Chapter 1: Growth Adaptations,
Cellular Injury, and Cell Death
Hyperplasia Metaplasia Dysplasia Increase in cell number
- Change in cell type due to
reprogramming of stem cell
- Proliferation of pre-cancerous cells -Reversible - -Reversible -Reversible Pathologic hyperplasia can progress to cancer
- Can progress to dysplasia
and cancer
- -Can progress to cancer
BPH don't increase risk of cancer
- Apocrine metaplasia don't
increase risk of breast cancer -Physiologic (ex-pregnancy) • Pathologic (ex - …) • Etiology: -Vit A deficiency (keratomalacia, myositis ossificans) •
Cellular stress (barret's esophagus) • Etiology: -Long standing pathologic hyperplasia or metaplaisa • Etiology: -Processes Properties Hyperplasia and Hypertrophy
Usually, hyperplasia and hypertrophy occur together •
Permanent cell undergro hypertrophy only – cardiac myocytes, skeletal cells, and nerves.
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Pathologic hyperplasia (not physiologic ex- pregnancy)can progress to dysplasia and cancer.
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Exception is benign prostatic hyperplasia (is pathologic but does not increase risk of cancer).
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Atrophy •can occur by decrease in cell number (apoptosis) or decrease in cell size. Decrease in cell size occurs by – ubiquitin-proteosome degradation of cytoskeleton and autophagy of cellular components
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Metaplasia •change in cell type.
Mostly affects surface epithelium. Ex – barret’s esophagus (change from squamous to columnar)
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MOA: occurs by reporgramming of stem cells •
Reversible •
Can progress to dysplasia and cancer. Ex – Barret’s. Exception –
Apocrine metaplasia doesn’t increase risk of breast cancer. Apocrine metaplasia seen when fibrocystic changes in breast occur.
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Vitamin A deficiency can result in metaplasia. Ex – keratomalacia and myositis ossificans.
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Mesenchymal tissue can undergo metaplasia (ex – bone, blood vessel, fat etc). ex – myositis ossificans – inflammation of skeletal muscle reads to metaplasia to bony tissue.
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Fig – myositis ossificans
Dysplasia disordered cell growth; proliferation of precancerous cells. Ex - Cervical intraepithelial neoplasia
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Arises from longstanding pathologic hyperplasia or metaplasia •
Reversible •
If dysplasia persists, it can progress to cancer. •
Aplasia Failure of cell production during embryogenesis. Ex – unilateral renal agenesis (failure to make 1 kidney)
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Hypoplasia decrease in cell production in embryogenesis. Results in relatively small organ. Ex – streak ovary in Turner syndrome.
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Vitamin A is necessary for maintainence of special epithelial tissue in body – ex – conjucitva of eye. Conjuctiva is a thin delicate membrane that covers eye. Deficiency of vit A can result in metaplasia of cells in conjucitva where cells thicken which is called keratomalacia.
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Fig – keratomalacia. •
Extras – Vitamin A is necessary for maturation of immune system. 15-17 translocation in pt genome causes acute promyelocytic leukemia. The translocation causes mutation in vit-A receptor – retinoic acid receptor. Mutation of receptors cause immune cells to be trapped in blast stage. Treatment for Promyelocytic leukemia is all trans retinoic acid (drug) which can bind to mutated receptor. Cells can mature and be neutrophil.
What is cellular injury? 1.
If cellular stress overcomes cell's ability to adapt, then cell gets injured.
-What does cellular injury depend on? 2.
Type of stress
-Severity
-Type of cell -neurons can withstand hypoxia only for 3-5mins. Skeletal muscle can withstand for a very long time.
-What are causes of hypoxia(low O2 delivery to tissue)? 3.
ischemia,
-hypoxemia (PaO2<60 mm Hg),
-low O2 carrying capacity (ex - anaemia, CO poisoning, methmeglobinemia)
-What is shock? -What are it's causes? 4.
Shock is a generalized decreased perfusion of a vital organ. Can occur by hypovolemia, cardiogenic, spetic, neurogenic, anaphylactic causes
-What is Budd chiari syndrome? 5.
Blockade of hepatic vein can result in hepatic infraction, aka budd chiari syndrome.
-Most common cause of budd chiari syndrome is polycythemia vera. Polycythemia vera is a disease with too much RBC which leads to clot formation. Another cause is lupus.
-What will PaO2 and O2 sat be in anaemia? 6.
PaO2 and O2 sat will be normal in anaemia
-What will PaO2 and O2 sat be in CO poisoning? 7.
PaO2 will be the same and O2 sat will reduce. CO binds to Hb 100 times stronger than O2.
-What are signs/symptoms of CO poisoning? 8.
Early sign is headache (ask a pt if he has headache if you suspect CO poisoning). Pt may have cherry red color skin.
-What is methemoglobinemia? 9.
Normally, Fe in hemoglobin is in 2+ state and can bind to O2. If it gets oxidized to 3+, it can't bind to O2 and this is methemoglobinemia.
-What will PaO2 and O2 sat be in methemoglobinemia? 10.
PaO2 will be the same and O2 sat will reduce.
-What are causes of methemoglobinemia? 11.
Oxidative stress - sulfa drugs, nitrate drugs. Also seen in newborns because their machinery to reduce Fe 3+ isn't good.
-What are signs/symptoms of methemoglobinemia? 12.
Cyanosis with chocolate colored blood.
-What is treatment of methemoglobinemia? 13.
What is treatment of methemoglobinemia? 13.
IV methylene blue - it generates moderators that will reduce Fe3+
-What are consequences of low ATP in cell? 14.
Lactic acidosis due to lots of glycolysis
-Disrupted Na/K pump result in Na accumulation and resulting water retention in cell
-Disrupted Ca pump result in Ca accumulation and random enzyme activation in cytosol
-What are reversible finding in cell of low ATP? 15.
Hallmark is cellular swelling - loss of microvilli, membrane blebing as it pulls away from the cytoskeleton, swelling of RER and ribosomes fall off (low protein synthesis)
-What are irreversible finding in cell of low ATP? 16.
Hallmark is membrane damage. End result is cell death.
-Cellular enzymes leak out (liver enzyme in hepatitis and cardiac enzyme in MI) and intracellular Ca increases.
-Cytochrome C from mitochondria leaks out to cytosol and activates apoptosis
-Lysozome enzymes will leak out and digest the cells. Ca in cytosol activates them.
-What is morphologic hallmark of cell death? 1.
Loss of nucleus
-What are the steps by which nucleus is lost? 2.
Pyknosis - shrinking of nucleus •
Karyorrhexis - breaking of nucleus to big pieces •
Karyolysis - big nuclear pieces broken down to molecular building blocks •
Explain necrosis 3.
Necrosis occurs as a result of acute inflammation to a large group of cells and is always pathologic •
Coagulative necrosis 1.
Liquefactive necrosis 2.
Gangrenous necrosis - dry and wet 3. Caseous necrosis 4. Fat necrosis 5. Fibrinoid necrosis 6. Types •
Describe coagulative necrosis 4.
Cell and organ structure is preserved by coagulation of cellular proteins
-Characteristic of ischemic infarction of any organ except brain
Fig - right is normal glomerulus and left is coagulative necrosis of glomerulus. Note cellular and organization structure is preserved with loss of nucleus.
Area of infracted tissue is often wedge shaped and pale. Wedge points to the blocked blood vessel.
-When does red infraction (hemorrhagic infraction) occur? 5.
Red infraction occurs when blood reenters a loosely organized tissue. Ex - ischemia of testis, lungs. (is red infraction a type of coagulative necrosis?)
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Describe liquefactive necrosis 6.
Necrosis in which enzymatic lysis of cells and proteins result in liquefaction
-Characteristic of brain (microglial cells destroy the tissue), abscess (neutrophils contain hydrolytic enzyme that destroy the tissue), and pancreatitis (pancreatic enzyme digest the pancreas and liquify; however surrounding fat will have fat necrosis)
-Describe gangrenous necrosis 7.
It is coagulative necrosis that resembles mummified tissue (dry gangrene). If infection occurs on dry gangrene, liquifactive necrosis occurs and is called wet gangrene.
-Characterstic of ischemia of lower limb and GI tract
-Describe caseous necrosis 8.
It is soft, friable necrosis with 'cottage cheese' like appearance
-It's liquefactive necrosis with debris that thickens the soup to make it cheese like
-Characteristic of granulomatous inflammation of TB or fungal infection (fungal cell wall and micobacterium thickens the soup).
-Fig - caseous necrosis Describe fat necrosis 9.
Necrotic fat with Chalky white appearance due to deposition of Ca. MOA - When fat cells die by trauma or when fat is broken down by lipase, fatty acids are released. In presence of Ca, saponification occurs which gives it the chalky white apperance. Ca accumulation happens by dystropic calcification.
-Characteristic cases - trauma to fat (ex - as in car accident trauma in breast), pancreatitis mediated damage of peripancreatic fat
-Fig - fat necrosis around pancreas What is fibrinoid necrosis
10.
Necrotic damage to blood vessel
-Proteins leak into vessel wall which results in bright pink staining of vessel wall in H&E
-Characteristic of malignant hypertension and vasculitis. Pre-eclampsia can cause fibrinoid necrosis of placenta. (benign HTN is chronic low increase in BP that cause slow damage. Malignant
hypertension is sudden super elevated BP that is a medical emergency - findings such as headache, renal failure, papilledema). Super high BP in malignant HTN can kill vessel wall cells.
-What are mechanism by which calcium can deposit in human tissue? 11.
Dystropic calcification
-Metastatic calcification
-What is dystropic calcification? 12.
It's a mechanism by which Ca deposits in a human body (it's abnormal as calcium is not supposed to just randomly accumulate). Mechanism - when there's a dead tissue, calcium can accumulate even if serum Ca is normal. Ex - in fat necrosis, in tumor as center of tumor might not get enough blood supply and die.
-What is metastatic calcification? 13.
What is metastatic calcification? 13.
Serum Ca or PO4 is elevated. This elevated stuff can force Ca to accumulate on tissue. It doesn't mean that pt has metastatic cancer.
-Apoptosis
Explain apoptosis. (apoptosis means falling of leaves) 14.
It is purposeful, energy dependent killing of small group of cells
-Examples - Endometrial shredding during menstruation, removal of cells in embryogenesis, CD8 cell mediated killing of virally infected cells
-What is mechanism of apoptosis? 15.
Cell shrinks (and becomes eosinophilic due to concentration of cytoplasm) and nucleus also shrinks and fragments.
-Apoptotic bodies fall from cell like leaves fall from tree. Then they are eaten by macrophage. No inflammation occurs
-Fig - compare the pink apoptotic cell to it's surrounding neighbors What is biochemical pathway leading to apoptosis?
16.
Caspases activate proteases that break down cytoskeleton. ○
Caspases also activate endonucleases that break down nucleus. ○
Caspase activation is the key step.
-What 3 pathways lead to caspase activation? (HY) 17.
Intrinsic mitochondrial pathway - Bcl2 is a protein whose function is to stabilize mitochondrial membrane so that cytochrome C from mitochondria can't leak out. Due to membrane damage (cellular injury), DNA damage, or decreased hormonal stimulation of cell (ex - endometrial cells in lack of estrogen), Bcl2 can be inactivated. Leakage of cytochrome C will then activate caspase.
-Example- FAS ligand binds to FAS death receptor (CD95) on target cell and target cell dies via activation of caspases. Case report - new CD8+ T cells from bone marrow undergo positive selection (I.e., if they can bind to self antigen on MHC-I molecule, they get to live) and negative selection (i.e., if they bind to self antigen on MHC-I molecule very strongly, they die) in thymus. The killing of these young T-cells in negative selection happens by binding of FAS ligand to FAS death receptor on T-cells.
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Another example - TNF binds to TNF receptor on target cell and cell dies. ○
Extrinsic receptorligand pathway
-Cytotoxic CD8+ T-cell pathway - When CD8+ cells recognize foreign antigen on MHC-I receptors, they release perforins that make holes on target cell. Then, they release granzyme that enter target cell and activate caspases.
-What is free radical? 1.
Atoms or molecules with unpaired electron in outer orbit •
Give example of physiologic and pathologic free radical? 2.
Physiologic - in oxidative phosphorylation, when oxygen receives 1, 2 or 3 electron, it's partially reduced and creates superoxide (O2.), hydrogen peroxide (H2O2), and hydroxide(.OH) free radical respectively. Only if O2 receives 4 electron, it becomes water. Of all free radicals, hydroxide free radical is most damaging (HY).
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Oxygen ----(accept 1 electron)---> Superoxide (.O2) ----(accept 1 electron)---> Hydrogen peroxide (H2O2) ----(accept 1 electron)---> Hydroxide (.OH) ----(accept 1 electron)---> Water (H2O)
ionizing radiation (creates hydroxide radical .OH), ▪
inflammation (in neutrophils, O2 is converted to superoxide by NADPH oxidase) ▪
Metals - iron and copper. Hemochromatosis and Wilson disease are disease of Fe and Cu accumulation in body - creation of free radicals are main way that the disease affect us. (Fenten reaction - reaction by which Fe generates hydroxide free radical (HY))
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Drugs and chemicals - acetaminophen, carbon tetrachloride. High dose of acetaminophen causes liver necrosis by free radical generation
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Thyroid hormones increase free radical formation ▪
Pathologic -•
How do free radicals harm the cell? 3.
Oxidation of DNA (lead to fast aging and cancer) and oxidation of proteins •
Peroxidation of lipids •
What are 3 mechanism of removal of free radicals? Give example of 3 enzymes. 4.
Antioxidants - vit K •
Metal carrier proteins - transferrin, ferretin •
Superoxide dismutase (gets rid of superoxide) ○
Catalase ( gets rid of hydrogen peroxide) ○
Glutathione peroxidase (get rid of hydroxide free radical) ○
Enzymes (HY) •
Give example of 2 free radical injury? (HY) 5.
Carbon tetrachloride (dry cleaning chemical)- CCl4 is converted to CCl3 (radical) by Cyp 450 in liver. It causes reversible damage to hepatocytes - cell swells --> swelling of RER causes ribosomes to fall off and apolipoprotein synthesis goes down --> liver can't repackage and send fat away --> fatty liver disease (VHY)
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Fig - T represents fat in hepatocyte; a hepatocyte is shown in circle
Reperfusion injury - During reperfusion of ischemic organ, immune cells will attack the dead tissue in presence of oxygen which will generate free radicals. More injury ensues. Classic example is blood troponin continuing to rise after reperfusion of heart after MI.
What is amyloid? 1.
Misfolded proteins that accumulates in extracellular space and damages tissue. Amyloid can't be removed and damaged organs must be transplanted
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What are characters of amyloid? 2.
Misfolded proteins have B-sheet arrangement •
Amyloid are congo red positive (appear apple-green under polarized light) •
Fig - apple-green appearing amyloid under polarized light Amyloid can be deposited systemically or locally
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What are 2 types of systemic amyloidosis? 3.
Primary amyloidosis - When Ig light chain deposits systemically (in form of AL amyloid), it's called primary amyloidosis. It's associated with plasma cell dyscrasias (disease) - when plasma cells make ton of light chain, they will deposit.
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Secondary amyloidosis - when SAA protein deposits systemically (in from of AA amyloid), it's called 2ndary amyloidosis. SAA is acute phase reactant that is increased in chronic inflammatory states, malignancy, and Familial Mediterranean fever.
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What is familial mediterranean fever (HY)? 4.
It's genetic disease with dysfunction of neutrophils that causes systemic amyloidosis. It's usually seen in people of mediterranean origin.
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Pt will have high SAA that deposits at AA amyloid •
Pt may present with acute fever and serosal inflammation (serosal inflammation of heart might mimic MI, of gut may mimic appendicitis)
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What are classic findings of systemic amyloidosis? 5.
Kidney is most commonly involved - nephrotic syndrome is seen •
Restrictive cardiomyopathy or arrhythmia •
Hepatosplenomegaly, malabsorption, large tongue •
How do you diagnose amyloidosis? 6.
Requires tissue biopsy (needs to be congo-red positive) - usually take from rectum or abdominal fat pads
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Describe senile cardiac amyloidosis (a type of local amyloidosis). 7.
Caused due to deposition of non-mutated serum transthyretin in heart. Transthyretin is 2ndmost
common protein in blood. •
common protein in blood.
Usually asymptomatic and seen in 25% of people >80 year •
Describe familial amyloid cardiomyopathy (a type of local amyloidosis). 8.
Caused due to deposition of mutated serum transthyretin in heart. •
Leads to restrictive cardiomyopathy •
Usually seen in african americans (5% carry mutation) •
Describe how type 2 diabetes has local amyloidosis in it. 9.
Due to insulin resistance, pancreas produces lots of insulin. A byproduct amylin is also produced that deposits in islets of pancreas and cause amyloidosis.
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Describe how alzhimer's has local amyloidosis in it. 10.
B-amyloid precursor protein (BAPP) on chromosome 21 makes AB amyloid plaques. (Most individuals with Down's syndrome have Alzheimer's by 40 year age)
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Describe how dialysis can cause local amyloidosis in joints. 11.
Beta2 microglobulin is a protein that structurally supports MHC-I on cell surface. In dialysis, B2-microglobulin isn't filtered well from blood. It then builds up in joints and cause amyloidosis. •
Describe how medullary thyroid cancer can cause local amyloidosis in thyroid. 12.
In MTC, overproduction of calcitonin leads to formation of calcitonin amyloid plaques in thyroid. (In FNA of thyroid, seeing tumor cells in amyloid background makes MTC more probable)
Chapter 2: Inflammation,
Inflammatory Disorders, and Wound
Healing
Process by which inflammatory cells, plasma proteins and fluid exit blood vessel to enter interstitial space
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1. What is inflammation?
Characterized by edema and neutrophil in tissue (presence of neutrophils define acute inflammation)
-Arises in response to infection or necrosis (necrosis is always followed by acute inflammation (HY))
-Goal is to clear pathogen or necrotic debris
-Part of innate immunity (very quick response)
-2. Explain acute inflammation
Toll like receptors (TLR)- present on cells of innate immune system (macrophage, dendritic cells) and adaptive immune system. In innate system, TLR recognize PAMP (pathogen associated molecular patterns)and DAMP (damage associated molecular pattern). Ex - CD14 (aka TLR-4) is a TLR on macrophage that recognizes lipopolysaccharide (LPS) which is shared by gram negative bacteria. (HY)
-3. How does TLR work?
NF-KB- NF-KB is a molecular switch that turns on acute inflammation (master regulator for both innate and adaptive immunity).
-Type 1 interferon (alpha and beta) - inhibit viral replication in cells
-3.1 What chemical is upregulated by TLR?
Explain production and metabolism of arachidonic acid (AA). 4.
Phospholipase A2 releases AA from phospholipid cell.
-AA can then be metabolized by cyclooxygenase or 5-lipooxygenase.
-Arachidonic acid metabolism
What are the products of cyclooxygenase pathway and what are their functions. 5.
Cyclooxygenase pathway produces prostaglandins (PG) - PGI2, PGD2 and PGE2. They increase vascular permeability and vasodilation. PGE2 also mediates feeeever and pain. Note that vasodilation happens at arteriole level and vascular permeability at post capillary venule level.
-What are the products of lipooxygenase pathway and what are their functions 6.
5-Lipooxygenase pathway produces leukotrienes (LT). LTB4 attracts and activates neutrophils. LTC4, LTD4 and LTE4 mediate smooth muscle contraction (vasoconstriction, bronchospasm, and increased vascular permeability (contraction of pericytes opens up space between endothelial cells)).
-What are 4 important things that attract and activate neutrophils? 7.
LTB4 (leukotriene)
-C5A (complement protein)
-IL8 (mechanism by which macrophage call neutrophil)
-Bacterial products
-TNF and IL1 (based on Abbas book)
-What are 3 ways that activate mast cells? 7.
Mast cells are found throughout connective tissue of body and are activated by
-Mast cells
Tissue trauma ○
Complement proteins C3a and C5a ○
Cross linking of cell surface IgE by antigen (2 or more IgE on a mast cell binds same antigen) ○
Mast cells are found throughout connective tissue of body and are activated by
-What is acute response of mast cells activation? 8.
Histamine is released which causes vasodilation and increased vascular permeability.
-Release proteolytic enzymes that kill bacteria or inactivate toxins
-What is delayed response (after 4-5 hrs) of mast cells activation? 9.
Mast cells produces arachidonic acid metabolites, particularly leukotrienes. (HY)
-What are three pathways of complement activation? 10.
Classic pathway - C1 protein binds to IgG or IgM which is bound to antigen (pneumonic - GM makes classic cars)
-Alternative pathway - microbial products directly activate complement
-Mannose binding lectin (MBL) pathway - MBL binds to mannose on microorganisms and activate complement
-Complement
How is membrane attack complex (MAC) formed? 11.
C3 convertase converts C3 to C3a and C3b
-C5 convertase converts -C5 to -C5a and -C5b
-C5b joins with C6 and C9 to make membrane attack complex (MAC) which pokes hole in cell and kill it.
-What are some key functions of complement proteins? (HY) 12.
C3a and C5a activate mast cells (stimulate degranulation)
-C5a is chemotactic for neutrophil
-C3b is opsonin for phagocytosis. Opsonins tag cells/waste for phagocytosis.
-MAC pokes hole in cell and kill it
-What is hageman factor (aka factor 12 in coagulation cascade)? -What systems does it activate? 13.
It's inactive proinflammatory protein produced in liver that's activated by exposure to subendothelial or tissue collagen, and during severe gram negative sepsis
-Plays imp role in DIC (disseminated intravascular coagulation - pathologic activation of coagulation cascade) and severe gram negative sepsis (sepsis activates hageman factor which in turn results in DIC) (HY).
-It activates complement system, coagulation and fibrinolytic system (this results in DIC), and kinin system
-Kinin system cleaves high molecular weight kinin to bradykinin. Bradykinin results in vasodilation, increased vascular permeability and pain). Note - bradykinin system has histamine + pain functions
-13.1. Explain kinin system.
What two molecules mediate pain? 14.
Prostaglandin E2 (cause feeever and pain)
-Bradykinin
-What causes rubor (redness) and calor (warmth)? 15.
Vasodialation due to arteriole relaxation mediated by - histamine (primary), bradykinin and PG.
-Cardinal signs of inflammation - rubor, calor
What causes tumor (swelling)? 16.
What causes tumor (swelling)? 16.
Increased vascular permeability at post capillary venule mediated by - histamine, bradykinin, lukotrienes, PG, and tissue damage.
-What causes dolor (pain)? 17.
Bradykinin and PGE2.
-What causes fever? (VHY) 18.
Macrophage release IL-1 and TNF. They go to perivascular cells of hypothalamus and increase activity of COX. (inflammosome also makes IL1)
-COX causes increase in PGE2 in hypothalamus which increases temp set point.
-Fluid phase - edema, complement activation etc ○
Neutrophil phase - peaks about 24 hrs ○
Macorphage phase - peaks about 2-3 days ○
(Note that acute inflammation is not defined by time. It can happen for days or weeks. It is defined by whether neutorphils are primary player. If pus is present, it's still acute.) What are 3 phases of acute inflammation?
1.
What are steps of neutorphil exit? What proteins are key in each step? 2.
Margination - Usually, heavy particles in blood are in center of vessel lumen. When blood vessel dilates, heavy particles come to edge of vessel and this is margination. It's first step of neutrophil arrival.
-Rolling - endothelial cells express proteins called selectins which act as speed bump so that neutrophils roll and slow down.
-Adhesion - cellular adhesion molecules (CAM) on endothelium binds to integrins on neutrophil resulting in adhesion. (HY)
-Transmigration and chemotaxis - transmigration happens across vessel wall of postcapillary venules, and chemotaxis is movement to infection site after transmigration. Neutrophils are attracted by bacterial products, IL8, C5a and LTB4
-Phagocytosis - enhanced by opsonins (IgG and C3b)
-What induces P selectin and E selectin? 3.
P selectin release is induced by histamine. They are released from Weibel-Palade bodies in endothelial cells (another stuff made by weibel-palade body is Von-willieband factor).
-E selectin release is induced by TNF and IL-1.
-What protein on neutrophils does selectins bind to? 4.
Sialyl Lewis X. It results in rolling .
-What upregulates cellular adhesion molecules (CAM) on endothelium? 5.
IL1 and TNF
-IL-1 and TNF
-What upregulates integrins on neutrophils? 6.
C5a and LTB4 (recall that C5a and LTB4 are 2 of the 4 things that attract and activate neutorphils - other 2 being bacterial product and IL8)
-5.5. What are major innate immunity cytokines?
What is leukocyte adhesion deficiency? Where is the mutation? 7.
It's autosomal recessive mutation of integrins at CD18 subunit.
-What are sign/symptoms of leukocyte adhesion deficiency (LAD)? (HY) 8.
Delayed seperation of umbilical cord (HY) - After childbirth, the umbilical cord shuts. Due to no blood through it, it undergoes necrosis. Active inflammation ensues. Neutrophils come and eat up umbilical cord. However, in LAD, neutrophils won't come much because adhesion process is bad.
-Increased circulating neutrophils (HY) - normally, half of neutrophils are in circulation and remaining half are stuck to endothelium of lung. Due to loss of adhesion, circulating
remaining half are stuck to endothelium of lung. Due to loss of adhesion, circulating neutrophils will increase.
Recurrent bacterial infection but lack pus formation (HY) - Pus is dead neutorphil in fluid. If neutrophils can't get into tissue, pus can't form.
-Where do neutrophils exit blood vessel? 9.
Post capillary venule.
-How does phagocytosis occur? 10.
Neutrophils engulf stuff and make phagosome. Phagosome merges with lysosome to make phagolysososme. (C3b and IgG are major opsonins)
-What is Chediak-Higashi syndrome? 11.
It's an autosomal recessive protein trafficking defect (microtubule railroad tracks in the cells are defective).
-What are sign/symptoms of Chediak-Higashi syndrome? (HY) 12.
Neutropenia (impaired cell division so low neutrophils)
Giant granules in leukocytes (newly made granules from golgi won't travel well to other parts of cell and pile up)
Increased pyogenic infections (phagosome merging with lysosome is impaired, so immune cells are less efficient at killing pathogens).
Immune fingings-○
Defective primary hemostasis (granules in platelets won't move well) ○
Albinism (a melanocyte supplies melanin to about 25 keratinocytes. As railroad transport is defective, it's melanin won't be transported to other keratinocytes) ○
Peripheral neuropathy - stuff from cell body of neuron won't be transported to axon endings well.
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It's symptoms are based on impaired microtubule railroad tracks
-Oxygen dependent and oxygen independent. •
Oxygen dependent is more efficient •
1. What are two mechanism of phagocytosis? Which is more efficient
It occurs in phagolysosome •
Oxygen is converted to superoxide (radical) by NADPH oxidase (rxn called oxidative burst). •
Superoxide is coverted to hydrogen peroxide by superoxide dismutase. •
Hyrodgen peroxide is converted to bleach (HOCl) by myloperoxide (MPO) •
HOCl kills organism •
2. Explain O2 dependent mechanism of phagocytosis. (HY)
Due to defect in NADPH oxidase, O2 dependent phagocytosis is bad and patient has chronic granulomas. Disease is autosomal recessive or X-linked.
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As pt can't phagocytose, more and more macrophage and neutrophils are called to site resulting in formation of granulomas.
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3. What is mechanism of Chronic granulomatous disease (CGD)?
S Aureus ○
P cepacia (often tested) ○ S marcescens ○ Nocardia ○ Aspergillus ○
4. What are 5 catalase positive organism that cause symptomatic CGD? (HY)
Most bacterias produce H2O2 which can be converted to bleach by myloperoxidase in body. Therefore, most bacteria can't cause CGD despite mutation in human NADPH oxidase. However, when bacteria have catalase, that destroys H2O2 and formation of bleach is reduced which results in CGD.
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5. Why do only catalase positive organism cause CGD?
2.1 Acute Inflammation (Part 3)
in CGD.
It's a screening test for CGD. In the test, solution turns blue if superoxide radical is present. It tests if NADPH oxidase is functional.
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6. What is nitroblue tetrazolium (NBT) test?
Most MPO patients are asymptomatic but have increased risk for candida infection. •
They have normal NBT test. •
7. What is clinical significance and NBT test result for people with myloperoxide (MPO) deficiency?
It's less effective and occurs via enzyme in secondary granules (ex - lsyozome and major basic protein).
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8. Explain oxygen independent phagocytosis.
Within 24 hours of resolution of inflammatory stimulus, neutrophils die by apoptosis. It creates pus. Pus is dead neutrophils in fluid.
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9. Describe the resolution phase of acute inflammation.
It peaks 2-3 days after inflammation begins. •
When monocytes get into tissue, they are called macrophage. They come to tissue in same steps as neutrophils.
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10. Describe macrophage phase of acute inflammation.
Phagocytotic killing of macrophage is mainly oxygen independent - via the enzymes in secondary granules. Lysozyme is main enzyme.
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Phagocytotic killing of neutrophil is mainly oxygen dependent. •
11. Contrast phagocytosis of macrophage with that of neutrophil.
Macrophage are managers which come in to check after 2-3 days of acute inflammation if neutrophils did a good job at clearing the damage.
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If good job is done, macrophage secrete IL-10 and TGF-B. They are anti-inflammatory and induce healing.
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If job is done poorly, macrophage secrete IL-8. It calls additional neutrophils to the site. •
If macrophage sense that the offending organism needs to walled off, they create abscess. Abscess is walled off area of inflammation.
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If macrophage sense that neutrophils can't do the job well (ex- neutrophils don't work well in viral injury), they initiate chronic inflammation by presenting antigen in MHC-2.
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Inflammation is bringing out immune cells into the tissue. In chronic inflammation, mainly lymphocytes are brought out. In acute inflammation, mainly neutrophils are brought out. •
It's delayed response (adaptive immunity) and more specific. •
Fig - chronic inflammation. Note the absence of multilobed neutrophil. Cell on left is lymphocyte. Middle cell is plasma cell (nucleus pushed to side, slight perinuclear halo). Cell on right is
macrophage (clock face nucleus). 1. What is chronic inflammation?
Persistent infection (most common) •
Infection with virus, mycobacteria, parasites, fungi • Autoimmune disease • Foreign material • Some cancers •
2. What are stimuli of chronic inflammation?
T cells
They are made in bone marrow and go to thymus. •
In thymus, they become specific to an antigen and develop into either to CD4 helper or CD8 cytotoxic cell.
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3. Explain development and maturation of T-cells.
T cells are activated when they recognize antigens presented on MHC molecules only while a second signal is present.
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Helper CD4 T cells read antigen from MHC II. MHC II present extracellular antigen and are present on antigen present cell.
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Cytotoxic CD8 T cells read antigen form MHC I. MHC I present intracellular or viral antigen and are present on all cells in body
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For CD4 cells, B7 on antigen presenting cell is the second signal that binds to CD28 on CD4 cells. CD40 on B cells also act as second signal that bind to CD40L on CD4 cells.
•
For CD8 cells, IL2 from CD4 cells is second signal for activation. •
4. How are CD4 and CD8 T-cells activated? What is their second message for activation?
Activated CD4 helper cells secrete cytokines. They have two subtypes - TH1 and TH2. •
5. What do activated CD4 cells do?
TH1 secrete IFN gamma that enhances phagocytic ability of macrophage •
TH1 also secrete IL2 which is T cell growth factor and CD8 cells activator •
6. Explain purpose and function of cytokines secreted by activated CD4 TH1 cells.
TH2 cause eosinophil rich inflammation and/or reduce inflammation by secreting IL4, IL5 and IL10. •
7. Explain purpose and function of cytokines secreted by activated CD4 TH2 cells.
2.2 Chronic inflammation
TH2 cause eosinophil rich inflammation and/or reduce inflammation by secreting IL4, IL5 and IL10. •
IL 4 cause class switching to IgG and IgE •
IL5 attracts and activates eosionophil, helps in maturation of B cells to plasma cells and cause class switching to IgA
•
Il10 (antiinflammatory cytokine) inhibits TH1 phenotype. •
They secrete perforins that make holes in host cell and secrete granzymes that activate caspase and induce apoptosis.
•
They express Fas ligand which binds to Fas receptor on host cell that activates apoptosis. •
8. How do CD8 T cells kill cells?
If there's a self-reactive T-cell, it will bind to MHC-antigen but the second signal won't be present. It will result in apoptosis or anergy.
-8.1. How is a self-reactive T-cell killed?
B cells
Immature B cells are produced in bone marrow. Naïve B cells express IgM and IgD. •
9. How are B cells produced?
Binding of antigen to IgM or IgD activates B cells. Then they become IgM or IgD secreting plasma cells.
•
B cells can phagocytose and present antigen to CD4 cells via MHC II. CD40 on B cell can bind to CD40L on helper T cell providing 2ndsignal for activation.
•
TH2 Helper T cell will secrete IL4 and IL5. IL4 and IL5 help in isotype switching of B cells, somatic hypermutation (aka affinity maturation), and maturation to plasma cells.
•
10. How are 2 ways by which B cells activated? How does isotype switching occur?
Granulomatous inflammation
It’s a type of chronic inflammation. It's defined by presence of epitheloid histiocytes (macrophage with abundant pink cytoplasm and elongated nuclei) (HY). You may also see multinucleated macrophages. In healthy tissue, macrophage have clear (aka foamy) cytoplasm.
•
Granulomas are surrounded by rim of lymphocytes and giant cells. •
Only a certain conditions give granuloma so they help to identify diseases. •
11. What is granulomatous inflammation?
Defining feature of noncaseating granuloma is lack of central necrosis. •
Reaction to foreign material - ex- leaking of breast implants ○
Sarcoidosis - hallmark of sarcoidosis is production of non-caseating granuloma in multiple organs (mainly lungs)
○
Beryllium exposure ○
Crohn disease - hallmark of Crohn is noncaseating granuloma. (hallmark of UC is crypt abscess)
○
Cat scratch disease - give star shaped granuloma in neck ○
Causes: •
Fig - noncaseating granuloma. Not abundant lymphocytes in periphery that indicates chronic inflammation. Note multinucleated cell. Presence of nucleus in epitheloid histiocytes means they are alive - making this noncaseating granuloma.
Characteristic of TB and fungal infections. If you see caseating granuloma, do AFB stain to look for TB, and GMS silver stain to look for fungal infections.
•
13. What causes caseating granuloma?
Fig - caseating granuloma. Note the central necrosis
Macrophage present antigen to CD4 T cells via MHC II •
After binding, macrophage also secrete IL-12 that induce CD4 cells to differentiate to Th1 subtype •
Th1 cells secrete IFN gamma which converts macrophage to epitheloid histiocytes and giant cells. Granuloma is hence formed.
•
These steps occur in both caseating and non-caseating granuloma •
Failure to develop 3rdand 4thpharyngeal pouch due to 22q11 mutation. •
1. What is DiGeorge syndrome (HY)?
T cell deficiency- problems fighting viral and fungal infection (due to lack of thymus as thymus develops from 3rdand 4thpouch)
•
Hypocalcemia (due to lack of parathyroid) •
Abnormalities of heart, great vessels, and face •
2. What are presentation of DiGeorge syndrome?
Pt have defective cell-mediated and humoral immunity (both T and B). •
3. What is SCID (severe combined immune deficiency)?
Cytokine receptor defects (main cause) •
Adenosine deaminase deficiency (second main cause)(HY) - enzyme necessary for deamination of adenosine and deoxyadenosine. In lack of enzyme, adenosine and deoxyadenosine accumulates in immune cells causing toxicity. •
MHC class II deficiency - CD4 won't be able to be activated. It leads to defective function of CD8 and B cells. •
4. Etiology of SCID?
Lack of T cells result in fungal and viral infections •
Lack of B cells result in bacterial and protozoal infections •
Increased opportunistic infection and be wary to give live vaccines. •
5. Presentations of SCID?
Sterile isolation (bubble babies) •
Stem cell transplant •
6. Treatment of SCID?
Name suggests pt lacks gammaglobulin (antibodies) in blood. There's a complete lack. •
Occurs because naïve B cells can't mature to plasma cells. •
Mutation is Bruton tyrosine kinase. It's a signaling receptor that helps maturation of B cells. •
8. What is X-linked agammaglobulinemia? What is the mutation?
Recurrent bacterial, enterovirus, and Giardia infection (HY). •
Enterovirus affects mucosa of GI tract. IgA protects mucosal surface, and lack of IgA results in enterovirus infection. •
Bacterial infection occurs because lack of antibodies affect opsonization. •
Giardia occurs for same reasoning as enterovirus. •
Presents after 6 month of life – because mom's antibodies last for about 6 months •
Don't give them live polio vaccines •
9. What is presentation of X-linked agammaglobulinemia?
Pt has low antibodies due to defective B or T cell •
10. What is common variable immunodeficiency disease?
Pt has increased risk of bacterial, enterovirus, giardia infection, often in late childhood. •
They have increased risk of autoimmune disease and lymphoma. (HY) •
11. Presentation?
This is most common Ig deficiency. Pt have low serum and mucosal IgA which increases risk of mucosal infections – especially viral.
•
12. What is IgA deficiency?
especially viral.
Note – pt with celiac disease usually have IgA deficiency.
Pt have too much IgM. •
13. What is Hyper-IgM syndrome?
Patient has mutation in CD40 or CD40 receptor. Due to this, B cells can't activate CD4. In lack of good CD4, cytokines necessary for Ig class switching is not produced. Pt will have low IgA, IgG, and IgE.
•
Presentation is recurrent pyogenic infections, especially at mucosal sites. IgG is a opsonin, low amount results in more formation of pus.
•
14. What is pathophysiology of Hyper-IgM syndrome? What is presentation?
Pt have thrombocytopenia, eczema, and recurrent infections. Pt have defective humoral and cellular immunity. •
Happens due to mutation in WASP (Wiskott-Aldrich syndrome protein) gene and is x-linked. •
15. What is Wiskott-Aldrich syndrome (WAS)? What causes it? (just memorize)
Deficiency from C5-C9 - increased risk of Neisseria infection (HY) •
C1 inhibitor deficiency - hereditary angioedema characterized by edema of skin (especially periorbital) and mucosal •
Fig - heriditary angioedema.
What causes autoimmune disorders? 1.
Overactive immune system or loss of self tolerance.
-What is epidemiology of autoimmune disorders. 2.
Present in about 1% of US popn.
-Most affects women. Classically affects women of childbearing age.
-Most autoimmune diseases are associated with other autoimmune diseases.
-What is etiology of autoimmune disorders? 3.
Environment triggers disease in genetically susceptible individuals.
-What happens in Lupus? 4.
Lupus is a systemic autoimmune disease in which autoantibodies can cause type II (cytotoxic -antibody bind and kill cells) or type III hypersensitivity reaction (antigen--antibody complex form and deposit in tissue causing damage).
-Systemic Lupus
What are clinical features of lupus? 5.
Malar 'butterfly rash' upon exposure to sunlight is classic sign
-Diffuse proliferative glomerulonephritis commonly occurs; other nephritic/nephrotic symptoms can occur too. Renal damage is common cause of death
-Pleuritis and pericarditis, myocarditis, endocarditis
-Libman-Sacks endocarditis - vegetations on both side of valve
-Antibodies against blood result in - anemia, thrombocytopenia or leukopenia. Infections due to loss of immune system also a common cause of death.
-CNS psychosis due to inflammation of -CNS
-Fever and weight loss (fever is sign of inflammation)
-Arthritis
-Fig - malar butterfly rash in lupus pt. Describe Libman-Sacks endocarditis. 6.
Mostly, endocarditis happens only on one side of valve (up or down). If it happens on both side of valve, it's called Libman-Sacks endocarditis and is characteristic of lupus.
-How do we diagnose lupus? 7.
ANA (anti-nuclear antibody) very sensitive for lupus - used for screening
-Anti-dsDNA very specific for lupus
What are three common drug that cause lupus? How do we diagnose? How do we treat? 8.
Hydralizine, procainamide and isoniazid
-Antihistone antibodies are specific for drug induced lupus
-Removal of drug causes remission of disease
-What is antiphospholipid syndrome associated with SLE? -What lab tests does it affect? 9.
Antibodies are made against proteins bound to phospholipid.
-Anticardioliptin antibody give false positive syphilis test.
-Lupus anticoagulant antibodies give falsely elevated PTT lab study but makes pt hypercoagulable.
-Why do you keep pt with antiphospholipid syndrome on lifelong anticoagulation? 10.
Because lupus anticoagulant antibodies make pt hypercoagulable and increase risk of stroke, DVT, hepatic vein thrombosis, placental thrombosis (pregnancy loss).
-What is sjogren syndrome? 11.
Type IV (lymphocyte mediated) autoimmune destruction of lacrimal and salivary glands with resulting fibrosis.
-Sjogren syndrome
What are clinical presentation of Sjogren syndrome? 12.
Dry eyes, dry mouth and recurrent dental carries (bacteria accumulates as teeth aren't washed) in older woman.
-Parotids may be enlarged due to fibrosis.
-"Can't chew cracker, dirt in my eyes"
-How do you diagnose Sjogren syndrome? 13.
Presence of ANA is sensitive
Presence of antiribonucleoprotein antibodies is specific (Anti SSA and anti SSB antibodies -Sjogren syndrome A and sjogren syndrome B)
-What other conditions is Sjogren syndrome associated with? 14.
Other autoimmune disorders - especially rheumatoid arthritis
-High risk for B-cell lymphoma (HY) - unilateral enlargement of partoid gland late in disease is indicative of B-cell lymphoma.
-What is scleroderma? 15.
Autoimmune tissue damage with activation of fibroblast and deposition of collagen (fibrosis) that thickens the tissue (also makes it tight and less mobile).
Fig- scleroderma hands 16.
What is diffuse type scleroderma? What are clinical presentation? How do you diagnose? 17.
Patient has diffuse skin and early visceral organ involvement.
-Esophagus most commonly affected - see solid and liquid dysphagia
-Diagnosis made by ANA and anti-DNA topoisomerase I antibody (aka SCL-70 antibody). SCL stands for scleroderma.
-What is localized type scleroderma? -What are clinical presentation? How do you diagnose? 17.
Patient has local skin and late visceral organ involvement.
-Calcinosis (calcification of skin), anti-centromere Ab ○
Raynaud phenomena ○
Esophageal dysmotility- see solid and liquid dysphagia ○ Sclerodactyly ○ Telangiectasis of skin ○ Presentation (CREST)
-Diagnosis made by anti-centromere antibody
-What is mixed connective tissue disease? How is it diagnosed? 18.
It is autoimmune tissue damage with mixed features of SLE, scleroderma and polymyositis (autoimmune damage of proximal muscles). Think of patient with bunch of autoimmune condition.
-Diagnosis made by presence of antibodies against U1 ribonucleoprotein.
What is regeneration? 1.
It's replacement of damaged tissue with native tissue.
-What is repair? 2.
Repair is replacement of damaged tissue with fibrous scar. It occurs when tissue lacks regenerative capacity or regenerative stem cells are lost.
-What are 3 different types of tissue based on regeneration capacity? 3.
Intestine - stem cell in mucosal crypt ○
Skin - stem cell in basal layer (most bottom layer of epidermis) ○
Bone marrow - hematopoietic stem cells (HSC). (HY - You can't identify HSC by microscope. Presence of CD34 molecule tells it's HSC)
○
Lungs - stem cell is type 2 pneumocytes ○
Fig - circles are the crypts of bowel
Labile tissue - they are continuously regenerating
-Fig - line showing basal layer of skin Liver
○
Proximal tubule of kidney - pt on acute tubular necrosis are put on dialysis until their proximal tubules regenerate
○
Stable tissue - they don't continuously regenerate but have the ability to regenerate if needed.
-Myocardium ○
Skeletal muscle
Permanent tissue - can't regenerate
Skeletal muscle ○
Neurons ○
What is granulation tissue (different from granuloma which occurs in chronic inflammation)? What are 3 important cell types in it?
4.
Fibroblasts (deposit type 3 collagen) ○
Capillaries ○
Myofibroblast (contract wound) ○
It's present in early phase of repair. It contains
-Fig - granulation tissue showing blood vessels, collagen and fibroblast. Contrast it with granuloma in chronic inflammation file.
What happens when granulation tissue is replaced by scar? What cofactor is needed? 5.
Collagenase removes type 3 collagen and replaces with type I collagen. It needs zinc as cofactor (HY).
-Where are 4 types of collagen found? 6.
Type 1 - bone (bone) - very high tensile strength
-Type 2 - cartilage (cartwolage)
-Type 3 - granulation tissue, embryonic tissue - very pliable/moldable
-Type 4 - basement membrane
-How do regeneration and repair happen? What are some key molecules? 7.
Fibroblast growth factor (FGF) - powerfully induces angiogenesis and skeletal development ○
VEGF - angiogenesis ○
PDGF - induces growth of endothelium, smooth muscle and fibroblast ○
TGF alpha - epithelial and fibroblast growth factor ○
TGF beta - inhibits inflammation, important fibroblast growth factor ○
They occur by paracrine signaling via growth factors. Some of them are
-Contrast wound healing by primary vs secondary intention. 8.
In primary intention, wound edges are brought together and there's minimum scar formation
-In secondary intention, edges are far away and granulation tissue fills the gap. Due to presence of myofibroblasts, wound shrinks quite a lot.
-Explain formation and structure of collagen. 9.
Collagen is formed as multiple alpha strands inside cells. Multiple alpha strands intertwine to make procollagen and come outside cell.
-Structure of alpha strand is Gly-X-Y, where X and Y are proline and lycine.
-In extracellular space, multiple procollagen are crosslinked via hydroxyl groups in proline and lycine to make collagen.
-lycine to make collagen.
Vitamin C is needed to hydroxylate proline and lysine.
-Crosslinking is done by lysyl oxidase which has copper as cofactor
-What are some common causes of delayed wound healing? (HY) 10.
Infection is most common cause
-Vitamin C deficiency - causes poor hydroxylation of lycine and proline.
-Copper deficiency - lysyl oxidase can't cross link procollagen well
-Zinc deficiency - type III collagen can't be converted to type I by collagenase
-Foreign body, ischemia, diabetes, malnutrition etc
-What is wound dehecence? 11.
Rupture of wound - commonly seen after abdominal surgery
-What is hypertrophic scar 12.
Scar tissue being big but localized to wound. Caused by excess type I collagen
-Fig- hypertrophic scar Describe keloid (HY)? 13.
Scar tissue way out of proportion to the wound.
-Caused by excess type III collagen
-More common in african american
-Classically affects earlobes, face, and upper extremities.
Define the following 1.
Neoplasia Neoplasia is cell growth that is monoclonal(arise from single cell),
unregulated, and irreversible.
-Contrast to hyperplasia (ex – hyperplasia of uterus during childbirth) which is polyclonal and is regulated.
-Desmoplasia Process by which tumor becomes firm (it is because neoplastic cells induce fibroblasts within the stroma to form abundant collagen)
-Carcinoma in site
(aka high-grade dysplasia) - when dysplastic changes involve entire thickness of epithelium (earliest form of epithelial malignancy)
-What are two ways to determining monoclonality? 2.
G6PD or androgen receptor isoforms,
-Ig light chain phenotype for lymphomas.
-How is monoclanity determined from G6PD? 3.
G6PD is a protein with multiple isoforms which is encoded in X-chromosome. Let’s say a female has isoforms A and B in her 2 x chromosomes. Due to random silencing of X-chromosomes, her A:B protein ratio in hyperplasia or normal condition will be 1:1. If the ratio is different from 1:1, it strongly suggests monoclonality.
-How is monoclonality determined from Ig light chain phenotype? 4.
The ratio of K to Lambda light chain is 3:1. If the ratio is different than this, it suggests monoclonality
-What are differences between benign and malignant neoplasm? 6.
Benign neoplasia Malignant neoplasia
Remain localized and do not metastasize
Invade locally and have potential to metastasize (don't have to be already metastasized)
Slow-growing Rapid growing
Distinct Infiltrative
Mobile Fixed to surrounding tissue
Name the lineage of following benign and malignant tumors: 7.
Cell lineage Benign Malignant (cancer)
Epithelium Adenoma Adenocarcinoma
Papilloma Papillary carcinoma
Mesenchyme Lipoma Liposarcoma
Angioma Angiosarcoma
Chondroma Chondrosarcoma
Osteoma Osteosarcoma
Lymphocyte doesn't exist Lymphoma
Melanocyte Nevus (mole) Melanoma (not melanosarcoma)
3.1 Neoplasia
Adenoma = tumor that makes glands
Papilloma = tumor that makes papillary finger like structures What are leading cause of death in adults in children? (HY) 8. Adults Children Cardiovascular disease 1. 1.Accidents Cancer 2. 2.Cancer Cerebrovascular disease 3. 3.Congenital defects
What are leading cancers by incidence and death toll in male and females? 9.
Cancer by incidence Male 1.Prostrate 2.Lung 3.Colorectal Female 1.Breast 2.Lung 3.Colorectal Cancer by death tolls Male 1.Lung 2.Prostrate 3.Colorectal Female 1.Lung 2.Breast 3.Colorectal
Table excludes squamous cell and basal cell carcinoma of skin - very common and malignant but rarely metastasize. Detected early and easily treatable.
-Lung cancer doesn't have easy screening test like others. It's usually detected late.
-What are some properties of neoplasia? 10.
Approximately 30 divisions before earliest symptoms arise (2^30 cells)
-Subsequent divisions results in increased mutations
-Cancers that don't produce symptoms till late (ex-ovarian, pancreatic, lung cancer- because lots of space to expand) will have accumulated tons of mutations and hence poor prognosis
-What area goals of cancer screening? 11.
Catch dysplasia before it becomes carcinoma (dysplasia is reversible)
-Detect carcinoma before clinical symptoms
-Tests Detection
Pap smear -Cervical intraepithelial neoplasia
Mammography -Breast cancer
Ductal carcinoma in-situ
-PSA (prostrate specific antigen) and DRE (digital rectal exam)
Prostrate cancer (usually grow on rectal side and doesn't produce urinary syndrome until late; BPH grows centrally and produce urinary syndrome)
-Hemoccult test and colonoscopy
Colorectal cancer
-Detect blood in stool (hemoccult test)
-What do carcinogens do? -What are examples? 1.
They damage DNA. Ex - chemicals, viruses, radiation.
-What are cancer associations of the following chemicals? (HY) 2.
Chemicals Cancer Remarks
Aflatoxins Hepatocellular carcinoma (most common cancer in some African countries)
- Derived from Aspergillus
flavus; -Usually contaminates stored grains -Alkylating agents Leukemia -Lymphoma -Found in chemotherapy drugs
-Alcohol Squamous cell carcinoma (SCC)of oropharynx and upper esophagus(another risk is tobacco)
-Pancreatic carinoma (EtOH causes chronic pancreatiis that incrases risk of cancer)
-Hepatocellular carcinoma
-Arsenic SCC of skin (women used to apply Arsenic to be fair-skinned) - test Arsenic poisoning from fingernail and hair follicles
-Lung cancer (Arsenic present in cigarettes)
-Angiosarcoma of liver
-Asbestos -Lung cancer (far more likely) and mesothelioma Cigarette -SCC of oropharynx and esophagus
Lung cancer
Kidney and bladder cancer (urithelial carcinoma -cells that line urinary tubes; most IMP risk factor: cigerrate - toxins from smoking in urine irritate the cells) -MOST COMMON CARCINOGENIC WORLDWIDE -Polycyclic hydrocarbons main carcinogen
-Nitrosamine Stomach carcinoma (intestinal type) (other stomach carcinoma is diffuse type but nitrosamine not associated)
- Found in smoked food;
responsible for high stomach cancer in Japan
-Napthylaine -Urothelial carcinoma of bladder Derived from cigarette smoke (excreted by urine)
-Vinyl chloride -Angiosarcoma of liver Occupational exposure
(used to make PVC pipes) -Nickel, chromium, beryllium, or silica Lung cancers - -Occupational exposure
1 Billion people smoke worldwide
-What are ongogenic association of the following viruses? 3.
Virus Cancer type
EBV -Nasopharyngeal carcinoma (Classic pt Chinese male, African person)
-3.2 Carcinogenesis (Part 1)
EBV Nasopharyngeal carcinoma (Classic pt Chinese male, African person) -metastasizes early; classic presentation is neck mass
-Burkitt lymphoma (Classic pt - African kids)
-CNS lymphoma in AIDS
-HHV-8 Kaposi sarcoma (tumor of endothelial cell) (Classic pt - 1. older Eastern european males take tumor out; 2. AIDS pt treat HIV; 3. transplant pt -reduce immunosuppression)
-HBV and HCV -Hepatocellular carcinoma HTLV-1 -Adult T-cell lukemia/lymphoma HPV (type 16,
18, 31, 33)
SCC of anogenital area (vagina, vulva, cervix, anus)
-Adenocarcinoma of cervix
-What are cancer association of ionizing and non-ioninzing radiation? 4.
Radiation type Cancer types MOA
Ionizing (nuclear reactor, radiotherapy) AML -CML
-Papillary thyroid carcinoma (Cherbonyl kids have lots of papillary cancer)
-Generation of hydroxyl free radical
-Nonionizing (UBV from sun most common)
Basal cell carcinoma of skin
-SCC of skin
-Melanoma of skin
-DNA damage (formation of too much pyrimidine dimers to be excised by restriction endonuclease)
-In xeroderma pigmentosum, restriction endonuclease is bad and pt has high risk of BCC, SCC and melanoma of skin
-What is most common cause of ionizing radiation in USA? 5.
2nd most common cause of lung cancer in USA ○
Radon (formed by decay of uranium) - present in soil and accumulates in closed space (basement)
-What are three systems to be disturbed in carcinogenesis? (HY) 1.
Proto-oncogene
-Tumor suppressor genes
-Regulator of apoptosis
-What are protooncogenes and how can they cause cancer? 2.
Proto-oncogenes are essential for regular cell growth and differentiation
-Mutation produces oncogenes that leads to unregulated cell growth
-Protooncogenes
What are examples of protooncogenes? 3.
Growth factors and their receptors
-Signal transducers
-Nuclear regulators (transcription factors)
-Cell cycle regulators (move cell division stuff around in cell)
-Normally, binding of growth factors to its receptor induces signal transduction. In nucleus, cell cycle regulators are activated that induce cycling of cells through G1 S -G2 - M stages of cell division
-What cancer are the following protooncogenes associated with and what's their function and mechanism of causing cancer?
4.
Cancer Function of
protooncogene
MOA of cancer
Growth factor
PDGFB -Astrocytoma Platelet derived
growth factor - Overexpression, autocine loop Growth factor receptors ERBB2 (HER2/neu) Subset of breast cancer - Epidermal growth factor receptor Amplification
RET -MEN2A, MEN2B
Sporadic MTC
-Neural growth factor receptor
Point mutation
KIT Gastrointestinal
stromal tumor
- Stem cell growth
factor receptor
Point mutation
Signal Transducers
RAS gene family -Carcinoma Melanoma -Lymphoma -(Found in ~70% of all cancers)
-GTP-binding protein Point mutation
ABL -CML
Some ALL
-Tyrosine kinase Translocation - t(9,22) with BCR
Nuclear regulators
C-MYC -Burkitt lymphoma Transcription factor T (8,14) involving IgH
3.2 Carcinogenesis (Part 2)
C-MYC -Burkitt lymphoma Transcription factor T (8,14) involving IgH (heavy chain)
N-MYC -Neuroblastoma Transcription factor Amplification
L-MYC Lung carcinoma
(small cell)
- Transcription factor Amplification
Cell-cycle regulators CCND1 (cyclin D1) Mantle cell carcinoma
Cyclin T(11, 14) involving IgH
CDK4 Melanoma Cyclin dependent
kinase
Differentiate benign and malignant neoplasia. 1.
Benign neoplasia Malignant neoplasia
Remain localized and do not metastasize
Invade locally and have potential to metastasize (don't have to be already metastasized)
Slow-growing (years) Rapid growing (weeks/months)
Distinct (well localized, ex - can isolate by breast exam)
Infiltrative (can't distinguish from surrounding breast tissue in physical exam)
Mobile (ex - you can grab a breast tumor and move it around)
Fixed to surrounding tissue
Classification of benign vs malignant requires biopsy
-What are histologic differences of benign and malignant tumor? 2.
Benign neoplasia (well-differentiated) Malignant tumor (poor differentiation) Organized growth
- Disoganized growth (doesn't look like tissue it's
growing in)
-Uniform nuclei
- Nuclear pleomorphism with hyperchromasia (very
dark blue)
-Low nuclear to cytoplasm ratio (more cytoplasm)
- High nuclear to cytoplasm ratio (less cytoplasm, big
nuclei)
-Minimum mitotic activity
- -High mitotic activity
Lack of invasion
- -Invasion
No metastatic potential
-Fig: Follicular thyroid adenoma (left) - note organized cell growth with colloid in between cells, uniform nuclei with lots of cytoplasm, minimum mitotic activity. Anaplastic thryoid carcinoma (right) - disorganized growth (cells look nothing like thyroid), large nuclei:cytoplasm ratio, nuclear pleomorphism, mitotic figure (very dark nuclei cell).
What's the absolute distinguishing feature between benign and malignant tumors? 3.
What's the absolute distinguishing feature between benign and malignant tumors? 3.
Potential to metastasize (benign tumors never metastasize, malignant tumors can metastasize)
-Immunohistochemistry
-Serum tumor markers
-What is intermediate filament? How is immunohistochemistry of intermediate filament helpful in grouping cancer? (HY)
4.
Intermediate filament are a type of cytoskeletal protein; different intermediate filament are present in different cell types.
-Immunohistochemistry of intermediate filament helps in identifying cell types in tumor.
-Cell type Intermediate filament present
Epithelium Keratin
Mesenchyme (connective tissue) VImentin
Muscle Desmin
Neuroglia GFAP
Neurons Neurofilament
What immunohistochemical molecules help identify cancer of following cell types? 5.
Cell type Immunohistochemistry
molecule
Prostrate PSA (prostrate surface antigen)
Breast epithelium ER (estrogen receptor)
Thyroid follicular cells Thyroglobulin
Neuroendocrine cells (small cell cancer of lung and carcinoid tumor)
Chromogranin (HY)
Melanoma S-100
Well differentiated neuroendocrine tumor = carcinoid tumor. Poorly differentiated neuroendocrine tumor = small cell cancer.
-What are serum tumor markers and what's their utility? 6.
They are proteins released by tumors.
-Screening (ex- high PSA) - still need biopsy for diagnosis ○
monitoring response to treatment (ex- PSA should drop after prostrate cancer surgery) ○
recurrence of tumor (ex - same pt returns 2 year later with bone pain; check for PSA to see if it's prostrate cancer again)
○ Useful for
-What does tumor grading of well differentiated and poorly differentiated mean? 7.
Well differentiated - tumor resembles parent tissue - good prognosis
-Poorly differentiated - tumor doesn't resemble parent tissue - poor prognosis
-Look at cellular architecture and nuclear morphology to classify differentiation
-3.5 What are some ways of identifying cell types in tumor?
What's staging of cancer? What's its value? 8.
Staging of cancer is based on size and spread
-It's no. 1 prognostic factor(more important than grade)
-Determined after final resection of tumor
-What's TNM staging of cancer? 9.
T = tumor size and depth (size important for solid organ tumor, and depth important for tubular organs like colon)
-N = spread to regional lymph nodes (2nd most important prognostic factor)
-M = metastasis (no. 1 prognostic factor)
-What are the steps in invasion and spread of tumor? 1.
Downregulation of e-kedherin (e-kedherin is an adhesion molecules that keeps epithelial cells attached to each other)
-Tumor cells attach to laminin in basement membrane
-Tumor cells produce collagenase that destroys collagen 4 in basement mebrane. This helps tumor pass through basement membrane
-Tumor cells bind to fibronectin in extracellular membrane and spread locally. It can now pass to blood vessel or lymphatics.
-How do metastatic cancer spread? 2.
Lymphatic spread is characteristic of carcinomas and less common for sarcoma.
-Hematogenous spread is characteristic of sarcoma and some carcinoma - usually follows venous drainage and seeds at first capillary bed encountered
-Seeding of body cavities - most common is peritoneum (ex - by ovarian carcinoma (omental caking)) but may also occur in the pleural or pericardial cavities, the subarachnoid space, and the joint spaces
-Fig: omental caking by ovarian carcinoma
What are carcinomas that spread hematogenously? 3.
Renal cell carcinoma - renal vein
-Hepatocellular carcinoma - hepatic vein
-Follicular thyroid carcinoma
-Choriocarcinoma (placental cancer - of trophoblast cells - function of placenta is to invade blood vessels)
Chapter 4: Hemostasis and Related
Disorders
Primary hemostasis - make a platelet plug
Secondary hemostasis - make fibrin mesh by coagulation cascade to stabilize platelet plug What are steps of primary hemostasis?
1. Vasoconstriction -Platelet adhesion -Platelet activation -Platelet aggregation
-What causes vasoconstriction? 2.
Vasoconstriction - mediated neurally and chemically. When endothelium is disrupted, endothelial cells secrete endothelin for vasoconstriction. NO and prostacyclin production goes down (they vasodialate).
-Endothelin - powerful vasoconstrictor
-NO and prostacyclin (prostaglandin I2)- vasodialator
-What happens in platelet adhesion? 3.
Platelet adhesion - VWF (von willieband factor) is a glue that binds to exposed collagen in damaged tissue. It then binds to glycoprotein VIII, and then glycoprotein IB (integrin IB) on
platelet. VWF mainly comes from endothelial cells storage unit -Weibel Palade body(HY), but are also found in alpha granules platelets. (another important factor in weibel palade body is P-selectin)
-What happens in platelet activation (aka degranulation)? 4.
thromboxane A2 (very powerful degranulator made by cyclooxygenase (COX)), ○
alpha granules (contain fibrinogen and VWF), ○
delta granules (contain SAC - serotonin for vasoconstriction, ADP which is necessary for expression of GP IIB/IIIA receptor by platelet and stimulates degranulation, and calcium that helps in secondary hemostasis)
○
Platelet changes shape after adhesion and is activated. It secretes
-What happens in platelet aggregation? 5.
A single fibrinogen is linked to multiple platelets via their glycoprotein IIB/IIIA. This creates platelet plug. Platelet plug is weak and needs secondary hemostasis (coagulation cascade) for stabilization.
-What are 2 classification of platelet disorders? 6.
