Gen Path: Goljan Rapid Review

Front 1

Hypoxia and Clinical Findings

Back 1

Def: Inadequate oxygenation of tissues leading to decreased synthesis of ATP.

MCC of tissue injury.

*** IF PaO2 (Pressure keeping O2 dissolved in Arterial blood) Decreases then SaO2 (%O2 saturation of Hb) must also Decrease ***

SSx= Cyanosis, Confusion, Cognitive impairment and Lethargy (Cyan confuses my lazy thinking)

Front 2

Hypoxia related Decrease in ATP synthesis

Back 2

1). ATP synthesis occurs in the inner mitochondrial membrane by the process of Oxidative Phosphorylation.

2). O2 is an electron acceptor located at the end of the electron transport chain (ETC) in the oxidative pathway.

3). Thus inadequate O2 or a defect in oxidative phosphorylation culminates in a decrease in ATP synthesis.

***no ATP, Na gets into the cell and brings H2O, with tissue hypoxia there will be swelling of the cell due to dec ATP*** (IS REVERSIBLE)

Front 3

O2 diffusion

Back 3

O2 diffuses down a gradient from alveoli, to plasma (increasing PaO2), and to red blood cells attaching to heme groups (increasing SaO2)

Front 4

O2 content equation

Back 4

[(HB g/dL x 1.34) SaO2] + [0.003(PaO2)]

Front 5

Causes of Tissue Hypoxia

Back 5

1) Ischemia = decreased arterial blood flow or venous outflow of blood.

2) Hypoxemia = Decrease in PaO2 (<40 mm Hg)

3) Hb related abnormalities = Anemia, Methemoglobin, CO poisoning, Factors causing Left shift of ODC.

***decreased Cardiac output, hypoxemia, anemia, Cyanide poisoning, CO poisoning***

Front 6

Ischemia

Back 6

DEF= Decreased arterial blood flow or venous outflow of blood.

Examples = Coronar Artery atherosclerosis, decreased Cardiac Output, Thrombosis of Splenic Vn, Thromboembolus.

*** Thrombosis of a muscular Art is the most common cause of Ischemia ***

Front 7

Consequences of Ischemia

Back 7

1) Atrophy
EX: Reduction in Cell size/tissue mass

2). Infarction of tissue.
EX: Localized area of tissue Necrosis.

3). Organ Dysfunction
EX: Heart Failure

Front 8

Pulse Oximetry

Back 8

Noninvasive test for measuring SaO2.

METHOD: probe clipped over a Pt's finger. Emits light at specified wavelength that identify oxyHb and DeoxyHb.

***Cannot however identify dysHbs (metHb, COHb) which normally decrease the SaO2. In their presence Pulse Oximeter reads a False HIGH SaO2 (that %O2 saturation in Hb is high, that more O2 is bound to Hb)***

In such cases you use Co-Oximeter which emits Multiple Wavelengths because it Id's dysHbs also.

Front 9

Hypoxemia

Back 9

DEF: Decrease in PaO2 (<40 mm Hg) [Low blood oxygen content]

Hypoxemia in following conditions:

1). High Altitude (decrease in inspired PO2)

2). Hypoventilation (resp acidosis) = Co2 retention in the lungs ALWAYS produces corresponding decrease in PaO2. ***ALWAYS when CO2 increases = PaO2 decreases***
Ex: depression of medullary resp center (barbiturates), Paralysis of diaphragm, Chronic Bronchitis.

3). V/Q mismatch (Normal ventilation/perfusion = 1)

4). Diffusion Limitation

5). Right to left Shunt

***4 major causes resp acidosis, ventilation defects, perfusion defects, diffusion defects***

Front 10

Causes of Hypoxemia
V/Q mismatch in VENTILATION DEFECT

Back 10

V/Q ratio DECREASES

Ventilation defect (IP shunting):
-Impaired O2 delivery to alveoli
EX= RDS aka Hyaline Membrane Dx **produces intrapulmonary shunting of blood, Decrease PaO2 than normal**

-NO gas exchange, lungs perfused but NOT ventilated.

***(PvO2=40 mm Hg, PvCO2=46 mm Hg --> ventilation defect --> Intrapulmonary shunt --> PaO2=40 mm Hg, PaCO2= 46 mmHg) ***

***100% O2 will NOT increase PO2***

Front 11

Causes of Hypoxemia
V/Q mismatch in PERFUSION DEFECT

Back 11

V/Q ratio INCREASES

Perfusion Defect (Inc in Dead Space):
-Absence of blood flow to Alveoli
Ex= **Pulmonary embolism (MCC of perfusion defect, prolonged flights -->stasis of blood in deep vns of LL-->thrombus-->pulm embolus)

-NO gas exchange, lungs ventilated but NOT perfused.

-Increase in Dead Space (O2 and CO2 exchange does not occur)

***100% O2 WILL increase PO2***

Front 12

Cause of Hypoxemia
DIFFUSION DEFECT

Back 12

-Decreased O2 Diffusion through the alveolar-capillary interface.

EX: Interstitial fibrosis (best ex is Sarcoidosis, a restrictive lung disease), Pulmonary edema or fluid from Heart Failure.

***Fluid in Ht failure, leads to dyspnea, you activate the J-reflex. It's integrated by the X nerve(vagus) which leads to dyspnea because of the fluid in the interstitium of the lungs where J-receptors are irritated***

Front 13

Hb related Abnormalities= ANEMIA (hypoxia & Hypoxemia)

Back 13

a). Anemia - decreased Hb conc (<7g/dL)
-NO Hypoxemia, only Hypoxia

** PaO2 normal, SaO2 normal, DECREASED Hb**

Causes:
- dec. Hb production (Fe deficiency.
- Dec production of RBCs (aplastic anemia)
- Inc destruction of RBCs (Hereditary Sphirocytosis)
-Inc sequestration of RBCs (splenomegaly)

Front 14

Hb related Abnormalities= MetHb

Back 14

DEF: Hb with oxidized heme group (Fe2+ to Fe3+)

Causes:
1). Oxidant stresses
EX = Nitrite and sulfur-containing drugs(oxidizing agents), sepsis, local anesthetics(benzocaine)

2). deficiency of cytochrome b5 reductase

Pathogenesis:

-Fe3+ cannot bind to O2
***Normal PaO2, Decreased SaO2***

SSx = Cyanosis (doesn't dissolve after O2 admin, MetHb >1.5 mg/dL), chocolate colored blood (inc deoxyHb)

Rx = IV methelene blue (1st), vit C as an auxillary.

***MetHb common in AIDs Pts due to administration of TMP-SMX for treatment of P. carinii***

Front 15

CO poisoning

Back 15

*Leading cause of death due to poisoning

Causes:
1) automobile exhaust
2) smoke inhalation
3) wood stoves
4) Methelene chloride (paint thinner)
5). **House fires** (CO and Cyanide poisoning)

Pathogenesis:
1). CO competes with O2

***dec. SaO2 without affecting PaO2***

2). CO (& CN) inhibits cytochrome oxidase in ETC.
3). left shift of ODC.

SSx:
1). Cherry red discoloration (skin, blood)
2). Headache (1st symptom)**
3). Dyspnea, dizziness (20-30%)
4). Seizures, Coma (50-60%)
5). Lactic Acidosis due to hypoxia.

Rx = 100% O2 via nonbreather mask or endotracheal tube.

***why no cyanosis in CO poisoning? cherry red pigment masks it***

Front 16

Left Shift OBC

Back 16

Hb with increased affinity for O2 (doesn't release O2 to tissues)

1). Dec 2, 3 bisphosphoglycerate (BPG)

2). Dec H+ (Alkalosis)

3). Dec Temp

4). Inc CO

5). Inc HbF

6). Inc MetHb

Front 17

Right Shift OBC

Back 17

Hb with decreased affinity for O2 (release O2 to tissues)

1). Inc BPG

2). Inc H+ (acidosis)

3). Inc Temp

4). Inc Altitude (intial left shift due to hypoxemia, resp alkalosis, hyperventilation, Inc 2,3BPG, thus right shift of OBC)

Front 18

Mitochondrial causes of ATP depletion

Back 18

A). Enzyme inhibition of Oxidative Phosphorylation
- dec in ATP synthesis
- CO and CN inhibit Cytochrome oxidase in the ETC

B). Uncoupling of Oxidative Phosphorylation
-carry protons from the inner mitochondrial membrane to mitochondrial matrix
**bypass of ATP synthase causes dec synthesis of ATP**
EX:
Thermogenin (natural uncoupler in brown fat of newborns)

Dinitrophenol (used in synthesizing nitroglycerin and to preserve wood)

Alcohol and Salicylate poisoning (mitochondrial toxins)

***Hyperthermia common complication of Dinitrophenol, alcohol and salicylate poisoning***

*due to this property Alcoholics are more susceptible to heat stroke on a hot day*

Front 19

Subendocardial Ischemia

Back 19

SSx = chest pain

***ST segment depression***


*ventricular hypertrophy in the presence of inc O2 demand(exercise) can also produce subendocardial ischemia*

Front 20

Free Radical Cell Injury (formation)

Back 20

A). Ionizing Radiation (OH-)
*** MC cancer from radiation is Leukemia due to OH- FRs***

B). Damaged Mito (Superoxide)

C). High conc of O2 (Superoxide and OH- FRs, H2O2{which produces OH- and peroxide O2-}

D). Oxidase reactions
-NADPH oxidase (neutrophil and monocyte cell membrane)
-myeloperoxidase combines H2O2 with Cl to form Bleach
-Xanthine oxidase (Superoxide FRs)

E). Drugs = Acetaminophen FRs in liver

F). CCl4 creates CCl3 FRs in liver

G). Cigarette Smoke = Quinone/hydroquinone FRs (tar), NO (FR gas made by macrophages and endothelial cells)

H) Metals = Iron, copper (fenton rxn)

Front 21

Free Radical Fxns

Back 21

1). steal e- from other molecules

2). Primarily target Nucliec Acids and membrane molecules
-DNA fragmentation and dissolution
-Lipid peroxidation of polyunsaturated lipids in cell and mito membranes

***Inc membrane permeability leading to inc cytosolic Ca2+ conc. Has 2 lethal effects:
1) enzyme activation =

a). phospholipase {inc cell and organelle membrane permeability}

b). proteases {damage cytoskeleton}

c). endonucleases {cause karyolysis}

2). Reentry of Ca2+ into Mito

**imp in ageing process**

Front 22

Neutralization of FRs

1) Superoxides

2) H2O2, OH-, and acetaminophen.

3) peroxide

4) oxidized LDL (lipids)

5) best neutralizer of OH-

Back 22

1) Superoxide Dismutase (SOD)
-converts SO FRs to peroxide and O2

2). Glutathione Peroxidase
-located in pentose phosphate pathway, neutralizes H2O2, OH- and acetaminophen FRs

3). Catalase (present in peroxisomes)- peroxide into O2 and water

4). Vitamins - stop e- stealing
-Vit E (L soluble) prevents lipid peroxidation in cell membrane, neutralizes oxidized LDL (which creates fatty streaks in atherosclerosis)

-Vit C (w soluble) reduce pollutants and cigarette smoke [Best neutralizer of OH- FRs]

5). Selenium- neutralizes FRs in cytosol

Front 23

CN poisoning

Back 23

Results from drugs (nitroprusside) and combustion of polyurethane products in House fires.

SSx= Initial CNS and CVS stimulation followed by CNS depression, Lactic Acidosis, Inc PvO2 and SvO2 (tissues cannot extract O2)

Rx - 2 stages

1). Amyl nitrite - produces metHb which combines with CN to form cyanmetHb.
2). thiosulfate - CN is converted to thiocyanate)

***commonly seen with CO poisoning***

***inhibits Cytochrome oxidase***

Front 24

Nitrite and sulfur containing drugs cause

Back 24

1) Met Hb

2) Hemolytic Anemia (G6PD deficiency)

***exposure to Dapsone, primaquine, TMP-SMX, Nitroglycerin/ Nitroprusside***

Front 25

What happens to Hb, SaO2 and PaO2 when there is:
a) Resp Acidosis
b) Anemia
c) CO/MetHb

Back 25

a) Hb stays same, DEC SaO2, DEC PaO2

b) Only Hb is affected, SaO2 and PaO2 are normal

c) Hb and PaO2 normal, DEC SaO2

Front 26

Anaerobic glycolysis

Back 26

Good - get 2 ATP

Bad - Increases anion gap (Metabolic Acidosis with tissue hypoxia) due to lactic acidosis in Anaerobic glycolysis.

***Denatures proteins and enzymes***(cells annot autodigest either)

***buildup of lactic acid leads to Coagulation necrosis***

Front 27

Exs of O2 Free Radical Injury

Back 27

1) reperfusion injury - oxygenated blood goes back to damaged cardiac muscle.

2) RDS - Children can go blind aka retinopathy of prematurity.

Front 28

Effects of Inc cytosolic Ca2+?

Back 28

1) enzymatic activation
a) phospholipase
b) proteases
c). endonucleases

2) Reentry of Ca2+ in mito
a) Inc mito membrane permeability
b) release of cytochrome c into the cytosol initiates APOPTOSIS

Front 29

MCC drug induced Fulminant (sudden and lethal) Hepatitis?

Back 29

Acetaminophen (due to Cytochrome P450)

Front 30

Where in the liver does acetaminophen toxicity manifest itself?

Back 30

Zone 3 hepatocytes (around the central vein)

Front 31

Tx for Acetaminophen toxicity? why?

Back 31

n-acetylcystiene AKA mucamist

***make more glutathione to neutralize acetaminophen FRs***

Front 32

What is Analgesic Nephropathy? FR cause of Analgesic Nephropathy?

Back 32

Def: destroyed ability to concentrate/dilute urine.

CAUSE
ASPIRIN +TYLENOL = Very bad for kidneys

acetaminophen = destroys the renal medulla (only recieves 10% of the blood supply, relatively hypoxic)

Aspirin gets rid of PGE2 (made in the afferent arteriole) = leaving Angiotensin II is left in charge of renal blood flow at the efferent arteriole.

Front 33

Normal physiologic Apoptosis (Embryo)?

Back 33

1). Y-chromosome: MIF, mullerian structures (uterus, cervix, and upper 1/3 of vagina) gone b/c of apoptosis. ALL mullerian structures degenerate by apoptosis.

***MIF is the signal for apoptosis via caspases (which destroy everything and wrap everything in apoptotic bodies to be destroyed, whats left over is Lipofuscin because they cannot be digested)***

2) X-chromosome: 1 functioning 1 barr body, ovarian route therefore through apoptosis gets rid of the wolfian structures (epidydymis, seminal vesicles, and vas deferens)

***Killing Cancer cells***

Front 34

What happens when the Thymus is absent?

Back 34

1) DiGeorge's syndrome

2) Tetany

Front 35

Coagulation Necrosis (grossly aka Infarction)

Back 35

-Results often from a sudden cutoff of bld supply to an organ i.e ischemia

-Lactic acid buildup leads to Coagulation necrosis

Mechanism:
1) denaturation of enzymes and proteins due to intracellular accumulations (Lactate or heavy metals like lead or mercury) and ionizing radiation.
2) Inactivation of intracellular enzymes prevents dissolution (autolysis) of the cell.

Microscopic:
1) indistinct outlines of cells within dead tissue
2) Absent nuclei or Karyolysis (fading of chromatin)

***primary type of necrosis in dead tissue***

Front 36

COAGULATION NECROSIS
Pale (Ischemic type) VS Hemorrhagic (Red type) Infarctions

Back 36

-Look at consistency of tissue

Good consistency = grossly look pale (inc density of tissue prevents rbcs from diffusing through the necrotic tissue thus pale)
-manifests in Ht, Kidney, spleen etc

Loose consistency of tissue = hemorrhagic infarction (loose textured tissue allows RBCs trickle out and diffuse through necrotic tissue thus appears red/hemorrhagic)
-manifests in Lung, small bowels

Front 37

Causes of Pale infarct in Spleen

Back 37

-Most probably due to emboli from left side of heart.

Causes of Emboli:
1) vegetation: infective endocarditis
2) mitral stenosis (group A beta hemolytic Strep) creates clots/thrombi.

Front 38

Which arrhythmia is most associated with embolization in the systemic circulation?

Back 38

Atrial Fib

-because there is stasis in the atria, clot formation, then it vibrates (little pieces of clot embolize)

Front 39

What is Dry Gangrene? MCC of non traumatic amputation?

Back 39

-dry gangrene is related to coagulation necrosis related with Ischemia. (no pus, no infection)

***dry gangrene of the foot is common in diabetics: the problem is in the popliteal artery b/c it has a small lumen(w/ athersclerosis even thrombosis it is dangerous)***

-MCC of non traumatic amputation is Diabetes (b/c it enhances atherosclerosis)

Front 40

Organs most likely to get Hemorrhagic (red) infarction?

Back 40

Bowel, testicle(if it underwent torsion), lungs.

Front 41

Organs most likely to get Pale (ischemic) infarction?

Back 41

Heart, Kidney, Spleen, and Liver(rarest to infarct b/c of a double blood supply)

Front 42

Causes of Bowel (hemorrhagic) Infarction

Back 42

Most Common: Adhesions from previous surgeries.

2nd MC: piece of small bowel trapped in an indirect inguinal hernia sac.

Front 43

Characteristics of Lung (Hemorrhagic) infarction

Back 43

-wedge shaped infarction near the pleural surface.

-effusion, which is an exudate.
-hemorrhagic with neutrophils

**inflammation of pleura leads to pleuritic chest pain (a knife-like pain on inspiration)**

Front 44

Liquifactive Necrosis

Back 44

***acute inflammation related to inflammatory condition w/ neutrophils***

Brain goes through Liquifactive necrosis (no structure thus leaves a hole) and you see a cystic space

**Liquifactive necrosis in most cases (except brain) refers to an infection when neutrophils are involved, producing an abscess or some type of inflammatory condition**

Front 45

MC site of infarction leading to liquifactive necrosis of the brain?

Back 45

Internal Carotid Artery
-thats why we listen for a bruit(a noise you hear when you have a vessel with a narrow lumen)
-this is also where a platelet thrombus develops over an atherosclerotic plaque, blocks the ICA and you end up with a stroke.

Transient Ischemic Attacks:
bits and pieces of atherosclerotic plaque chip off and produce TIA, which produces motor and sensory abnormalities that go away w/in 24 hrs.

Front 46

What is analogous to Fibroblast in the Brain?

Back 46

Astrocyte

Front 47

How does Staph. aureus form Abscesses?

Back 47

-the gram +ive cocci in clusters (b/c of coagulase). Coagulase is why you see abscesses.

-coagulase converts fibrinogen into fibrin, so it localizes infection (neutrophils can't get out because of fibrin)

Front 48

How does Strept cause infection?

Back 48

-releases hyaluronidase, which breaks down Glucoseaminoglycans in tissues, and infection spreads through the tissue (cellulitis)

Front 49

Liquifactive necrosis in Abscess of Lung (not infarct)

Back 49

-yellowish areas, high fever, and productive cough.

-gram stain showed gram "+" diplococcus, which is strept pneumoniae.

Front 50

MCC of bronchopneumonia

Back 50

Strept Pneumoniae.

Front 51

Caseous Necrosis

Back 51

only 2 things will produce caseation:

1). Mycobacterial infection (including atypicals)
2). Systemic fungal infection. (histoplasma)

***caseation is due to the lipid cell wall of the organisms that leads to the cheesy appearance***

Front 52

NON-Caseating granulomas

Back 52

1) Sarcoidosis

2) Crohn's dx

*b/c they're not related to mycobacterium or systemic fungi*

Front 53

Enzymatic Fat Necrosis

(what enzyme would be elevated?)

Back 53

Unique to Pancreas

-enzymes are breaking down fats into FFA's, which combine with Ca salts forming chalky white areas of enzymatic fat necrosis (chalky white due to saponification)

-can be seen on xrays b/c have calcium in them.

***Pt epigastric distress, w/ pain radiating to the back = pancreatitis (esp seen in alcoholics)

Histologically- bluish discoloration, which is calcification (a type of dystrophic calcification)

***Lipase***

Front 54

Traumatic fat necrosis

Back 54

Resulting from trauma (female breast)

-it can have calcifications, and can look like cancer on mammogram.

**difference between cancer and traumatic fat necrosis is that cancer is painless**

Front 55

Fibrinoid Necrosis (-oid means looks like, but isn't)

Back 55

-Necrosis of immunologic damage
(limited to small muscular arteries, arterioles, venules and glomerular capillaries)
-Looks like fibrin, but isn't fibrin.

EX: Palpable purpura = small vessel vasculitis (immune complex type III HS Rxn)

EXs include vasculitis, lupus glumerulonephritis, any immunologic damage!

Front 56

Hepatic Triad

Back 56

Hepatic artery, Portal vein and bile duct

**Liver also has a dual blood supply**

Front 57

1). Sinusoid organs and characteristics

2). Fenestrated organ

Back 57

1). Liver, Bone marrow, Spleen

-GAPs between endothelial cells (so rbcs and inflammatory cells can fit through them).

2). Glomerular basement membrane (tiny pores through the cell for filtration)

Front 58

RHF how does that affect the liver?

Back 58

Concept:
-portal vn and hepatic artery blood goes through sinusoids, eventually taken up by the Central vn --> hepatic vn --> IVC --> right side of the Heart.

***RHF (blood fills behind failed heart) therefore the live becomes congested with blood, leading to nutmeg liver or congestive Hepatomegaly/Hepatopathy***

Front 59

What happens when you block

1) Portal vn

2) Hepatic vn

Back 59

1) nothing it is before the liver

2) Budd Chiari syndrome (blockage by thrombosis), liver gets really congested.

Front 60

Which zone of the liver is most susceptible to Injury?

Back 60

Zone 3

-area around the central vn, because it gets the least O2 from the blood and is farther away from the Triad.

***this is also where Fatty change is***

Front 61

Yellow fever (Aedes aegyptii) attacks what zone of liver?

Back 61

Zone 2

-where it causes "Midzone Necrosis"

Front 62

MCC cause of Fatty change in the Liver?

Why?

Back 62

ALCOHOL


Reasoning:

***Inc Synthesis of VLDL***

-In glycolysis, DHAP is converted by NADH rxn to Glycerol 3-PO4 (with the G3P shuttle you get ATP, but ALSO G3P is the BACKBONE of TG's)

***In the liver, this lipid fraction is VLDL***

-our endogenous TG's are synthesized in the liver from G3P derived from Glycolysis.

[restricting fat will NOT decrease the synthesis of VLDL, but restricting Carbs will]

Front 63

Brief overview of Alcohol Metabolism in conjunction with Fatty liver change

Back 63

-In alcohol metabolism NADH and Acetyl CoA are everywhere.

*Acetyl CoA --> acetate (Fatty Acid) in the cytosol and Ketone bodies (*acetoacetate, *beta-hydroxybutyrate, and acetone)

*these two are found in alcoholics.

***NADH cause pyruvate to form Lactate in Anaerobic glycolysis***

Front 64

What type of metabolic acidosis is always seen in alcoholics?

Back 64

1). Lactic Acidosis

-because an Increase in NADH converts pyruvate to Lactate.

2). Ketoacidosis

-Increased NADH drives the Acetyl CoA into making Ketone bodies (mainly Beta-hydroxybutyrate)

Front 65

Why do Alcoholics have Fasting Hypoglycemia?

Back 65

-Pyruvate is forced to become Lactate due to Increased NADH

***so in a fasting state an alcoholic is going to have trouble making glucose by Gluconeogenesis (for that you need pyruvate to start it)***

NO Gluconeogenesis = NO maintenance of fasting blood sugar.

[in a fasting situation, liver glycogen stores are depleted and maintenance of blood glucose depends entirely on Gluconeogenesis]

Front 66

Mechanism of Kwashiorkor

Back 66

Protuberant abdomen in these pts is there for 2 reasons

1) decreased protein intake which decreases oncotic pressure, leading to Ascites.

2) BIGGEST Reason, Huge liver related to fatty change.

***VLDL needs apolipoproteins to be able to get out of the liver***

[In this case the fatty change is due to a problem in exporting the VLDL out of the liver because of Lack of apoproteins]

Front 67

What is ferritin and what is it a good marker for?

Back 67

Soluble form of circulating Fe

-marker for Fe in bone marrow.

[Test of choice for Fe related problems like Fe deficiency or Anemia of Chronic Dx or Fe overload diseases like hemochromatosis and hemosiderosis]

Ferritin inc in overload, dec in deficiencies.

Front 68

What is Hemosiderin? What stain is used for Hemosiderin?

Back 68

Insoluble form of Fe storage

-Stored in macrophages and bone marrow.

-Prussian blue

Front 69

Define Dystrophic Calcification? Features? EXs?

Back 69

Abnormal Calcification

Features:
-Damaged tissue that gets calcified.
**serum Ca is normal**

EX
-seen in enzymatic fat necrosis (calcifications in pancreas, chalky white areas on x-ray are a result of dystrophic calcification)

-atheromatous plaques (causes serious tissue damage)

Front 70

MCC of Aortic Stenosis and presentations of Aortic Stenosis?

Back 70

-MCC is Congenital bicuspid aortic valve --> damage --> valve becomes calcified (dystrophic calcification)

Presentations:
-Murmurs (Rt 2nd intercostal space)
-Differences in BP in upper and lower extremities
-Aortic regurgitation

Front 71

What is Metastatic Calcification and its mechanism?

Back 71

In cases of Hypercalcemia or hyperphosphatemia. Calcium is deposited into NORMAL tissue.

**Inc Ca and Phosphorus**

**high phosphate levels very dangerous will take Ca and drive it into NORMAL tissue**

[Imp in renal failure because if the pt has hypercalcemia and hyperphophatemia, need to dialyze phosphate, b/c it will drive Ca into normal tissues like Heart, conduction system, renal tubules and the basement membrane aka Nephrocalcinosis]

Front 72

Cell Membrane Defects

A) RBC membrane defect
B) Ubiquitin

Back 72

A) Spherocytosis: defect in spectrin. Absence of Spectrin does not allow the RBC to form a Biconcave disk, thus forms a sphere.

***if you don't see a donut its Spherocytosis***

B). Is a stress protein, high ubiquitin = high stress.

***When Intermediate filaments (Keratin, Desmin, Vimentin) get damaged the Ubiquitin marks them for destruction***

Front 73

Ubiquitin Special Examples

Back 73

1). Mallory bodies- Ubiquinated Filament(keratin) products in the liver.
EX= Alcoholic hepatitis

2). Neurofibrillary Tangles(stain silver) are ubiquinated neurofilament.
EX= Alzheimer's Dx, Huntington's Chorea and Jakob-Creutzfeldt Dx

***Tau Protein is associated with Neurofibrillary tangles***

3). Lewy bodies ubiquinated neurofilaments.
EX= Parkinson's Dx

Front 74

Different Types of Cells (Histology)

Labile cells

Back 74

1) Labile: where the division is via a stem cell (BM, basement membrane of skin, base of the crypts in the intestine)

*pharm=cell cycle specific and cell cycle non-specific drugs, labile cells are most affected by these drugs b/c they are constantly in the cell cycle*

[complications of these drugs due to BM suppression are diarrhea, mucocitis, and rashes on the skin make sense because they are messing with the labile cells]

Front 75

Different Types of Cells (Histology)

Stable cells

Back 75

1) are in the resting phase, G0 phase.

[most of the parenchymal organs like liver spleen and kidney, and in muscles only smooth muscles]

-they can undergo division, but most time they are resting, and need a stimulant to get into the cell cycle and divide (hormones or growth factors)

EX= Estrogen in women help in proliferative phase of menstrual cycle.

**why is smooth muscle a Stable cell? because it can undergo hypertrophy and hyperplasia**

Front 76

Different Types of Cells (histology)

Permanent Cells

Back 76

1) can no longet get into the cell cycle, and have been permanently differentiated!

EX= Skeletal & Cardiac muscle, and neurons.

***can only undergo Hypertrophy***

Front 77

G1 phase of the Cell cycle

Back 77

-Most variable phase of the cell cycle (as is proliferative phase in menstrual cycle, shortened or lengthened)

**cancer cells have longer cell cycle= longer G1 phase, and vice versa**

Front 78

Cyclin dependant Kinase
"Kinase" always means

Back 78

Phosphorylation

-usually phosphorylation involves activating something, dephosphorylation inactivate something.

***Glucagon is a phosphorylater*** (glucagon is more likely to phosphorylate and activate protein Kinase)

***Insulin is a dephosphorylater***
(Insulin would dephosphorylate and deactivate protein kinase)

Front 79

Inactive Cdk4 is activated by?

Back 79

-Activated by Cyclin D (made by the G1 phase)

Front 80

What are the two suppressor genes in the regulation from G1 to the S phase in the Cell cycle?

Back 80

1) RB (Retinoblastoma) Suppressor Gene.

2) TP53 suppressor gene.

**Real checkpoint in the cell cycle is the {Transition from G1 to S phase}** (b/c if there was a mutation goes to S phase then you run the risk of CANCER)

Front 81

RB (retinoblastoma) suppressor gene

1). What Chromosome?
2). Fxn?
3). How does the cell go from G1 to S phase?

Back 81

1). Chromosome 13.

2). makes a protein, Rb protein, which prevents the cell from going from the G1 to the S phase.

3). The active Cdk4 (activated by Cyclin D which is made in G1) phosphorylates the Rb protein (thus inactivating it) so it can go from G1 to S phase.

*HPV makes E7 knocks off Rb suppressor gene* (if Rb gene is inactivated by pt mutation --> NO Rb protein --> NO regulation from G1 to S phase --> Risk of Cancer
[retinoblastoma, osteogenic sarcoma, breast cancer]

Front 82

1). If there is a mutation in the G1 phase, how is that checked so the cell does not go into S phase? What is its fxn

2). On what chromosome is it located?

Back 82

1). TP53 suppressor gene (aka p53 suppressor, TP = tumor protein) is a tumor suppressor gene.

Fxn:
It makes a protein product that inhibits the Cdk4 thus Rb protein would not be phosphorylated resulting in the cell remaining in G1 phase and cannot go to S phase.

2). Chromosome 17

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What are the Important characteristics of TP53 or p53 suppressor gene?

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aka guardian of the cell.

***TP53 suppressor gene is the #1 most IMPORTANT gene for human CANCER***

**HPV makes E6 which knocks off the TP53(p53)** [NO regulation and cell would always go from G1 to S phase and potential for CANCER]

**inhibits cell from going into th S phase and gives cell time to detect abnormalities in DNA, if so repair them and then onto S phase, if not repairable = Apoptosis**

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S phase

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Synthesis phase

-everything is doubled, including DNA and chromosomes (from 2N to 4N)

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G2 phase

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where tubulin (protein for microtubules) is made.

***IMP for microtubules of the mitotic spindle***

***Tubulin is blocked by Etoposide and Bleomycin***

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where do the following drugs act in the Cell cycle:

1) M-Phase

2) G2 phase

3) S phase

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1) Grieseofulvin, Paclitaxel, vincristine, vinblastin (vinca alkaloids)

2) Etoposide, bleomycin

3) Methotrexate

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A Pt with rheumatoid arthritis has macrocytic anemia, the drug responsible for this does what? and works on what phase?

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A) Methotrexate - it blocks dihydrofolate reductase.

B) works at the S phase

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This drug used to be used in Treatment of Acute Gouty Arthritis but because of side effects is no longer used. Where would it work?

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Colchicine - M phase

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Types of Growth Alterations (cell adaptations)

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1) Atrophy - Dec in cell size and mass.

2) Hypertrophy - Inc in cell size and mass.

3) Hyperplasia - Inc in # of cells (increased Mitosis)

4) Metaplasia - Replacement of 1 adult cell type into another.

5) Dysplasia - Disordered cell growth (Precursor to Cancer)


***Ahmed Has HaPpy Mood Disorder***

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Growth alterations/ Cell adaptations

ATROPHY

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-Dec in tissue mass and cell dec in size, enough organelles to survive.

Ex= Hydronephrosis, Atrophied brain, Lou gehrig's dx (muscle atrophy), endocrine related (hypopituitarism, thyroid gland atrophy), CF (pancreas), Atrophy of kidney.

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Mechanism of ATROPHY in

1. Hydronephrosis
-MCC cause?

2. Atrophy of Kidney
-Cause?

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1) the type of growth alteration here is Compression Atrophy which causes thinning of cortex and medulla.

Reasoning = atrophy is b/c of inc pressure on the cortex and medulla that produces ischemia, thus blood flow dec and produces atrophy of renal tubules.

1. ***MCC is Stone in ureter***

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Mechanism of ATROPHY

1) Atrophied brain
-MCC? other causes?

2) Muscle atrophy
-causes?

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1) ***MCC is Atherosclerosis***

***if there is degeneration of neurons in layers 3, 5, and 6 (EX alzheimers)***(related to Beta Amyloid protein, which is toxic to neurons)

2). Many causes for atrophy i.e bedridden, disuse, Lou Gehrigs Dx degeneration of neurons in muscles etc.

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Endocrine Related ATROPHY

1) Hypopituitarism

2) Thyroid Atrophy

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1) causes atrophy of adrenal cortex (specifically Zona fasiculata and reticularis NOT glomerulosa because ACTH has nothing to do with stimulating the aldosterone release)

Fasiculata- makes glucocorticoids (cortisol)
Reticularis- sex hormones are made (17 ketosteroids and testosterone)

2) Taking thyroid hormone leads to thyroid gland, b/c there is a dec in TSH and therefore nothing is stimulating the thyroid gland.

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Growth alterations in "CYSTIC FIBROSIS" and what gene on which chromosome

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Atrophy of the Pancreas
-b/c CF has problems with thick secretions, they block the ducts so the exocrine part of the gland cannot make fuilds b/c of pressure blocking the lumen of the duct which leads to atrophy --> results in malabsorption in ALL children with CF.

***CFTR regulator gene on CH 7***

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What Growth alterations are seen AORTA with atherosclerotic plaque?

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-Leads to Atrophy of Kidney and Secondary HTN (renovascular HTN, due to HIGH level of renin coming out of that Atrophied kidney and by default the other kidney would have hypertrophy with dec renin)

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Growth Alteration HYPERTROPHY

In Hypertrophy of Cardiac muscle, suppose there is block before the G2 phase what would be the number to chromosomes in the cell?

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ANS= double the number, 4n (because after S phase everything is doubled)

1n is like sperm
2n is normal diploid cell
3n means cancer or trisomy Dx

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Growth Alteration HYPERPLASIA

Common EX.

1) what are the effects of unopposed Estrogen?

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-Proliferative phase of Menstrual cycle (inc in # of endometrial glands, inc in cell division/mitosis)

1) In unopposed estrogen, you could end up in cancer, because progesterone is not there to oppose estrogen(hyperplasia to atypical hyperplasia to endometrial cancer)

***only exception is benign prostatic hyperplasia***

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1) Where would you see RBC HYPERPLASIA? why?

2). Methotrexate in Psoriasis on elbow?

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-COPD

*b/c the hypoxemia causes the release of hormone EPO(erythropoietin)*

2). Ex of hyperplasia (unregulated proliferation of squamous cells in the skin)
***raised red plaque with silvery scales corresponding to EXCESSIVE STRATUM CORNEUM***(this is why methotrexate works here b/c its cell specific for S phase and prevents basal cells from proliferating!)

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Where is EPO(erythropoietin) made?

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-endothelial cells of the Peritubular capillaries (kidneys)

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What are the results of HYPERPLASIA of Prostate Gland?

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***All hormone stimulated glands undergo HYPERPLASIA NOT HYPERTROPHY***

Results:
***Bladder wall hypertrophy(related to an inc in afterload), because there is narrowing of the opening of the urethra because of Prostate hyperplasia***

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Metaplasia of Lower Esophagus

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-Lower esophagus there may be mucous secreting cells and goblet cells present (they should be squamous normally) **AKA Barrett's esophagus which is a precursor to adenocarcinoma**

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What is the MC cancer of the Esophagus and what is its MCC?

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**barret's esophagus is a precursor to adenocarcinoma**

#1 cancer in the US now is Adenocarcinoma of the Esophagus.

***MCC is GERD which is a precursor to esophageal cancer***

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What is the lining of the mainstem Bronchus? an EX of Metaplasia in the mainstem Bronchus is?

Increased goblet cells in MB is an example of? (which growth alteration)

Increase goblet cells in Terminal Bronchi is an example of?

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**Ciliate Pseudostratified Columnar**

-EX= Smoker, squamous metaplasia

**Inc Goblet cells in MB = Hyperplasia (because normally there are goblet cells in MB)

**Inc Goblet cells in terminal Bronchiole = Metaplasia (there are no goblet cells in TB normally)

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Goblet cells in Stomach are an EX of?

what is the MCC of adenocarcinoma of the Stomach?

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-Are abnormal (should be in the intestines only) This is an ex of glandular metaplasia which is a precursor for adenocarcinoma of the Stomach.

***H.Pylori causes damage to the pylorus and antral mucosa produces a chronic gastritis with intestinal glandular metaplasia, which is a precursor for adenocarcinoma***

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1). What is the MC precursor of ENDOMETRIAL carcinoma?

2). What is the MC precursor for adenocarcinoma of the STOMACH?

3) What is the MC precursor for ESOPHAGEAL adenocarcinoma?

4) What is the MC precursor to Squamous Carcinoma of the LUNG?

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1) Endometrial hyperplasia, unopposed estrogen.

2). Glandular Metaplasia (H. pylori, inc in goblet cells not normal)

3). Glandular metaplasia (Squamous to Glandular epi)

4) Squamous metaplasia (leads to squamous dysplasia --> Cancer)

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What are the 2 parasites that produce Cancer?

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1) Clonesis sinesis (Chinese liver fluke) - leads to Cholangiocarcinoma [carcinoma of the bile duct that drains bile from the liver to sm. intestine]

2) Schistosoma hematobium (in the urinary bladder) - converts the transitional epithelium to undergo Squamous metaplasia (leads to Squamous dysplasia to Squamous Cancer)

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Give some Exs of Dysplasia?

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1) Squamous dysplasia of the Cervix (HPV type 16)

2) Mainstem Bronchus Squamous Dysplasia.

3) Actinic Keratosis (aka solar keratosis) precursor for Sq. cell carcinoma of the skin****usually related to a farmer or anybody with a perdominantly sun exposed area*

***even though basal cell carcinoma is the most common carcinoma of the Skin AK does not predispose to it***

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MC Skin carcinoma?

MC Esophageal Carcinoma?

MC cancer from Ionizing radiation?

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1) Basal cell Carcinoma.

2) Adenocarcinoma of the Esophagus (lower 1/3 of esophagus)

3) Leukemia