. Anaerobic glycolysis is the only other source for ATP that does not require the oxidative pathway- produces 2 ATP.


HYPOXIC CELL INJURY
(Inadequate Oxygenation of tissue with decreased synthesis of ATP)

1. ISCHEMIA
A. Def: Decreased arterial blood flow to tissue

B. Normal PaO2 and SaO2
C. Causes; Occlusion of an artery (eg. Coronary artery atherosclerosis), MCC: **decreased cardiac output (e.g. left sided heart failure) **oxygen content is normal

2. HYPOXEMIA: decrease in PaO2
A. Respiratory Acidosis: I PACO2 (CO2 retention) always decreases in alveolar PO2, PaO2 and SaO2

D PAO2 D PaO2 D SaO2

B. Ventilation Defect:
Massive Atelectasis (collapse of the respiratory unit in the lungs)
1. Def: Impaired O2 delivery to the alveoli for gas exchange with decrease in PaO2 and SaO2
Ex: Respiratory Distress Syndrome (RDS) with decreased synthesis of surfactant and subsequent collapse of alveoli; Adult respiratory distress syndrome.

2. Mx: Leads to intrapulmonary shunting of blood: perfusion of alveoli occurs without O2 exchange. Giving 100% O2 does not significantly increase PaO2

3. D O2 Content: Hb, PaO2, SaO2


D PaO2 D SaO2

C. Perfusion Defect:
e.g.: Pulmonary embolus
1. Def: absent blood flow to alveoli (e.g. pulmonary embolus) with decrease in PaO2 and SaO2
2. Increase  Dead Space: alveoli contain O2 but there is no gas exchange.
3. Since not all the vessels are occluded, giving 100%O2 raises the PaO2 by allowing more O2 exchange in normally perfused lungs.
4. D O2 Content: N Hb, D PaO2, D SaO2
DPaO2 DSaO2

D. Diffusion Problems:
1. Def: O2 cannot diffuse through the alveolar-capillary interface.
e.g.: Interstitial fibrosis, pulmonary edema
2. Decreases PaO2 and SaO2
D O2 Content: N Hb, D PaO2, D SaO2

3. HEMOGLOBIN (Hb) RELATED ABNORMALITIES:
A. ANEMIA:
D [Hb] decrease Hb concentration
1. DO2 Content: D Hb, N PaO2, N SaO2 (gas exchange is normal)
2. Iron deficiency is MC Anemia

B. METHEMOGLOBINEMIA:
With Iron Fe+3, HEME cannot bind O2
1. D O2 content: N Hb, N PaO2, D SaO2
2. Causes:
- HEME group is oxidized by NITRO/SULFA compounds (drugs with NITRITES or SULFUR), water, particularly in the mountains or on farms where the water is often contaminated with Nitrates.
- Deficiency of Methemoglobin Reductase
3. Clinical:
• Cyanotic (not reversed by O2)
• Blood is chocolate colored from increased deoxyHb
• Giving 100% Oxygen O2 does not correct the cyanosis
4. Left shifts the ODC
5. Treatment (Rx):
- IV Methylene Blue (activates Methemoglobin reductase) is the gold standard for Rx.
- Ascorbic acid: reducing agent that is used as ancillary therapy (reduces Ferric Fe+3 to ferrous Fe+2)

C. CARBON MONOXIDE CO POISONING:
1. Def: CO has high affinity for the HEME group in RBCs, hence lowering the SaO2 without affecting the Hb or the PaO2.
CO competes with O2 for binding sites on HEME Iron.
2. D O2 Content: N Hb, N PaO2, D SaO2
3. CO poisoning also:
• Left shifts the O2 dissociation curve (ODC) [or O2 Bind Curve OBC]
• Inhibits Cytochrome Oxidase in the Oxidative Pathway (electron transport chain (ETC)
4. Causes of CO poisoning:
• Car exhaust
• Space heaters
• Smoke inhalation in fires
• Wood stoves
5. Rx:
• 100% O2, which displaces CO from the HEME group
6. S/S:
• Headache first symptom
• Cherry red color on skin  Carboxyhemoglobin (masks cyanosis)
7. Chronic Effect:
• Necrosis of Globus pallidus leading to Parkinson-like findings

D. FACTORS LEFT-SHIFTING OBC:
High affinity of Hb for O2
Left shifted ODC causes tissue hypoxia: I affinity for O2 (does not release O2 into blood)
i.e. :
• D 2,3-biphosphoglycerate (BPG)
• Alkalosis
• CO
• Methemoglobin (MetHb)
• Fetal Hb (Hb F)
• Hypothermia

E. CLINICAL CORRELATION:
Right shifted OBC (decreased affinity of Hb for O2)
1) I (increase) 2,3 DPG
2) Fever
3) Acidosis
4) High Altitude: Respiratory alkalosis increases the rate of glycolysis, hence increasing conversion of 1,3 BPG into 2,3 BPG, which offsets the effect of Respiratory alkalosis in left-shifting the OBC.

4. PROBLEMS WITH OXIDATIVE PATHWAY IN MITOCHONDRIA
Inner mitochondrial membrane pathway transfers electrons to O2 and creates energy to pump protons into the intermembranous space for production of ATP
Carbon Monoxide CO and Cyanide CN:
• CO and Cyanide CN inhibit Cytochrome Oxidase in the ETC
• Blocks Oxidative pathway in the Mitochondria even though O2 may be present as an electron acceptor.
• Protons are no longer entering the intermembranous space No ATP is synthesized.
Cyanide Poisoning: Systemic asphyxiant
• Poisoning is common in the setting of combustion of polyurethane products during residential fires
• Accidental poisoning
• S/S:
- Bitter almond smell to breath
• Rx of Cyanide Poisoning:
- Nitrites: amyl and sodium nitrite  create Methemoglobin MetHb competes with Cytochrome oxidase for cyanide.
- Thiosulfate: combines with Cyanide from Cyanmethemoglobin nontoxic Thiocyanate.
5. UNCOUPLED OXIDATIVE PHOSPHORYLATION IN MITOCHONDRIA
A. Mitochondrial poisons render the entire inner mitochondrial mb permeable and carry protons with them (ATP synthesis): poisons include:
• Dinitrophenol
• Pentachlorphenol (used to treat wood to prevent insect invasion)
• Thermogenin (natural uncoupling agent in newborn brown fat that keeps internal temperature up)
• Alcohol and Salicylates also damage the mitochondrial and produce a similar result, but they are not uncoupling agents.
• Rate of chemical reactions increases to produce more NADH and NADPH potential for hyperthermia.
6. ARTERIOVENOUS SHUNTING
Direct communication of arterial system with venous system (microcirculation is bypassed): AV fistula from trauma.

Effects of a Decrease in cellular ATP
1. Cell must utilize anaerobic glycolysis to generate ATP
A. In tissue hypoxia, Phosphofructokinase (PFK), the rate limiting reaction in Glycolysis, is activated by:
• Low citrate: most important factor
• Increase in Adenosine Monophosphate (AMP)
B. Net gain of 2ATP and no gain in NADPH:
• NADH is converted into NAD+ when pyruvate is converted into lactate
• NAD+ is used to produce 2 more ATP
C. Decrease in Intracellular pH from Lactate production:
• Denatures cellular enzymes and other proteins (called coagulation necrosis)
• Produces an increased  Anion Gap metabolic acidosis.

2. Impaired Na+/K+ ATPase Pump
A. Na+ and water enter the cell producing cellular swelling: first histologic sign of tissue hypoxia.
B. This is a Reversible change if O2 is restored.

3. Ribosomes fall off rough the Endoplasmic Reticulum- Decreased protein synthesis

Causes of Irreversible Cell Injury due to tissue hypoxia
1. Disruption of the cell membrane:
• Most important factor
• Lipid Peroxidation by Free Radicals FR: reversed by Vit E
2. Damage to Mitochondria
3. Calcium in Irreversible Cell Injury:
• Accumulates in the Cytosol: Ca++ ATPase Pump disrupted
• Activates Enzymes:
- Cell Mb Phospholipase (enhances Lipid Peroxidation)
- Enzymes in the nucleus (produces Nuclear Pyknosis)
• Enters mitochondria: produces electron dense deposits and destroys mitochondria
• Contribuyes to coagulation necrosis along with the intracellular buildup of lactic acid.

Summary of sequence in Hypoxic Cell Injury
1. Hypoxia: decrease Oxidative Phosphorilation in mitochondria leading to a decrease ATP
2. decrease ATP leads to:
• Increase Anaerobic glycolysis: decrease intracellular pH from lactic acid, decrease glycogen
• Dysfunction of Na+/K+ ATPase Pump: Reversible cellular swelling
• Ribosomes detach from RER: decrease protein synthesis, fatty change->
3. Irreversible Cell Membrane Injury:
• Intracellular release of Lysosomal enzymes damages membrane
• Endogenous activation of phospholipases (influx of Ca++ into cytosol) with release of toxic lipid products.
• Cytoskeletal alterations: activation of proteases by Ca++
4. Irreversible Nuclear changes:
• Activation of nuclear enzymes by Ca++
• Nuclear Pyknosis and lysis
5. Irreversible mitochondrial dysfunction:
• Entry of Ca++ into mitochondria with activation of phospholipases causing destruction of inner and outer mb
• Ca++ produces large densities

ENZYME MARKERS CELL DEATH
• Transaminases  Hepatitis
• Creatine Kinase  Skeletal/cardiac muscle
• CK:MB  Cardiac muscle
• Amylase/Lipase : Acute Pancreatitis
• LDH ½ flip  Myocardial Infarction (Troponin)

FREE RADICALS:
Unpaired electrons in the outer orbit
1. Examples.-
• Superoxide: O2* generated FR inactivated by Superoxide Dismutase (SOD)
• OH* : generated by ionizing radiation and iron
• Peroxide: Inactivated by catalase and Glutathione (GSH)
• Drugs/Chemicals:
- Acetaminophen (inactivated by GSH)
- CCl4 converted into CCl3-
2. Iron Increases the synthesis of OH*: FRs via the Fenton reaction. FRs are the Mx of damage in Iron overload diseases: e.g. Hemochromatosis.
3. Lipofuscin accumulates in cells damage by FRs in the normal aging process and in atrophy: indigestible lipid from lipid peroxidation that gives tissue a brown appearance.
4. Clinical Examples of FR damage:
A. O2 Dependent myeloperoxidase (MPO) system in neutrophils/Monocytes
B. O2 toxicity due to superoxide FR damage: e.g. Retrolental fibroplasia leading to blindness in newborns
C. Ionizing Radiation:
• Generates Hydroxyl (OH) FRs in tissue from Radiolysis of water in cells
• Damages DNA with potential for cancer (e.g., Squamous skin cancer)

D. Iron overload conditions
E. Acetaminophen toxicity***: Acetaminophen is converted by the hepatocyte Cytochrome system into FRs that act on sulfhydril groups in the hepatocyte cell mbs.
• MCC of Fulminant Hepatic Necrosis due to drugs: See necrosis around central vein in the liver
• Acetylcysteine/therapy (Mucomyst) replenishes GSH, which neutralizes the drug FRs
F. CCl4 poisoning in dry cleaning industry: CCl4 converted by Cytochrome system into CCl3 FR  Liver cell necrosis with fatty change.

APOPTOSIS:
Individual cell necrosis
1. Def: genetically determined internal programmed series of events leading to individual cell death.
2. Functions of Apoptosis:
A. Hormone-dependent involution of tissue in adults:
• Involution of lactating cells with withdrawal of Prolactin
• Endometrial cell breakdown after withdrawal of Estrogen/Progesterone in the menstrual cycle
• Prostatic atrophy after removal of dihydrotestosterone (castration, drug induced, old age)
• Atrophy of Thyroid with inhibition of TSH
B. Programmed destruction of cells during embryogenesis:
• Loss of mullerian structures in male fetus by mullerian inhibitory factor or Wolffian structures in female fetus
• Development of lumens in the intestines
C. Involution of the Thymus in an adult
D. Cell death related to injurious agents:
• Viruses (e.g. HBV infected cells)
• Cell cycle specific chemotherapy drugs
• Tissue hypoxia
• Ionizing and UV light radiation
E. Death of tumor cells
F. Pathologic Atrophy of parenchymal obstruction due to duct obstruction:
• Atrophy of pancreatic exocrine cells with duct obstruction by thick secretion in Cystic Fibrosis
• Atrophy of Parotid gland due to stone in the duct
G. Cytotoxic T cell-induced death of target cells
H. Programmed cell death involved in old age

3. Sequential mechanisms of Apoptosis
A. Signals Initiating Apoptosis:
• Injurious agents: Radiation, free radicals, toxic agents
• Withdrawal of growth factor or hormones
• Receptor-ligand interactions on the plasma mb of cells
• Tumor Necrosis Factor
B. Activation of CASPASES, a group of cysteine-proteases that sets into motion an enzymatic death programs:
• Endonuclease activation leading to nuclear fragmentation (first steps in actual cell death)
• Activation of proteases that breakdown the cytoskeleton
• Transglutaminase activation with increased cross-bridging of proteins
C. Mitochondrial Injury
D. Formation of Cytoplasmic blebs that fragment into apoptotic bodies that are surrounded by cell mb and contain cytoplasm, packed organelles, with or without nuclear fragments
E. Phagocytosis of Apoptotic bodies by neighboring cells or macrophages which destroy the bodies in lysosomes.

4. Microscopic appearance:
• Cell separates away from neighboring cells
• Deeply Eosinophilic staining cytoplasm
• Pyknotic nucleus
• No or minimal inflammatory infiltrate

TYPES OF CELL NECROSIS
Necrosis is widespread damage to tissue as opposed to apoptosis, which is individual cell necrosis.
1. Coagulation Necrosis
A. In Coagulation Necrosis the tissues is dead but vague outlines of what used to be living tissue can still be identified: e.g. can identify cardiac muscle, but striations are fading out and nuclei are disappearing
B. Coagulation Necrosis is most often due to thrombosis of a vessel (e.g. artery or vein) and less commonly due to the effect of heavy metals (e.g., Lead, Arsenic mercury) on tissue (particularly the proximal tubules of the kidneys)
C. The Gross (visible to the naked eye) manifestation of coagulation Necrosis is called and Infarction of which there are two types:
• Pale Types of Infarction (Increased density of the tissue prevents RBCs from diffusing through the Necrotic tissue) e.g.: heart, kidney, liver (least likely to infarct due to dual portal vein/hepatic artery blood supply), Spleen
• Hemorrhagic Types of Infarction (loose textured tissue allows RBCs to diffuse through tissue) e.g.: small bowel, Lungs, testicles.
D. Dry gangrene:
• Predominantly coagulation necrosis when there is no infection: e.g. Diabetic food
Wet Gangrene:
• Is predominantly Liquefactive necrosis (see below) when there is infection.
2. CNS Infarcts
A. Example of Liquefactive not Coagulative necrosis
B. Brain tissue has cells with numerous lysosomes and all the enzymes cannot be denatured by Lactic Acid, hence there is an autocatalytic effect in the cell.
C. Brain tissue has very little structural integrity (held together by processes from Astrocytes), therefore the cells breakdown easily and leave a cystic cavity.

3. Liquefactive Necrosis
A. Usually refers to neutrophils-dependent enzymatic destruction of tissue
B. Examples include:
• Abscesses : usually staphylococcus aureus owing to coagulase production
• Cellulitis: usually Group A Streptococcus infections due to Hyaluronidase
• Wet Gangrene: e.g. Gangrenous toe becomes infected with anaerobes and neutrophils destroy tissue
• Brain Infarct/abscesses
4. Caseous Necrosis
A. Cheese-like material noted on gross exam of tissue: represents lipid material in granulomas from macrophage destruction of typical/atypical TB and systemic fungi
B. Other types of Granulomas are non-caseating:
• Crohn’s Disease
• Sarcoidosis
5. Enzymatic Fat Necrosis in Acute Pancreatitis
• Release of Amylase and Lipase from damaged Pancreas
• Fatty Acids combine with calcium to form Chalky White areas in the pancreas (called Saponification): Calcium deposits can be seen on X-***
6. Fibrinoid Necrosis
A. Necrosis of Immunologic Injury with protein material appearing like Fibrin
B. Examples:
• Small Vessel Vasculitis: Henoch-Schonlen purpura
• Rheumatic Heart disease vegetations on Mitral valve
• Immunocomplex glomerulonephritis: e.g. SLE
7. Gummatous Necrosis in Tertiary Syphilis-
Rubbery masses that are very destructive in tissue


FATTY LIVER

1. Alcohol MCC
A. Increased NADH in the metabolism of alcohol causes a build-up of dihydroxyacetone phosphate (DHAP), an intermediate in Glycolisis: DHAP produces Glycerol 3-phosphate, the carbohydrate backbone of TG
B. Increased Acetyl CoA in alcohol metabolism is used for fatty acid (FA) synthesis
2. Kwashiorkor
Fatty liver due to decreased synthesis of Apolipoproteins necessary to coat very low density lipoprotein (VLDL)
3. Miscellaneous.-
• CO poisoning
• Shock
• Drugs: Tetracycline, Amiodarone
• Reye’s syndrome



HEMOGLOBIN - DERIVED PIGMENTS
1. Bilirubin
A. Unconjugated Type:
Lipid soluble: end product of macrophage metabolism of Hb in phagocytosed RBCs
e.g.: Rh hemolytic disease of the newborn
B. Conjugated type:
Water soluble: conjugated in the liver; e.g.: Obstructive Jaundice: stone in the common bile duct.

2. Hemosiderin
B. Storage Iron consists of 2 forms:
• Soluble Ferritin
• Insoluble Ferritin
C. Soluble Ferritin; is the primary Iron storage protein
• All cells in the body contain Ferritin: Liver and Bone Marrow macrophages are two biggest storage sites.
• Small amount circulates in blood and correlates with Iron stores in macrophages in the marrow: best screening test for Iron disorders
• Serum Ferritin is  decreased in Iron (Fe) deficiency; and Increased in Iron overload disease (Hemochromatosis, Hemosiderosis), Anemia of chronic disease, Sideroblastic Anemia.
• It cannot be visualized by microscopy and does not take up the Prussian Blue stain for iron.
D. Insoluble hemosiderin is a product of Ferritin degradation:
• Visualized as Golden-yellow granules in the cytosol of cells (e.g. hepatocytes, marrow macrophage)
• Stains positive with the Prussian Blue Stain
• See above for hemosiderin excess, Hemosiderin stores are absent in iron deficiency: first finding in Iron deficiency but requires a bone marrow exam to evaluate its stores.
3. Hematin:
Black pigment derived from acid effect on Hb
Responsible for Black Tarry stools (melena) associated with peptic ulcer disease.


DYSTROPHIC CALCIFICATION
1. Definition.- Calcium deposition in damaged tissue in the presence of a normal serum calcium/phosphate. (Psammoma bodies-> calcifications occur in Meningiomas.ex. pap. Ca of thyroid or ovaries.
2. Examples:
• Atherosclerosis plaques
• Enzymatic fat necrosis (visible in plain films)
• Damaged cardiac valves (e.g. bicuspid aortic valve)
• Periventricular calcification in congenital CMV infections (Monckebeigs medial calcification sclerosis.

METASTATIC CALCIFICATION
1. Def: Increased serum calcium and/or phosphate leading to the deposition of calcium in normal tissue
2. Examples:
• Nephrocalcinosis, in primary hyperparathyroidism - calcification of tubular basement membranes
• Calcification of basal ganglia in primary hypoparathyroidism

CONGENITAL SPHEROCYTOSIS
Genetic example of a membrane defect: AD disease with a defect in Spectrin in the cell Mb results in RBCs with too little membrane (spherocytosis)

EXAMPLES OF UBIQUINATION OF DAMAGED INTERMEDIATE FILAMENTS
1. Mallory Bodies.- Ubiquinated (marked for destruction by Ubiquitin) Keratin intermediate filaments: microscopic feature of alcoholic hepatitis.
2. Lewy body.- Ubiquinated neurofilaments from degenerated Substantia Nigra neurons in Parkinson’s disease.
3. Neurofibrillary tangles.- Ubiquinated neurofilaments in the brain in old age/ Alzheimer’s.

CELL TYPES IN TISSUE:
1. Labile cells: Contain Stem Cells with >1.5% of the Stem Cells in the cell cycle at any one time.
A. Ex:
- Bone Marrow Stem Cells
- Stratum Basalis of Skin
- Intestine- Stem cells at the base of the glands
B. These cells are most affected by radiation and S phase chemotherapy drugs due to their high rate of mitotic activity.

2. Stable Cells: cells that are usually in the Go (resting) phase of the cell cycle
A. Must be stimulated to enter the G1 phase by:
- Hormones (e.g., Estrogen)
- Growth factors (e.g. epidermal derived growth factor)
- Loss of parenchymal tissue (e.g. removal of liver tissue)
B. <1.5% of the cells are in the cell cycle at any one time
C. Examples:
- Most parenchymal cells in organs; e.g. hepatocytes, renal tubular cells, endothelial cells.
- Smooth muscle: not striated or cardiac cells
- Astrocytes / other Neuroglial cells
D. Stable cells have the capacity to undergo hypertrophy and / or hyperplasia.
3. Permanent Cells:
A. cells can not enter the cell cycle
B. Ex:
• Skeletal cardiac muscle can only HYPERTROPHY
• Neurons

CELL CYCLE
1. Inactive CDK (Cyclin-dependent Kinase) is activated by Cyclin D (see diagram)
A. Cyclin D is synthesized in the G1 phase of the cell cycle: key phase of the cycle
B. G1 phase is the most variable phase: this would be the phase that explains either a shorter or longer cell cycle than normal.



cdk= Cyclin-dependent Kinase
Rb (hypophosphorylated form) inhibits cell from going from G1 to S phase
Rb phosphorylated form allows cell to go from G1 to S phase
2n= normal amount of DNA in a cell, 4n is after duplication of the DNA prior to mitosis.

• Inactivated cdk is activated by cyclin D, which is synthesized in the G1 phase of the cell cycle.
• The Rb suppressor gene on chromosome 13 produces the Rb protein, which inhibits the cell from moving from the G1 phase into the S phase.
• When Rb protein is phosphorylated by active cyclin D/cdk complex, the cell passes into the S phase and finishes the cycle.
• The p53 suppressor gene (‘guardian of the cell”) located on chromosome 17 produces a product that inhibits the active cyclin D/cdk complex, hence preventing phosphorylation of the Rb protein and keeping the cell in the G1 phase for repair of DNA defects, or if they are too extensive, time for apoptosis.
• Inactivation of the Rb suppressor gene results in the loss of the inhibitory effect of the Rb protein in keeping the cell from entering the S phase.
• Furthermore, inactivation of the p53 suppressor gene allows the active cyclin D/cdk complex to continually Phosphorylate the Rb protein, which allows the cell to complete enter the S phase and complete cell division.
• Inactivation of either the Rb or p53 suppressor gene leads to unrestricted cell growth and the potential for cancer Hypertrophy is thought to be a block at the G2 phase (tubulin synthesis), while hyperplasia is thought to be a problem after Gm (mitosis) phase such that cell continues to enter the G1 phase and progress through the cycle again.

2. Rb suppressor gene on chromosome 13 produces the unphosphorilated Rb protein.
• Rb protein prevents the cell from moving from the G1 phase into the S phase: S phase functions include chromosome replication and organelle replication.
• Phosphorylation of the Rb protein by the active Cyclin D/cdk complex allows the cell to pass into the s phase and finish the cycle which includes the G2 phase (Tubulin synthesized) and the M phase (mitosis).
• Inactivation of the Rb suppressor gene: Loss of the inhibitory effect of the Rb protein on the cell allows the cells to constantly enter the S phase once they are phosphorylated.
3. p53 Suppressor Gene functions on Chromosome 17
A. Produces a protein product that inhibits active cyclin D/cdk complex
1. Prevents phosphorylation of the Rb protein and keeps the cell in the G1 phase
2. Allows cell to repair any defects in DNA (“Guardian of the cell”): cells incapable of repair undergo apoptosis
B. Inactivation of the p53 suppressor gene: active cyclin D/cdk complex continually phosphorylates Rb proteins and cells continually mitose.
4. Important concept:
• Inactivation of either the Rb or p53 suppressor gene leads to unrestricted cell growth and the potential for cancer.
• E6 and E7 gene produces in HPV inactivate both of these suppressor genes.

Examples of Growth alterations
1. ATROPHY.- Decrease in cell/tissue mass
A. Characteristics include:
• Less organ weight
• Wrinkled capsular surface
• Less mitochondria
• Increase Lipofuscin in cells
B. examples:
1. muscle in a cast: disuse of muscle leads to atrophy
2. Thyroid gland in someone taking excess thyroid hormone: decrease in TSH from increase in T4 causes atrophy of thyroid
3. Renal artery atherosclerosis: affected kidney is atrophied, while the contralateral kidney is hypertrophied (compensatory)
4. Compression atrophy of renal cortex by hydronephrosis
5. Carotid artery atherosclerosis: cerebral atrophy due to apoptosis of neurons (called “red neurons”) in layers 3,5,6
6. Atrophy of pancreatic ducts and islets cells in cystic fibrosis: thick ductal secretions obstruct the lumen leading to glandular atrophy and fibrosis (fibrosis destroys islet cells)
7. Patients on long-term corticosteroids develop atrophy of the zona fasciculate and reticularis in the adrenal cortex, since ACTH does not stimulate aldosterone synthesis.
C. Agenesis: anlage (primordial tissue) is absent (e.g. renal agenesis)
D. Aplasia: anlage is present but never develops
E. Hypoplasia: anlage develops incompletely; however, the tissue that is present is histologically normal.
2. HYPERTROPHY: Increased cell size
A. Cell has passed the S phase but cannot enter the Gm phase: cytosol and nucleus is larger (4n) since it contains organelles for two cells.
B. Examples include:
- Left ventricle hypertrophy
- Removal of kidney and hypertrophy of remaining kidney
3. HYPERPLASIA: Increase in number of cells
A. Common alteration in hormone excess states
B. Can progress to dysplasia and cancer if left unregulated
C. examples:
1. Hormone excess states:
- Unopposed estrogen  endometrial hyperplasia
- Prolactine induced lactation
- RBC hyperplasia-hypoxia leads to Erythropoietin stimulation of erythroid Stem cell.
2. Persistent injury to tissue: e.g. regenerative nodules in cirrhosis
3. Psoriasis: hyperplasia of squamous epithelium
4. Clinical examples of equal hyperplasia/hypertrophy:
- Uterine smooth muscle hyperplasia/hypertrophy in pregnancy
- Iodine deficiency leading to a goiter.
4. METAPLASIA: replacement of one adult cell type by another adult cell type, which may be squamous (squamous metaplasia) or glandular (glandular metaplasia)
A. Mucous secreting columnar cells normally undergo squamous metaplasia to replace Exocervical Epithelium: may progress to squamous dysplasia/cancer if HPV is present.
B. Schistosoma hematobium eggs in submucosal venous plexus in the bladder cause mucosal squamous metaplasia, which may progress to dysplasia/cancer.
C. Squamous epithelium in the distal esophagus undergoes glandular metaplasia (mucous secreting cells/Goblet cells) due to acid injury (gastroesophageal reflux disease); this is called Barret’s esophagus and may progress into dysplasia and adenocarcinoma.
D. In chronic atrophic gastritis due to Helicobacter pylori, normal glandular cells undergo glandular metaplasia with the formation of Goblet cells and Paneth cells, which are cells that are normally present in the intestinal epithelium; this intestinal metaplasia is a precursor for gastric adenocarcinoma.
5. DYSPLASIA: Atypical hyperplasia with the potential for evolving into cancer.
A. Dysplasia is a pre-malignant growth alteration
B. In the above examples, note that:
* Squamous metaplasia may progress into Squamous Cancer &
* Glandular metaplasia into Adenocarcinoma.
C. Examples of Dysplasia:
- ACTINIC (solar) KERATOSIS: A UVB light derived dysplasia that is a precursor for squamous cancer of the skin
- CERVICAL DYSPLASIA: Precursor for cervical squamous cancer (usually related to HPV 16 or 18 )
- LEUKOPLAKIA in the mouth in smokers and/or alcoholics: dysplasia that may progress to squamous cancer.
- DYSPLASTIC NEVUS: Atypical nevus that may progress into a malignant melanoma.

Hope you find it interesting

[SMS]

Hi,
Please let me know where from you found these notes ?
Please reply.

[somdatta.gupta]

hi, it is very nice of you to take so much trouble and post the notes on the net. I have an older version of Papi's notes, and your notes are slightly more updated, which i found useful. More in sync with his lectures, with more drug examples.
I have a question though. Where did you get his new notes? Is it available on the net? I have his 1998 notes, are they much different from his newer ones?

I hang on to his notes avidly, because they are my only means of studying the subjects. If you think they are important, could you please tell me where i can get them ?
Thanks

[maixungphong]

I love these notes.

[coke]

hi, can you post more of the review notes from Dr. G
thanks

[josephmedman]

this is great stuff..if you can..keep it coming..great review..let me know if you need anything from my side..

[Meepemoli]

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[GFLIP]

nice notes