CELL INJURY: BASIC CONCEPTS Cell injury : Any disease taking place in the human body at a microscopic level is because tissues are not « functioning properly due to cell damage or not able to function properly Causes of cell injury: At the level of cells 1. Physical factor ~ eg. temperature -> too high temperature -» eg. burn injury less than normal ; sub zero temperature + eg. frostbite 2. Exposure to chemicals 3. Exposure to infections 4. Genetic ~ MC cause of cel! injury at the level of cells is Hypoxia ~ Hypoxia -+ (Hypo ~ less, Oxia~ oxygen) when a cell is having less oxygen with it for purpose of utilization, that is called as Hypoxia a LU ~ 0 diffuse from alveoli into blood. in blood, there are RECs which contains Hb inside them. Hb combines with O* available from diffusion process and forms oxyhaemoglobin. This oxyhaemoglobin goes into different cells or tissues and utilize this O°. ~ 4 coramon causes of Hypoxia ~ 4. Hypoxie type Hoh altitudes pulronary disease 2. Anemie Hp Anemia Non functional Hb Eg. (a) CO poisoning (COHb) (b) MetHe (Fe® Fe) 3. Stagnant hypoxia + Ischemia 7 Congestion 4. Histotoxie Hypoxia+ Cytochrome LO cyanide - MC Cause of hypoxia is ischemiainjurious agent = injurious agent x —_t —, Cell injury ft Reversible Irreversible ‘ Cell Death Severity of injury is affected by - . 1. Duration 2. Nature of cell Sensitivity of cell in body to any kind of injury : Neuron > Cardiac tissue > Skeletal Muscle (Most sensitive cell) Fibre Fibre > Fibroblast (most resistant cell) D vn souscueREVERSIBLE CELL INJURY = 10" + Mitochondria affected -+ 1ATP 4 : Affects ~ Parts or functions of the cells which are mainly energy consuming or energy dependent + 1. Cell membrane 2. Endoplasmic reticulum 3B. Nucleus 4 Cell membrane -+ 2x LATP = | Activity of pump + 1 Na’ inside cell @ 4 nat 1 water inside i ; v Cellular swelling z (£ microscopic feature) . cet Suells op - When cell swells up, additional changes seen are : + Loss of microvilli «Swelling up of organelles «Myelin figures - are small é spiral Fragments derivéd either from cell membrane or membrane of organelles. Myelin figures are made up of phospholipids. ~Sometimes cellular swelling is mentioned by the tera hydropie change 2. ER + Normally ribosomes on surface protein synthesis LATP energy Ribosomes break away ~ 1 protein synthesis accompanied by less formation of secondary and tertiary structure of proteins 3. Nucleus + 102 -» T Glycolysis +1 pyruvate 1 Acidosis 1 lactate- ne 6 + ome Curing, Appearance of Cpateng deposition Nudeus Of, eromatin makrial) = Clumping of chromatin is only nuclear change associated with reversible cell injury= More inside - More Na’ outside ~ More Ca” ~ Mechanism of irreversible cell injury ~ Hypoxia 4.402 + ATP + Energy dependent Ca pumps fats ie t1Ca’ 11. Ene ation Deposition a mitchondi ATPases / nucleases (mitochondrial densities) Phospholipase 4 Lysosomal enzymes Dysfunctional mitochondria Cell Death ~ Nucleases + Pyknosis ~ Karyorhexis a ~ Karyolysis e Figknosis Q-— @ Karyorhexis : ila & Karyolysis Necrosis CSmeor pattern) - Normal cell - single dark hand nucleic material is unbroken - Necrosed cell - diffuse staining nucleic material unbroken & pattern is given k/as smear patternae ~ Phospholipase activation = Phospholipase activation ‘ = Cell membrane damage 1g. Cardiac cell (intracellular enzyme i. Troponin) Reversible cell injury irreversible cell injury 4 ‘ ~ cell becomes bigger ~ cell becomes bigger = no membrane damage ~ membrane damage ~ enzymes won't leak out ——_- enzyme present in cardiac cell will leak out = enzyme level normal ~ increased enzyme level = Angina -Mi NECROSIS = Cell death - changes -» necrosis ~ subtypes 4. Coagulative necrosis ~ tissue will be having firm appearance + denaturation or inactivation of hydrolytic enzymes + most common subtype of necrosis that we observe in the tissue + most common cause of coagulative necrosis is ischemia in solid organs leading to formation of localized area k/as infarcts sZenker's degeneration - enteric fever / typhoid Coagulative necrosis in skeletal muscle is is commonly followed by neutrophilic infiltration is is associated with "tombstone appearance” 2 Liquefactive necrosis / Colliquative necrosis ° Hydrolytic enzymes 4 Damage to tissue architecture = cause of ischemic injury to brain = pus formation DR. SPARSH GUPTA3. Caseous necrosis : Cheese like necrotic material - -™% = Systemic fungal infections (histoplasmosis) ~ coag necrosis + liquefactive necrosis 4. FAT necrosis = fat / lipases ~ injury to omentum tissue ~ injury to breast tissue - Acute pancreatitis 4 Gallstones / Alcohol ‘ Lipase activation Lipa fatty acids 4 Ca2+ Yellow like + saponification chalk like deposits 5. Fibrinoid necrosis = Vessel wall injury Immune complex (type 3 hypersensitivity reaction) 4 : . (42 Damage to plasma protein in the vessel wall o 4 Inside the vessel wall deposition of plasma protein ~ Malignant hypertension - Aschoff body = Ischemia + secondary infection = Ischemia = Lower limb involvement - Bowel ~ liquefactive necrosis ~ Coagulative necrosis = higher chances of bacterimia, purification ~ both dey & wet gangrene scan in diabetes mellitus=Programmed cell death 1 Controlled by genes = Single cell = Small group of cells ~ Physiological or pathological Genes a) Q ~ ps3 gene ~ BCL - 2 gene ~ bea-xs gene ~ BCL - XL gene * Glucocorticoid + 1 * Sex hormone — 1 PHYSIOLOGICAL embryogenesis F515 & f > uf +— k ThC-S000 TLE15009 —Tic-5000 endometrium P — estrogen S + Prog. MENSESPATHOLOGICAL Retinitis pigmentosa t t Rods cones 1 t Diva light Day light Apoptosis of rods + night blindness * Viral infection 1 Councilman body PATHWAYS OF APOPTOSIS Intrinsic pathway SH/ 1 GF +1 BCL 2 activity BCL 2 replaced by BAK /BAX 4 T mitochondrial permeability t 1 cyto 'C in the cytoplasm 1 1 activity of APAF - 2 1 LmownaenInitiator 1 activity of CASPASE 9/10 1 Executioner stimulate (CASPASES 3/6/7) 1 Activity of + Proteases + endonucleases 1 Cell death Extrinsic pathway Severe damage -+ FAS - L or TNE vey 7 TNF @/eAS FADD (ONY ange Caspase - -8 wl A ofa te 3.8 Death eSHmulate Apeptesi ‘Ckp \adder Nomal P a paton) ‘ell Apoptosis Neots mea pattern Flipping 2 Annexin V + 4 of apoptosis Annexin AZ ~ Hairy cell leukemia (oc eot apoptotic al No Inflammation Di orsursncumaNECROPTOSIS + Characteristics + Programmed cell death “. Carpase independent cell death Important for pathogenesis of conditions like free fo Caspase. Radicals ectvetion * Parkinsonism. { * Pancreatitis + Fighting infections like CMV -+ Carpase inhibitor so {O[tipds Gell dents PYROPTOSIS: Caupate, Ini eg cel dest + Pyro means pyrexia or fever + Caused by bacterial infection —» associated with formation of multi molecular complex inside WBC known as Inflammasome formation 4 Caspase 1 & 42 4 IL-1 formation 4 fever FREE RADICAL INJURY + Free radiedl injury :~ unpaired electron in its structure + Highly reactive molecules + Associated with - Radiation ~ Reperfusion injury ~ Heavy metal injury (Cu/Fe) ~ Infections Fe2+ Fe3+ Fenton's reaction $0, 0, + HO > On Hydrogen] (HYDROXYL RADICAL) L Peroxide 1 Free radical fp LaddJ causes Damage to DNA/P/lipids 1 Auto-catalytic reaction 4 Cell Death © Most dangerous free radical - hydroxyl radical © Damage from free radicals can be prevented by :- Antioxidants Antioxidants 2) Vitamin A/C/E 2) Plasma proteins Transferrin (Fe) Cerruloplasmin (cu) 3) Enzymes 0, ~ 0, ———*,,_H,0, + OH sop Glutathione /( gsh \ Catalase peroxidase — gs-sq HO HO 2) Superoxide dismutase 2) Catalase 3) Glutathione peroxidase f 5 DR. SPARSH GUPTASUBTYPES OF APAPTATION. 3) Atrophy —e'A’ means absent “trophy. means growth = atrophy means | in number + 4 in size of cell or tissues = reasons for atrophy -+ protein degradation 4 Proteins are attached to ubiquitin 4 They get available for proteasome (a part of cell) 4 Proteasome destroy the proteins ~ in short, ubiquitin attached proteins are going to be destroyed by proteasome = Atrophy can be seen as a physiological as well as pathological change Example -» (A) PHYSIOLOGICAL () Atrophy of notochord (i) Atrophy of ductus arteriosus ~ it is a structure present in fetal life and not required after baby is born. So cells in this gets destroyed. (B) PATHOLOGICAL () Malnutrition -» babies suffering from this have lower weight as comparison to other age related babies (ii) Disuse Atrophy -+ patient suffering from the fracture of forearm bones, a plaster cast is tied to heal the bones but patient is asked to exercising his hand muscles to keep blood supply normal, No usage of thenar and hypothenar muscles of hand over a period of time will undergo shrinkage and decrease in size. To avoid this movement of muscles are advised to done and is a part of physiotherapy regimen (iil) Senile Atrophy -+ - Due to old age, gradual deposition of lipids on blood vessels ~ Cerebral artery in brain is going to develop atherosclerosis 4 Blood supply to brain is going to decrease causing deficiency of Ach.1 Meyernet Nucleus 4 — Loss of memory (reason) Neurons contain Senile Dementia Acteylcholine (Alzheimer’s Disease) “ 4 memory (iv) Pressure Atrophy- obstruction at urinary outflow level 4 More urine gets accumulated inside the kidney i Compression of the cortical part of the kidney 4 Cortical part undergoes atrophy So absence of growth of cells, either decrease in number or size of cells leads to atrophy New concept regarding atrophy -» Earlier it was considered as totally benign condition, but now it is considered that in some conditions, it is a premalignant condition. Premalignant condition 4 Endometrial cancer -+ (usually elder patients) Type 2 Type 2 4 4 t estrogen (females have endometrial (suffer from endometrial atrophy) hyperplasia) = patients have p53 gene mutation 4 Increases the risk of type 2 endometrial carcinoma 2Hypertrophy ——t"hyper" means excessive "Trophy" means growth DR. SPARSH GUPTA= It is an t in the size of individual cells 4 Over synthesis of structural proteins ~"This can be an example of physiological as well as pathological condition Example -» (A) PHYSIOLOGICAL (0) pregnancy -+ t in the size of cells of uterus and breast (ii) Puberty (ii) Bodybuilders + when they go to gym, pump iron or lift heavy weight 1 1 stress on the skeletal muscle fibres 4 Skeletal cell are permanent, do not multiply 4 That is why stress cause in t of size of cells (E_PATHOLOGICAL @ Cardiac patients + Particularly hypertension (i?) Stricture presence -» Narrowing of lumen and intestine : 4 Area prior to it undergo hypertrophy Heart pumps into aorta 4 Pressure in left ventricle is more than the pressure in the aorta 4 In case of HTN, LV have to exert more force 4 Over time, LV gets hypertrophy 4 Risk of cardiac failure B. Hyperplasia "hyper" means increase “*plasia’ means number ~ It means t no of cells = Can be a physiological change [BPrepLadderExample -» Physiological (D pregnancy (ii) puberty (involvement of uterus and breast tissue in both condition) (B) Pathologi¢al () Endometrial hyperplasia (pre-cancerous condition) 4 Females having this have high risk of endornetrial carcinoma She should be followed Up IF she develops it, To prevent endometrial it should be detected at earliest carcinoma i (i) Prostatic Hyperplasia (Benign prostatic hyperplasia) + Androgen dependent condition | ~ Testosterone is not responsible for BPH 1 Sa Reductase Di - hydro testosterone (DHT) . t in no of cells 4 Clinical syrnptoms of patient [elderly man presenting with delayed micturition, problems with starting the stream, stream is not |_of proper strength, he can not control it going washroom again & again 4 + in the size of prostate ~ This BPH takes place around the urethra zone ~ Periurethral zone enlarges 4 ~ If prostate in this area gets enlarged 4 it will compress the urethraIt is important to know because of two reasons: (il) BPH is not @ risk Factor (0 if patients symptoms are seen for the development of Ca with the help of DHT 4 Relief can be provided’ to patient by Decreasing the concentration of DHT By giving Finasteride to inhibit enzyme Sa reductase prostate as this is a benign condition 4 Reduces size of prostate in elderly male patients and provide symptomatic relief ~ So hyperplasia may or may not be a precancerous condition like atrophy which may or may not be a precancerous condition (4) Metaplasia concentration & hemosiderin = Prussian Blue-> Purple granules Perls Reaction = Hemochromatosis~ more presence of hemosiderin granules = tron deficiency anemia- concentration of hemosiderin in bone marrow reduces LIPOFUSCIN / LIPO CHROME/ FREE RADICAL INJURY PIGMENT = Brown Colored Pigment ~ Perinuclear = Shows lipid peroxidation with free radical injury \ conditions associated with intracellular deposition of lipofuscin: | Ke Protein energy malnutrition Cancer Aging ~ Wear and tear pigment = Brown in atrophy Various theories of aging: 2) Collagen eross linking 2). Free Radial injury- most accepted theory 3). DNA damage / defect in enzyme DNA helicase 4), Telomere shortening Certain disorders in aging:~ D Werner syndrome- DNA helicase defect (:. OF pre- mature aging) 4 DNA damage Sirturins- new set of modecules 1 Alter DNA ‘ ASe free radial damage 4 4Se in insulin resistance (in diabetes) 4 15es lifespan [Bppreptadder2). factors to increase sirtuins in body +12). {Calorie intake 2). Red wine consumption regularly CALCIFICATION Deposition of calcium Calcification Dasivophds Tak 7 Metastatic People with normal calcemia Hyper calcernia Ca deposited in dead /degenerated tissue 1 Deposited. in living tissue Egs:- (R/A/T) gs: 2) Tubereulosis of lymph node 2) Parathyroid Horvacne 2) Cardiac valves in condition Rheumatic 2) Vitarain D Heart disease 2) Parathyroid Horraone t p. Adenoma 3) Atherosclerosis cRE 4). Tumors 2) Vitamin D intoxication m— Meningioma 1 O-) Papilary Cancer Ovaries Granulomatous Disease s-\ salivary glands 1 1/ Thyroid {-€ OH enzyme 4 increased calcitriol Psammoma bodies 3) Milk Alkali <———> Syndrome 4) Metastasis { Osteolysis eas Ca” intracellulary -> Mitochondria * Ca deposit in organs eee, Lungs aatr soma Sage Blood Vessels (Cormonest) (Systemic arteries and pulmonary Veins) "Cas deposition directly will not affect Parathyroid gland PHARMOLOGICAL RELATION WITH CALCIUM Ca* -> Tetracycline (Radio- Labeled) Bone remodeling [ipPrepLadderBASIC CONCEPTS AND VASCULAR CHANGES OF ACTE INFLAMMATION INJURY, 4 RESPONSE OF BODY CHANGES IN BLOOD VESSELS CHANGES IN CELLS CLASSIFICATION INFLAMMATION Aarte Inflammation Chronic Inflammation + at Short Duration Long Duration -Neutrophils = Monornuclear W8Cs Lymphocytes and monocytes. ACUTE INFLAMMATION VASCULAR CHANGES 2) Vasoconstriction -> 1% changes 2) Vasodilation 4 Hyperemia -> Redness (Rubor) increased temperature (Color) 3) Inereased vascular permeability Seo ermal C&ndethekah = eens, Ffisa 4 tnloncn isthe Na) | “Inuessed ” cons | Permeability= Increased Permeability of [- Fluids ExUpATE —{ - Cells 4 |___ - Proteins SWELLING (Tumor) = Most common mechanism associated with increased vascular permeability is endothelial cell contraction. = M/C -» endothelial cell contraction. 4 Arteriole/ capillary / post Capillary Verules (Commonest vessel involved) = In Normal Vessels ~ Extravascular fluid in extra vascular space 4 Drained by Lymphaties 4 Injury increased permeability of cells, proteins. 4 Increased in lymphatic Flow 4 Sometimes bacteria and toxins also going to enter inside lymphatic + Lymphangitis ’) EC Contraction 4 Immediate transient response ii) EC DAMAGE -> Delayed prolonged response / leakage | 4) STASIS Dilated vessel 4 Leakage of fluid rich in protein de cells to outside Y brewed yous —? | : Concentration of blood inside the vessel increases 1 OR, SPARSH GUPTABlood will become viscous 4 Decreased blood flow 1 Stasis (Reduction in the velocity of the blood) VIRCHOW's TRIAD - Associated with thrombus formation. = 3 Components ec Inpry Aneated Change Vn Coagutatit eed fo Vicenon's “Fried ord * Stasis * Turbulence = Inflanimation is prothrombotic stage. ‘Summary: 4 vascular changes 4 Vasoconstriction 4 Vasodilation 4 increased permeability 4 Stasis [jPreptadderCellular changes ina normal situation WGC + all the cells move in Centre of blood vessel Fluid move in periphery So as to mininsize the cells move in the Centre resistance to low of blood If bacteria tnt in intravascular Space - Easy to kill If bacteria tnt in extravascular Space - WBC's -> periphery 4 Speed fix themselves WBC intravascular ' Extra vascular + Come to bacteria & kill Cellular Changes . intravascular Changes Extravascular changes 2 pop 70. 12 intravascular Changes Sialyl ~ Lewis — ? ? ever 2) Margination-> WBC's move to periphery 2) Rolling -> WEC's roll over speed breaker. [ Selections are tnt Complementary molecules tnt on Surface of WBC-> Sialyl- Lewis- \ Ns Responsible for the process of loose adhesion‘ 1 Velocity of movement of WBC 4 Rolling Selectins -> = ESelectin _( Endothelial Cells) -PSelectin (Endothelial Cells); Platelets =LSelectin (Leucocyte) WEIBEL PALADE Body-> an intracellular body tnt on endothelial cells Contains .willebrand factor + Selectins La © e 3 _-e O7OT79, 3 22 3) Adhesion ~ Integrin tnt on surface of WBC ~ Molecule interacting with integrin- Adhesion molecules ICAM / VCAM Example of firm adhesion Integrin made up of -> CDLLA /LFA 4) Transmigration across the border movement Intravascular -> Extravascular-> Diapedesis Depends on CD31 molecule (PECAM) Molecule WBC -> Collagenase (Facilitate movement of WBC from Blood Vessel) Leucocyte adhesion disorders (LAD) LADI LAD It ~Seen in pt. ~ Seen usually because of problem in selectin molecule / Who are having receptor (Sialyl-Lewis x) Malfunctioning of DR. SPARSH GUPTAIntegrin (LFA /CDIl) LADI H/0 delayed separation of umbilical lord : ro Fr oe 3 oo nis coe * (Comany cep 4) Orme Stach wee, CoO a Developing RBC Fucosyle (T) (+) H molecule is attached to cell surface 4 Additional molecules can attach themselves to surface of RBCs ~> blood group A => blood group B If A chain is attached B chain ASB chain Recurrent Infection is common finding LAD It * Fucosyl transferase enzyme defect * Rarest blood group-> Gorbay blood Group Fucosyle (1) (+) = No H Antigen + Bombay blood group 4 Rarest blood group —> AB» Universal recipient No A & B only -> O -» Universal donar (can't be given to ) H antigen is tat bombay blood group Blood transfusion reaction occursEXTRA VASCULAR CELLULAR CHANGES & APPLIED ASPECTS |_. CHEMOTAXIS:- Chemo -Chemicals taxis-slow = Undirectional movements of white blood ces towards bacteria ~ Chemical responsible for interaction are bacterical products ~ Other factors: Cn 2) IL-8 (Interleukin-8) Endogenous Molecules 3) LTB, (Leukotriene B,) ~ Steroids inhibits the process of chemotaxis LEUCOCYTE ACTIVATION:~ _——— + Multiple components are there F je 6 a)Recognition of target cell Pe Lewocyte Paton + wee Microbes 4 4 + Mannose <-> Mannose Scavanger R <-> Some complementary particles 6 b) Engulfment: Intake of bacteria by WBF + Pseudopod formation 7 _ 1 _ (Actin polymerisation) + Opsoniztaion -- Bacteria tastier (Opsonins) Preferential eating up of the Bacteria eg + Ffragment of 1,G + Ob + Fibrinogen/ C-RP eg: Immunodeficiency disorder B Celt ‘ J 4 Immature. ———_—_——+ Mature———+ Plasma ——# Ig Beell Tyrosinkinase BCell Cell_Bruton's disease + X linked recessive disorder + Bell defect + Hypogamma Globulinemnia ‘ 4 4 AGB Blood Defective opsonization C-R, ~ C ~ reactive peptide 4 Cachohydrate Ag Preumococcus + Killing of bacteria: : Lh Siatein Lagpeieene lyst protein 1 Defect 4 Chediak Higeshi Syndrome vis Chediak-Higeshi Syndrome + Recurrent infections + 4 Melanin ~ albinism + Myelin — neurological manifestation + Platelets defects — bleeding manifestation + CNS involvement neurological defects + Increased risk of Hemorrhage + Dec inamnunity + Albinison SEE ESnneeneeeeeenenne + Peripheral smear — presence of giant granules inside the cellsee, OXYGEN INDEPENDENT KILLING AND - NEUTROPHIL EXTRACELL OXYGEN INDEPENDENT KILLING Most efficient bacterial mechanism ~ CATHELICIDIN ~ LYSOZYMES (Physiological secretions) ~ LACTOFERRIN ~ MAJOR BASIC PROTEIN -+ in cosinophils ~ damage to parasites Neutrophil Extracellular Trap (NET) 2. Normal neutrophils, bacteria surrounding it * 4 captures bacteria Pseudopod formation : ‘ # Destroy it * 2 Bacterial load high ~ in sepsis J cytokines t Platelet activation Chromatin 4 NET formation ~ Chromatin has high concentration of antimicrobial substances ~ Bacteria gets trapped and destroyed - killing of bacteria ~ killing of WBC 3. Nuclear antigen exposure 4 ANTI NUCLEAR ANTIBODY 1 T AUTOIMMUNE DISORDERS 1 NET — SLE Systemic lupus erythematosus FBjpreptadderPREFORMED CELLULAR CHEMICAL MEDIATORS CHEMICAL MEDIATORS CELLULAR MEDIATOR : PLASMA MEDIATOR - 1 ~ Histamine - Nitric oxide - KININ SYSTEM ~ Serotonin = Cytokines = coagulation / CLOTTING SYSTEM| = Hydrosomal enzyme | - Arachidonic acid metabolites | - COMPLEMENT SYSTEM CELLULAR PREFORMED MEDIATOR 2. Histamine Source + mast cell / basophils / platelets 1 Richest source Function -> 1. Vasodilation 2. Increase in vascular permeability 3. Itching 4. Bronchospasm exten (tc) S ye ® 1. IgE cross linking pone 2. Physical -» temperature @ 3. Vinuses 4, Anaphylatoxins * eg. of Anaphylatoxins BEE VENOM * Compliment proteins (C3a / C4a / C5a) * Drugs + Morphine / a~ TC / Vancomycin - LV. -> slow {f Vancomycin 4 Rapidly given ‘ Fad man radeon BjpreptadderacSerotonin /. 5 - HT (hydroxy tryptarmine) Source ~* GIT / Platelet / CNS ‘ (ENTEROCHROMAFFIN CELLS) Maximum amount of serotonin Function + Action same as histamine + vasodilation in small vessels — vasoconstriction in large vessels 3. Lysosomal Enayme 4 Killing of bacteria (by mechanism called respiratory beret) f 5 DR. SPARSH GUPTANITRIC OXIDE Chemical mediators produced right at the time of inflammation, FRESHLY FORMED CHEMICAL MEDIATORS 2. NITRIC OXIDE (NO) _ L - arginine Nitric oxide Synthase (NO) (NOS) 4 | t5es action of guanylyl cyclase 4 te GMP + ‘Smooth muscle relaxation t vasodilation NO free radicals (peroxynitrite) : + Killing of bacteria > Has 3 isoforms = eNOS - present in endothelial cells [ = iNOS = inducible form / inflammation = nNOS ~ neurons - NO 1 GMP - vasodilation PDE -V (phosphodiesterase - V) Ss GMP Young Male + impotency _tcGMP. Vasodilation (inhibition OF PDE -V) ~ VIAGRA sildenafil (inhibits PDE - vy Causes vasodilationARACHIDONIC ACID METABOLITES ~ 2nd group of mediators = Cell membrane - PHOSPHOLIPIDS (inflammation) | phospholipase A, ARACHIDONIC ACID (20 carbon fatty acids) cyclooxygenase (COX) PGG2 smite PGH, + Rate limiting enzyme : PHOSPHOLIPASE A, Pg I, / Prostacyclin PQD/E/F, TA, Platelet inhibitory 1 1 Molecule Clubbed PG * thromboxane A, + endothelial cells - pain * Platelets or + derangement Blood vessels in functioning of = Ise in platelets aggregation Dual action hypothalamus ~ vasoconstriction 1. Vasodilation ~ opposite action to Pgl, 2. Platelet inhibition Elevation in body ~ (balance in inflaramation) Temperature (PYREXIAXE,) balance is going to be ~ T vascular permeability tilted Pharmacology link Excessive inflammatory response 1 C/E 1 ANTI INFLAMMATORY DRUGS 1 Inhibition of phospholipase A, + STEROIDS OR Inhibition of COX ~ (NSAIDS)COX enzyme | ~ Predominant type = endothelial cells ~ Stomach : - produced at time of ~ Platelets inflammation * PG in stomach protective for gastric wnucosal chances of gastritis NSAIDS (both have anti inflarnmatory action) Inhibit COX 1 / COX 2 Inhibits only COX 2 1 1 NON SELECTIVE "SELECTIVE COX COX INHIBITORS INHIBITORS (no effect on protective gastric ‘Mucosal Pgs) Side effect of non selective COX inhibitors — effect on protective prostaglandins = 1 in visk of gastritis Selective COX inhibitors + given to patient with H/o gastritis NON SELECTIVE COX INHIBITORS ~ inhibits COX 2 in platelets 1 4 formation of thromboxane A, inhibits COX 2 in endothelial cells 4 Lin formation of Pl, ~ they maintain the balance Don ssunsvcurSELECTIVE COX INHIBITORS ~inhibits COX 2 enzyme present in endothelial cells only “+ COX 1 enzyme not inhibited + concentration of prostacyclin 1ses + effect on THA, - Tse + tse in visk of myocardial infarction ~+ avoided in pts with H/o CAD, thromboembolic event, family history, elderly ARACHIDONIC ACID ,_ cot See 1049 PGs leukotriene A, 7 THA, (LTA) (IG MOLECULE ~ Lt, LTC, /D./ E, | Chemotaxis - acts on LT receptors | very powerful BRONCHOSPASM * SRS -A (slow reacting substance Anaphylaxis) STEROIDS — 1 formation of arachidonic acid, ZILEUTON _- inhibition of phospholipase LTA, [ 5 - lipoxygenase inhibitor LT receptor blocker. ~ blocking leukotriene receptors Antagonist (montelukast) Inhibition of _Comensme 4 11 LTS 4 bronchospasm Asthma like symptoms [DRUG INDUCED ASTHMA] 4 NSAIDS3% PATHWAY A 1 22-LOX [22-lipoxygenase] Lipoxins (AA metabolite) 1 Anti inflammatory (DO NOT CAUSE INFLAMMATION) Pathogenesis of CAS disease AD - long standing inflammatory condition L AA + Fish oils (omega 3,6 fatty acids) (1 formation of (414 Formation of inflammatory mediators) Inflammatory t Chemicals ttt) 4CAD 4 DR. SPARSH GUPTACYTOKINES -» Peptide molecules = cell Types: ~ INTERLEUKINS 7 TNFa =JNTERFERONS ~ Cytokines are PLEIOTROPIC in nature (one cytokine have 4 action) = Cytokines has redundancy property (4 cytokines cause single action) ACTION:= [— LOCAL EFFECT + EC / FIBROBLAST L_ SYSTEMIC EFFECT IL-1. = sites + brain IL-6 > bone marrow L-a + liver [Jin appetite central action twp | ~~ [t COX -+ C/F = Fever ] + when cytokine acting of bone marrow - 2. tt Tle 2. DIC Certain situation with t white blood cells + 1 N Action on liver te TE ~ Acute phase reactantsESR - Erthrocytesedementation Rate ESR & Fibrinogen Concentration @ Example of condition of having nearly zero ESR ~ AFIGRINOGENEMIA PYBOGENIC CYTOKINES:~ Fever — exogenous + Bacterial Toxins endogenous: Foiled / IL 6 / TNFa CNTF + any change in temperature of body as high body temperature cause elimination of several virus OXYGEN Dissociation Curve > 02» WBC -+ Resp. Burst =+ Systemic inflammatory response syndrome ~ SIRS Criteria» > 2 out of 2.RR>24/ min 2. HR > 90 / min 3. TLC (> 12000 / ml) (< 4000 / ml) ( 10% band cells) 4. Temp (9 38°C ; < 36°C) =» SEPSIS:- SIRS + documented infection + Identified by new marker 4 C-RP/ PRO - calcitonin LINE A= 414 severe suppression of appetite + CACHEXIA + CANCER CHRONIC STATE_|TNF a has been given as [CACHECTIN] + Majority of cytokines -» inflanumnation 4 Except Anti inflammatory Cytokines = IL-10 IL-6 + TGE-B + IL-4 > ADIPONECTIN IL 2+ MC systemic effect of inflammation 1L.2~ autocrine; tT cells IL 4 B cell prolip / Differentiation IL 5+ 8 cell prolip / Differentiation IL 6 > systemic effect of inflammation IL 7 + B/T cells 4 SCID (severe combined immunodeficiency disease) IL 22 - t platelets IL 3 + proliferation of hematopoietic cells IL 40 - anti inflammatory action INTERFERONS -> (IFN) SOURCE USES a + [L (leucocyté)| > Anti viral mcs =| F (fibroblast)| > multiple sclerosis y Lr eellsy_} +» Macrophage activation + Chronic gran diseases (tract)PLASMA CHEMICAL MEDIATORS (KININ SYSTEM) PLASMA + Kinin System Inj to BV Xil—>x lla | Pre-kallikrein—> kallikrein Kininogen—> Bradykinin Actions = T venular perms ~ pain - vasodilation ~ lung + spasm Bradykinin ANg | Kininase ACE Metabolite ANgIl 1 1 BP ACEQ~ 1 BP 1 1 Bradykinin ~ -[dry cough] ~ angioedema©) 20 Proteins + Immunity + Regulation of normal function 7 ot Cee ~o, : Co Oucssia® — Igela Ga © Car GiGlala [Pack | Crass oe ee Gees M = Membrane ~-Gaord) A - Attack C - Complex 1a Ag damage Normal - 1 infections *C/CSC. ( Early proteins) 2 T Autoimmune diseases ( SLE) “Cc, « Severe pyogenic infections *C/C/CSC, (late C proteins) © T Neisseria + 1 Toxoplasmosis °C, ——> No disease (BopreptadderREGULATORY C PROTEINS 4. C, Inhibitor 6, SINE activated C,tp C syst. C, INH. deficieneg ttt C activation t release Of Cu. / Cu t Hereditary angioedema 2F Dom + Edema [oral mucosa / larynx / GIT] +Non pitting edema 2.€D,,/ Factor B / Factor H | teont. Ale. pathway Defect L, +++ € system 1 EC damage 1 Atypical hemolytic uremic syndrome ) (=) 4 S Jee pnoe platters + ew pameptoperta Ceronyma} Nechernal M6 urin) C., + Anaphylatoxin “+ opsonization *C,, + Anaphylatoxin = chemotoxin *C,,~ formation of MAC 1 Cu.) Ag destructionCLOTTING SYSTEM. COAGULATION CASCADE INTRINSIC EXTRINSIC BV injury tissue factor - xt —> Xia ws vita xt —> Xla x, Ka at Ss. @ X Gyr xa 8 Prothrombin ==> thrombin Fibrinogen —> fibrin Fibrinogen + fibrin (soluble) (insoluble) Fibrinogen - opsonisation < Thrombin + chemotaxis Hemophilia +1 bleeding wos B-4 tc - a2 < Prothrombin time (PT) aPTT (activated partial thromboplastin time) «Platelet Free plasma + Room temperature «Within 2 hes ‘Additive + PT 1 | Tissue thromboplastin aPTT ~ kaolin / silica Plastic tube / syringes——— 4 . J Extrinsic pathway Intrinsic pathway CP Vat K for adtivation ¥ Carboayb” inting factor 7/4/30 & tentcottngprttns protein c/s Glaarnati, 1 Ca, + 1 Clotting 1 Blood Banks ACD ~ Acid citrate dextrose 21d *CPD - A cit. PO+ dextrose adenine 35d +SAGM + saline adenine glucose mannitol 42d Cit / Pot Citrate + 4 Ca,. +4 clottingINTRODUCTION = Ongoing Inflammation ~ Associated with tissue destruction -> HALLMARK FEATURE = Repair or healing by body : == Longer duration-» Mononuclear WBC'S required : 4 ‘Monocytes / Lymphocytes - Chemokines [~_ @ Chemokines -> IL-8 b Chemokines -> MCP/Eotaxin 1 Chemokines -> Lynphotaxin = IL-8 -> Neutrophils = MCP/ Eotaxin -» Monocytes / Eosinophils = Lymphotaxin -> Lymphocytes —>» Acute inflammation -> L Chemokines predominate - Lifespan of macrophage very large ~ Lifespan of monocytes may be 2-2 days = Macrophages present in 4 ~ kidney — Mesangial cell om ~ Liver ~ kuppfer cell + - Brain - Microglia ~ Bone — Osteoclast Morosiass Monocyre MACROPHAGE ~ Spleen — Littoral cell ~ Tissues / organs like Placenta — Hoff bauer cell = Inflammation due to presence of granuloma Granuloma formation seen in :~ ~ Tuberculosis — - Inflannmatory Bowel disease ~ Sarcoidosis = Syphilis ~ Vaseulitis = Malaria ~ Cat seratch disease [Bppreptadder— Se = CASEATING GRANULOMA seen in T.B - NON CASEATING GRANULOMA seen in sarcoidosis = GUMMA lesions seen in syphilis (7 DURCK GRANULOMA seen in Malaria = STELLATE GRANULOMA seen cat scratch disease Inflammatory Bowel disease CROHN'S DISEASE ULCERATIVE COLITIS (Granuloma formation) = Vasculitis -» GRANULOMATOUS VASCULITIS _—_ Egs, OF Grains Vasculitis / Say Temporal Arteritis Takayasu Arteritis Churg Strauss Syndrome —— Granulomatosis: With Polyangiltis EPITHELOID CELLS Macrophages 4 Activation + Epitheloid Cells + Epitheloid cells not same as epithelial cells = Derivation of macrophages, produced | - Normal cel lining epithelium, lining by activation body cavity as protective function ~ Present in granuloma - Round nucleus Slipper shaped nucleus ~ perform phagocytosis Cannot perform phagocytosis Have secretory function GIANT CELL formation GIANT CELL:- Fusion of activated macrophages Subtypes of Giant Cell: 2) Langhans cell ST) Languas ees @ ~ Nuclei in periphery in horse shoe pattern = Seen in Tuberculosis ~ Don't confuse with langerhans cell present in skin having secretory function|2) Foreign body giant cell = Nuclei in haphazard pattern . = Been in non-absorable sutures /TALC(chroni¢ inflammatory conditions) — Foreiqn GBooy Giant Cew 3) Warthin ~ Finkeldey cell ~ intra-viral inclusions present = Seen in viral infections - measles —? Woaetnn Finre ney Cel 4) OWL-EYE APPEARANCE/ REED-STERNBERG CELL ~ Two prominent nuclei like mirroe images of each other showing OWL~EYE = Reed Sternberg cell seen in hodgkins lymphoma H > Ow EXE APPEARANCE One Reap STERNBERG CELL 7 5) Touton cell = nuclei present = fatty droplets present giving foamy cytoplasm appearance ~ seen in Xanthoma patients 4 Tousen Ce) — XANTHOMA Dow snesncaWOUND HEALING - Day Finding ° - Blood clot - Blood clot + neutrophilic infiltration 2 - Blood clot + neutrophilic infiltration + thin epitheliuns layer 3 - Granulation tissue Macrophages + fibrous tissue + angiogenesis as - Granulation tissue + 1Collagen deposition (type-tl) 14 - t1Collagen deposition + fibrous tissue Collagen IN gets degraded + MMP 1 Depends on Zn* Wound caused because of a sharp object PRIMARY UNION: = Sharp injury ~ Edges are wound are close to each other - | Loss of Connective tissue ~ Body heals more rapidly Wound caused because of a blunt object SECONDARY UNION - Blunt object ~ Edges of wound are rough = Sear formation ~ Scar is made up of fibroblast ~ Due to influence of chemicals Fibroblast -> Myofibroblast t Can contract Size of sear 4 ‘ Scar contraction Or Wound contractionDelayed wound healing = Foreign body presence = Immunodeficiency ~ Persistance of infections ~ diabetes mellitus = drugs -» steroids = Radiation exposure EXCESSIVE HEALING / ABNORMAL HEALING ~ Keloid formation -» Extragranulation tissue grows beyond margins - Hypertrophic Scar -> Extragranulation grows vertically within margins ~ In proliferation of fibroblast -> steroids ~ keloid is present over skin overlying the sternum & can also be present in the ear lobes ~ Inside the lesion steroid injection is given 4 4Size J smensonINTRODUCTION TO IMMUNITY IMMUNITY INNATE ADAPTIVE * Non- Specific + Specific No Memory * Memory (+) INNATE IMMUNITY-> BARRIERS —2) Barriers ‘Anatomical -> Skin Physiological-> Secretions like sweat, Saliva, tears. 2) Protein Molecules ~C-Reactive Protein/ Lectin / Compliment Proteins / surfactant in lungs. 3) Cells-» Neutrophils / macrophages / NK Cells or natural Killer cells * NK Cell -> Prominent example of innate lymphoid cells. ~> Responsible for recognition of viruses infected cells / mutated cells or cancer cells. BACTERIA-> PAMP (Pathogen associated molecular Pattern) + ~ Required for infectivity of bacteria INFLAMMATION-> DAMP (Damage associated molecular Pattern) PATTERN REGOGNITION RECEPTORS + Present on surface of immune cells + Identify PAMP and DAMP molecules Example “ie Crype ue e-Kg* EN Fra] [inflarmmasome, CASPASE (Bacteria / + kK / uric acid ) ROS B-cells Effective against extra T-cells => Effective against intra + cellular organisms like bacteria 4 cellular microbes e.g. viruses. Ig Secration Cellular immunity ‘ Humoral Immunity [PreptadderT.CELL © Developing in the Thymus © Present in . are = Lymph node (Para cortex) = Spleen (PALS- Periarteriolar Lymphoid sheath) Pant T maveeee, =~ GIT (Intra- epithelial lymphocytes) 7 Do %6 STRUCTURE: a cB 1 >) £149] monee 2 Molecules T-cell receptor co Present a CD molecules + CD 2G...,., Cbuoe on surface + T-cell receptor:~ Physiological function (comes in contact of antigen) + T cell never gets activated by free antigen =. CD molecules:~ useful for identification of -» CD1|2|3|4|5]7|8 T-cell + Additional molecules:~ CD28...CD40L * PAN-T-MARKER:-CD3 + Co-stimulatory Signal:~ CD28 Treell ———_ €D, T-cell (Helper) CD, T-cell (Cytotoxic) Subtypes: TH, -> Type IV HR ¥ IL-2] IFN ganna + TH, -> Type | HR Las + TH,,-» IL-27 (Fungi, Autoimmune disorders)Immune Cells- Natural killer. Cell Lymphocytes-> * Denved from precursor cell called as HSC (Hematopoietic Stem Cell) HSC-> Lymphoid stem cell - i y — ‘ T-Cell ; B-cell NK Cell (Thymus) (Bone Marrow) Natural killer cells-> «Most important example of Innate Lymphoid cells (ILCs) + ILCS-> They secrete T-cell like cytokines eg Interferon gamma but they have not having T-cell receptor. #NK cell was earlier given name of large granular Lymphocyte (LGL) + One of the very important defense mechanisms of body to fright virus infected cells and to take care against cancer cells/ Tumor cells. ae stv ® 5 Ae in @ens — (GRE Cs eo + All normal cells in the body are going to be having an expression of molecule on its surface which is called as MHC-I molecule. + Property of MHC-I molecule is it is not only present on the surface of all normal cells but this is going to be having its interaction with the inhibitory receptor. «If normal cells of body gets infected with virus or mutated, a new molecule is expressed on surface of mutated cell and going to activate the stimulating receptor NK cells stimulated and attack the cancerous or mutated cell Sea" *NK calls have presence of certain . molecules on their surface CD26 and CD56 cou(&®) co one Se 9 q «When there is attachment of antigen on the antibody, Inmmunoglobulin G is going to attaching itself to CD16 molecule. When Fe component of the Immunoglobulin interact with CD16 molecule, it activates Nk-cell. Then NK-cell destroy the antibody coated Ag. This kind of destruction of the antigenic cell by presence of coated antibody given the name ADCC (Antibody Dependent Cell Medicated Cytotoxicity)BASIC CONCEPT + IMMUNE SYSTEM ACTIVATION Infectious organisms Infectious organisms - ‘ 4 intact epithelial barrier epithelial barriers are not intact 1 4 No infection Ag enters the body out / oo | phagocytosed by Antigen presenting cell edie ls [1 | breakdown in different peptides 7 Antigenic peptide expressed on APC moves into circulation Teell ran | complementory receptor Cegjere Effector mney < Memory + -Lst step entry of pathogenic molecule into body + 2nd step phagocytosis of pathogenic molecule by APC + 3rd step expression of Ag peptide on APC & moves into circulation + 4th step - APC - affects T cell & activates immune system APC ~ + Process the antigens & bring them to T cell receptor MHC molecule - pathogenic Ag is expressed ~ different T cell activation is dependent on MHC molecule MHC4 = MHC2 —! t fl . | eA, cor cor = | “Bre i‘Types of APC's 0) Professional APC (+++MHC) i) dendritic cell - skin interstitial tissue also known as langerhars cell i) B - cells ii) Macrophages 4) Non professional APC (+MHC) } Fibroblast ii) Endothelial cells i) Thymic epithelial cells Ag > APC - surface LesTine SeynehL Extemal antigen - signal 2 + co-stimulatory signal Self antigen - signal 2 only ‘ T cell Anergy [non activation of T cell] + Co stimulatory signal @— Cd28 (activation of T-cell) OQ CTA = 4 (self antigens & inhibit the activation of T cell) PD-2RHI PATIBI + Group of genes present on chromosome number 6 + Aka HLA (Human leukocyte antigen complex) 4 + located on short arm of chromosome 6p UA B c DP DQ-R y')_) im Date) D 4 + + = MHC | molecules Eg = MHC Il molecule ~ present on nucleated -6,10,./@ 4 Cells ~ TNF -@ All antigen presenting cell ~ on surface of platelets - 240 OHase Professional ACPs Non professional ACPs 1 | ‘ Examples Examples ~ Dendritic ~ Fibroblast ~ Bells ~ Endothelial cells ~ Macrophages ~ Thymic epithelial cells MHC I * MHC Ii } 4 \ activation of CD, T cells i a+) BY" . Aes & Biloanaiseram, Activation of CD, T cells 4 tele 4 tied Vieaetinn + CD, T cells are always double the number of CD, T cells 2:4» CD,: CD, + CD, T cell are MHC Il restricted cells * CD, T cell are MHC | restricted cells (BpPrepLadder* Detection of MHC 1 - Allo antiserum Detection of MHC I! ~ mixed L reaction 4) Establishment of genetic association of genes: Examples : > -HLA DR, / DR, ( A/W type 3 DM) + -HLA B,, (A/W ankylosing spondylitis) 2) Organ transplantation : + Gene matching or MHC/HLA matching + Matching of gene is detected by "Tissue typing’ Mixed L reaction Mierotoxicity Assay 3) Paternity disputesTYPE | HYPERSENSITIVITY REACTIONS: : 0 At * Anaphylactic type 4 a 2 * namediate 7} iu elemmediate type " poe gel OE = al ~ First exposure D “ 2. whenever there is any breach + antigen enters inside body 2. Captured by APC antigen presenting cell 4 taken into Circulation 3. TH2 cell responsible for secretion of IL-4, IL-5,IL-13 4, II-#, IL43 ~ causes an t in no. of eosinophils 5.IL-5 - formation of IgE 6. Stage of sensitization (first exposure) 7. Mast cells with attachment of IgE antibody (modified mast cell) 2nd / repeat exposure of antigen * Antigen-Ab reaction on surface of mast cells 4 Degranulation and activation of mast cells beeper + “ _7 tee) Pree] rathaae, cheaters, —s FF creme Release of chemical mediators (histamines, PGs, LTS) + Early phase of elinical symptom * Cytokines ~ responsible for late phase of clinical symptoms % Tet THe ILA 13 ~ Clinical symptoms: 1. Histamines & PGs - —Vasodilation 2. Histamines & LTS - Bronchospasm 3. Histamines - Itching 4. Cytokines = Whole process of inflammationTupeLHR Examples: 17Asthma 2. Allergy Food allergy Dermatitis Rhinitis Atopy - when genes are responsible for causing allergy (genetic predisposition for causing Type | HR) Chromosome 6p (location) 3. Exposure to drugs - Antibiotics ~ penicillin 4 can precipitate Anaphylactic Shock 4 DOC (adrenaline) * adrenaline reverses the action of anaphylactic shock 0.5 ml / IM ‘4. Insect bites 5. Casoni's test - done to diagnose the infection caused by echinococcus which causes hydatid cyst disease * Hydatid cyst disease + cystic masses in different organs of body, most commonly hepatic tissue Followed by pulmonary tissue 6. Prausnitz - Kustner reaction A+ Atopy B + Bronchial Asthma C -» Casoni's test D > Drugs 4 DR. SPARSH GUPTA,TYPE JIHR (CYTOLYTIC HR) A) Opsonization followed by phagocytosis [classical finding n type I! HR - formation of antibody against fixed tissue antigen] © Gfx OD “poser agg) 194 08 ADCC - Antibody dependent cell mediated cytotoxicity 3g) -2-+©) system xb Membrane attack complex (MAC) NN Ag destroyed Important in: + Rh incompatibility + Blood transfusion reaction + Autoimmune - haemolytic anemia - thrombocytopenia B) Complement Activation (inflammation) Ag + Ab formation + © activation + C,a (chemotactic molecules) 1 Influx of WBCs (neutrophils and macrophages) ‘ Secretion of inflammatory chemicals ‘ Tissue darnage Examples : - Acute rheumatic fever ~ Good pasture syndrome - ANCA - mediated vasculitis (Prepadder+ Rheumatic fever : Short throat - 4 Caused by bacteria 4 Strep. Pyogenes M protein Cardiac (structure similar with tissue glycoprotein) Joint Ns iSkin + Infection induces activation ~ release of enzyme - tissue damage of immune system + A/W molecular mimicry’ + © Antibody induced tissue dysfunction Examples : Myasthenia gravis + formation of autoantibody against receptors + Muscle weakness = Ab contribution to tissue dysfunction + Grave's ds + Pernicious anconia 9 ah + insulin(®)diabetes Neve (@® —? Ab y—* Ach Myasthenia gravis Blood transfusion reaction good pasture syndrome, grave's ds immune haemolytic anemia, thrombocytopenia Rheumatic fever hyperacute transplant rejection PA, pemph. Vulgaris ~ 3 4 DR. SPARSH GUPTATYPE til, HR TYPE Ill, HR / Immune Complex Disease = *Ab formation -> (Ag) Pathogenesis:- Ag Entry 1 Ab formation 1 Ag-Ab Complex formation |~ PHASE | 1 Deposition in Organs ~ PHASE I (Lymph Node/ Skin/ Kidney/ Serosa/ Small blood vessels) 1 * Tissue Damage by 2. Ag-Ab Complex formation -> Direct injury to endothelial cells I Thrombus formation in small vessels 1 Ischemic Damage 2Activation of complement system in any organ which are having deposition 1 Release of chemicals like C,,, Chamotatic Chemicals 1 Increased Permeability 1 More Influx of WBC like neutrophills & macrophages 1 More release of chemical mediators of inflammation 1 Tissue Damage 1 Clinical SymptomsComparison of type Ill. & type | HR TYPE lll. HR TYPE |. HR Time of onset+ Ag = C/E appear with in short span of tine ' " (40-44 Days) mw cor Nature of Antibody *1gG, IgM that can activate complement system + IgE Complement system activation t Serum C, decreases + Decreased Serum C, level in blood (C3 Hypocomplementeria) Is an evidence that a patient is having active phase of immune complex disease + Examples of inumune Complex Disease S -> serum Sickness / SLE H -> Henoch-Schonlein Purpura (HSP) A -> Arthus Reaction R -> Reactive Arthritis P -» Post streptococcal glomerulonephritis (PSGN), Poly arthritis Nodosa (PAN)TYPE IV HR «cell medicated HR DELAYED TYPE HR 2" exposure ~ TH, cell -» modified TH, cell | 2 exposure - Ag -> APC -> TH2, cell (manwaary) ‘ 1 Activation 1 = IL-2/ I-L 42 - Interferon~ ganama = Lymphotaxin 1 Formation of Granuloma CONDITION OF DELAYED HR R i bh Rheumatoid Arthritis ™ —> Multiple Sclerosis Chandra —> Contact Dermatitis Is —> IBD PSORIATIC —> Psoriasis DIABETIC —> DM (I) & TB —> Tuberculosis (Mantoux test) €D,T.CELL ACTIVATION Target cell —» CD, T Cell Jl 4 v PERFORIN-GRANZYME M4) FAS-L v ¥ (+) CASPASE FAS > CELL DEATH < . T-Cell - Virus infected / cancer cell ~ Graft Rejection Moped TH,Cell GRANULOMATOLERANCE = It is reduced response of immune system to any kind of antigen Self tolerance = It is reduced response of immune system to self antigens ~ Reasons why the immune system is not going to be reacting in case of self antigens can be because —_ of two important Factors: —Central tolerance ™ 4. Deletion £ negative selection = Organs are central lymphoid organs = Tolerance taking place in thymus and bone marrow = We will have deletion or selective selection. of B and T cells which are self reactive * Clinical Significance _ - T cells ave negatively selected because Of the gene called as autoimmune Regulatory gene ~ Alteration in this gene, self reactive T and activated are going to persists causing autoimmune Polyendocrinopathy 2. Receptor Editing =A cell whose receptor identifies a self antigen ‘ Antigens will come into contact with receptor ' The body will change the shape of receptor Editing the shape of receptor ‘ Jit will not recognize the self antigen ~ This is taking place importantly in Beells Peripheral tolerance = Sometimes circulatory B or T calls enter into peripheral circulation 2 Anergy ~ functional decrease in response (i) expression of self antigen + causing an interaction b/w CTLA - 4 and PD 1 molecule 4 they will not allow T cells to move in a forward direction and activated (ii) reduced interaction b/w B7 molecule and CD28 molecule + Teell anergy (iit) | interaction b/w CD40 and CD40-ligand 4 B cell aneray 2. Tregulatory Cells 4 CD24 T cells (high motels expression) cpas Foxp3 Secretion of IL-10 / TgF- + Induce activity of CTLA~4 and PD-1 + 4 in activation of immune cells ~ physiologically, the T regulatory cells are important for the acceptance ofFetus at the time of pregnancy Pathologically, T regulatory cells have Functioning problem, they cause v CD25 functioning Problem Foxp3 defect ‘ ‘ CD25 defect IPEX syndrome ’ (immune dysregulation t risk of multiple Sclerosis polyendocrinopathy enteropathy X-linked syndrowne) 3. Apoptosis of self reactive B/T cells By FAS molecule 1 expressionlof FAS molecule Interaction with its FAS-ligand Activation of éxtrinsie pathway of apoptosis Self reactive B/T cells are getting destroyed * if there is a defect in this mechanism B/T cells are not destroyed Cause autoimmune proliferative syndrome (ALPs) 4. Antigen sequestration (to hide) ~ IF antigens are sequestered, they will never come into contact with inmune system 4 They will activate the immune systern = Example of organs + immune privileged sites ‘ B - Brain E - Eye T - testis = Importance -» injury / Trauma ‘ Antigens hidden, now come out into systemic circulation 4 Activation of immune system ‘ Autoimmune disorder ~ Eg. traumatic injury in one eye 4 cular antigens come into systemic circulation 4 Activate immune system We find damagé to both eyes DR. SPARSH GUPTAAuto-Immune Disorders Introduction ~ Immune System of body activates against itself in Autoimmune disorders. That can be because of: (0. Genetic Factors -> (a) Failure of Tolerance (0) HLA-Genes -> eg HLA-B 27 ( Ankylosing spondylitis) (c) Non-HLA Genes -> eg PTPN-22/ NOD-2/ IL-2 ~> PTPN-22. — Causes abnormal lymphocyte activation and proliferation-> increase risk of AID ~ NOD-2 ~ Any kind of disregulation of the functioning of this gene because of polymorphism is going to result in abnormal activation of immune System which could be contributing mechanism for the development of inflammatory bowel disease. IL-2® - is responsible for controlling no. of T-Regulatory cells (I). Infections ~> (a) — Increase Co-stimulatory signals (APC) (6) ~ Molecular mimicry — is applicable in development of Condition Rheumatic Fever (©) ~ Polyclonal B cell Activation — Multiple groups of B cells get activated. Out of 4 group of B cells, + particular group of cells acquire spontaneous mutation -> Produce auto antibodies (8) (B) (8) {8} = _ Auto-Ab -> increase risk of AID ¢g : EBV, HIV (D) Spread of Cryptic Epitopes- Cardiac Tissue —““*"_ Darnage + Inflammation + Surrounding one areas get exposed - When Infections present for long duration, these are resporsible for maintaining, low levels of IL-2. 1 Required for maintainence of TReg cells ~ When there is too much hygiene i.e. have no Infections-> Extremely less Formation of IL-2 -> Low percentage of T regulatory cells -> increase risk of Auto immune disorders. This paradoxical concept is known as Hygiene Hypothesis. AL Miscellancous-> a. Release of Sequest. Ag b. Exposure to Sunlight (UV light) ¢. Explosure to drugs like sulphonamide, Hydralazine, Isoniazid, Procainamide d. Hormones (Auto immune disorders are MC in females because of role of estrogen and progesterone in the pathogenesis of this kind of condition) [BbPreptadderAuto immune Disorders SLE :~ Blood + organs In these | patients Auto-Ab(+) |causes damage to blood cells (e.g - TYPE 2 HR) ‘Type 3 Hypersensitivity Reaction (HR) “227d - Also associated with HLA-DQ genes ~ UV associated with exposure to -Rays ~ Associated with Drugs. (like sulphonamide) ~ Presevice of Certain type of infections Certain Infections => NETs - © Protein Def (C4/ C2/ C4) ane ibe clinically => MD SOAP BRAIN Malar Rash Discoid Rash Serositis Arthritis Blood-> Auto-Ab Oral Uleer Renal System Photosensitivity Anti-nuclear Antibodies Immunological defects Neurological Manifestation ~ IF person have > 4 out 11 essentially required to make diagnosis for SLE ~~ Organ involved Oral cavity:- Presence of Pain less ulcers ~ Joints:~ Non- Erosive Arthritis ~ Skin:- Presence of Rash at Bridge of Nose, Extending to Mallar region. ("Butterfly Rash") This type of rash increases (UV-Rays) ~ Pulmonary tisswe-> Pleuritis called as shrinking lung Syndrome - Kidneys -> GN (Development of Glomerular Nephritis) >it is type 4 GN also called Diffuse Proliferative GN J This is most common sub type of GN seen in patient suffering from SLE ~>Wire-loop like structure= Cardia Tissue > 1) Pericarditis - Most common 2) Endocarditis 1 Known as LIBMAN SACK ENDOCARDITIS (Lower surface endocarditis) IF SLE -> LSE SPLEEN => Blood vessels have "Onion skin appearance" concentric rings Antibodies Auto-Abi- ANA - Most Sensitive (Anti-Nuclear Antibody) [ Anti-smith Ab Highly Specific Antibody for SLE diagnosis L_ Anti-DS DNA Antibody J Anti-RoAb |- Neonated Lupus 1 [CHB] (Congenital Heart Block) “Associated with Subacute cutaneous Lupus Antibody:- Anti-@Ab -> Psychosis More common Neurological Manifestation seen in Antibody Anti-B, gp . Ab :- seen in 9 (Repro) ~ This Patient has Recurrent Abortion. ? ~ Induces Prothrombotie State [High risk of DVT / HVT / Stroke] APLA Syndrome (Anti-Phospholipid Antibody) (Also named) ca 2 (Unknovm cause) (Known cause) -> Most common condition Associated with 2° APLA is SLE ~ Anti-B, gp has Ab 2 Additional significances:~ Responsible for causing elevation of aPTT (invitro) ~>This kind of antibody react with CARDIOLIPIN Ag. >This used in VDRL +f antibody react with cardioli in Ag and results & VDRL (+) ~>VDRL. test performed in Syphilis L DR. SPARSH GUPTA~> IF Pt do mot have sexually transmitted disease called -> [False + VDRL] Diagnosis for APLA:= dRWT = Detection of Auto-Ab LECELL + (N)/(M) (may be Neutrophil or Macrophage) 1 (seen in vitro) = Contains Presence of damaged or injured cells called LE cells ‘Tneatment:- Administration of Steroids Drug induced Lupus S/H/I/P S = Sulphonamides H - Hydralazine History of these drugs intake 1 = Isoniazids P - Procainamide = These Pt are not having involvement of Kidney & Brain For diagnosis of such Patients: - No involvement of Kidney & Brain ~ Detection of Anti-Histone Ab(+) ~ History of S/H /1/ P Reason of Developing such Condition:~ These Patient develop such Because of :~ HLA DRE DRE [BprreptadierOther Autoimmune Disorder SJOGREN SYNDROME:~ » Lacrimal gland ; | Lympho. infiltration Salivary gland | 1‘ Fibrosis DRY EYES / DRY MOUTH Sieca Syndrome -> 2° -> * rheumatoid arthritis LB: 1) Auto- Ab)» ANA(+) Oe ANTI= (RO) Ab SS-A ANTI-La Ab $5-B + ~ Vasculitis ~ Renal inflammation = Longer duration 2) LipB. ‘ toc Sjogren Syndrome 4 1 Marginal zone lymphoma SYSTEMIC SCLEROSIS. (SCLERODERMA) * t FIBROUS TISSUE DEPOSITION Skin, Organs * Linear scleroderma (MORPHEA) Hard Skin Organ (-) * Limited scleroderma Initial => Blood Vessel 7 Forearm 4 Raynaud's disease [ Finger Skin Face 4 Later Stage -» Organs ~ Associated with late visceral involvement C- CaleinosisR- Raynaud's Pr Tale E- esophageal Dysmotility S- selerodactyly T- Telangiectasia Crest Syndrome i anti- centromere Al{+) * Diffuse Scleroderma * Skin « organs ] early involvement * Esophagus -» dysphagia * GIT-» Malabsorption * Cardiac fibrosis * Lungs, Kidney (Most common cause of death in diffuse Scleroderma pt. is pulmonary disease) * anti- (D)NA [to]poisomerase + Ab) anti-SCl-70Ab+) + diff. Scleroderma Total organ involvement * Ana (+) * Anti- RNA polymerase {Il Ab * Acute onset * Renal (selero. Crisis) * Cancer MISSED CONNECTIVE TISSUE PISEASE:- ‘ SLE |Selerosis| Sjogren syndrome ‘ Anti-4, RNP (+) Ab => Renal involvement is less common -> Steroid admin. yields better response Dermatomyositis:-> Derma -> Skin Myo -> Musles S-> supporting blood vessels - eter gastric cancerSkin Museles * heliotrope rash * Proximal muscles * gottron papules Distal mus. Antibodies -> ANA (+) Anti- Jot Ab (+) -> Pt. will be having mechanic hands Additional Antibodies~ Anti-M: 2 Ab(+) Lg skineee ~Anti-@iss Ab (+5 ] -» ®ara neoplasm Anti p40 Ab (+) (Juvenile variant) B,-> dermatomyositis * Perimysial infla. cD, T-cells * Perifascicular atrophy Polyruositis * Skeletal muscle invol. Present * Skin not involved 8,-> endomysial inflammation t €D, T-cells CD, Cells CD, T cell A + i Skin Muscles Female -> Plasma cells + T-cells (Tissues) + 1g G4 * Idiopathic retroperitoneal (F) * Riedel thyroi * Mikuliez syndrome * Autoimmune pancreatitis R-> drug of choice rituximab BPreptadder| ieee GRAFT / TRANSPLANT 7% > Host | Host ane a aan Groft Vs» Host achvotion Diseese Transplant (qvao) Regek ” GRAFT REJECTION Immune System activation Direct Pathway Indirect Pathway 1 1 Donor APC Host APC 1 1 Host T-cell (+) Host T-cells (+) 1 4 Cd, T-cells CD, T-cells cD, T-cells Macro phage -Tubulitis Ab (+) mediated Inflammation Activation _-Endotheliitis damage SUBTYPES OF TRANSPLANT REJECTION 2) Hyper Acute Transplant Rejection : -> (minutes to hours) ~ because of preformed AbO * Multiparous female * Previous Recipient * Previous Blood Transfusion ~ Preformed Ab —» graft vessel t = EC Injury + thrombus formation = Neutrophilic infiltration ~ It is an example of type 2 HR. ~ Graft Rejection occurs within minutes to hours 2) Acute transplant Rejection = It is an example of type 2+4 HR =~ Transplant is rejected within Days to week+ _2 components Acute Humoral Rejection Acute Cellular Rejection 1 Ab y Ag Direct Pathway 1 (+) Complement System €D/ cD, T-cells 4 1 C, deposition * cerebellar infiltration / Tubulitis 1 * Endothelitis Damage to glomeruli & Vessel Damage 3) Chronie graft Rejection ~ Graft rejected in many months to years. ~ It is an exavaple of type 2 HR + 4HR Chronic humoral Rejection Chronic Cellular Rejection ! 1 Ab(+) CD, T-cell (+) 1 1 Graft vascularity Inflaramation - Mononuclear infiltration - — Glomerulopathy = Internal Fibrosis/ Tubular Atrophy DECREASED RISK OF REJECTORY * HLA- matching - HLA - ala|e -HLA-ORB2 — Mostly used - HLA- DQ ~ Transplantation in Adults — 6|8 alleles should match. ~ At the level of DRBI-> chances of rejection are more. -> CORD BLOOD SAMPLING: > HLA AlB|DRes. = 4/6 Alleles should match * On the basis of source 1) Auto graft-> Self 2) Allograft -> Different Person some species 3) Isograft-> Identical twins 4) Xenograft-> Different species * Drugs-> T-cell activation most common reason for rejection. 4) Decrease inflammation-> Steroids 4 cRSnsnGuem2) Decrease Lymphocyte Proliferation-» MMF (Mycophenolate Mofetil) 3) Decrease T-cell activation-» Tacrolimus 4) IM. Ig # (0) cell (+) Ab (+) 4 Plasma pheresis -> Decrease in number of T-cell -> Post transplant lymphoma are example B-cell lymphoraa.rr — RUNT DISEASES (in animal) HoST a T? = Transplant in the body of host start attacking the body of host Host=> Immuno compromised Graft/ transplant -> Immuno competent Eg. - Hematopoietic Stem cells = Solid organ transplant (liver) = Un irradiated blood transplant a Acute GVST (<100 days) Chronic GVST (2200 days) S- Skin-> RASH ~ Dermal fibrosis {+ Intestine -> Blood Diarrhea ~ Stricture Formation L- Liver-> Jaundice ~ Cholestasis jaundice - Peruritus = Thymic Abnormalities GRAFT -> Leukemia cells (destruction of cancer cells) Graft V, Leukemia Effect ~> Invadiate the pt. -> immuno compromised + Transplant Immuno completent cells 4 GVL GraftIMMUNOPEFICIENCY DISORDERS Inamunodeficiency disorders Primary Secondary or = Congenital Acquired + Leucocytes f- Complement proteins + Lymphocytes Leucocytes Disorder 1) Leucocyte adhesion disorders Ye -+ defect (LAD) in adhesion -» tsed or repeated attacks of infections 2) CHS - CHEDIAK - HIGASHI SYNDROME ~ defect in lysosomes transfer protein 3) Chronic Granulomatous disease (CGD) ~ deficiency of NADPH oxidase 4) Myeloperoxidase (MPO) deficiency Complement Protein Defects tsed risk of infections Lymphocytes B Cell Tell 4. DI - GEORGE SYNDROME Chromosome . 22q » TBX 1 gene defect (long arm) 4 Failure of 3rd / 4th pharyngeal pouch ‘ Thymus, parathyroid gland formation cardiac tissue, big blood vessels - component of 224 I deletion syndrome, has multiple variants ~ 2nd variant - velo-cardio-facial syndrome Manifestation - CATCH 22, C+ Congenital cardiac defects A Abnormal facies T+ T cell defect C+ Cleft lip / palate H+ Hypocalcemia 22 + Chromosome 224 I 2. Bruton's Disease / x-linked agammaglobulinemia ~ B cell defect, x linked “Boys >>> girls EBpPrepLadder= BIK defect B cell tyrosine kinase (required for Formation adequate B cells) = 4sed B cells -— 4 Plasma cells —t 4 in antibodies = absence of antibodies in blood 46 cells - Cortical area of LN, splenic tissue 4 Underdeveloped = B cells required for figuring against external organisms (extracellular organisms) -ulg oe opsonization 14 -» 1sed risk of infections Clinical Manifestation = Only after 6 months -+ maternal antibodies get depleted lg = tsed risk of infections preumococcus / H. influenzae IgA - enterovirus (polio) / Giardia (mal -absorption) Not to LIVE POLIO VACCINE ~ ¢ paralytic poliomyelitis Be given|__ECHO VIRUS -+ ¢ encephalitis C fi i cv 2 important ~Beell malnutrition ctor required % BAPE ICOS (inducible co-simulation) ‘ 4 T cell activation - B cell maturation defects ~ Concentration of Igs in blood | repeated attacks of SINO-PULMONARY infections C tsed Bacterial / viruses/ giardia Differences from Bruton's Disease: 4) Childhood / Adolescence 2) Not x-linked, equal predilection (female = male) 3) B cell number is normal, (problem in maturation) 4) Hyperplastic areas Ag ———> B cell number ttt but are not able to differentiate 4 localisation of B cells hyperplastic CVID patients increased risk of ~ Autoimmune disease + Rheumatoid Arthritis (RA) = t cancers (lymphoid, stomach cancer) 4. IgA deficieney - we ig deficiency ~ tsed respiratory infections / GIT /Uro-genital mucosa 4 DR. SPARSH GUPTA- 2 problems High vriskof High risk of auto immune disorders Allergies + 4 SLE /RA Blood transfusion 4 IgA (Foreign antigen) Anaphylaxis TH IGAL MQG, / Ge 5. Hyper IgM syndrome ~ B cell is responsible for activation of T cell ~ Bell, T cell interaction due to CD40 | . k = = Complementary molecule CD40L TOT —A7eey ~ This interaction leads to seeretion of cytokines IL-4, IL-5 bc coe CDMOL ~ First antibody produced is gM later Ig G/A/E ~ known as class switching / isotype switching (interaction b/w CD40 and CD40L) ~ Hyper IgM syndrome -» defect in CD40 or CD40L class switching does not take place 4 Predominant antibody is |gM tt gM ———> awe reacts with 4 opsonisation | blood cells ~ Autoimmune hemolytic anemia - Thrombocytopenia Bacterial infections, ~ Leucopenia fungal preumocystis jirovecii ~ It is X- linked (CD40L) >>> autosomal recessive (CD40) 6. Severe Combined Immunodeficiency Disease (SCID) ~ B cell /T cell requires certain molecules and enzymes ~ Causes DEFECT IN CYTOKINE ENZYME DEFICIENCY RECEPTOR - Adenosine deaminase ~ x-linked variant ~ Autosomal recessive condition ~ Problem in functioning of Gavarna chain unit Adenosine deaminase ~ Metabolism of deoxyadenosine ~ Accumulation of metabolic deoxyadenosine4 Toxic for T-lymphocytes Cytokine receptor = Important for functioning IL-7 / IL-5 required for functioning of Nk cells = IL-7 - trouble with activity of T cell JIL-7 /IL-25 + 4 NK celll activity (natural killer) 4 T cell activity = B cells do not have decrease in their number = Tells required Pilg = Both T cell and B cell are defective B cell - extracellular organisms - t Bacterial infections T cell + intracellular organisms -+ viral infections / t fungal infections = Poor prognosis = Pt. to be kept in sterile environment = SCID, early example of diseases for which successful GENE therapy completed 7. X-linked Lymphoproliferative Syndrome - SLAM protein - Surface lymphocyte activation molecule 4 J activation of B cell / T cell / NK cell 4 4 EBV clearance Fulminant infectious +B cell tumors mononucleosis - Direct problem with SLAM or with associated protein 2. Ataxia telangiectasia = Multiple findings > Ataxia > Vascular malformations > Neurological Deficits = | immunity + t tumors Gene -» Chromosal 11 AT™ protein» DNA damage sensor i Activation of ps3 gene 4 Activation of apoptosis - Also effects class switching process ~ Acquisition f mutations, t tumors, proper antibody synthesis does not take place normglly, high risk of inumuno deficiency DR. SPARSH GUPTAWISKOTT - ALDRICH SYNDROME = WASE gene -» X chromosome 4 ‘parm ~ Classical triad Recurrent infections 4Platelets. Eczema = Change in antibody profile “Woe Might -lA > normal / t -We >t ~ peripheral swear : small size platelets Secondary Immunodeficiency Disorders Causes Infections +» HIV Protein energy malnutrition (PEM) Malignancy / Metastasis 4 spleen function [BjPreptadderAMYLOIDOSIS - Group of condition -> extracellular fibrillar protein deposition t ~~ Organomegaly - Pressure atrophy of adjacent cells = Normal protein-> 2°/3° -> functions In case of situation where protein happens to be misfolded de can be destroyed < Intracellulary via proteasome Extracellulary via macrophage ~ Causes<—Overproduction - misfolding 11 ‘Altered | Mutated - misfolding 11 ~ Eg. Transthyretin (TTR) [Transport of thyroid protein] Overproductionof TTR Mutated TTR 4 4 sentile systemic Familial amyloidotic amyloidosis Poly neuropathy - Amyloid: fihrethary protein 45% cases made up of P component in 5% individuals. = Non branching fibrils Classification. Generalized Locialized Hereditary = Primary amyloidosis — Plasma cell dyscrasias = Normal plasma cell-> Ig secretion If their alteration of plasma cell abnormal anti body production will be there is over production of light chains of antibody leading to formation of amyloid. = Chemical nature — AL Amyloid Light (Chain) ~ Most common 2. Secondary Amyloidosis —— Chronic inflammation (RA|TB) None (hodgkin's Iymphoma renal cell carcinoma) ~ Etiology cytokines -> [they will act on liver] (IL-2 / IL-6) t 11 SAA Protein [BpPreptadder~ Chemical nature of amyloid:- AA (Amyloid Astociated protein) Eg of chronic inflammatory condition familial mediterrnean fever: (PYRIN)-> Fever +Serositis Re-> Colehicine Eg: Chronic renal failure 1 Dialysis 1 11 B,- Microglobulin protein CKD-> AB, 2Locelized Eg- 4. Alzheimer's disease a - — Chr.22 - APP =X 1 Amyloid Precursor Protein ate B-Palque Trisomy u 2: Neuronal damage uy Dementia 2. Medullary thyroid cancer 'C' cells-> Calcitonin tt ot t Chefnical Nature - A Cal ‘3. DM- type 2 1 IAPP/ Amylin. AIAPP 3. Hereditary:— * Familial MED. Fever:~ (chemical nature AA) * FAM.AMYLOID. Polyneuropathy Chemical nature ATTR Mutated TTR Senile Systemic Amyloidosis -» ATTR normal TTR Organs:- going to involved are 4. Cardiae-» 1° Amyloidosis aM, - Arrhythmia ~ Restrictive cardiomyopathy L DR. SPARSH GUPTA2. kidneys: ~ Most commonly affected & most severely affected. = Mesangium ~ increased kidney size (Begins with in) 3. Hepatic tissue-> 111 in size => space of disse “ Spleen Sinusés = SS olicles (Red pulp) (white pulp) 1 1 Lardaceous Spleen Sago Spleen 5. Joints 1-> Knee Wrist -> CTS (carpal tunnel syndrome) 6. Skin -> Amyloid deposition in perivascular area 1 Pinch purpura 7. Gl tract-> Tongue 111 4 Oral Mucosa ~> Biopsy Rectal Abdominal fat aspiration Diagnosis:- 1. Microscopie examination by using staining a. Congo reds— Normal light — pink red appearance \ pears microscope - Apple green birefringen b. PAS ¢. TWioflavin T SS : 2. Electron microscopy non- Branching fibrils 3. Spectroscopy - X-Ray ~ Crystallography] B plated structure 4. tmmunostaining 5. Scintigraphy Radiolabelled Serum amyloid P J Amyloid 6. Gross Specimen- enlarged size & waxy appearance lodine on the cut surface -> Yellow color I Dilute H,So,-> blue / VioletGENETICS (INTRODUCTION) «Study of genes + Salient features of genes + Location on chromosomes + Encodes certain proteins * No. of genes discovered :- 20,000 + % of genes for coding proteins:- 1.5% Genetic Disorders Chromosomal Single gene Multi-factorial Disorders disorders (Genes + Environment) 1 (N) (Ss) -DM (Number Aneuploidy) (Structural defect) HTN OM: = t Metacentric (middle) Co) Metacentete Sub-metacentric(slight side to the middle) ]'X’ Chromosome Submetacentuic Acro-centric (towards one end) J "Y' Chromosome, 33/14/15/21/22 Z| Accocervaie Telo-centrie (right at the tip) J Not seen in case of humans | Telocentuie Autosomes ‘Sex Chromosomes (1-22) om KARYOTYPING:~ * Study of Chromosomes *Samples - Amniotic Cells = Skin fibroblasts ~ Peripheral blood lymphocytes *Colchicine:~ (M) arrest Staining Patten: ~ Most commonly used Giemsa -> 'G' Banding ~ Fixative:~ Carnoy's fixative (Methanol: Glacial acetic acid) BiaStructural Defects (Chromosomes) ~ Deletion / insertion:- Both leads to an alteration in genetic composition 67 =. ‘ Noxmel Anserion, Anyersiors inversion:~ Pericentric —— + + Paracentric [Liew Ge) =) AME = MY] * Isochromosome -> xq/174/12p 2 Division of chromosome along an axis perpendicular ----7) to the normal expected axis 2 ~ commonest isochromosome -> Xq ’ = Development of malignancy -> 174 : — Xyliay /h, = Development of high chance of testicular tumor -> 12p 1$0¢hramesone yay (bP * Translocation 6 bf} f f = [ t(8:24) -> Burkitt's Lymphoma J] » ~ Robertsonian Translocation :~ Characterised by the eon presence of two long arms of a chromosome and ce op” the second cell has two short arms of chromosomes (topecasrion ~ Robertsonian Translocation =—— ~ Aerocentrie chromosome bap. = Down Syndrome (Chromosome 14/21) a» — O a Rin Cgomoseme WL) + qyrner tyra DR SPARSH GUPTA* ANEUPLOIDY ~ Associated with Anaphase Lag an (nt %n-8) = Meiotic non-disjunction wo (rn) (n-2) LAW (n-3) #9 (2n-3) Monosomy (presence of one chrorncsorne) (n) Normal gamete (n=3) => (2nt4) Trisomy (presence of 4 extra Chrorasome) TRISOMY (Most common-Trisomy 26) Autosomal Sex Chromosome Trisomy 13 -> Patau Syndrome + XXX - Superfemale Trisomy 18 -> Edward Syndrome + XXY - Klinefelter Syndrome + Trisomy 21 -» Down Syndrome + XYY ~ Supermale MONOSOMY ‘Sex Chromosome XO-> Turner Syndrome (Zero survival chances) (Only monosomy that is Compatible with life)SPECIFIC CYTOGENETIC DISORDERS = Pown syndrome = TRISOMY 23 It is characterized by trisomy 24 = Most common chromosomal disorder in humans = Most common inheritable cause of mental retardation ~ Reasons for one extra chromosome 2.1: Genetic basis i. Meiotic Non-disjunction ~+ most common cause of Down Syndrome (45%) ~+ chances are higher in advanced maternal age Stage | Stage I * Down's syndrome = Only trisomy 18 occur at stage Il +All trisomy occur at stage! Edward's syndrome ii. Robertsonian translocation + 4% cases = It affects chromosome 21 and 14 ~ Causes Down's syndrome iii. Mosaicism - Least common cause = It can be seen because of the unequal distribution of chromosomes at the time of mitosis called mitotic non-disjunction responsible for the formation of two different type of cells in the same individual mai nn m's syndrom C - Congenital Cardiac Defect H ~ Hypotonia { - Increased gap b/w great toe and second toe L - Leukemia (ALL, AML-M7) D - Duodenal Atresia H - Hirschsprung disease A - Absheimer's disease S - Simian crease P - Protruding tongue R = Rolling of eyes © ~ Occiput (flat) B - Brushfield spots L - Low nasal bridge E - Epicanthal folds M = Mongolian slant Screening #1F a couple is having down's syndrome suffering baby and they are planning for second baby, we follow screening to check the chances of down's syndrome in second baby 1 Af Ast baby is having sporadic Down's syndrome caused by meiotic non-dysjunction 1 Second baby is healthy especially if maternal age is more (Bi Preptadder - dlii If 4st baby is having Robertsonian translocation is an example of familial condition 4 Defect b/w Chromosome 14 and 22 in other gametes 4 Chances of developing baby with Pown's Syndrome. Test of Screening 1 Triple test Concentration of AFP / heg / estariol to 1 Mevel Tt level 4 level 2. Quad test Concentration of AFP / heg / estariol / Inhibin-a 1 a4 1 tlevel slevel tlevel tf level 3. Radiological findings *Nuchal translucency is seen Features of other trisomies (23/18) (Edward syndrome / Patau syndrome) Congenital cardiac defects + Renal defects + Mental retardation *Rocker ~ bottom feet (foot with convexity towards the ground) * Patau Syndrome -+ (trisomy 43) - polydactyly = palate defects ~ Eye defects ~ Microcephaly * Edward syndrome - (trisomy 18) - Meiotic non-dysjunction at the stage of Meiosis Il ~ Extra / prominent occiput = Micrognathia - overlapping fingers Turner syndrome - Characterized by loss of 'X' chromosome Causes 1 Presence of one chromosome which is less than normal called classical Turner syndrome + 45°XO = It occurs due to defective gamete formation 2. Formation of ring chromosome formation affecting chromosome X + 46Xr(X) ~ There is defect at the level of genes resulting in the formation of a ring, loss of two ends causing urner syndrome 3. Isochromosome formation affecting the long arm of chromosome X -+ 46 Xi(Xq) ~ Short arm is lost in the patients ~ Loss of genes 4. Mosaicism - Individual is having two different set of cells 4¢XX / 45XO Clinical features De smesicie tis the most conumon cause of primary amenorrheaC - Cardiac defects L - Lymphedema (H/E) © ~ Ovaries (streak) - 4 fertility W ~ Webbed neck N = Nipples (wide space) S - Short stature Barr Body ~ no .of X chromosome -1 Normal female -» Turner syndrome +0" Barr body Klinefelter Syndrome ~o Phenotype + 47XXY - Patient have infertility Clinical Manifestations - Tall stature -11Q ~ Hypotonia ~ Barr Body + + - Feminine manifestations -+ Gynecomastia ~ Testicular atrophy | testosterone No development of secondary L sexual characteristics 1 FSH TLH ~ 1 Autoimmune Disorders (SLE) = risk of cancers (testicular tumours) -+ Teratoma (breast cancer) More commonly seen cancer 1 Ductal Carcinoma ~ Congenital Cardiac defects + t risk of mitral valve prolapse * Defective gamete formation is because of 1t age of parents 1 Maternal age + Down syndrome 1 father age + M - Marfan syndrome O ~ Osteogenesis imperfecta N - Neurofibromatosis A - Achondroplasia LYON'S HYPOTHESIS = Only 't! X chromosome - Active= 2nd -+ inactive under the influence of Xist Gene = Barr Body 1 1 DNA Methylation (Perinuclear structure 1 At the interphase) Inactivation of 2nd chromosome (At the blastocyst) = No of Barr bodies Male -> XY -> 0 Femlae -> XX ->1 Tumer Sydrone -> XO-> 0 Klinefelter Sydrone -> XXY ->3 Super female -> XXX ->2SINGLE GENE DISORDERS Single Gene disorders Classical Mendelian inheritance Non-Mendelian Inheritance TT (Or non-classical Mendelian Inheritance) Autosome Sex Chromosome 2) Genomic Imperinting 2) Mitochondrial Inheritance Dominant Recessive |— ‘Y' linked 3) Trinucleotide Repeat Expansion LL '' linked ~ XLR 4) Germaine Mosaicism -XLD Mendelian inheritance: (N) gene -> 2 allele 4 Same Locus 2 Genotype -> genetic make up of Individual Hemozygous trait Heterozygous trait AA aa Aa 1 1 1 Recessive allele A a A *Dominant Allele - Allele which is able to express itself even in Heterozygous state is called Dorninant Allele + Recessive Allele ~ which is not able to express itself in a Heterzygous state is called Recessive Allele *Co-Dominance — 2 different alleles are going to express themselves eg Blood Grouping Genes, HLA / MHC genes isorders -> + Even in Heterozygous state -> have sufficient amount of expression + 50% progeny affected *Patient ~> at least 1 parent affected associated with term vertical Inheritance Affects both females and males equally *# Classically involved with structural proteins *2types of Mutations ~ loss of function of mutation (MC) = Gain of function *Characterised by Incomplete penetrance, variable ExpressivityTe SINGLE GENE DISORDERS Single Gene disorders Classical Mendelian Inheritance] ‘Non-Mendelian inheritance OF (Or non-classical Mendelian Inheritance) Autosome Sex Chromosome 2) Genomic Imperinting 2) Mitochondrial inheritance Dominant Recessive -— 'Y' linked 3) Trinucleotide Repeat Expansion L_ ‘x’ linked - XLR 4) Germline Mosaicism -XLD Mendelian inheritance: (N) gene -> 2 allele ! ‘Same Locus 1 Genotype -> genetic make up of Individual Hernozygous trait Heterozygous trait AA aa Aa tot 1 Recessive allele Aa A Dominant Allele - Allele which is able to express itself even in Heterozygous state is called Dominant Allele ‘Recessive Allele — which is not able to express itself in a Heterzygous state.is called Recessive Allele *Co-Dominance — 2 different alleles are going to express themselves eg Blood Grouping Genes, HLA / MHC genes rainant, Even in Heterozygous state -> have sufficient amount of expression + 50% progeny affected + Patient -> at least 1 parent affected associated with term vertical Inheritance «Affects both females and males equally Classically involved with structural proteins »2types of Mutations - loss of function of mutation (MC) ~ Gain of function + Characterised by Incomplete penetrance, variable Expressivity [Bp Preptacder+ incomplete Penetrance -> There are 100 people with defective gene, out of 200 only 80% are having development of a disease. Environmental factors are actually responsible for outcome of gene expression. So disease has 80% penetrance (means have clinical manifestation) + Variable Expressivity -> With respect to expression of clinical manifestation, there is variation in different patients * Pleotrophy -> more than one system is affected Examples of Autosomal Dominant Disorders -> Vo =» Von willebrand disease / VHL syndrome Familial -> Fara. Aden. Polyposis Hyperchol POORA -> Polycystic Kidney Disease D -> Dystrophia Myotonica © ~> Osteogenesis Imperfecta M -> Marfan Syndrome, MEN syndrome 1 -> Int. Porphyria N ~> Neurofibromatosis - 4 A> Achondroplasia N ~> Newrofibromatosis - 2 T -> Tuberosis Sclerosis Sex-Linked Disorders Y-linked (Only males affected) * Patient transmit disease to son (Father ) Eg Hair on pinna *Y ~> Acrocentric -> Fertility X-linked (father to son transmission of disease is zero) 1) X-linked Recessive Disorder 2) X-linked Dominant Disorder 1) X-linked Recessive Disorder -> €g, MC sex-linked pattern of Inheritance ~ X-linked genes codes for Enz. Genes = ¢- More common 9-XX! ~> Heterzygous (have no this condition) xx Dee soasicur«incomplete Penetrance -> There are 100 people with defective gene, out of 300 only 0% are having development of a disease. Environmental factors are actually responsible for outcome of gene expression. So disease has 80% penetrance (means have clinical manifestation) + Variable Expressivity -» With respect to expression of clinical manifestation, there is variation in different patients «= Pleotrophy -> more than one system is affected Examples of Autosomal Dominant Disorders -> VO -> Von willebrand disease / VHL syndrome Familial -> Fam. Aden. Polyposis Hyperchol POORA -> Polycystic Kidney Disease D -» Dystrophia Myotonica O -> Osteogenesis Imperfecta M => Marfan Syndrome, MEN syndrome 1 -> Int. Porphyria N -> Neurofibromatosis — 1 A ~> Achondroplasia N -> Neurofibromatosis - 2 T -> Tuberosis Sclerosis Sex-Linked Disorders Y-linked (Only males affected) «Patient transmit disease to son ( Father ) Eg Hair on pina *Y -> Acrocentric -> Fertility X-linked: (father to son transmission of disease is zero) 1) X-linked Recessive Disorder 2) X-linked Dominant Disorder 1) X-linked Recessive Disorder -> ¢g. MC sex-linked pattern of Inheritance = X-linked genes codes for Enz. Genes = ¢- More common oe 9-XX" -> Heterzygous (have no this tno condition) xx! LD nsnusiornExample of diseases having X-Linked Recessive Disorders Less -> Lesch-Nyhan syndrome h -» Hemophilia (A) / (B) € -> Color Blindness / CGD gis ~> G-GPD deficiency Detected in -» Duchhene Dystrophy A> A-Caamma globulinemia (Beurton) Fragile -> Fragile X Syndrome Women -> Wiskott-Aldrich syndrome 2 X-linked Dominant disorders -> «Affected Males -> transmit disease to daughters (XX‘) -> SO% progency ‘Involve structural proteins (Less common) t P 1 1 uw Alport syndrome Vitamin D® Rickets Incontinentia Pigmenti Hota — Huntington's disease Hai - Hereditary Spherocytosis - + Examples of disorders characteristically causing an involovement of Enzymatic Proteins g inborn Errors of metabolism. *ARD is able to express themselves only when present in Homozygous state -> associated with an early onset of clinical manifestations. ‘Associated with complete penetrance High chances of these disorders, particularly if there is presence of Consanguinous Marriage eg in Paris, Muslims *Patient -> Parents are carrier, so siblings have high chance of development of disease, it is example of Horizontal Inheritance. eins o ive Dis *Friedrich’s Ataxia *Sickle Cell Anennia * Thalassemia ] Hematological Conditions + Wilson's disease (Cu metabolisrn) *s Hemochromatosis (Fe wera | Metabolic disorders + Homocystinuria + Alkaptonuria _ Glycogen Disorder ‘* Inborn errors + Lysosomal DisorderExample of diseases having X-Linked Recessive Disorders Less => Lesch-Nyhan syndrome h -» Hemophilia (A) / (B) ¢ =» Color Blindness / CGD 9 is -> G-GPD deficiency Detected in -> Duchhene Dystrophy A-> A-Caamma globulinemia (Beurton) Fragile -> Fragile X Syndrome Women -> Wiskott-Aldrich syndrome 2 X-linked Dominant disorders -> «Affected Males -> transmit disease to daughters (XX‘) -> SO% progency + Involve structural proteins (Less common) A v Uy P 1 1 LH Alport syndrome Vitamin D® Rickets incontinentia Pigmenti Hota — Huntington's disease Hai - Hereditary Spherocytosis Auto somal Recessive Disorders -> «Examples of disorders characteristically causing an involovement of Enzymatic Proteins eg Inborn Errors of metabolisrn. *ARD is able to express themselves only when present in Homozygous state -> associated with an early onset of clinical manifestations. «Associated with complete penetrance “High chances of these disorders, particularly if there is presence of Consanguinous Marriage eg in Paris, Muslims. «Patient -» Parents are carrier, so siblings have high chance of development of disease, it is example of Horizontal Inheritance. Examples of conditions of Autosomal Recessive Disorders *Friedrich's Ataxia #Sickle Cell Anemia + Thalassemia ] Hematological Conditions + Wilson's disease (Cu metabolism) + Hemochromatosis (Fe niet | Metabolic disorders * Homocystinuria + Alkaptonuria _— Glycogen Disorder sInborn errors. <<» Lysosomal Disorder BNON-CLASSICAL INHERITANCE DISORDERS 1. Geonomic imprinting:- =It is an example of condition characterized by -> Diff. gene expression dependent on Parent of origin ~ Epigenetic Regulation DNA Methylation ~ Histone Deacetylation ro ‘Lrprinted Imprinted + 3 -~—! & Deletion of gaternal Chromosome copy This condition Called PRADER WILLI SYNDROME -> Due to: 3. Deletion of parental chromosome 2.Uniparental Disomy -> Charatezied by (Maternal Chromosome) 3. USNORP C/F :- - Mental Retardation ~ Obesity (tt Ghrelin) ~ Hypotonia ~ Hypogonadism = Hypogonadism ~If deletion maternal copy results into :- ANGELMAN SYNDROME ~(Reason for development ) -> UPD (Paternal) Clinical Manifestations of Angelman Syndrome S - Seizures A ~ Ataxia R = Retardation | = Inappropriate laugh These Patients sometime called - Happy PUPPETS ~PWS / Angel Man Syndrome -MC cune Albright Dystrophy ~Beckwith wiedmann Syndrome 2 Mitochondrial inheritance (Also called maternal inheritance) -Mt DNA -> OVUM / SPERM If defective Mt DNA is present in ovum, IF defect is present in Mt DNA of sperm, it will result in defect in progeny it will result in normal progeny Defective female Defective male defective. normal normal Y normal ovum = — sperm ovum — sperm aida ghee emai nate “Toncattnbe male child female child child child [BppreptadderExamples of conditions having this =MELAS ie. (Mt encephalopathy, Lactic acidosis & stroke) -LEIGHS DISEASE = NARP (Neuropathy, ataxia, retinitis pigmentosa) ~ LEBER'S DISEASE Mitochondrial /Maternal inheritance is governed by Extra Edge ~ Population Genetics 3. GERMLINE MOSAICISM :- Autosomal Disorder -» One affected parent Rare condition -> No affected parent Person -> Normal -> Post Zygotic Mutation GONADAW CELLS PROGENY / Next generation -» They have clinical Manifestation ~ more than / progeny is affected eg. seen in Osteogenesis imperfecta Tuberous Sclerosis 4. Triple Repeat Mutations:- Characterized By (1) Long Nucleotide Repeates C- Cytosine defective ®| (G) — G- Guanosine Neuro Degenvative Manifestations (i) Dynaraic in nature Amplification (Gametogenesis) PREMUTATION -> MUTATION €g. a) HUNTNGTON'S Disease:~ - CAG —> HUNTINGTIN (It is a eg. of Neurotonic Molecute) Cause - Dawage to caudate Nucleus Cause clinical manifestation of Disease called CHOREA b) GAA -> FRIEDRICH ATAXIA ¢) CTG -» MYOTONIC DYSTROPHY 4) Fragile X Syndrome:~ (FMR-1 gene Mutation <- Characterized by) C/F ->2" . Most common cause of Mental Retaradtion ~ Face ~ Mandible | large/bigger than normal ~ Testis (Macro-orchidism) | - Everted EARS * In such Patients there is -> CGG Repeats -» Oogenesis (stage when repeats occur) = It does not take place at time spermatogenesis ¢ -» -> -> Grandson - Having more severe disease ~Called as SHERMAN'S PARADOX Di orswaicura~ Chances of MR is much more in grandion rather then in his brother Because of Phenomenon of Anticipation Reason of Anticipation uc => Prensutations -> Mutation ~The affected side of chromosome is not appeared so called fragile X syndrome ke appears as Fragile.HEMATOPOEISIS: BASIC CONCEPTS ~ Hematology — Study of the blood and it's relative disorders ~ Hematopoises / Eruthropoises — refers to the process in which there is Formation of different type of blood cells Process depends on ~ Hematopoietic stem cell (HSC) Properties - Pluripotent cell ~ Self-renewal Process of Eruthropoises — Starts during fetal life Fetus 3 weeks of age 1 - HSC ent in yolk Sac & Mesoderm - Aorta ~ Gonads - Mesonephros at 3 months at Birth HSC moves to HSC +nt in bones (bone marrow) Hepatic tigsue Spleen ~ Lymph nodes Birth -> ““* Bone Marrow (all bones) > Puberty 1 HSC +nt in BM. Axial sete” Nil of long bones [Hematopoietic (50%) SC is replaced by fat cells (50%)] BM Examinatic BM aspiration BM biopsy 4 ‘ Salah & Klima needle Tissue taken 1 Process t Decalcificated —ansied 1 Architecture of BM is appreciated Trephine biopsy needle /Jamshed''s needle a2 BM Biopsy -> adults -> Ideal site for taking tissue 1 Posterior Superior iliac spine Obese person -> Anterior Superior iliac spine Child -> Anterior end of tibiausc 4 Multipotent stem cell Myeloid stem cell Lymphoid stem cell 2. Big cell-20 microns ~ Small than MSC-15 microns, condensed nucleus ~Big nucleus - 0-2 nucleoli -3-4 prominent nucleoli ~ cytoplasm No granules 2. Cytoplasm — granular use Msc When matured Beell Tell Natural killer cell Granalucyte / Erythroid / Monocyte (colony - Megakaryocyte — forming Units) CFU TC 7) G-cru M-CFU 1 1 Granulocyte — Monocytes ~Neutrophilis ~Basophils ~Esinophils wee ~ Myeloid SC e.g. of Trilineage stem cell ~ Once myeloid SC is formed it can't get converted to Lynphoid SC (Committed Cells) Growth Factor- RBC -> Erythropoietin - or recombinant derivative of erythropoietin DARBOPOEITIN Platelet -> interleukin-33 ~ OPRELVEKIN GM-CFU -> GM-CSF - SARGRAMOSTIN G-CFU -» G-CSF - FILGRASTIM IRBC WBC Platelets -> Pancytopenia 4 Aplastic anemia -Myeloproliferative disorders ~ Extra proliferation of myeloid stern cells 1 RBC WBC 1 PlateletsRBC Development and Classification of Anemias RBC Myeloid stem cell | Erthyroblast | size Normoblast 1 Nucleus Reticulocyte 1Hb RBC N:C Synchrony Erthyroblast - 3" detection (EM) Early Intermediate -> Hb (Routine stain) Late Polychromatophilic cell — intermediate stage Late -» Reticulocyte -> Nucleus thrown out RETICULOCYTE = Cell having meshwork like appearance ~ 2" non-nucleated cell in RBC's ~ SUPRAVITAL STAINING — detection in living state + - New Methylene Blue (preffered one ) - Brilliant cresyl Blue RETICULOCYTE COUNT Bone Marrow activity -> Reticulocyte count(o.s-2%) 1 Bone Marrow Examination Conditions in which RC count altered (sed) 1 Hemolytic anemia 2. Fe/ FA/ B,, Supplementation 1Sed Reticulocyte Count 1. Aplastic Anemia 2. Deficiency of Fe / FA/ By, 3. Leukemia / Metastasis 4, Myelofibrosis CORRECTED RETICULOCYTE COUNT Corrected reticulocyte count = Retic count X Hb (Pt) Hb (Normal) a Retiecoumt. Hb (PE) = (2) -> whoch is normalPROPERTIES OF RBC Biconcave shaped & Proteins responsible :~ Spectrin (most important protein to maintain shape) BL ~Band 3 ——wCoo ~Ankyrin © ov © 3 ow lexibility Central 1/3 Pallor EP PARAMETERS. - - Getrl 1. MCV- Average volume of normal RBC 80-100 fi Si. 2. MCH- 27-33 pg 3. MCHC -MCH -> 34-37 g/dl (normal in megaloblastic Anemia) MCV 4. Hematocrit - Packed cell volume 45% = O45 (N) 5. Red cell Distribution width RDW ~ Index which tells about variation in RBC size. ! Anisocytosis Normal value - 12.5-24.5 MCH = Total amount of Hb No. of RBCs ~ Color of RBC 4 Less valve of RBC - Hypochromic RBC Mev ~ Normal ~ 80-1008 - <80 fl — small in size RBCs 4 Microcytic RBCS Causes of Microcytic RBC S ~ Sideroblastie Anemia 1 = Iron deficiency Anemia T ~ Thalassemia A ~ Anemia of chroni¢ Disease (AOCD) L = lead Poisoning - MCV > 400 fi ~ Big size RBCs 1 Macrocytic RBCS Causes of Macrocytic RBCS (Let harry mug up the causes) L = Liver disease H ~ Hypothyroidism DR. SPARSH GUPTAM ~ Myelodysplastic syndrome C ~Cytotoxie drugs Cell Nutrient deficiency ‘all. sutrient deficiency. —— 8. deficiency FA deficiency - B,, / Folie acid deficiency - Methotrexate - Alcohol ~ Phenytoin 1B. 1 IFA NC Asynchrony AGC Asynchrony ~ IRBC size ~ Nucleus is immature - Megaloblast = Size of megaloblast classically is >430 Al CLASSIFICATION OF ANEMIAS 1. Based on size of RBC MICROCYTIC ANEMIA MARCROCYTIC ANEMIA. NORMOCYTIC ANEMIA t Can be associated with ~ Myelofibrosis Radiation ~Metastasis - Renal disease = Depending upon etiological factor: - |. Decreased RBC production Fe / FA/ B,; Thalessemia AOCD / Aplastic Anemia Mt. Blood kc ‘Acute aon = Wl. tSed destruction- Hemolytic Anemia 8 > Q) 1 RBC Destruct 4 LFroduc? 1. Blood Loss © te * YF e/ Fal Ow Thalistemin x hoc) Aplastis mamuis [BPreptadderIRON DEFICIENCY ANEMIA. Physiology of tron metabolism ~ Absorption of iron = Transportation of iron = Storage of iron - Chief site - duodenum - Duodenum cells - 4 molecules (i) DMT2 - ferrous form (it) Cytochrome 'C' reductase (iit) Ferroportin (iv) Hephaestin Increased tron absorption Decreased iron absorption HCL (gastric acid) ~ Phytates vec - Carbonates Amino acids -Tannate Sugars ~ Tetracycline Serum iron : ¥ (Fe>T) sr 100 - 120 mg/ml B. Percentage transferrin saturation fr 2 =33%= 4/3rd +(F5) “ , 7 c C. Total iron binding capacity (TIBC) ‘ TIBC + 300-360 mg/ml : Transferrin 3. Storage of iron: Inside liver & bone-marrow Iron -> Macrophages of liver & bone-marrow -» Iron internalize + ‘ Transferrin Ferritin 4 Hemosiderin Fervitin*® _3. Transferrin Bone marrow ferritin 0 Serum ferritin Serum ferritin ® ___a. Serum TransferrinIron Deficiency ~ Less dietary iron intake | ~ Decreased of absorption ~ increased requirement of iron > Growing children > Pregnancy > Reproductive age group of females = Blood loss > Stages of Iron Deficiency ~oe (i) Decrease in storage form of iron BS, Fe Se. Oe > Decrease in bone marrow ° gfe 23Y — store & decreased PRE os Ee > Serum ferritin is there Jib af. oe OF j (ii) tron deficient erythropoiesis: a EE ef008 woe, a = Serum iron Wb tJ oecg@y ¢ y 2805 ~ nage TF saturation W\ 230.0% 200 Sedna. @! - TIBC ttt (ili) tron deficiency anemia : ( RBCs are directly affected > Microcytosis ¥ , > Hypochromia zy yy = Anisocytosis 1 — Poikilocytosis ¥ ft # % Fatigue / pallor / | growth Dyspnea / palpitations © a 9 Loss of hair (Alopecia) Koilonychia : PICA 9 ©) Diagnosis 1. Bone marrow examination ‘ = decreased staining (prussian blue) > Micronormoblast 2. Blood > \Hb + MCH 4 / MCV4 / MCHC} — Peripheral smear > Microcytic / Hypochromic = Anisocytosis / Poikilocytosis3. Iron Profile : Serum ferritin 1 Serum iron 44 % T, saturation 4 TIBC tt 4. Special investigation > STR >1s Log (S. ferritin) LDA Ss. Te Free Erythrocyte Protoporphyrin FEP — ttt 6. Mentzer index tt —Mcy __>13 IDA RBC Count Thalassemia Trait > IDA > | Reticulocyte count IDA > Mentzer index is high Thalassemia > reduced Mentzer index———— . - ro ANEMIA OF CHRONIC DISEASE ~ Pt. has chronic inflammation 4 Secretion of cytokines L-4/L-6 ¥ - t Bone Marrow Liver - | action of erythropoietin = t Hepcidin] positive acute phase reactant + = t Ferritin = {se no. of RBCS ~ | transferrin ] negative acute phase reactant No change in their morphology = Hepcidin - inhibition of iron ~ Normocytic, normochromie (iron inhibitory protein) Anemia ~ Microcytic, hypochromic anemia ~ more common type of anemia of CD ai? - IRON PROFILE OF AOCD IDA 1. S. ferritin tt w 2% Transferrin uw u saturation 3. Serum iron Mh a 4.78C(T) ttt AOcD IDA rum in = as os log (Ferritin) Treatment: IDA + oral iron supplementation AOCD ~ Iron supplementation will not work 4 Treat underlying cause ~ joint problem - infectious condition = primary condition (BppreptadderSIDEROBLASTIC ANEMIA = Important cause of microcytic, hypochromic anemia Normal Metabolism of Her Suceinyl CoA Vit Be | Aminolevulinie Acid Synthase (ALA) Pyridoxine ¥ rate limiting enzyme Aminolevulinie Acid 4 ALA- Dehydrogenase PORPHOBILINOGEN PROTOPORPHYRIN Fe Ferrochelatase HEME ~ any defect in these enzymes will result in $4 Heme 4 44 Hemoglobin + Microcytic, Hypochromic RBCS CAUSES: Congenital acquired (more common causes) ~Erayme deficiency ~ 4) WB. (pyridoxine deficiency) due to ISONIAZID therapy or dietary problem. 2) Over consumption of alcohol ~m/e (poison for mitochondria) reaction in mitochondria will not take place Fervochelatase bd heme 3) Lead poisoning affects ALA- dehydrogenase, Ferrochelatase ' 14 HEME => AnemiaAt CELLULAR LEVEL ectoporph- Macho ndeia, We Ringed Sideroblast (iron granules in ring like fashion) Ls fa %, % . ot ~? 4 ee °* Leakage of intracellular iron 4 IRON OVERLOAD ~ IRON PROFILE * Serum Ferritin tt * Serum Iron tt * % T, Saturation tt * TIBC uu = Increased free iron inside mitochondria ~ Free radical damage to mitochondria = RBC-> altered appearance ~ Free iron- damage to RBC precursor 4 DR. SPARSH GUPTA5. Ferritin % T, Saturation S. tron TIBC Serum transferrin. receptor/ Log (Ferritin) Mentzer Index (IDA and Beta Thalassemia) MCV RBC Count IDA, ratio increased In Thalassemia 1 <3MEGALOBLASTIC ANEMIA increased size of RBC's Megaloblastic Anemia -> increased size 4 < FA|B.,|drugs (def) (N:C asynehr) B,, deficiency-> Normal -> ~ Int factor = Pan enzyme (duod.) = Hleunn (site of absorption) B,, required for rapidly div. cells SS DNA synthesis Homocysteine : —? Methionine tL, Methyl- malonyl CoA Suce. CoA + Myelin 4 Etiological factors:~ * 4 Decrease intake -> vegan * § Decrease absorption * Increase requirement Decrease IF = Child ~ pancreatic dis = Pregnancy ~ Weal disease (FISH TAPE WORM) ~ Lactation ‘BLIND LOOP SYNDROME’ 4B, can cause * 3) Blood / BM ~ Pancytopenia ~ Dyserythropoiesis RBC -> * Macro-ovalocytosis * Basophilic stippling (+) * He J Body (+) Ow @ wsc->“Hyper segmented neutrophit” Platelets -> smooth appearance "Beefy tongue” 3) CNS-> decrease myelin PN -> 4 * Pheri. Neuropathy * ase /dese tract 4 Sub-Acute Degeneration © sAcD Clinical Features :- Anemia + Jaundice + Neurological clinical symptoms De-> 4) Blood-> MCV increase MCH increase MCHC-> MCH ---> (N) Mev Bssophie sipping (+ Howel jolly body (+) © Hyper segmented neutrophils 2) Serum B,, levels 3) H M mmCoA > Succ. CoA = Serum Homocysteine increase + tt MmCoA Lg Mmemia (Blood) Mmuria (urine) 4) Bone Marrow -> Hyper cellular BM Known as ineffective Erythropoiesis 444._reticulocytes PRENCIOUS ANEMIA-> * Auto antibodies (+) 1 - Decrease (iF + B,,) (Most specific antibody) - teal © Mt ~ Parietal cells s Presence of these antibodies can cause-> DR. SPARSH GUPTA"448, * Changes in stomach -» Intestinalization 4 (Diagram 28:30) Fundus| body of stomach ‘ Increase cancer Diagnosis:-> 2) Auto Ab (+) Schilling test + not useful for finding deficiency of B,, useful for finding the cause of B,, deficiency Treatment:~ B12 Supplementation * Blood 74 reversal * Neurological c/f 2—» stay where they are "Cancer tt (same progression) * 4 Decrease intake 4 G * Drugs responsible — (Jejuenum) ool Fee < Methotrexate ocrs Clinical Features : -» Megaloblastic anemia * No neurological symptoms a: 1) S. folate 44 2) RBC folate 41 - best investigation 2) Figlu test (H) ——* filglu ———+ glu. Acid FA => Presence of figlu in urine of patient. Megaloblastic Ane! Decrease Bus Decease FA * Neurological symptom present - Absent * MMCoA oy) ‘Treatment:-> > B,.+ FA should be given ++ Only FA can worsen the neurological symptoms [Bppmptadierbe es _— Factor Platelets Damaged RBC 4. Macro-Angiopathic Hemolytic Anemia 2. Miero-Angiopathic Hemolytic Anernia = Factor : Prosthetic Cardiac Valves [Aortic valve >>> Mitral Valve] (because pressure gradient is much higher in Aortic valve) ~ Aortic stenosis (Severe Aortic Stenosis) ~ Synthetic vascular grafts = Cavernous hemongioma a : ia: - Factor : HUS / TTP / DIC ~ ECLAMPSIA ~ SCLERODERMA ~ MALIGNANT HTN ~ MARCH HEMOGLOBINUREA (Hburia)HEMOLYTIC ANEMIAS BASIC CONCEPTS AND CLASSIFICATION . , Lysis of RBC - contributing to anemia Characterized by RBC destruction +4 oxygen carrying capacity of blood ‘ 4 oxygen in organs (hypoxia) + Renal Hypoxia ‘ Kidneys stimulated 4 to release Erythropoietin ‘ Acts on bone marrow 4 cause + RBC production Here in hemolytic anemia there is excessive destruction of RBCs that cannot be compensated by bone marrow Causes of Hemolytic Anemias 1. Intracorpuscular HA es F Inherited Acquired Hereditary ~ PNH (Paroxysmal Spherocytosis Nocturnal Hb. uria) - GePD deficiency = Thalassemia = Sickle Cell Anemia 2. Extracorpuscular HA Non immune mechanisms - Clostridium ~ RH incompatibility 1 - Autoimmune HA TOXIN ~ Snake venom ~ Sequestration ~ Mechanical damage (Angiopathic HA) - March HB URIA ([BpPreptadderHemolytic anemia T RBC destruction + © RBC lysis t tog 4 TLHD Tt uncongenital bilirubin 1 1 Release of Jaundice Free Hb t 1 Haptoglobin 4 Hemopexin 4 Hp-Hb Complex 4 1 in serum haptoglobin levels Free Hb present — in blood (Hb emia) — in urine (Hb uria) > altered urine colour Free Hb > Methaemoglobin + (Met Hb uria) Fe2+ ~ Fe3+ (Met Hb emeia) Renal Hemosiderosis * When proximal tubular cells has hemosiderosis inside them s__Lot of damage to the renal tubules # Chronic HA ~ 111 UCB ~ Calcium Bilirubinate + gall stone (Pigment Gallstone) 21 Epo 1 bone marrow activity 1 Hypercellular BM t T Reticulocytes L TMCV (Inside Systemic circulation) (Outside Systemic circulation) INTRAvascular HA EXTRAvascular HA 1. Chances of Hb emia is tt Lt 2. Chances of Hb uria is ttt 2. Cant ort 3. Serum Hp level Ut 3. Mild decrease 4. Size of splenic + hepatic tissue is normal 4. t size of splenic + hepatic 5. Seen in G@PD deficiency, PNH tissue 5. Sickle cell anemia, hereditary spherocytosis 4 DR SPARSH GUPTAHEREDITARY SPHEROCYTOSIS INTRACORPUSCULAR CAUSES OF HAEMOLYTIC ANEMIA ~ Inherited disorders Problem can be + membrane ~ Enzyme + Haemoglobin Hereditary Spherocytosis lee Normal RBC ~+ biconcave shape flexible => Spectrin Ankyrin Band 3 Band 4.4 Membrane defect + Ankyrin > Band 3 > Spectrin CO ofS ore (ger Sma FIPS House eo CON one egrets Loss of Hater Spherical RBC - loses flexibility HS + spherical cells ~ eaten up by splenic macrophages ~ extravascular Haemoglytic anemia ~+ Phagocytosis Clinical features = Anemia (ty!) - Jaundice ~ Splenomegaly Autosomal dominant Diagnostic tests - Bone marrow exarnination - t cells ~ Blood examination + 1 Hb / TLDH / Iserum Hp - MCH (normal) ~MCV (reduced) -MCHC= MCH_~ (increased) cv OSMOTIC FRAGILITY TESTS cm Peripheral smear show ~ spherocytes No Centra) RBC -+ Hypotonic solution Palier C+ On 070-28 ~——_> nS O — & *— [Bj PrepLadderTime taken for RBC to burst in Lessen in HS, as RBC are fragile / tosmotic Fragility pac 4m RBC s Autohemolyser -- 0.9% NaCl EAC ; >45% RBC destruction Ectacytometry To detect shearing stress of RBCS Treatment Elective Splenectorny + Anemia Severity + reduced * Shape of RBC = still spherical * Chances of infection + By capsulated bacteria Complications 1.Aplastic crises 1 Bone marrow activity + 1 erythroid precusors-» parvovirus 2. Increased risk of infection (Post splenic removal) 3. HS + chronic hemolysis + 1 gallstones 4. HS -+ Ankyrin > BAND 3 + Spectrin defect + Hereditary elliptocytosis 4 DR.SPARSH GUPTA,Ge PD DEFICIENCY (2) ENZYME DEFECT - G6PD Deficiency- Glucose 6 Phosphate Dehydrogenase Deficiency. (GePD) G6PO, ——_———* 6 - phosphogluconate a NADP NADPH ast GSsG HO, H,0 (Oxidative stress) (Water) ~ GePD Defect:~ 1 RBC-> increase susceptibility to oxidative damage 1 beftsy Denaturation of Hb P | 1 HEING Body (+) Direct Damage to RBC Decrease Flexibility t 1 Intravascular Hemolysis 4) Bite cell a, 2) SPHEROLYTE 3) Blister Cell 1 Extra Vascular Hemolysis ‘Symptoms :-> ~ Oxidative stress -> HEMOLYSIS 1 Due to = Infections (Pneumonia | SEPSIS) ~ Drugs (Antimalarial Drugs-> Prima Quine, ATT Drugs) = Food (FAVA BEANS) Reason: - GoPD deficiency — XLR-> UNSTABLE Enzyme X- Link Recessive Disorder 1 uthGOPD deficiency -> STRESS-> (EY ->|Self-limiting hemolysis (most cormmon in population) GoPpD- (J GePD-A' >| |GePD-A > || GePD-(M) 7 T T T Normal Slightly t* wer dub ty? (Least half-life) er 2) History -> (Male> Female) 2) Blood sample -> + Decrease Hb + MCH + Mev } Normal + MCHC ~ Peripheral Smear [> Bite cell 1 |» Blister cells Ly spherocytes - OC) - HEINZ BODY also appeared in such patients - Appeared by Crystal violet stain ~ Presence of spherocytes: represent Differential diagnosis (DD) - HS = G6PD deficiency ~ Infections (Clostridium) ~ Auto immune hemolytic anemia _— eT STE (Most common to find Spherocyte) 3) GoPD Level Estimation ~ Electrophoresis -> Subtype = Sodium Nitrate-> called. Methemoglobin \ Reduction assay (Has Brown Color indication (+) ) Advantage of GéPD GOPD def. -> RAPID clearance of RBC 11 Plasmodium Falciparum Re:~ No Drug, not to given suspha drugs or alternate drug advised 4 DR. SPARSH GUPT:HEMOGLOBINOPATHIES: SICKLE CELL ANEMIA 1. Hb. Defects:~> Decrease quantity -> THALASSEMIA Decrease quantity -> Sickle Cell Anemia 4, Sickle Cell Anemia:-> Caused because of point mutation Point mutation -> B, Amino acids E@eamic acid (normal) Qiiline (sickle Cell Disease) brormal GOES (VELCOMA) By ey It is (POLAR) it is (NEUTRAL) Hb-> Tetramer-> ym 2B BIB -> 0, B, = HbA (Normal) 2X€— BIB’ -> «. B,-> HbA (60%)- Sickle cell rate (SCR) &, B', -> Hbs (40%) BY/B* -> ox, B’, - Hbs (SCD) In this case when both B chains are affected No HbA Any HL@=> RBC -> | decrease solubility of He having Hos Precipitation ‘ Polymerisation Y SICKLING 4. Amount of Hb HbS-> increase Sickling HbF and HbA-> | Decrease Sickling why SHOE cE ~ Hydroxgurea Both drugs ~ DECITABINE. 2. ACIDOSIS. 3. EXERCISE 4. DEHYDRATION» (MCHC 1 Increase) S. Time of RBC for circulation Splenic tissue / Bone Marrow-> Sluggish flowReversible Sickling 402/ water Normal RBC ~<———— Sickle shaped RBC (Reversible Sickling) 02/ water 102/ Iwater (IRREVERSIBLE SICKLING) (IRREVERSIBLE SICKLING) 1 Increase Stiffness 1 Increase Stickiness 1 Increase flexibility 1 Increase Adherence to E/C 4 1 Trapped in Spleen MICROVASCULLAR 1 Occusion Extravascular Hemolytic Anemia ures:=> 3 A — ~ Jaundice - Anemia ~ Increase spleen Size = Decrease growth Most common-> VASOOCCLUSIVE Crisis 1. Brain-> Coma/ decrease consciousness stroke 2. Bone -» |. Small Bone involvement -> hand - foot syndrome I. Long Bone-> Avascular NECROSIS of Neck of Femut Buaseular Nec % Neck of femur Gay ~ H-(called 'H' shaped vertebra, [——) or COD FISH/ FISH MOUTH = Y__]_ ~ Ya! Sunpe VERTEBRA [ues | fits, IV. Skull: oe pe + cues “Haw on ens” AMPeReonCE(“Hair ON END APPEARANCE" crew cut Appearance) V. Skin=> Having Chronic Non- Healing Leg alcers Mi. Spleen-> Initial-> TSize Congestive SPLEENOMEGALAY Later-> Arterial occlusion 1 Ischemic Damage 1 Fibrosis of Spleen 1 ‘This type of fibrosed spleen is called AUTOSPLENECTOMY VII. Pulmonary -> Acute Chest Syndrome 1 ~ Pain in Chest ~ Dyspnea - decrease O, in Blood Mil. Males -> Painful erection -> called as Priapism Vasoocelusive Crisis- Organ involved ~ Brain - Bones = Skin - Spleen ~ Pulmonary ~ Penis 2. APLASTIC CRISIS => 1 Increase Bone Marrow activity PARVOVIRUS 2. HEMOLYTIC CRISIS- INFECTION-> 111 Spleen 4, SEQUESTRATION CRISES: 111 Spleen -> Hypovolemia Diagnesin-> 1, Bone Marrow- Increase Cells / t Increase RETIC count 2 Blood — Increase . SLDH/ Increase SERUM BLLIRUBIN | . PTLe - TESR Peripheral Smear 4 Sickled Cells + ~? ADD Chemical called 000-0 00 Dithionite — Metabisulfite. Test (& Results in) { cannot differentiate ——_ SCT/ SCD2.Hb electro phoresis:- Glutamic acid -> valine (Polar) (Neural Amino Acid) ~ a (Normal) (Sbie-cel (Serte-cot me “oma —_— — = (HDA) ~ "© — as tH) ~ Experts are required to perform this test 4. HPLC-> Hb (High Performance liquid chromatography) HPLC 1 IOC ~ (investigation of Choice) 4S e * 1 Hb Pathies scpeiaiagune eases CO ROA O7O7R 2-J—~9-I-0-0°R SCA-> JOsmotie Fragility Seen in - Hb Pathies - THALASSEMIA ~ SEVERE IDA - Hbe HbC :-> Be-> Glutamic ACID-> LYSINE BD owseresicurs~ Skull -> hair on end appearance - Vertebra-> H-Shaped vertebra Appearance - Fish mouth vertebra Appearance - Cod- fish Vertebra Appearance Re-> -0; = IV Fluid ~ Analgesics - Antibiotics Drugs -> To increase cone. OF Hemoglobin = eg- HydroxyureaThalassemia (Quantitative Disorders) HbA -» 20 - 40 genes -> chrt6 2B - 2B genes -> chr, 14 ax-Thalassemia — gene deletion B- Thalassemia — gene mutation - (MC) Normal -> HbA / HbF / HbA, 0B, 7 &Y, 7 05, sh 1% 3m 8-> Normal B Chain formation B -> Partial B Chain formation 8° -> No B Chain formation Promote Exon Intron 1 Splicing Ribosomes 1 Translation -» B chain formation * Eunction of Promoter — it will increase the synthesis of Beta chain -—* Exon = express itself * Splicing result in MRNA ~ Transcription * Mutations ; ~ Splicing mutations -> B’ > > > B° (Intron > Exon ) = Promoter mutations -> (8 chain produced are less) - Chain termination mutation -> formation of stop codon 4 & Clinical Possibilities : Normal - B/B - 44-47 gms /dL. 1. B/B' - Mild anemia -> Thalassemia Minor > 10gm /dL. Thalassemia Trait + — - asymptomatic =No Blood transfusion 2. B'/B" - Moderate anemia -> Thalassemia intermedia -> 6-9 gm/ dL. = often blood transfusion Bipreptadder3. B°/B" - Severe anemia -> Thalassemia Major -> Hb < 6gmw/ dL B78 - H/O multi blood transfusion B= Thalassemia Major. Relati ess of x-chains t a-chains precipitatg in normoblast Direct damage to normoblast 1 No. of actual RBC's (ineffective erythropoiesis) Escape into circulation 1 Trapped in splenic tissue 1 A ener haemolysis Severe Anemia 1Bone marrow activity Extramedullary Hematopoiesis 1 Occur in — liver ~Spleen = Bones where not (N) Observed Eg: Facial, Skull Manifestations — Frontal bossing - Malocelusion (d/t involvement of Mardible and Maxilla) ~ Flattened nasal bridge Referred to ' CHIPMUNK FACIES’ ~ Skull - ‘Crew cut appearance! OR ‘Hair on end! appearance = Presence of + iron from Bone Marrow More win absorbed from Gl Tract Multiple Blood transfusion tron Overload ~ Cardiac ~ Pituitary ~ Pancreas ~ Liver ~ Parathyroid ~ Results in cardiac / endocrine failure 1 Death CLE := serve anemia ~ Stunted growth ~ Chipmunk facies ~ 111Size of liver and spleen (Massive hepto spleen omegaly) Be Dr Pritesh Singh1) Blood investigation - Hb || - MCV IL - MCH iL - MCHC | = Peripheral Smear — Microcytosis, Anisocytosis, Poikilocytosis = Target cells = Basophilic stippling (due to RNA in cytoplasm) = 1 Reticulocyte Count # Anemia ttt ~Nucleated / AB (N) normoblasts 2) Osmotic Fragility 111 3) 10C- HPLC (High Performance liquid Chromatography) Ny - HOF 6 - HbA, cB ratio -> 1.1 (Normal) -> 30:1 (Thalassemia major) ~ Pathogenesis is very similar to Thalassemia raajor = Untensity ~ Mild anemia - No H/O Blood transfusion ~ Peripheral Smear -> everything at mild intensity - Male d ~ Female? ~Thalassemia Major ~Thalassemia Major -> No Marriage -T Trait -T Trait -> Autosomal Recessive 25% Baby with that major Screening ~ Osmotic Fragility — ‘NESTROF TEST" (Naked eye single test red cell osmotic Fragility test) ~ Filled with hypotonic saline (Sel) - 0.2m of blood = Wait for 30 minutes act Antble Confirmation — HPLC of Hb B - | HbA a— 7 om art) 8-11 HbA, (23.5 gm / dL) G taal Test t ‘Thalassemia trait # (DA (iron def. anemia) ~ (By HPLC) - MC ~ RDW Red Cell distribution width - T. Trait - Normal = IDA = itt ~ MENTZER INDEX mcv T Trait - «13 [Bpreptadder RBC Count = IDA - >43(t)ALPHA THALASSEMIA - Gene deletion ~ Chromosome 16 has 4 a genes + 2a chains Situations aa| aa Normal (400% chains) taala- > asymptomatic (75% a chains) Wa | a~ ~ Trans a deletion asymptomatic (SOtachains) aa| -- + Cisa deletion (asians) (SO% achains) CiSa deletion + a thalassemia trait 1 marries a person with same trait Baby Thalassemic (aThalassernia major) IM a-| -- 25% of a chains 1 I Ho. 1 High chance of precipitation High oxygen affinity 1 Damage to normoblast 1. [Hypoxia to tissue 1 2. Extravascular hemolysis (EVH) in spleen ~ fetal life - non availability of a chain 1 (gamma) Gama, tetramer More severe hypoxia L (uD 4 Hydrops FetalisPAROXYSMAL NOCTURNAL HEMOGLOBINURIA Inherited causes of IHA (Intracorpuscular Hemolytic Anemia) Problem in membrane, hereditary spherocytosis, GePD deficiency hemoglobinopathies sickle cell anemia or thalassemia ACQUIRED INTRACORPUSCULAR HEMOLYTIC ANEMIA - AKA PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) = Present in adulthood, not a pediatric disorder Normal Function Cell ~ Phosphatidylinositol glycan A gene (PIG-A gene) ~ On X chromosome psscoe) - Synthesis of transmembrane protein 4 GPI linked protein (Serves as an anchor) ar Cxom) 4 Attachment molecule for additional proteins ist molecule + CDSS (decay accelerating factor, DAF) 2nd molecule + CD59 (Membrane inhibitor of reactive lysis, MIRL) Brd molecule + C, Binding protein These molecules are protective for normal cells of the body Cause decrease in spontaneous activation of complement protein PNH + defect in myeloid stem cells \ ml} tecynec/O” Malfunctioning of PIGA gene ‘ a, Defect of GPI protein IM] J oy Miss oF FE Pre + Cy cDss- cpsa- fl CD59 = tm same person presence of normal as well as abnormal cells because of an acquired mutation = Group of RBC / WBC and platelets which are CDSS and CD54 positive + Group of RBCs, WBC and platelets which are CDSS and CDS@ negative BIPHENOTYPIC PICTURE ~ Co-existence of two different types of morphological cells Pathophysiology ~ Normal expression of CDSS, CD54 — no complement mediated damage = Loss of GP! protein + no protection Eiprepadder_ —_ Complement activation - destruction of RBCs / WBCs / platelets ‘ PANCYTOPENIA RBC Normal person at Night ~» 4 respiratory rate + 1 CO2 retention » t H+ +» ACIDOSIS (also in daytime) 1 Stimulation of Hb uria + Intravascular + Damage to complement (altered color urine) hemolysis RBC system V/H CC WBC - dysfunction -» alteration of membrane protein - tsed risk of INFECTION (4 se in no.) expression PLATELETS - 4 platelet count - altered function tsed tendency to cause aggregation Intravascular hemolysis + Free Hb + NO 4 tsed tendency of thrombosis Concentration of nitric oxide (NO) will decrease NO has anti platelet aggregation action Thrombosis m/e seen in cerebral vein / hepatic vein Hepatic vein thrombosis + BUDD CHIARI SYNDROME <{sror} + Cerebral venous thrombosis -» DEATH (life threatening) Diagnosis FLAER - flow cytometry (fluorescein labelled pro-aerolysin) ° = Investigation of choice BS oj> > (Gear) Funnel shaped instrument with additional tubing tise j Anticoagulant solution (sample) is added into funnel + cells to be tested Through additional tubing, put tagging molecules (FLAER) Normal RBC has CDss, CD54 - Add anti CD54 - Molecule present + ANTIBODY ATTACHED ~ Laser lights used for detection of cells which did have the molecule b OR SPARS EUPTA- Forward or sideway scattering - If antibody present -» will be detected on counter screen If not present -» cannot be detected on counter PNH finding Biphenotypic appearance (CDSs, 54 positive) ; (CDSS, 54 negative) 2. Activity of complement system = In presence of sugar / acid HAM'S ACIDIFIED SERUM TEST Take sample of patient blood add acidified serum in small quantity ‘ Activation of C system Sucrose Lysis test - Take sample add sucrose 4 Destruction of RBCs Myeloid cells Pathogenesis “ Myelodysplastic Aude abnormal austoimrnune, daonder ache bratfechon v oubs antibody, foumaton MYELODYSPLASTEC pis ai PI padein cell STEM, L [ijprepLadderTreatment * PNH + 11C proteins damage ‘ C, convertase inhibitor (Eculizumab) 4 —<—<—<= “Oly ly [ as "Membrane attack complex 4 activity of C system Definitive treatment of PNH 4 STEM CELL TRANSPLANTATION 4 DR. SPARSH GUPTAAUTOIMMUNE HEMOLYTIC ANEMIA Extracorpuscular Hemolytic Anemia * immune mediated hemolytic anemia AUTOIMMUNE HEMOLYTIC ANEMIA © Immune system gets activated against self antigens SUBTYPES 1 1 1 Warm autoimmune hemolytic Cold autoimmune hemolytic anemia anemia 1 1 Antibody attaches itself at a Antibody attaches itself at temperature 37°C lower temp. # IgG >>> IgA * IgM >>> IgG Warm AIHA Cor uo = Classically seen because of IgG / IgA - Bind at 37°C ~ Idiopathic L = Autoimmune disorders (SLE / Rheumatoid Arthritis) O >>> Cancers (CLL) Drugs ( * a - Methyldopa * Penicillin quinidine) * splenomegaly is characteristics finding Peripheral Smear Finding * Spherical RBCs Diagnosis - Routine investigation T LDH /T unconjugated bilirubin / SHb = Blood : P/smear + Spherocytes are present ~ Presence of Auto Ab = can be present on RBC surface ~ in serum (Free Form) For detection of these antibodies, COOMBS Test is performed4. 4 4 On RBC Surface Serum (free) 1 4 DIRECT COOMBS TEST INDIRECT COOMBS TEST * Jaundice /Anemia / Splenomegaly Peripheral Smear finding + Spherocytes+ } Hereditary Spherocytosis 1 COOMBS TEST - COLD AHIA Ab attaches at < 37°C Variants : Cold Agglutinin disease + Formation of IgM produced Against '' Ag of REC IgM + 't Ag of RBC 1 Binds to RBC @ cold temperature 4 Clumping / Aggregation of RBC } 4 ‘ Acrocyanosis — At body temperature (37°C) + Detachment of IgM - IgM + C proteins + C,, attachment on RBC (special affinity for’ KUPPFER cells) ~ When C,, attached RBC enters systemic circulation, they gets destroyed (example of Extravascular hemolysis) Cold Agglutinin Disease = Associated with IgM ~ Conditions include + Mycoplasma Infections + Malignancies ~ Infectious Mononucleosis + Waldenstrom Macroglobulinernia Diagnosis ~ Cold Slide Test 2. Cold Hemolysin Type WgG + 'P Ag of RBCCO —~ BIC > © cavaiion HA MAC RenaTIN v Tvju Binds @ 4°C ~ C Activation at 37°C Clinical Manifestations - Hburia * Cold Hemolysin (DONATH - LANDSTEINER Ab) 4 Paroxysmal Cold Hburic (PCH) * Seen in case of Children (history of viral infections) AHIA —————__ 4 L Warm Cold 4 4. + GA 1 4 1 ~ Agglutin disease - Hemolysin disease © Destruction - IgM ~1gG Location: Spleen Site of destruction: ( Biphasic Ab) Liver - Extravascular = Intravascular hemolysis hemolysis because OF complement activation EppreptadderINTRODUCTION TO WBC DISORDERS Development of WBC Myeloblast -»Pro-myeloblast->Myelocyte->Meta Myelocyte->Band cell->(M) cell (lmmature) ds (Mature WBC) ~ Size of cell 4 = Replication 4 = Maturation Infection -> WBC Serve infect ———————P WB + Band. CIS co. ss pers cnatain) (Pneumonia Bacterial ends) 1 Shift to the left Phenomenon Disorders affecting WBC JWwBC twee Leukopenia Benign Neoplastic 1. Leucocytosis 2. Leukernoid rxn Leukemia Lymphoma (mild to moderate in TLC) 1 pic wee N >L OM %E >B (Never let monkey eat banana ) e | (50-70%) Round Kidney Bilobed cells with Blue colored nucleus shaped red granules granules, (20-40%) nucleus (0-5%) (0-2%) (8-10%) NYLOM7EDB @©0@606 Neutrophil -> tat time of bacterial infection ~ Necrosis ~ Acute inflammation ~ Drugs ~ steroid ~ Lithium Lymphocytes -> - Viral infections = Chronic inflammatory conditions [BppreptadderLL Monocytes -» - Chronic inflarnmation - Cancers Eosinophils -> - Allergies ~ Parasitic infections = Hodgkin's lymphoma Basophils => = Alleray = CML Leukemoid reaction Resembles cancer but it is not a cancer TLE -> 40,000 Ail + Preumonia * infective endocarditis + Sepsis twee + KAWASAKI DISEASE D/D -> CML -> LAP Score LAP Score - | in mature WBC LAP Score - 4 in CML Neoplastic WBC proliferation ‘Leukemia ~ Characterized by the involvement Of the bone marrow very extensively by cancerous cell 4 Move to systemic circulation (blood) 1 Involves liver, LN, spleen, brain Lymphoma ~Tumor arising from lymphoid tissue - Involvement of liver, LN, spleen ~ Formation of descrete masses of cancer cells. Inside the different organs 1 Blood involvement Leukemia can change into lymphoma & vice-versa Leukemia = Lymphoma C/E - Leukernia 2. IRBCs \WBCs {Platelets -> Pancytopenia ~ Fatigue - Pollar ~ Fever = Petechie 2. Wiseosity of blood 1 Sluggish Circulation 3. LN pathy / Hepato splenomegaly Headache / cranial nerve palsies 4b DR SPARSH GUPTALeukemia - Pancytopenia + Hepato-splenomegaly = Descrete masses in LN or Liver & spleen => Lymphoma Pathogenesis — Immature Process of | MATURE WBC WBC different OR Immature WBC —+ Apoptosis ~ Maturation arrest => cells do not mature properly —~ Rapid rate of proliferation Immature WBC gradually become smaller in size, |Potential of replication Cancer can arise at any stage. tmamature WBC + Mature 4 4 Acute onset/Acute Leukemia Gradual onset H/0 Pancytopenia H/0 Long history ~ Fatigue Chronic leukemia ~ Pollar ~ Fever Short history eg. of - Precursor cell leukernia ~ Peripheral cell leukemiaHSC CE G Wee THD ~ Myeloblast stained with MPO(+) - Stain with TAT (+) ~ Granules in cytoplasm called ~ No Granules in Cytoplasm along Auer rods present with condensed nuclear ~ Exercise proliferation of Myeloblast| - Excessive proliferation of lymphoblast, this this cancer is AML cancer is ALL + Lymphoblast and Myeloblast are also present in bone marrow of normal person. Percentage is only 4-2%. In acute Leukernia, BM has high percentage of Lymphoblasts pli Myeloblast according to wHO> >20%. + 10C in acute leukemia is bone marrow examination. Risk factors-> . Genetic -> . Fanconi Anemia . Bloom Syndrome . Ataxia Telangiectasia . own Syndrome ALL(overal) AML(Age <3 Years) + Acquired~> . Radiation exposure . Exposure to chemical like Benzene| smoking . Infection-> EBV|HTLV-3 . Drugs-> Anti- cancer drugs blastic Leukemia-> * MIC leukemia seen in case of children © C|F-> Sudden onset of clinical symptoms + Fatigue / fever / petechiae + Hepatosplenomegaly / Lymphadenopathy © Sternal Tenderness present © Genetic defect-> Mutation:~ + Hyperploidy / Hypoploidy © Trisomy 4/7/10 + t{32:23); (4523); (4:22). IOC is BM Examination + Hypercellular + Blasts > 20% © Lymphoblast-> Staining Tdt{+) PAS(+) * Blood -> + TLC increases * Decrease Hb © Decrease platelet count © Lymphoblasts + Aleukemie Leukemia-> cancer cells present only in bone marrow, cancer cels,| Lymphoblasts are not detectable in the peripheral circulation. So |OC is BM examination. + Immuno phenotyping- WHO classification of ALL: Lymphoblast Pre-B ALL Pre-T ALL ‘Seen more common ~ Seen less Common Characterized by extensive involvement - Characterized by extensive of BM involvement of thymus Peak age is 3 Years ~ Peak age is puberty Associated with mutation in factors - Associated with mutation in factors liter EBF/ PAX-s like NOTCH gene Good Prognosis = Poor prognosis €D19|20 markers present ~ CD1|2|5|7 markers present Prognostic Factors:-> Better Prognosis Worst Prognosis PLOIDY . Hyperploidy .#(4:22) . (12:21) . . Trisomy 4|7|20 RACE . White - Black AGE . 1-10 Years . <1 Year / > 10 Years GENDER . Girl » Boy No. of CELLS + Less Blasts - More Blasts ORGANS = + Less involve « More —Thymus Nast SUBTYPE + Pre-{B) ALL = Pre- TALL INFILTRATION + Lesser + Higher b DRL SPARSH CATASTEROIDS| DRUGS @) Oo RESPONSE Re> AntiCancer Drugs V -> VINCRISTINE A -> ASPARAGINASE P -> PREDNISOLONE D -> DAUNORUBICIN Methotrexate-> is given to kill tumor cells metastasized in the brain © Intrathecal Route of administration is used to give this drug © Definitive treatment is allogenic Bone Marrow Transplant| — ACUTE MYELOGENOUS LEUKEMIA Risk factors + Anti cancer drugs [strong association] Viruses [poor association] © (8:23) /t (15)47) / inv 16 t (16:26) «© Age + 50-60 years © Myeloblast B) Classification of AML + FAB classification M, + Minimally differentiated AML M, + AML without maturation M, + AML with maturation M, ~+ Acute promyelocytic leukemia M, + Acute myelomonocytic leukenia M, ~ Acute monocytic leukernia 1M, + Acute Erythroleukemia M, + Acute megakaryocytic leukemia + MM, M,, My - stains +ve for myeloperoxidase + M, ~ stains +ve for non specific esperare + -M, = stains +ve for PAS stain + M7 cD43/62 + AML - M, + €(8;21) + chloroma + AML = M, = ¢(35;27) = auer rods +++ t (45:47) 1 PML-RAR gene 1 AVit A activity 1 4 Differentiation of the cells 1 1 immature cells / cancer cells 1 RAR Mucin +++ eHL ine. * a (on 8) (ce ae Endothelial cell damage L Dic 1 DEATHRx - 1. Vit. A (all trans Retinoic acid) t ATRA + Differentiation of cells 2. Arsenic trioxide «© M, - AML + most common type + down syndrome ~ platelet derived growth factor - myelofibrosis © Most common AML is M,-AML [adults] «© Most common AML in infant - M,-AML * Most common AML in Child - M,-AML WHO Classification : > 20% blasts I AML with specific genetic efects + t (8;22) > t (15317) > t (16;16) (best prognosis) Il AML (therapy related) (worst prognosis) Tl AML with multilineage dysplasia + with or without the development of myelodysplastic syndrome (poor prognosis) IV AML (NOS) (intermediate prognosis) . Acute onset of clinical symptoms * — Chloroma t (8:21) + CD45 => CD43 = lysosomes . Proptosis * — Granulocytic Sarcoma © M, & M, > Gura Hypertrophy + Infiltration of the skin (leukemia cutis) . t (15;17) + DIC - death Diagnosis 1. Bone marrow investigation (IOC) + myeloblast 1 - MPO - NSE - SBB 2. — Immunotyping - CD41/é1 - AML - M, * CD45 + AML-M, 3. CytogeneticsCHRONIC LYMPHOCYTIC LEUKEMIA (CLL) > adults * Radiation is not an etiological factor * Chromosom 114 deletion / 17p (-) / 13q(-) / trisomy 124 / Notch - © Mutation in B-cells -> Plasma cell’ -> 1g (abnormal Ig (Function less) ~> 11 infections + (Auto-Ab (IgG) -> AIHA) * Most common leukemic Peripheral smear -> % ¢ ee °? e' Ps =,3) oo Se @ Send Cals q L cal aaa a . ] ‘e Clinical Features :~ ——Gashet 9 CG 6 @ + Elderly 6.8. © Gradual onset t Asymptomatic © Fatigue / cervical LN (+) / Fever (+) © Hepatomegaly / Splenomegaly Diagnosis :~ 1. Blood -> ALC > 5000 cells / ul 1 JHb / 1TLC P/s -> [Smudge cell] Auto-Ab (+) ->[Coombs test] 2. BM Examination -> Hypercellular ; 11(L) cells 3. LN -> gross -> effaced t Proliferation centres oO e poli exotion fh) ®” Ceretnes 4. Immunophenotyping -> B cell tumor -> CD,, (+) Dz, (+) €D,, (+) CD, (+) [BpPreptadderCLL t Additional mutation 1 (aaa Sudden 1 LN Spleen Richter Syndrome :~ Prognostic Factors :~ Poor Prognosis -> 1. 139 (-)/ 17p (-) 2. Zap 70 (+) 3. Notch mutation 4. absence of somatic hypermutation Treatment :- drug of choice — Fludara bine — IbrutinibCHRONIC MYELOGENOUS LEUKEMIA TH Radiation Benzene Most conumon is CML Translocation (9:22) Philadelphia Chromosorne 1 BCR - ABL Fusion Gene 4 ci) ate mer me) wt Formation of 210 KDa Protein 1 1 11 Myeloid ~ Apoptosis Proliferation © Most common is WBC + Then platelets v CML Middle age Asymptomatic Massive enlargement of spleen Hepatomegaly (sometimes) Enlargement of Lymph Nodes (rarely) Investigations 4. Blood . 11 TLC /t Platelets 2. Bone marrow examination © OnDLC +t Eosinophils, t Basophils © D/D + Leukemoid reaction (t LAP score) © IRCML +1 LAP score Hypercellular WBC ~ different stages Retieulin t Histioeytosis having sea blue cytoplasm called Pseudo-Gaucher Cells3. CML -+ Serum B,, tt 4. Cytochemistry -+ 11 LAP score 5. Detection of Philadelphia Chromosome 1 FISH 1 Fluorescent dye is used to do a tagging of gene called ABL gene 2% dye is used to do a tagging of BCR gene L Both colours are present together Detection of DNA Technique used is Southern Blot Stages * Chronic Phase -+ Accelerated Phase + Blast Phase (called triphasic cancer C/A/B) = 1 Mutations -+ becoming more undifferentiated + < 40n + 40-14% + >20% (blasts) (blasts) (blasts) * 3-6 yrs + 6 months + 3 months ~--worsening of clinical-~ ---+ symptoms of patients * sudden enlargement of spleen Sudden enlargement of lymph nodes 1 Blast crisis Blast Phase Lymphoblast Myeloblast (30%) (70%) Pluripotent stem cells (cell of origin) CML - Ph. Chr. ~ tyrosine kinase + Proliferation of tumor cells * Inhibition of tyrosine kinase by Lmatinib, cancer will be treated * It is known by the name of oncogene addictionOo ee PERU MYELOPROLIFERATIVE DISORDERS ® Tyr. @@@ | Proliferation @ Kinase @©@®@ | %, ® + DPATyr. Kinase-> increase cell numbers (RBC/WBC/Platelets) © Myelo fibrosis (Spent phase) + Additional mutation -> acute leukemia Example of Myeloproliferative Disorders:— + CML-» increase WBC + Polyeythernia vera-> increase RBCs + Essential thrombocythemia-> increase platelet + Myelofibrosis POLYCYTHEMIA VERA-> YAK 2. Tyr. Kinase (+) Valine -> Phenylalanine 617 Position : + Increase RBC's; increase WBC / Increase Platelet eres viscosity increases risk of bleeding Responsible abe For Neurological Symptoms Periph. Circulation Hepatic vein thrombosis. Increase venous thrombosis — { Arterial thrombosis Deep Vein thrombosis Pt. also have- Increase neutrophils-> increase LAP Increase basophils-> Histamine ) Lead to © Pruritis * Flushing «Peptic ulcer disease Diagnosis:-> YAK 2 mutation (+) Increase Hb EPO -> RBC increase -> Hb Increase t oO + Low levels of Serum Ep.Dehydration (N) (Nn) (N) pv at v (N) COPD/ High Altitude £ t v Ectopic Epo t tt (N) PY Proceeds to Acute leukernia Rx + Phlebotomy * Drugs ESSENTIAL THROMBOCYTHEMIA -> YAK 2 Mutation -> Most common MPL Mutation Calreticulin Mutation Essential thrombocythemia -> Increase Platelets atu Increase venous thrombosis Increase bleeding Ery thromelegia-> occlusion of . Decrease transform. PRIMARY MYELOFIBROSIS-> JAK 2 Mutation > MPL Mutation Decrease spent phase ; small vessels ation to leukemia Increase no. of neoplastic megakaryocytes BM fibrosis/ increase collagen Ineffee. Epo C3 Oa TEAR -VROP Ree E|M|H Increase in size of spleen Leukoerythroblasts (immature RBC's / WBC's) BD va sresicuerPrimary myelofibrosis Teardrop RBC Classical triad Ab. (N) Platelets| Leuco-ery blast ‘es BMA v Dry tap + CML- ow ET ° 2° MF Bone Marrow examination decrease LAP } Increase LAP BM Biopsy Investigation of choice}Myelodysplastic Syndrome ~ Characterized by Hyper cellular Bone Marrow and presence of cytopenia OT 88 edo “ Matunation defect Mutation’ NEFF. ERVTUROPOELSIS ~ Subtypes of MDS Eg. of pt. having H/O Exposure to Drug therapy / Radiation + After 2-8 Years 4 MDs ~Genetic Defects-> ~ Chromosome Sq (-) -> Seen in Adults pts = Monosomy 7-> Seen in children ~ Trisomy 8 -> Chromosome no.8 is going to be having presence of growth factor or proto oncogene known as MYC. - 3 copies of MYC-> More Proliferation of cells but these cells are not able to mature MDS” RBC WBC Platelets 4 Yaga ye ae @ Sideasbbots Youn- dal Mega tanger re LaddC/F :> Fatigue / Petechiae / fever Dx-> 2) BM — Hyper cellular 2) Peripheral smear — Pancytopenia, cell living reduced, Ringed sideroblasts, Pseudo Pelger Huet cell, Pawn- ball Megakaryocytes Re-> 1) Allogeneic Bone Marrow Transplantation ( In young pts) 2) Azacytidine (Safe derivation is decitabine) -» (-) DNA Methylation 3) Lenalidomide (used in pts having 5q (-))HODGKIN'S LYMPHOMA LYMPHOMA Lymphoma Hodgkin's Non = Hodgkin's © Characterized by involvement of ~ Lymph - node involvement lymph nodes + No extra nodal involvement ~ Extra nodal involvement like liver, Spleen * Cervical and mediastinal lymph nodes - Waldeyer's ring and mesenteric Affected group of LN involved © Contigous spread = Non = contiguous spread + Staging relatively predictable ~ Staging relatively unpredictable * Good prognosis ~ Poor prognosis HODGKIN'S LYMPHOMA Etiology + Epstein Barr Virus (EBV), other factors! Beell > LLNE-KB = T cancer cells GC / Post G ALI-KB REED STENBERG CELL Classical RS Cell + 15-45 in diameter ' * OWL ~ EYE APPEARANCE ' * CD45+/ CD 30 + for identification on surface of RS Cell * Presence of Aneuploidy + -+ more than normal number of copies of chromosome 2p VARIANTS OF RS Cell 1, Lacunar Cell * Associated with release of TGF-B 2. Mononuclear Cell ~ Single nucleus ~ Prominent nucleolus 3. Lympho — Histiocytic Cell / Popcorn Cell + Irregular indentation in nucleus + No prominent Nucleoi * CD15 / CD30 absent © CD20+marker/BCLé +Cytokines and Chemicals Secreted by RS Cells RS CELL Cytokines 4 + 4 © IL -43 +1 REEDSTENBERG CELL * IL-5 1 EOSINOPHILS * TGF B- ~ Bands, nodule formation + M-CSF +1 Monocytes HL -+ RS Cell + Inflammatory Cells RS — like cells seen in : * Infectious mononucleosis © Solid tissue cancers © Immunoblastic ymaphoma CLINICAL PRESENTATION OF HODGKIN'S LYMPHOMA + Painless, rubbery lymph node + 4 Cervical 1 Cervical lymphadenopathy * Constitutional syraptoms + Fever ('B' symptoms) + Night sweats + Weight loss PEL ~ EBSTEIN FEVER SLA + Para neoplastic syndrome 1. Pain in affected LN after Alcohol consumption 2. 2! Amyloidosis INVESTIGATIONS 1. CUTANEOUS ANERGY 2. Excisional lymph node biopsy t Microscopic Examination Classical HL Non classical HL 1 1 RS Cell CD 1s+ cD 15/30 - cD 30 VARIANTS OF CLASSICAL HL 4. Nodular Sclerosis = Most common H in world = Equal in both male and females = Nodules + (lacunar eel) ~ Young Adults more commonly affected2. Mixed Cellularity HL = M/C HL in INDIA = RS Cells / Plasma Cells / Eosinophils / Lymphocytes = Mononuclear RS Cells + ~ BIMODAL DISTRIBUTION = Young Adults, > 5 years - Maximum development of 'B' symptoms Mix. Cell HL + BHARAT ® +B" symptoms ++ = Bimodal distribution 3. LYMPHOCYTE — RICH HL ~ Elderly pts - RS Cell + Mononuclear RS cell (Predominate) ~ Better Prognosis TRS Cell - Poorer prognosis Tt Lymphocyte - Good prognosis 4 LYMPHOCYTE - DEPLETED HL ~ Elderly pts = HIV + pts = Hodgkin Cells + (Atypical Histocytes) - WORST PROGNOSIS NON CLASSICAL HODGKIN'S LYMPHOMA 1 © RS cell - CD 45/ CD 30 - cD 20+ «BEST PROGNOSIS © Popcorn Cell / LH ~ Cell + (METASTASIS OF HL NODAL DISEASE > SPLENIC TISSUE > LIVER > BONE MARROW DISEASE TREATMENT OF HL + Anti cancer Drugs A ~ Adriamycin B — Bleomycin V = Vinblastine D — DacarbazineNON HODGKIN LYMPHOMA Parts of LN - Mantle zone -> Mantle zone lymphoma = - Germinal centre -> Follicular, diffuse large B cell lymphoma, CA Burkett’s lymphoma = Marginal zone -> Marginal zone lymphoma Mune Ge "Rene ae id tn 2) Mantle zone (ymphoma ~Arise from naive ‘B' cell ~Translocation (14, 14) -> Cyclin D2 + (Overactivity) + + Cells 4 Tumor development C/F:- Diffuse Lymph adenopathy LNB, -> CDS (+) €023 (-) Cyclin D, (+) -> IF absent 4 SOX-11 2) Marginal Zone Lymphoma [—— Malt -> Gi tract / respiratory tissue Site of origin Extranodal -> Orbit / Stomach = Its an example of indolent tumor - development -> Chronic B cell stimulation HPylori Auto immune disorders (Rheumatoid arthritis) (Sjogren syndrorne /Hashimoto thyroidiotis) 4 ‘Translocation (24;48) Initial stage -> good response with antibiotics Late stage -> Antibioties doesn't work ~ Alternative modality MC site for Malt tissue -> lleurn MC site for malotoma in Gl tract -> Stomach If the tumor cell already have a presence of t(21;18) => Less response to chemotherapy GEPreptadderGerminal centre @) Follicular lymphoma (24,38) MLL-2 mutation i Responsible for causing tt bel-2 (anti apoptotic gene) Mutated B cells should die by process of apoptosis 4 Over expression of bel-2 ‘ Mutated B cells survive ‘ Formation of follicles in LN ~ Painless enlargement of LN (+) ~ Indolent D, — immunophenotyping €D29/20 (+) BCL-2 (+) eps (-) ~ Centroblast, Centrocytes are +nt -> Buttock cells Follicular Lymphoma -> acquire additional mutations -> Diffuse large B-cell lymphoma ) Diffuse large B-cell Iymphoma - 50% -> idiopathic - 30% -> BCLtt-6 - 20% -> H/0 follicular lyraphomma M/C — subtype of Non-Hodgkin Lymphorna Seen in person [— Imnunosuppression (HIV / Transplant) -> EBV Human herpes virus subtype-8 (AIDS) -> 2° effusion lymphoma accusation Follicular [ymphorna —eaubaions diffuse large B-cell lymphoma ¢) Burkitt's Lymphoma * t(8;14) -> t c-myc gene -> tf mitosis * (2:8) * €(8;22) ~ associated with tumor lysis syndrome Dx > LNB. ~ dark background in the slide because of rapid proliferation of the tumor cells 4 associated with phagocytic cells or the macrophages try to destroy or eat tumors (Starry - sky appearance) ~ Associated with Burkitt's lymphoma 4 DR SPARSH GUPTA3 Subt Enderaic Sporadic Hiv - 100% - EBV ~ seen in developed world 4 immunity ~ Jaw bones & = abdominal mass (+) maxilla affected ~ ent in Africans Prognosis => worst HAIRY CELL LEUKEMIA ~ B-cell tumor - Characterised by involvement of bone marrow, spleen, liver -M>F CLE - massive splenomegaly (red pulp of spleen involved also seen in hepato splenic lymphoma ~ Infections (Atypical raycobacteria) D,-> 4. Blood investigation ~ Pancytopenia Phase contrast microscopy -» Hairy projections Staining -> TRAP (+) 2. lmmunophenotyping - CD11 (+) - CD25 (+) - CD103 (+) = ANNEXIN A - best marker for identification 3. Bone marrow examination BM aspiration Bm B, 4 Dry tap ~ Honey comb appearance/ Fried egg appearance R, — DOC — CladribineCutaneous T-cell lymphoma CD, T cell tumor —, Blood Skin + 4 SEZARY SYNDROME EPIDERMO TROPISM Responsible for formation of Pautrier's microabscess 4 Mycosis Fungoides S> LN> BM 869.0007, eeu 3 CEREBRIFORM 00 0% vers t+ » 92 " 8.008 ¢ if cerebriform nucleus tnt in oo Blood ‘Skin Sezary Syndrome Mycosis Fungoides Predilection for involvement of skin 4 Exp. OF CLA (+) / CCR4 / CCRIO Associated with Generalised exfoliative erythroderma Anaplastic Large Cell Lymphoma ~ Child / young adult ~ Hallmark cells / Horse shaped nuclei with lot of cy ~ CD30 (+) -> means anti CD30 (+) is useful for management Prognosis => Good 4 DR. SPARSH GUPTA,LANGERHAN'S CELL HISTIOCYTOSIS ~ BRAF mutation (+) ~ Arise from Langerhans cell birbeck granules +nt 4 Tennis racket appearance Markers -> CD1a / S-100 / HLA-DR 1-> Letterer-siwe disease =< 2yrs = Multifocal, multi systemic ~ Lytic lesions (multiple bones) ~ Skin lesions (seborr dermatitis) 2-> Eosinophilic granuloma = Unisystem Exopthalmos Calvarial defects 3-> Pulmonary Langerhans cell histroicytosis ~ Adult smokers ~ Disease regression if - X smoking Diabetes Insipidous Hand Schuller Christian triad [BpPrepLadderPLASMA CELL DISORDERS Plasma Cell Dyscrasias: Plasma Cells: + Coming form 8 cell Agt secretes © Bell —>Plasma cell Ye Ig (L/H) (Polyclonal Ab) + Mutation of plasma cell + overproduction (L/H) 2 AKA + Monoclonal Gammopathy + Paraproteinemia * Protein Electrophoresis * tmamunofixation Electrophoresis * Quantity of protein = Quality am | -ABBEL ae | wth sae 8 \eevlarataaniie ay nT u be Gal + on cc i } il MI Classification ul | MONOCLONAL GAMMOPATHY * MGUS Monoclonal Gammopathy of unknown significance * Multiple Myeloma [ overproduction of both light & heavy chains but light chains are produced more in comparison to heavy chains] * Lymphoplasmacytic Lymphoma (1 in no of plasma cells & lymphocytes) * Heavy Chain Disease (Predominant production of heavy chains of Ab) Coramonest: MGUS|re MULTIPLE MYELOMA ~ Involvement of multiple sites in the different bones of skeletal system ~ It is example of monoclonal gammopathy = Overproduction of light chains/ heavy chains = Commonest heavy chain produced -> Garama and alfa chain Pathophysiology Beell 4 Mutation t Bone marrow plasmacytosis # Chromsosme 134 deletion, sometimes chromosomes 17p deletion # Translocation of chromosome 11 and 14 + IL-6 secretion 4 (+) Plasrna cells Replacernent of the IL-6 / TNF-« cells of Bone marrow secretion + + Pancytopenia + Osteoclast } Osteoblast 4 Pathological fractures (vertebral coloumn > Ribs > Skull) ‘ v ‘ Backache Painful Headache Punch ’ respiration out Lesions * Hypercalcemia * Normal Alkaline Phosphatase Activity M Proteins + Bleeding + Coagulation defects 1 Viscosity of blood -> Neurological Manifestations 4 Infectious -> Death Light chains overproduction Extra light chains toxic to kidney cells -> Renal failure Light chains -----~> Arnyloidosis Light chain in urine -> Bence Jones Proteins Multiple Myeloma --> 1% Patients ---> Non secretory MM (BPrepLadderNormal Plasma cell -> Cart wheel Nucleus Com? ""“" 2) Bone Marrow Biopsy -> Investigation of choice Bone marrow plasma cells > 10% + A) Presence of any one of the myeloma defining eventsl » (B) A- Evidence of Tissue Impairment C- Hypercalemia (Ca is > 13mg /dl) R — Renal insufficiency A -> Anemia (<10g / dl) B -> Bone lesions (2 4 Lesion) B-> 24. out of following should be present } = Clonal plasma cell > 60% >1 focal lesion (MRI), >Smm Serum Involved : uninvolved free light chain ratio > 100, 2) Blood Investigation -> ttt ESR Normocytie/normochromic Anemia tt Serum calciurn Normal Alkaline Phosphatase levels Serum and urine protein detection Immuno fixation electrophoresis--» serum protein electrophoreses 3) Urine Investigations -> Bence Jone's Proteins detection Heat coagubility tests 4) X rays -> Skull Spine Show osteolytic Lesions Pelvis 4 DR SPARSH GUPTA5) lmmunophenotyping -> Normal ----> CD44 / 38/ 45 (+) Plasma cells (MM) -----% > CD138 (+), CD45 (-) €D29 (+) or CD39 (-) cDs6(-) cDse(+) Monoclonal proteins -> Electrophoresis -> M SPIKE MM ~--> IgG (Produced in maximum amount) Treatment:- Lenalidomide + Bortezomib Steroids Diffrential Diegnosis 2. Monoclonal gammopathy of unknown significance (MGUS) ~> Asymptornatic ~> Characterized by -> BM plasma cells <10% -> Para proteins is <3g /dl 2. Smol dering Myeloma -> BM Plasma cells (10-60%) -> Slight elevation of para proteins >39/dl ~> No Myeloma defining event >6O% 10-60% >39/dl MDE not seen Plasma cells <120% Para proteins <3/dl MDE (+)WALDENSTROM'S DISEASE AND HEAVY CHAIN DISORDERS Lymphoplasmacytic Lymphoma (WALDENSTROMS Macroglobulinemia ~ Associated with MYD88 Mutation ~ Presence of M Spike ~ Presence of increased Ig M in blood Multiple Myeloma L) Ig Grr IgA 2) Proliferation of plasma cells 3) Higher chance of :~ - Hypercalcemia tt C_] = Renal dysfunction + R ~Anemiae +A ~Bony Lesions = +B 4) Splenomegaly is not present Heavy Chain Disorder 2) Alfa Heavy Chain Disease (SELIGMANN Disease) ~ Presence of Mediterranean Lymphoma ~ GI tract Involvement >> respiratory tract ~ Most common example of HCD common: Lympho palsmacytic Lymphoma IgM Proliferation of plasma cells, lymphocytes, Mast cells Normal Serum Calcium © normal R. A. BL Less Common Hepatomegaly/ Splenomegaly Present 2) Gamma Heavy Chain Disease (FRANKLIN'S Disease) ~ Lymph Node enlargement = Splenomegaly/ hepatomegaly ~ Fever, Malaise ~ Anemia = Involvement of WALDEYER'S Ring ~ Palatal edema - Rheumatoid Arthritis 3) Meu (u) Heavy Chain Disease = Patient Suffering from CLL (Chronic Lymphocytic Leukemia)ee # Bleeding Di Normal hemostatsis- Extra loss of blood prevented by hemostatsis Components * Blood vessels ~*_ Vasoconstriction + Platelets ___y Temporary hemostatic plug + Coagulation cascade» Permanent hemostatic plug Platelets + Endothelial cells WGG@REGATION injury tien Expression of von willebrand factor wT i yc (weibel-palade bodies) 1 as UE 6 eo viv. ee | sssin Appears on surface of endothelial cells wig i ~ Platelet have expression of surface molecule -> Glycoprotein 18 interacts with Von willebrand factor Attachonent of platelets with endothelial cells k/as PLATELET ADHESION Platelet. iad activated Change in shape of platelets Release of granules (degranulation) Epc of molecule on surface GP Ib Additional platelets at site + Facilitated by fibrinogen (protein molecule) 1+ GP 16 Platelet Aggregation (temporary hemostatic plug-weak) 2 Adhesion ~ Gp Lb; VWE 2 Activation — Degranulation ; TA, ADP 3 Aggregation - Gp 1.b ; fibrinogen Activation of coagulation cascade 4‘ Fibrinogen + fibrin (stand like molecule) (Soluble) (stronger bond formation Insoluble) FUNCTIONAL PLATELET DISORDERS + Bleeding * Normal platelet count * Défect in adhesion / activation / aggregation [Bbrreptacder1 Adhesion defects Malfunctioning Gplb Wwe 1 4 BERNARD SOULIER ‘W Disease DISEASE [peripheral smear-GIANT PLATELETS] 2 Platelet activation defects Drugs responsible for inhibiting -TA, > Aspirin -ADP -> Clopidogrel 3. Platelet aggregation defect Me ion Gp I1.b fibrinogen 1 GLANZMANN'S Hypovinogenemia DISEASE Investigation Platelet defects * tin bleeding time (time taken for bleeding to stop) Clotting defect + Prothrombin time, activated partial thromboplastin time + PT -> indicator for extrinsine pathway + aPTT -» indicator for normal functioning of intrinsic pathway H RD! Platelet defects + superficial bleeding (skin/mucosa) * Petechiae (Ab —> platelet Ag formation Platelets ———————> Circulation Coated wtih antibody ¥ Splenic phagocytosis Clinical Features = Gum bleeding /Hematuria / Melena - Petchiae - Purpura - Acute TP - Hemorrhagic bullae = MIP = Diagnosis of exclusion = Spleen size - normal - BTt - Platelet comp. reduced 4 - Pt. Normal apTT - Coorab's test positive - BM examination - Megakaryocytic thrombocytopenia Management - Acute - symptomatic management - Chronic - Wg ~ SplenectomyHEMOLYTIC UREMIC SYNDROME (HUS) + It is of 2 Types + 1" subtype is typical HUS - Acute gastro enteritis (E-Coli 0157/H7) Shigella dysenteriae 1 Release toxin 1 Platelet rich thrombi + 2% Subtype is atypical HUS Atypical HUS:~ + Mutation of © proteins (CD,, / Factor H) + Drugs < Mitomycin & Ticlopidine 1 Platelet rich thrombi Hus:- Renal Failure = or RAT Syndrome MAHA ————> Thrombocytopenia C/E * Child -> H/0 Diarrhea (Bloody) 1 Renal Dysfunction + purpura Diagnosis: * BT Increase PT & Normal + aPTT, ‘Treatment: - Dialysis THROMBOTIC Thrombocytopenic Purpura (TTP) Normal individual + Liver- secretion of ADAMTS 13 (protease) ~ damage to VWF clurmps Diseased :- * Deficiency of Adamts 13 (UPSHAW- SCHULMAN Synd) increased von- willebrand + AB Formation -» ADAMTS 13 factor clumping 1 Drugs Platelet- thrombi +++ cre Decrease P/C Renal failure MAHA CNS Feature Fever fi] Pr ‘Treatment:~ Removal of Auto-Ab by Plasmapheresis .. f * It is an example of (Thrombosis Hemorhagic Disorder) Dead fetus 2 Obstetri¢ causes :- X Placenta (Retain) Amniotic Fluid embolisen 2 Infections: - 3. Cancer, Malignancies Stomach AML-M, Colon Pancreatic 4. BURNS / Surgery / Trauma Pathogenesis:~ cause + Obstetric + Infections endothelial cell injury * Cancer 1 Which is responsible for widespread thrombi * Surgery/ Burn / Trauma 1 Tissue Factor 4° Event |[(widespread thrombi +++) or Vascular occlusion) = Platelets/ clotting Factors consumption = Ischemic damage ~ Plasmin Activation - Miero-Angiopathie Hemolytic Anemia (MAHA) increased risk of Bleeding (2° Event) fed Oo BERMY Se ope Diagnosis :-> + Decrease Hb; decrease P/C. Imerease LDH Increase Bilirubin + P/C-> Schistocytes (+) (MAHA)-» Microangiopathic Hemolytic Anemia) + BT- increase PT- Increase aPTT- increaseFibrinogen :->D-E-D (Fibrinogen) 4 D-E-D=D-E-D 4 1 1 D-E-D = D-E-D 1 Plasmin Active (+) D=D (D-DIMER)<- called — * D-Dimer: - St is suggestive:- 4 = increased plasmin bic - Fibrin Clinical Manifestation/ Features:~ 1. (Brain)-> Most common affected 2. (Cardiac tissue)-> decrease \cardiac output (Co) \decrease Dyspnea 3. (Kidney)-> ATN 4. Adrenal gland -» Hge +++ (Meningococcemia) 4 | WATER HOUSE ~ FRIDRICKSON SYNDROME Rx :-> Treatment of primary cause Sw sunsscieFactors-> ‘Most common Hemophilias Hemophilias -A Factor- 8 1 Liver -> Sinusoidal endo. Cell &e KUPFFER CELL Kidney -> Tubular Epithelial Cell Hemophilia A is an x- linked disorder. = 90 %-> Decreases ~ 10 %-> Functional defect of factor-8 = Intrinsic pathway Affected. tf Factor 8 ~ Mild :-> 6-50% - Moderate: ->2-5 % Factors 8 ~ Severe: -> < 4% Factor 8 cle -> ~ Child (male>>>female) ~ H/O Trauma 4 Result in ——Hemarthrosis Hematoma - H/0 Bleeding +++ Circumelsion Todt Extraction Biagnosis:~ 4. P/C -> Normal & PT-> Normal BT -> Normal & PTT- Increases 2.Factor- 8 Levels -> Decreases Desmopressin ‘Factors -> Humate Cryo Precipitate.~ Caused by Decreased factor -4 Also called christmas factor = So this is also called as “Christmas disease” ~ It is also an example of X- linked recessive Diagnosis:- BT PIC PT aPTT 1 1 1 1 Normal Normal Normal Increases Buz 1. Factor @ 2. Fresh Frozen Plasma Factor Inhibitors :-> ~ Antibodies -> Decreased clotting factor activity Factor :-> 1. Recipient -> decreased clotting factors 2. Pregnancy 3. Autoimmune Disease / Disorders 4. B-Cell cancer. Diagnosis Isolated increased aPTT Add If Heparinase Add Heparinase if 1 Norvaal aPTT Increase aPTT t = Hemophilia = Factor Inhibitor. (4:2 Patient & Normal Plasma) Hemophilia Factor Inhibitors 4 t Normal aPTT 11 Increased aPPT (delayed Prolongation of aPTT)YON WILLEBRAND DISEASE YON WILLEBRAND factor (WWE) = It comes from Endothelial cells - From megakaryocytes } pet Sources = From hepatocytes (v.small) # gene for it is present on chromosome number 12. 4. Transport of factor Vill. — higher half life th = 2.4 hours 1 WF (enhance the half life) t % = 42 hours 2. Platelet Adhesion wwe {Platelet Adhesion Untrinsic Pathway Activity 1 1 TBT VaPTT ‘SUBTYPES * Type | WWD - vWF * Type tl wD * Type Ill WWD - WWF Type . vWD -> WWF ~ Most common ~ Autosomal dominant, mode of inheritance Type lll. WD-> 11) VWF = Most severe forma - Autosomal recessive mode of inheritance ‘Type Il. WD -> ~ Normal WF levels ~ Qualitative defect = It also has sub types -> (2A) most common | 28 2C|2D ~ Autosomal dominant mode of inheritance cnt . 1. Mucosal bleeding (Petechiae / Purpura / Epistaxis) 2. Tissue bleed ( race) Diagnosis:- P/C ~ normal (N) PT — normal (N) wp BT — Increased ( + ) aPTT - elevated (1) [PrepLadder* RISTOCETIN AGGLUTINATION TEST (RAT) Ristocetin _—_——————- ow) GPIB & V WF <> = 5 Ritoce hn rarer RISTOCETIN TEST :~ Formalin fired platelets + PLASMA (person) Ristocetin Normal people -> RAT (+ve) ~> aggregometel WD person -> RAT (~ve) Fini ’ *6T ;apTT * PT(N); P/C(N) * RAT (-ve) * WE Assat Management - Desmopressin — to stimulate the release of vWF from endothelial cells (in middle case) ~ Cryoprecipitate — In serve cases A DR SPARSH.GUINTRODUCTION TO GIT Gastro Intestinal Tract Histologically, 4 layers are seen + Mucosa -+ Epithelium + Submucosa - Presence of nerve plexus- Meissner’s Plexus + Muscularis Propria + Inner layer ~+ Circular muscle Auerbach's Plexus / Myenteric Plexus + Outer layer + Longitudinal muscle © Serosa + It is -ve in esophagus Meissner's Plexus :~ Associated with secretory activity of Gastro Intestinal Tract Auerbach's Plexus :- with motor activity of GITINTRODUCTION = 25 ems (adults) CONSTRICTIONS 1. 6" (15 cms) — upper esophageal sphincter 2.4" (22.5 ems) ~ Aortic arch 3. 12" (275 ems) ~ Left Bronchus 4. 16" (40 ems) - Lower esophageal sphincter MOST COMMON SITE FOR ESOPHAGEAL PERFORATION M/C site — Upper Esophageal Sphincter (UES)- ETIOLOGY UES ~ latrogenic — Instrumentation + Stratified Squamous Non-Keratinised Epithelium LES Dysfunction » When LES is not working properly Les REFLUX ESOPHAGITIS * Inflammation of esophageal mucosa CAUSES + TLESR - Transient Lower Esophageal Sphincter Relaxation © Smoking j © Alcohol + Obesity * Overeating Some uncommon causes- © Pregnancy * Hiatal Hernia CLE of Reflux Esophagitis © Retro Sternal Chest Pain (Burning) * Sour Brash * Teeth Discoloration + Reflux Esophagitis also known as gastro esophageal reflux disease (GERD) [BPreptadderDIAGNOSIS. 3. 24 hour pH study 2. MANOMETRY ~ Decrease of pressure at level of LES 3. Endoscopy + Biopsy Stem Cell Stratified Squamous Epithelium Intestinal Columnar Epitheliun ——>_ METAPLASIA. ——> BARRETS ESOPAHAGUS . : Eg. of intestinal columnar metaplasia al Banret '5 ea 1 re esophagus Dysplasia _ 1 ee teeter Cancer + IF unchecked for longer time can result in formation of Adenocarcinoma MANAGEMENT OF BARRET'S ESOPHAGUS / REFLUX ESOPHAGITIS 2. 1 HCI + Protein Purnp inhibitors 2. Prokinetic drugs — drugs which increase / stimulate peristalsis 3. Surgery + Fundoplication DIAGNOSIS ICE. + Goblet Cells@ LvsALCOHOL INDUCED ESOPHAGEAL DISORDERS Alcoholics =H Mallory Weis Tear BOERHAAVE SYNDROME F MeN i aS Muscle Affected (Muscle ruptures) = 4.GE junction (most common location) ~ Chest pain - Hematemesis - S/C emphysema (BprepLadderACHALASIA CARIDA + Motor disorder + Absence of relaxation in esophagus + Narrowing of lumen in lower part of esophagus Histology of GIT Stimulatory neurons Inhibitory neurons 4 4 + T Smooth muscle contraction = Secretion of Nitrie Oxide / vi active Intesti i + Secretion of substances Acetyl Choline P (vaso -active Intestinal Peptide) + Loss of inhibitory neurons High muscle tone Improper motility Or Abnormal Types Based on Cause Primary Secondary = Cause is unknown = Damage to neurons / infections CHAG'S DISEASE (Trypanosoma Cruzi) - Varicella Zoster Virus CLE © Dysphagia (L. >>> S) Solid + greater force of gravity Liquid - small sips, required pressure not generated + Weight loss +1 time taken by food to pass Secretion of toxins Irritation of esophageal epithelium CHRONIC rerranow Followed by CHRONIC INFLAMMATION Dysplasia Malignancy © IF not treated on time -+ esophageal carcinomaDIAGNOSIS SPARSH GUPTA 4. 10C = Manometry -+ high tone of LES 2. Barium Swallow = Tapering of lumen tne - Bird beak appearance Treatment 2a 1. Drug Therapy —=— AIM: Relaxation of muscle 4 t Decrease activity of Acetylcholine Muscle relaxants 1 = Calcium Channels Blockers BOTULINUM Toxin (in affected part of esophagus) 2. Definitive Treatment = Decrease pressure 1 SURGERY 1 HELLER'S MYOTOMY (Cut open muscle) Covaplications 4. Aspiration Pneumonia = Most common 2. Chronic AC +1 SCC - Less common = DangerousESOPHAGEAL CANCER Esophagus lined by stratified squamous epithelium Barret's esophagus lined by intestinal columnar epithelium Microscopic / hiostologic variants Adeno carcinoma - M/e type - Lower 3/3 - Developed countries, USA = Squamous cell carcinoma ~ M/c subtype = Upper or middle 1/3" = INDIA, developing countries Risk Factors For Squamous Cell Cancer Smoking / alcohol Intake of nitrosamines (food preservative, grilled / Smoked food) Chemical Carcinogens Intake of HOT drinks Chronic Achalasia Carida (motility disorder, muscle tone 1, Release of toxins, irritant to esophageal mucosa) Pluramer Vinson Syndrome Tylosis et palraris Deficiency of Zn / Mb / Vit. A/C PLUMMER VINSON SYNDROME Aka Patterson Kelly Brown Syndrome More common in females, middle aged Classical Triad IDA Atrophic glossitis (Red beefy tongue) Esophageal webs - abnormal protrusion from the upper esophageal lining ay For Adenocarcinoma ~ Barret's esophagus identified by pressure of goblet cells ~ Obesity ~ Difficulty in passage of Food bolus ~ Dysphagia = T time taken in passage of food t Irritation to esophageal liningTylosis et Palmaris * Congenital + Hyperkeratosis of palms and soles (thickening) * Abnormal differentiation of squamous lining of esophagus C/E of esophageal cancer + Malignancy 1 Abnormal Growth 1 Narrowing of lumen 1 Dysphagic (solid >>> liquid) 4 (ignorance of signs) Dysphagia worsens + Hallmark presentation 2. Weight loss 3. Chest Pain 4. In advanced stages, involvement of: ~ Hoarse voice (RLN) ~ Cough (tracheal infiltration) DIAGNOSIS 1. Endoscopy with Biopsy = 4 anatomical narrowing (Normal) ~ Additional narrowing (abnormal) Biopsy Findings malignancy (a) Goblet cells Colummnar epithelial cells 4 Adenocarcinoma (b) Squamous cells 1 sce2. Barium Swallow Metastasis * Liver (commonest site) * Regional LN = Upper 2/3" -+ Cervical LN ~ Middle 1/3" + Mediastinal LN Tracheo bronchial LN = Lower 2/3" = Cardiac or gastric LN/ Celiac LN Spread of cancer facilitated by absence of serosa Prognosis * Poor Treatment © Surgical + Partial or total esophagectomy RAT. TAIL APPEARANCE* Parietal Cells + IF ~ HCl (Ach / H / 9) * Chief cell -» pepsinogen * Foveolar cell -+ mucin + g - cells (Antrum) + gastrin + Gastrin -» HCI secretion * Epith. Regenerative capacity tt * Mucus * HCO, * Prostaglandins * COX = responsible for prostaglandin synthesis * NSAIDS inhibit COX - fran.ACUTE AND CHRONIC GASTRITIS ACUTE GASTRITIS: - Alcohol -~ dilatation of gastric mucosa = Drugs + NSAIDS / Cancer Chemotherapy drugs = Uremia — t amount of urea in blood ~ Stress -» ICU Bums = curling ulcer ICT t (cushing ulcer) CHRONIC GASTRITI: = Hpylori / Auto.imm / uremia / radiation / GVHD Type ‘A’ gastritis (8%) Autoimmune gastritis» CD4T cells@ ‘ * involve. OF fundus & body PC damage Of stomach + Achlorhydria + G cell stimulation * t Gastrin levels * t neuroendocrine tumor . TA ‘Type 'B' Gastritis + (22%) “Most cormonly involves antrum Hpylori 4 Urease / + Cag A —~ VAC-A a Gastrie inflammation H pylori with silver stain \ Duodenal ulcer Gastric / Stomach Cancer Reactive T — cells ‘ Factor 4 Polyclonal B ~ cell Proliferation + Maltoma Maltoma baat (BpPreptadderPEPTIC ULCER DISEASE = Uleer : damage to mucosa ~ Seen as a case of chronic gastritis = Commonest site - first part of duodenum (duodenal cancer) ~ Next site - at stomach (antrum —~ lesser curvature) | ~ Third location - near Gastro-esophageal junction 125 * First part of duodenum D1, + Presents at level OF lesser * Mostly anterior wall. curvature * Associated with H.pylori +++ (Body-Antrum junction) Infection * Hpylori + / NSAID, Smoking *Characterised by Hypersecretion | * Acid Secretion - normal OF acid * Food -» | Pain * Food + t Pain * Weight Gain * Gradual weight loss Biopsy t Brunner Gland COMPLICATIONS 1. Bleeding +» Duodenal Uleer [source : Gastro duodenal artery] > Gastric ulcer [left gastric artery] Bleeding :- Most common Complication * Hematemesis :~ Gastric ulcer | * Melena :~ Duodenal Ulcer 2.Perforation Peritonititis DEATH Perforation :- Commonest Complication resulting in mortality3. Gastric Outlet obstruction (more Fibrosis leading to obstruction) 4 Taking place at DL 1 Repeated episodes of vomiting —_ 4Het A Fluid * | Cl- in blood 4 * Metabolie alkalosis Intravascular dehydration +4 K+ (blood) + * Aciduria Activation of RAAS 4 t Na+ / water retention (4 K+ 7 He in body) + UrineGastric Outlet Obstruction Da. + Adult -» Stomach Cancer := Commonest site Malignancy * Duodenal Uleer :~ always benign * Gastric ulcer :~ can be associated with cancer, Malignancy DIAGNOSIS 1. Urea Breath Test 4 UREA (radio labelled) Put a breath analyser 4 Water ‘*H.pylori > Urease [ Urea 14 C02 14 2. Endoscopy + Biopsy [Most confirmatory diagnosis] Benign Malignant * Small ulcer * Big in size * Flat margins * trregular folds * Regular folds * Prominent margins * No necrosis / (heaping margins) Hemorrhage + Greater curvature * Presents mostly at lesser curvature 3.CLO Test ~ Indicator medium having dye = Discoloration indicates +ve test 17 = Useful in detection of H.pylori Ss; ) Red Trea i= 1 Proton Pump Innitor 2 Antibiotics Triple drug therapy L DR. SPARSH GUPTAGASTRIC TUMORS Most common benign tumor ~ Leiomyoma Most common malignant tumor + Adenocarcinoma Most common malignant tumor which bleeds + Leiomyosarcoma Most common mesenchymal tumor Gastro intestinal stromal tumor (GIST) GASTRIC ADENOCARCINOMA: Risk Factor: = Smoking / Alcohol ~ Nitrosamines - HPylori Oo - Autoimmune gastritis Oo Oo = Blood Group A - H/O Previous gastric surgery ~ Nutritional Deficieney ~ Menetrier’s disease —(Fov. Cell 111) = CDH, mutation ~ E-cadherin = APC gene mutation + 1 adenomatous polyps Most common location for stomach cancer : Antrum Clinical Features: - Early satiety or Post prandial heaviness (earliest sign) ~ We. loss (M/C) ~ Abdominal Pain DIAGNOSIS : Endoscopy + Biopsy (Investigation of choice) Classification * affects Mucosa / Submucosa * Good prognosis Lauren's Classification Intestinal Type Diffused Type * Localised cancer * Diffused infiltration (tumor cell separates out from each other) ca © 0 o > dill infiMaation 90 @ * Covamonly associated with APC * CDH, mutation mutation + 4 (Codes for E-cadherin) Spit. * Better Prognosis * Poorer Prognosis Best Prognosis : Superficial spreading type; Metastasis Organs involved: 9 vibes * Liver - (M/C) r a panko * Lungs | * Ovaries - (B/L) [KRUKENBERG TUMOR] | 5) * Lymph nodes i ond edale, 2. Virchows lymph nodes: left sided supraclavicular lymph node enlargement 2. Irish lymph node: left sided axillary lymph node enlargement 3. SMJ nodule: Periumbilical group of lymph node enlargement POD (Pouch of Douglas): Blumer's shelf GASTRO INTESTINAL STROMAL TUMOR (GIST): * Cells of cajal : responsible for motor activity + controls [Myenteric plexus + Aka Pacemaker cells of GIT * Any mutation of cajal cells : causes 111 proliferation i.e. 11 tyrosine kinase resulting in cancer * Definitive maker + CD-117 / C-kit + CD-34 + D/O/G-3 Treatment + IMATINIB : inhibits tyrosine kinase NON-HODGKIN LYMPHOMA: * M/C extranodal site : stomach (normal individual) + M/C extranodal site : CNS (iramunocompromised patient) Dom sousicurSMALL INTESTINE AFFECTING DISORDERS A. Malabsorption Disord = Pt. Complaint of diarrhea 4.Celiac Sprue:- ~ Pt. is associated with HLA - DQ, / DQs Cereals + Gluten E.g. (W/0/B/Rye) 4 Gliadin + Tycell Ab > Iga ~ Anti Gliadin Ab + ~ Anti - tissue T glutaminase - Anti Endomysial Ab + IgA + Dermal Papillae involve + -» Dermatitis herpetiformis CLE: ~ Diarrhea I . - ABD Pain (i e 5 vill ~ Skin fo mn / iagnosis= my 9 ype 3 10C := Intestinal Biopsy 7 ~ Site of intestinal biopsy - Duodenal | \1 r ' Mf —s villous artaaphy Sitti a ta CS - Mucosa thickness - Normal + Lymphocytic infiltration Celiae Sprue:- ~ Pt. has malabsorption + skin ~ Duodenum -» IDA ~ Pt. has Enteropathic T cell lymphorna - Repeated Duodenal Biopsy + 10C - 2 times done2. Ab + -» Anti - TTG +++ ~ This is best antibody to male Dx > Anti - Endomysial + 3. Skin Bx Rx 1. Cereal Substitution: ~ W/0/B/Rye —— Maize / Rice Changed to 2. DH - Dapsone 3. Steroids 2. Tropical Sprue J \ ~ It has infectious disease -» E. coli = Total intestinal involvement 7 » = It is an example of Benign condition - They release good responseto antibiotics in treatment 3. Whipple's Disease: ray Oo Tropheryma whippelii - 4 Bi Intestine / CNS / Joints / LN Lacteal -» systemic circulation TW causes -» Macrophages in lamina propria | + ROD ~ shaped Bacilli + Ly cactet $C 4 L comp -» obstruction -» Diarrhea Dxi- Biopsy 1. PAS + ; DIASTASE RESISTANT Granules 2. ROD shaped Bacilli +Carcinoid Turaor Arise from neuroendocrine tumors Positive for certain markers Eq for - chromogram - NSE Site of origin = GI Tract ( most common) overproduction of -»5 HT ~ Bronchus ‘ In midgut + S HIAA( 5- hydroxyl Indole Acetic acid) = Tumor is malignant ~ Extra serotonin secreted | 4 Carcinoid Syndrome fn urine oat Gat > Cleat seemanine \ ~ Flushing ) - Diarrhae j. / ~ Asthma like features AY’ ~ Systemic Fibrosis -» Right side of heart affected - Tricuspid valve -» Insufficiency ( Regurgitation) mad = Pulmonary valve -» Stenosis (TIPS) s H ' v A (Systemic fibrosis) 1 4 4 1 ‘ Hepatomegaly Intestinal Vasomotor Asthma like symptoms Right side of Heart symptoms _ Symptoms (Blushing) Diagnosis 1) Screening Test 24 hour urinary level of HIAA 2) Plasma conc. OF chromogram At t 3) Biopsy + electron -» Granules ( Chromogram A) Microscopy NSEINFLAMMATORY BOWEL DISEASE * Common in young fernales 4 Immune system activation 4 Gut bacteria * Organs involved are: 1 GIT + Abd. pain / Diarrhea (Bloody) 2 EYE — uveitis 3 Bile ducts + jaundice 4 Joints > Migratory arthritis 5 Skin -» pyoderma gangrenosur / Erythema nodosa + Inflammatory bowel disease 2 variants: 1 CROHN'S DISEASE: Any part + Least common: rectum ‘ Most common : ileum + Skip lesions + Cobblestone mucosa At microscopic level : associated ¢ ‘ Granulorna formation ~ a il ohn ey * ASCA antibodies are present +S - Skip lesions@ 1 - tleuna (m/c) S - S.C + ASCA@ T - Transmural inf (granulorna@) E - Excessive fibrous tissue deposition (Creeping fat appearance) R - Recturn (spared) * String sign + CD ‘ < Skin [BiPreptaddeMeura -» t oxalate + SC — kidney 1 stones Te 2.ULCERATIVE COLITIS: Colon ‘ Rectum De Retrograde v 1céo1D coLon 4 ac ecru Pancolitis * Crypt abscess (At microscopic level) P OH 8 Poeuds Polyps + Pseudopolyps ® Yr + Megacolon (toxic) wae * Loss of Haustrations + Lead-pipe appearance + p - ANCA@/ vasculitis C/F Abdominal pain Jaundice Diarrhea JOINTS * t colon cancer * Ule. + ulcers mucosa é& submucosa C > continuous involvement O - originate - rectum L = lead pipe appearance 1 > t (pseudopolyps) T > Toxic megacolon ' ts lcecie severity / t colon cancer + Presence of p- ANCA / granuloma @ : AF; om sousPolyp's & Colon Cancer Polyps- growth projecting into lumen of intestine Types Non-Neoplastic Neoplastic + Inflammatory polyps -Adenomatous polyps + Hyperplastic + Hemartomatrus polyps Be Peutz Jegher Polyp-» Jejunum + Juvenile Polyp->Rectum (small child Increased risk of stomach / colon cancer * Peutz Jegher Syndrome Colon Cancer * Seen in eldery patients + Arise From rectum > signaoid colon * Arise from columnar cancer + Adenocarcinoma ~ histologically Risk Factors MM. (BD | Genetic factors Il. Environmental factors (2)- HNPCC / LYNCH Syndrome L DNA repair genes->(MSH & MLH genes -> Micro satellite stability 1 Mutation 1 1Cancer LYNCH Syndrome ! C/E/O Syndrome x Colon/ Endometrium/ Ovaries + Right side of colon is affected + <50 years (2) Familial adenomatous polyposis( FAP) APC gene -> chromosome 5q-> | adenoma 1 Mutation -> 111 adenonatous polyp L Risk colon cancerVariants of FAP ‘) Classical FAP At least 100 adenomatous polyposis Retinal pigment epithelium hypertrophy ii) Turcot syndrome Classical FAP + CNS Tumors i) Gardner Syndrome -> FAP Osteoma = Fibromatosis UI, Environmental factors * Dietary lipids ~ Dietary fibers + Pelvic irradiation - NSAID's (asprin) + S.bovis endocarditis - HRT + Uretero Sigmoidostomy WL. Inflammatory bowel disease — Crohn's disease Ulcerative cholitis ~ degree of dysplasia is more ~ Higher predilection of development of cancer Colon cancer ‘Ascending colon Ca Descending colon cancer or : or Right sided colon cancer Left sided colon cancer or Distal colon cancer + Manifesting in the form of = MC seen in rectum or left side of Ulcerative mass colon as an example of circumferential Mass * Ulcerative /fungating type ~ Alteration of bowel habits Of cancer 4 ~ Rectal carcinoma- | S/S of anemia Bleeding P/Rectum Dw susicmn |+ Elderly patient (stretching of wall) * Weakness, fatigue, difficulty in 1 Breathing, palpitations Tenesraus + Associated in lynch syndrome Spurious diarrhea 4 Napkins-ring appearance In younger patients Diagnosis- 1. Colonoscopy + B, -» 10C 2. Fecal occult blood loss 1 * definature diagnosis is made with help of histological diagnosis only. M/E / Guaiac test These tests help in confirmation of diagnosis 3. Tumor markers tt Carcin embryonic Antigen a Recurrence Radiological sign - On barium anerma-> Apple core appearance Screening * Colonoscopy (+)Family history * Fecal occult blood test | Metastasis © * Liver -MC © * Lymph nodes So * Ovaries - bilateral ovarian enlargemen R, ~ surgery * FOL/F/OX / FOL/F/IRI - drug regimen Signet Rug APP, Perme(s PU) ‘xa Oxaliplati trinotecan Anal Cancer + Squamous cell carcinoma histologically + Surgery not preferred TOC - Chemotherapy + Radiotherapy EBpPreptadder NIGRO'S REGIME* | Cilia activity "Smoking INF tt * Kartagener syndrome + Dynein defect Bronchiectasis Situs inversus ————» Sinusitis 4 ‘ Dextrocardia + reduction in fertility MENTATION om PERFUSION [®] Alveoli -» Preumocytes LRA NANER tre or 1 u + + Lining * surfaétant * repair function Reid's index + A/B - <0.4 Scanned with CamScannerOBSTRUCTIVE LUNG DISEASES Diagnosis of choice -» (pulmonary function test) * Spirometry * FEVS Wt "RVC y Ratio FEV Rvitt Decreases FvC 4 t Total lung capacity EMPHYSEMA:-> Abnormal permanent dilatation -» Acinus JZ res aroncins! ' 'e—-acinus > Damaging Protective * Elastase t + * anti - elastase damage 4 Neutrophils / macrophages Of. ~ anti trypsin clinically 2. Pan-acinar emphysema: * Whole acinus* Cause is ,-AT deficiency * Base of lungs are involved 3. Distal acinar emphysema: * M/C seen in smokers 4 (spont. pneumothorax) * Upper lobes of lung are most commonly involved 4, Irregular emphysema: * Patchy involvement of lungs is seen * Most commonly histologically seen Clinical features: Elastin ——Alv. recoil maintain patency ~ Alveoli will become dilated and airway have tendency to collapse * Commonest clinical manifestation : Dyspnea * Dyspnea + wt. Loss with n/o smoking indicate malignancy * Pursed lip breathing * Air trapping flat diaphragen S barrel chest * Pts. are known as (pink buffers) * In later stage -» | pO, - right ventricular failure 2. CHRONIC BRONCHITIS: + presence of prod. Cough for duration of at least or minimum 3 months for at least 2 consecutive years — cause : smoking . : + (nenaton \ 2 infection <—— mucus production ‘ * Stasis * pro. cough < tt pACO, (alveolar Co,) 4 PAO, + pao, ti Leads. cuanotic discoloration (arterial to 7 oxygen) 4 DR.SPARSH GUPTClinical features :~ * Productive cough * Fever * Patients are known as (Blue-bloater) 4 pa0, + V0 t TPR ‘ Pulmonary hypertension 4 Re. V failure + Cor pulmonale A « MReids index B Chu. bronchitis 4 SQ metaplasia 4 Dysplasia + 1 risk of bronchogenic cancer * Pts. will not have amyloidosis Chest X-Ray > pulmonary hypertension 4 Prominent markings COPD - (E) + chronic bronchitis * Most common risk factor smoking ‘smoking 1 tAch ‘ Spasen 2) Quit smoking 2) O, supplements ~ tes the life of patient 3) Ipratropium (anti - calinergenic drug) 4) Antibiotics 3. BRONCHIAL ASTHMA: * Reversible condition Extrinsic Asthma + Ext antigen = Type | HR te~- Children > H/O— eczema \ atopy Intrinsic Asthma -» * Viruses = Occupational disease = Exercise = Drugs -» NSAIDS * Intake of NSAIDS will lead to spasm * Most common NSAID responsible Aspirin SAMTER'S TRIAD ASA intolerance Asthina Nasal polyps ‘ Seen in adults Clinical features: ~ Wheezing - D/C + nocturnal ~ Resp. alkalosis Microscopic examination:~ + Airway remodelling Sputum + Curschman spirals c ~ Creola bodies + a > Charcot - leyden erystals 4 DR.SPARSH GUPTA* ADAM 33 gene — ¢ fibrosis + SM * YKL - 40 protein tt = severity of asthma BRONCHIECTASIS: Chronic necrotising infection + abnormal permanent dilation of airway Risk factors : * Kartagenic syndrome * Cystic Fibrosis * Obstruction— FB Numer * Necrotising inflammation (TB / Staph. Aureus / adeno) Allergic broncho pulmonary aspergillosis Clinical features:~ * Prod. cough / D / clubbing 4 pad, + cor pulmonale HRCT scan -» *honey-comb" appearance Tram-track appearance * Bronchiectasis involves of the lung * Bronchiectasis is a benign condition * Pt. are at higher risk of developing 2° amyloidosis Bronchiectasis +X cancer Chr. bronchitis +t cancer] preptaddeNE RESTRICTIVE LUNG DISEASE Restrictive Disorders-+ Spirometry - FVC 44, TLC 4, FEV, 4 FEY. t FVC _ ratio = RLD are characterised by 4 compliance of Lungs, | Diffusion capacity of lungs CIE -+ Cough, Dyspnea, t respiratory rate (Early stages) = Honeycomb lung (late stages) Etiology ~ Chest wall disorder Etiological Factors < Neuromuscular Disorder / Obesity / Kyphoscoliosis Interstitial Disorder Int. fibrosis / Preumoconiosis /Hypersensitivity Preumonitis/ Sarcoidosis ¥ Idiopathic Pera. Fibrosis - or Cryptogenic F Alveolitis Cause - Unknown - Characterized by presence of Alveolar Epithelial Cell Injury = Recurrent attacks of Alveolitis + secretion of TGF-B fibrosis oh Affects lower ‘Subpleural lobe of lung Factors + 4. Age -» elderly 2. Genetic + Telomerase / Mucin / Surfactant 3. Environmental -» Smoking CI/F + Cough, Dyspnea, tRR M/L -» Usual int. pneumonia In elderly stages -+ tt Fibrosis -+ Fibroblastic Foci Late stages -+ tt collagen and | cellular Both co-exist in Int. Pheumonia -+ Honeycomb Fibrosis Prognosis -» In medical, it is bad TOC - Pulmonary or Lung Transplant R/O- << Drugs» Bleomycin / Mtx / Amio (Rule out) ~ Radiation2. Non - specific Int. Pneumonia + Idiopathic / Connective tissue disease CI/F -» Elderly (Non smoker) Female ~ Cough, Dyspnea M/F Cellular Pattern Some stage Fibrosing Pattern Lesions co-exist - NO Fibroblastie Foci = NO Honeycombing High Resolution CT scan - B/L Reticular opacities present 3. Cruptogeni¢ Organising Pneumonia: CVF -» Cough, Dyspnea M/F -» Masson Body -» Presence of organized tissue seen in alv. Ducts and bronchiole = No honeycombing - No Int. Fibrosis Px — Steroids |. Preumoconiosis -» Example of condition seen due to inhalation of dust particles (1-5 ) which is responsible for activation of alveolar rnacrophages -» secretion of cytokines -» Fibrosis Examples - 1. Silicosis © M/C ; | Quartz - involve upper lobes of lungs -ttTB/ t Cancer Chest X-Ray -» Egg Shell Calcification ~ Silicosis also called Grinder's disease ~ t Exposure of silica in case of people working in Sandblasting industries Il. Asbestosis -» Insulation S Plumbing ~ Asbestos particles are of 2 types -» Serpentine (curvy) - less pathogenic + Amphibole (straight) 4 (more dangerous and pathogenic) ~ Pleural plaque -» M/C lesion my) DR. SPARSH GUPTA= Int. Fibrosis~ Deposition of proteinaceous material on surface is associated with term known as Ferruginous Body or Asbestos body ~ Asbestosis is responsible for starting of base of lung = Exposure can lead to high risk of development of cancers ~ Example of dangerous dust particles which can act as both initiator as well as promoter chemical ~ Pts. can have 2 lung tumors -» 2. Bronchogenic carcinoma (exposure of 15-20 yrs) mc 2. Mesothelioma (exposure of 25-30 yrs)- most specific I, Beryliosis -» Exposure to beryllium in industries + nuclear > Aerospace ~ Responsible for development of Int. Fibrosis + Non caseating granuloma in different organs of body ~ High risk of cancer IV. Coal Worker's Preumoconiosis -+ Associated with exposure to coal dust (A) Pulm Anthracosis -» No Cl/S > Dust cells + (8) Simple CWP -» Nodules + — Elastase enzyme released + Cent. Emphysema (C) Progressive massive fibrosis -» Complicated CWP ~ Pts having Black Lung V. Bagassosis + Sugarcane Dust 4 Spores = On destroying the fungal spores, sugarcane dust becomes non pathogenic which is achieved by 2% propionic acid spray VI. Byssinosis - Inhalation of cotton dust particles ~ Seen in textile workers Also known as Monday's chest disease =Pneumoconiosis Rheumatoid Arthritis 4 Caplan's Syndrome BBppreptadderINFECTIOUS LUNG DISEASE PNEUMONIA, PNEUMONIA - Infection of pulmonary parenchyma Tupes ‘Typical Pneumonia / Air Space Pneumonia = Bacterial infection - 4. Accumulation of alveolar exudate (Hallmark) = Fever (high grade) ~ Productive cough ~ Pleuritis ~ Signs of consolidation ‘Sputum examination = Positive in + Gram staining ~ Culture ‘Types.of Pneumonia LOBAR PNEUMONIA ve i ——~ = Extensive involvement of complete lobe Logan PNEUMONIA BRONCHOPNEUMONIA ~ Patching involvement of basal lobe ~ Bilateral ~ Extremes of life (children, old age) Causes of Typical Preumonia Bloweno- 1. Strep Pneumonia ~PuevmonsAl = Community acquired pneumonia (CAP) = Rusty sputum 2. Staph. Aureus Secondary pneumonia Abscess formation 3. Klebsiella Alcoholic + aspiration Red currant jelly sputum (thick mucoid sputum) 4. 1H, influenzae ~ Acute exacerbation ~ Chronic Bronchitis = Type B (most virulent) (HIB vaccine) GGppreptadder5. Pseudomonas = Burns ~~ Cystic fibrosis = Inwmaunosuppression = Hospitals ©. Legionella - Humidified air ~ Water (source of contamination) = ICU (air conditioning ducts) = Preumonia ~ Diarrhea (GIT involvement) = CNS (altered sensorium) ~ Self limiting upper tract infection: PONTIAC FEVER = Damages JG cells 4 4 Aldosterone secretion ‘ TK/HY Na’ ~ Can be identified with the help of silver stain ‘Staging of Pneumonia: 4 stages No treatment for pneumonia is taken |. STAGE OF CONGESTION ~ Characterized by Auid in alveoli 4 ~ (1-2 days) bacterial, neutrophils IL. STAGE OF RED HEPATIZATION = RBCs present in uid = Fibrin deposits = (3-4 days) ll. STAGE OF GRAY HEPATIZATION ~ Lysis of RBCs thus loss of red color _- 5-8 days __- Extensive deposits of fibrin IV. STAGE OF RESOLUTION Phago ~ neutrophils , macrophages + of cellular debris Cytosis Or Bacteria removed by presence of WBCs ATYPICAL PNEUMONIA - Non bacterial etiological factor ~ Characterized by interstitial inflammation Who - Mononuclear cell infiltration sansCF ~ Low grade fever = Dry cough ~ Malaise / myalgia ~ No signs of consolidation Investigation = Sputum ~ Negative gram stain = Radiological examination ~ Chest X-Ray interstitial (inflanmation markings in pulmonary tissue) PROMINENT INTERSTITIAL MARKING Associated organisms : 2. Mycoplasma = We cause = IgM + Autoimmune hemolytic anemia (cold) = Males ~ In closed space (hostels, etc) 2 Chlamydia - and m/c cause = CAD (high risk) 3. Pneumocystis jiroveci ~ Fungus - HIV patient - Cup shaped = Silver stain 4. Coxiella burnetii ~ Rickettsial infection = Does not require vector ~ Causes 'Q' fever 5. Viruses a. influenzae = Type A (atypical pneumonia) ~ Gets complicated by presence of Staph. Aureus (secondary pneumonia) ~ Kid having H/O viral infection 1 Aspirin Reye syndrome b. Respiratory Syncytial Virus (PSV) - Children - Bronchiolitis ¢. Cytomegalovirus (CMV) - OWL EYE inclusions = | immunosuppression (HIV / AIDS / Transplant procedure) d. Measles ~ Koplik's spots / rash = WARTHIN FINKELDEY giant cells (jpreptadderPULMONARY TUBERCULOSIS AND LUNG DISEASE Pulmonary TB ~ Developing countries ~ Due to immunosuppression seen in developed world as well Types Primary Pulmonary Tuberculosis ~ 2" involvement of lung because of mycobacterium tuberculosis ~ DROPLET INFECTION ~ Subpleural lesion \ ‘ Hilar area (high airflow rate) Periphery Lower part of upper lobe Or upper part of lower lobe + Involvement of regional lymphatics t ee i Enlargement of hilar LN ¢ Ghon's Complex ~ Subpleural lesion + lymphatics + Hilar LN ~ IF it gets calified k/as RAENKE'S COMPLEX Lipoarabinomannan (LAM) - Mycobacteria responsible for LAM ~ Structural component of mycobacteria = inhibits macrophages ~ 2" cell which is going to be infected at time of inhalation of mycobacteria are the alveolar - macrophages f ~ For initial 3 weeks of infection 2. After 3 weeks, Cytokines-+ interferon 4 Activation of macrophages + Granuloma CONTAINMENT OF INITIAL INFECTION Os, cbigate ceache Ree ie sition= Mycobacterium (obligate aerobe) 1 no sufficient amount of oxygen INACTIVATED 4 Destroyed 4 Caseous necrosi Secondary Pulmonary TB» Age / AIDS t +ve risk (immunity compromised) CAUSE Reactivation Fresh infection in Most cases 4. Right lung better air supply 2. Apical region maximum oxygen availability - APICAL LESION Apical lesion Supraclavicular Infraclavicular 4 + Publ's focus ASSMAN'S focus = Immune is activated quickly 4 Granulorma formation 4 Caseous necrosis + Drains through airway 4 leading to CAVITATION (common finding) ~ HILAR LN not enlarged ~ Cough - release of mycobacteria from lungs into environment ~ Dissemination of mycobacteria from lungs into blood vessels, lymphatics + involvement of other organs AFFECTED ORGANS iN - w/e extrapulmonary organ - LN fuse with each other + COLD ABSCESS 2. Kidney ~ Tuberculous pyelonephritis ~ Through hernatogenous spread ~ Pus cell in urine Macconkey media, STERILE PYURIA 3. EYES ~ PHLYCTENULAR CONJUNCTIVITIS Type hypersensitivity reaction4. FAR ~ Tuberculous otitis media Hallmark feature - multiple perforations in tympanic membrane 5. CVS - constrictive pericarditis ©. Bones - POTTS SPINE 7. Adrenal Gland = Insufficiency ~ DAMAGE = India 8. Liver ~ simmond's focus ~ Simon's focus + primary pulmonary TB 9. GIT = ileum - TRANSVERSE ULCERS 4 complication Stenosis 10. Brain - RICH FOCUS - Basal surface involvement ~ TB meningitis + COBWEB COAGULUM cle ~ Cough (>2 weeks) ~ Fever (low grade, evening rise) ~ Hemoptysis - w/e source + Bronchial artery ~ Pulmonary artery (uncommon) 4 ~ RASMUSSEN'S ANEURYSM - Significant weight loss Investigations - tt ESR ~ Leukocytosis ~ Sputum examination + Early morning sample + Concentration of sputura + PETROFF'S METHOD ~ staining + ZiehI ~ Nelsen stain (ZN stain) = Acid Fast bacillus (rayeolic acid) ~ Culture + LU media (slow growth) > BACTEC MEDIA (faster growth) (Brook's media)- PCR — Polymerase chain reaction ~ Nucleic acid amplification ~ Advantage + picks up very low bacilli load in sample Pleural Effusion ~ pleural trap -» light yellow colored fluid 4 STRAW COLORED FLUID 4 tt Adenosine Dearninase (ADA) (molecular marker or enzymatic marker) - Radiological investigation > mass miniature radiography Treatment Anti Tubercular Therapy (ATT) LUNG ABSCESS = Collection of pus Factors 1. Aspiration - cormmonest cause = § consciousness ~ Alcohol, anesthetic gas ~ Food particles (m/c) 2. Septic embolism ~ Infective endocarditis = Septic embolic coming From cardiac tissue into different organs of the body including lungs 3. Post pneumonia taph aureus Klebsiella 4. Obstructive neoplasnn CLE ~ High grade fever ~ Productive cough ~ Expectoration of foul smelling sputum Diagnosis: good antecedent history, X-Ray Cavitation, Air Fluid levelRESPIRATORY DISTRESS SYNDROME Seen in adult and new bom Adults ~ Sten as a component of Acute Lung Injuring - Sudden onset of severe hypoxemia- Bilaterally pulmonary infiltrate (without H/O of heart disease) ~ Severe acute lung injury variant :- ARDS Etiology: Direct Lung Injury ¢— in Direct Lung Injury | - Gram (-) Sepsis - Aspiration ~ Shock - DIC / heroin / Pancreatitis * Endothelial cell Injury ‘Type Itt Exudative Auid accumulating Preumocyte 1 Damage Hyaline Membrane 4 (Stiff Lung) Decrease surface tension 1 Alveolar Collapse 4. Dydpnea 2. Increase Respiratory Rate 3. interstitial Fibrosis Radiological Exdamination ~ Chest X-Ray Bilateral infiltrates (+) gives "white out” appearance to lung. ~ Pulmonary capillary wedge pressure: ~ . When pressure in lung is <28mm Hg, non- cardiogenic cause * Diffused alveolar damage (Histological Hall mark) Management:- Refractory to O, therapy 1 Decrease surface tension responsible Alveolar collapse For 1. Treatment of choice :- management of Primary cause 2. Positive and expiratory pressure (PEEP):~ increase | O, diffusion / Alveolar opening. 3. Steroids Neonatal Respiratory Distress Syndrome Surfactant:— ~ Secretion begins at 28 weeks of gestation (in the form of lamellar body) ~ Present in Type Il Preumocytes (BppreptadderSurfactant: made up of substance called as Lecithin — DPPC (Biochemical composition of surfactant) Dipalmitoylphosphatidy choline Physiological Action:~ * | Decrease surface tension -> | decrease Alveolar collapse * Surfactant production can increase in presence of Steroids / hormone like Thyroxine * Decrease in production of surfactant :~ is caused by Insulin Risk Factors:— 4. C-Section 2. Prematurity 3. Matemal diabetes (fetal increase insulin)Decrease in surfactant -> causes increases in surface Clinical Factor: - ~ Respiratory distress (appears within hours) - 1 Increase respiratory rate ~ Hypoxemia Radiological Examination: ~ White out lung ~ Ground glass lung (attributed to the presence of granularity) Management:~ Steroids to mother Artificial surfactant to body CPAP (endotracheal tubes) Complications:— 1. Hypoxemia (decrease O,)-> Higher chances of development of patent ductus arteriosus (PDA) Higher chances of NEC necrotizing enterocolitis 2. Supplemental oxygen 1 Free radicals Retinal damage Bronchopulmonary dysplasia (BPD) 3. Decrease glucose Lb DR SPARSH GUPTA,SARCOIDOSIS, HYPERSENSITIVITY Preumonitis And desquamative interstitial pneumonia SARCOIDOSIS = Exposure to unknown antigen 1 CA, T cell activation ‘ Non-caseating granulom = Involvement of (2) lung -> — -— M/C |— Interstitial fibrosis |_ U/L pleural effusion CIE L_ Dyspnea (M/C) ~2)LN ~ B/L HILAR lymphadenopathy 4 POTATO NODES > 3) Skin (a) LUPUS PERNIO ~ Purple to violet colored rash seen on nose and checks ~ b) Erythema nodosum ~ Painful nodules on lower limbs - 4) EYE - UVEITIS -> CANDLE WAX DROP ~ 5) LIVER, Bone marrow, spleen -» GRANULOMATOUS LESIONS Liver-M/C of non-infectious granulomatous lesion ~ ©) Endocrine glands (Pituitary) ~ 7) Muscle weakness, fatigue Diagnosis:= 2. SACE ttt 2. Serum calcium tt Imerease in activity of 4 alpha hydroxylase 4 Vit D / calcitriol 3. Cutaneous Anergy 4. Non-caseating granulomas -most characteristic 5. $-Schaumann body (Ca A-Asteroid body (stellate inclusions) R-Residual body 6. Broncho-alveolar lavage (BAL) Fluid Cd4 : CD8 T cell C tt S1/15:4Treatment; - ~ Spontaneous rewrery = Steroid HYPERSENSITIVITY. PNEUMONITIS: ~ Aka Extrinsic Allergic alveolitis = Known Antigen C Alveolitis Interstitial pneumonitis ~ Acute exposure -> 2" times, antibody formation Repeat -> Ag +Ab -> Immune complexinj formation = Type Ill. Hypersensitivity reaction = Chronic exposure [— non-caseating granuloma L_ Type Iv. Hyperse ~ Type Ill. + 1V. ~> mixed hypersensitivity reaction = Type IV >>> Type Ill, HR Antigen responsible ‘SUBTYPES 1. FARMER'S Lung Thermophilic-actinomycetes 2. PIGEON Breeder's Lung Bird excreta (protein) Bird feathers 3. Humidifier’s lang - Bacteria cle Acute phase - antigenic exposure 14-6 hours Cough / dyspnea / fever For few hours to days 4. Chronic phase Antigenic exposure-> interstitial fibrosis 4 Progressive dyspnea/ respiratory failure 1 Cyanosis ‘Treatment ~ Avoid exposure to known antigen = lmmunosuppressive therapy- STEROIDS DESQUAMATIVE INTERSTITIAL PNEUMONIA (DIP) = Exclusively seen in smokers - Characterized by presence of macrophages-> involvement of air spaces CLE = cough, dyspnea Interstitial fibrosis Treatment ~ Steroids L DR. SPARSH GUPTA,LUNG TUMORS a. S Be Malignant = Bronchial Adenoma —™“. ~ Hamartoma v x Bronchogenic — Metastasis/Cannon ball Metastasis (m/e) cancer -» Colon Ca -> Choriocarcinorna -> Breast ca BRONCHIAL TUMOR, = Subtype of carcinoid tumor = Well differentiated neuroendocrine cells = It is chromogranin positive - Vascular tumor - Biopsy is contraindicated « - Recurrent hemoptysis Hamartoma - Developmental walformation - Pre neoplastic lesion ~ Characterized by presence of disorganized tissue present at anormal site - M/C location : LUNGS - Inversion mutations -> Malignancy Chest X-ray : Pop Corn calcification BRONCHOGENIC CARCINOMA Risk Form 2. Genetic factors - P53 gene- most dangerous - L-MYC gene ~ K-RAS gene ~ Epidermal growth factor receptor gene (EGFR) ~ ALK gene RET|MET gene 2. Non- genetic factors ~ Smoking 1. Most dangerous 2. Release of PAH (polycyclic aromatic hydrocarbon) 3. CYPIAL ~ Air pollution ~ Asbeitos ~ Radiation &Xenon, Radon (decay of uranium)clr = Cough (w/e) = Weight loss = Dyspnea = Hemoptysis = Involvement of RLN 4 Hoarseness Investigations 4. Radiological examination 2. Sputum cytology 3. Bronchoscopy + Biopsy 1) Best microscopic examination or histopathological examination 2) Immunohistochemistry (markers) Presence of 1. Kerati Inter cellular bridge Pearls = Squamous cell carcinoma Popes positive 2 Mucin, glands = Adenocarcinoma 4 - Thyroid transcription factor positive - NAP-A (+) ~CK 7 (+) 3. Small cells = Neuro secretory granules - SALT and Pepper chromatin ~ Basophilic stain (AZZO PARDIEFFECT) = Diagnostic of small cell carcinoma 1 = Chromogranin positive - TTF (+) absence of NAP- A - Low molecular weight Ck 7|8|28 4. LARG CELLS ~ No kerdtius glands, neurosecretory granules ~ Diagnosis of EXCLUSION ~ Presence of CD56, Synaptophysin, chromograninVariants of BRONCHO GENIC CARCINOMA 2. Squamous cell cancer - m/e India | = m/e in vnales, srmokers ~ central location near hilum CENTRAL = Cavitation is sun Location ~ LATE METASTASIS = Very good prognosis ~ Cells => Parathyroid hormone related peptide (PTHrp) 1 Hyper caleemia 2. Small cell cancer - Males, smoker ~ Strongest association with smoking ~ Central location better chance of diagnosis ~ BEST response to Anti cancer Drugs Radiotherapy oR Chemotherapy ~ WORST prognosis - Very aggressive ~ Maximurn chances of early metastasis ~ Surgery cannot be performed ~ Presence of neurosecretory granules Secretion of LACTH | 1 Cushing syndrome 2. ADH -> SIADH (hyponatramia) 3. Calcitonin -> hypocelemia 3. ADENO CARCINOMA - Overall most common - WORLD - Females >>>males = Non- smokers ~ Peripheral location ~ Secretion of mucin - Thrombophlebitis ~ Clubbing ~ Aka SCAR. Cancer ~ Pre-cancerous stage: Adenocarcinoma in situ spread tumor from one lung to the other (AERO GENOUS SPREAD) ~ Excellent prognosis (noninvolvement of basement) (BPreptadder- obstruction of airway membrane = SUFFOCATION (may cause death) 4. LARGE CELL CANCER = Non - Smokers ~ Peripheral location = Estrogen release -» GYNECOMASTIA Metastasis = Adrenal gland -> we organs affected -» Adrenal insufficiency = CNS-> swuall cell cancer > Bones - Liver Complications 3. PAN COAST TUMOR ~ Peripheral cancer = Most common example of adenocarcinoma ~ HORNER SYNDROME -> MAPEL ~ Miosis (constriction of size of pupil) ~ Anhidrosis (absence of sweating) ~ Ptosis (drooping eyelids) ~ Enophthalmos (shrunken eyes) ~ Loss of ciliospinal reflex 2 Superior Vena cava syndrome (SVC) ~ Obstruction to venous input coming from upper part of the body (head) ~ Bluish dusky congestion 3. RLN — Hoarseness of voice 4 Compression of Ca|T3|T2 = Shoulder pain = Pain > inner side of arm Paraneoplastic Syndrome : - Group of manifestation sun is patients suffering from cancer which cannot be explained by direct spread of cancer or metastatic spread of cancer or production of hormones which are indigenous to a particular tissue ~ Hypercalcernia: Squamous cell carcinoma = Cushing syndrome ; SIADH, hypocalcemia ; Small cell cancer ~ Lambert ~ Eation syndrome: antibody formation against pre-synaptic calcium channels = Small cell carcinoma ~ Muscle weakness ~ ACANTHOSIS NIGRICANS — hyperpigmentation of skin, thickening of skin ~ SVC syndrome : Small cell cancer ‘Lung Cancer Small cell cancer ——_— Non-small cell cancer ~ Aggressive ~ Better Prognosis = Poor prognosis B PrepLadderBREAST -1 ~ Breast tissue is a hormone sensitive tissue Hormones ~ Estrogen~ Responsible for alveolar and ductal growth ~ Progestrone-responsible for alveolar differentiation LACTATION-» 2 hormones are released oxyTocIN PROLACTIN 1 1 Required for the process stimulation for lactogenesis of milk ejection In milk production —- f , ef Main duct Lbale 7 = | smaller duetules piu 4 Lobule (terminal duct lobular unit) (TDLU) (Functional unit of the breast tissue) / Stroma L Tra luminal Breast tissue Se Myoep thelial Epithelial cells = Outer myeopithelial layer ~ Inner specialized colunanar cells called luminal cells which require Vitamin A for its differentiatio Anatomicalimportance Contino Max density of the breast tissue is upper outer quadrant Prainage (Lymphatic) WW) 2. Upper outer quadrant -> Axillary lymph modes 2. Inner part of tissue > Internal Mammary lumph nodes MC site for CA breast -> upper outer quadrant Least chance site for CA breast -> Lower inner quadrant NIPPLE DISCHARGE * GALACTORRHEA ;- ejection of milk outside the period of lactation Due to :-> Mechanical stimulation of the nipple Drugs -> oral contraceptive pills,Anti-histamine drugs Prolactinoma Endocrinological disorders << Hypothyroidisen BLOODY ;- seen with intraductal papilloma (MC) Ductal carcinoma GREENISH :- seen in mammary duct ectasia PURULENT:- seen in acute mastitis [BjprepLadderINELAMMATORY CONDITIONS 1. ACUTE MASTITIS :~ seen in young females, who are breast feeding staph aureus 1 Breast tissue 4 Development of pus Clinical features :~ Pain Fever Purulent nipple discharge swelling Diagnosis :~ Ultrasound ‘Treatment :- NSAIDS Penicillin antibiotics Aspiration Incision & Drainage * Breast feeding is not contraindicated in acute mastitis 2. ZUSKA'S DISEASE (Periductal Mastitis) Etiology- smokers -> vitamin A \1 -> squamous metaplasia -> obstruction Clinical features :- 1. Sub-areolar mass 2. Pain =) 3. Redness 4. Nipple Retraction S. Fistula 3. MAMMARY DUCT ECTASIA:~ seen in females after menopause, & they are Multiparous -(5'*-6" decades of life ) Dilatation 1 Accuraulatic Nipple discharge Rupture . 1 Inflammation = No association with smoking = No association with squamous metaplasia Clinical features - = Green ~ brown nipple discharge = Sub - alveolar mass Miceoscopie Examinatiod.= chronic granulomatous inflammation # also k/a plasma cell mastitis BD onsssesicum4. FAT NECROSIS i= With H/O trauma or surgery ra Dystrophic calcification Caney x Mammography M/E.:= fat necrosis -> foreign body giant cells Macrophages 5. LYMPHOCYTIC MASTOPATHY:- * Autoimmune etiology ~ female, high chance for developing type | DM or autoimmune Thyroid disease Clinical Features :- > 3 hard mass tissue Biopsy :~ Presence of atrophy of duets & lobules Dense collagen stroma Lymphocytic infiltration BENIGN EPITHELIAL LESION * Non-proliferative breast changes/ Fibrocystic changes-> * Proliferative Breast disease < Without atypia With atypical hyperplasia * Carcinorna in situ 2. NON-PROLIFERATIVE BREAST CHANGES (Fibrocystic Breast Changes) RR=1 AR=3% pluse- dome a. Cysts-> -> Blue-Dome Cyst cyst 6. Fibrosis => inflammation -» fibrosis 4 ¢. Adenosis -> Increased no. of acini per lobule Apocrine metaplasia:-not going to progress into malignancy or cancer ~ Painful lesion , 2 layers ~> eg. OF incidental finding (b) Selerosing Adenosis-> increased in the amount of collagen -> microcaleification on mammography (Bprepadder(c) Complex sclerosing lesion -> Dense collagenous stroma > Epithelial component radiationg At micro / Radio -> mimic invasive carcinomas Given the name of "RADIAL SCAR” (A) Papilloma :~ = intra ductal papilloma , complete. ; ty tans ds incomplete compression Complete compression 1 1 S body dls Serous Discharge Bloody discharge 3. PROLIFERATIVE BREAST DISEASES WITH ATYPIA RR-4-5 AR=13, BTR ATYPICAL LOBULAR HYPERPLASIA (ALH)- MC Benign Lesion = young female = single or waultiple ; bilateral +# after renal transplant is seen -> cyclosporine -> B/L multiple fibro adenoma ~~ Well-circumscribed ~ Freely-rmobile lump is called "BREAST MOUSE” Gross Appearance -> = Well defined margin ~ Grey to white nodular ~ Slit like spaces ~ Glistening surface Microscopically -> * PERICANALICULAR -> stroma around epithelium * INTRACANALICULAR-» too much of stroma showing compression Management ~> Excision Phylloides Tumor ; Excessive proliferation of stroma t Leaf like projections 1 BULKY BREAST With of gain of function (24) HOX B43 expression 1 Higher grade— eee Clinical features- > 60 year of female Palpable mass - Majority of the tumors are low grade tumors ws no metastasis ~ Some can be high grade =, metastasis = Hematogenous spread = No lymphatic spread D/D from FIBROADENOMA 1Stroma Histologically Sporadic -> <35 yrs of age => 2° tumor -> after radiation therapy / edema = Malignant ~ Most common ~ Poor prognosis (sporadic variant)GENERAL CONCEPTS NEOPLASIA ~ Excessive or uncoordinated growth which continues even after removal of the stimulus. - am Tumor cells example of monoclonal growth. ermal 209-4 Loo o-+ 3 00 7? O oc” = MC enzyme for monoclonal growth- GePD O-t10-2429 4 9 o8 ° 00 OD NEOPLASM Z Mors PARENCHYMA STROMA - Firm tumor Secretion of some factors 1 Stroma formation 1 Desmoplasia occurs DESMOPLASIA ~ Linitis plastica CLASSIFICATION OF TUMOR (Linsims= reaenien ) = Slow growth ~ Rapid growth = Capsule (+) = Capsule (+) ~ Well differentiated - Poorly differentiated = Daughter cells similar in appearance & | ~ Daughter cells dissimilar in appearance & function to function to parents parents Better prognosis Poor prognosis NOMENCLATURE OF TUMORS ‘Suffix~"orma" BENIGN Tumors Eg. Fibroma Osteoma Chondroma Prefix type of tissue 1, Adenoma- Glands 2. Presence of finger like projections PapillomaMalignant Tursors Eg Carcinoma Sarcoma 1. Adenocarcinoma 2. Chondrosarcoma 2. CHORISTOMA Normal tissue (+) 4 Extopie site 2. HAMARTOMA, Abnormal tissue (+) 1 Normal anatomical tissue Commonest site for hamartoma is lungs (respiratory tissue) Hamartoma have certain mutations present which in future may progress to malignancy so they are Preneoplastic lesions TERATOMA ~ Arising from more than one germ cell layer = From totipotent cells ~ Cormmonest site of origin- Gonads = MC extragonadal site- Mediastinum FEATURES OF NEOPLASIA |_ANAPLASIA = Total absence of differentiation of the tissue PROPERTIES OF ANAPLASIA 4) - Extremely (i) High N:C ratio © ” - For normal cell - N:C vatio- 1:4 = For tumor cell N:C ratio~ 1: @® e Cri) I PLEOMORPHISM @ = MT NC ratio oO ML ABNORMAL MITOSIS a" “ee ~ Reed sternberg cell seen in Hodgkins Lymphoma Reas steeunens com DR. SPARSH GUPTAee V.IRREVERSIBLE CONDITION - eg. Anaplasia * Anaplasia is hallmark feature of malignant transformation. MALIGNANT TRANSFORMATION Normal cell =» Metaplasia (Reversible change) 4 Dysplasia 4 Anaplasia (cancer) ~ NiC increase = TIT NC ratio ~ Pleomorphism (+) tee ~ Early stages — Reversible = lereversible condition Advanced stages Irreversible ~ Abnormal mitosis & abnormal giant cells = RAPID RATE OF GROWTH ~ No. of divisions -> Clinical Symptoms development (30 divisions) = Minimum mass of turnor cells - 10% cells “1g ~ Maximum mass of tumor cells compatible with life 30" cells ~ tkg MECHANISM Giycolysis nace TCA cycle / Krebs Cycle ~Cancer cells -> O, (+) -» Aerobie glycolysis ! Warburg effect ~ Pyruvate -> Intermediates -> Growth factors meres Ee Ge we 18 FDG — Radioactive glucose -> emit radiation 1 ‘o\ PET SCAN tunvasion i) ~ Tuwor cells secrete certain factors- - VEGF (Vascular endothelial Growth factors) and FGF (Fibroblast growth factors) causing angiogenesis = tf no angiogenesis maximum area invaded by tumor cells = 3-2 mm = Molecules inhibiting angiogenesis - Angiostatin. - Endostatin re = Drugs inhibiting angiogenesis ~ Bevacizumab Lene NeCARCINOMA IN SITU CARCINOMA no involvement of basement membrane - Basement membrane is affected IV. METASTASIS ~ Most reliable feature of a malignancy i Eg. (MC features for diagnosis) —_ Pheochromocytoma _— @) NS Follicular thyroid tumor 3 EXCEPTIONS OF MALIGNANT TUMORS ~ No metastasis eg 3. Basal cell carcinoma (Skin) 2. Glioma Metastasis affecting different organs 3) Lymphatic spread Carcinoma Except + RCC have Hec hematogenous Choriocarcinoma) spread Clinical significance ~ Sentinel lymph nodes| gate keeper | caretaker LN SP ~ 7° Vv [ Central lymph node exami tion (radio dyes) () of tumor cells (+) tumor cells 1 1 Better prognosis poorer prognosis ~ Classically seen in pts of breast cancer | vulva cancer | melanoma 2. HEMATOGENOUS Spread ~ Seen in sarcomas 4 Except ~ Clear cell | have Sarcoma f lymphatic Spread ~ Rhabdonyosarcoma ~ Hematogenous Spread can be through:- Vein (easy penetration) Artery (Greater thickness) So majority venous spread in comparison to arterial spread ~ Lungs and liver commonly affected. 4 DR. SPARSH (DIRECT SEEDING ~ Involvement of body cavities £g.- Pleural cavity — in lung cancer mesothelioma ~ Pericardial cavity - Cardiac Tumor - Peritoneal cavity (M/C body cavity affected) Deposition of surface of peritoneum known as Omental caking - Malignant Ascites ~ Accumulation of fluid in peritoneal cavity. Classically seen in feraale of Ovarian tumors Zz DIAGNOSIS: ff eit! = Tumor markers 2. erie (BOTH) 4. Regulation of apoptosis + Alteration in Apoptosis regulatory genes — Self sufficient in Growth Signal ~ Proto oncogenes + oncogenes ‘ (Normal) (1) Factors :~ - Point mutation —— ~ Over expression t Activity of Genes ~ Translocation nh Normal Cell ro) Gt ‘Types of Proto oncogenes: ® Now ©. Cyelins ~ Growth factor (GF) ~ Growth Factor Receptor (GFR) = Signal Transduction Protein (STP) - Nucleus Transcription factors ~ Cyelins Growth Factor: ~ PDGF -» SIS Gene : GLIOMA ~ HgF > HgF gene : Liver cancer2. Growth Factor -+(R)Assoc. TYR. KINASE = ERB - B, -» Lungs ~ ERB - B, / HER-2 -+ Breast cancer - RET -+ MEN Il Syndrome -» P/MCT 3. Signal Transduction Proteins: RAS / ABL / [I-catenin / BRAF () GDP - RAS 2, am RAS (INTACT) KW GTPase MAPK (weurofibromiSe PISK / AKT Cell Replicates RAS MUTATION - COLON Ca + K-RAS - common type Kidney and bladder + H-RAS Melanoma -»+ N-RAS- (4,22) Ah? 4 ek A :) «od (om 3) fame BR faslen gm (i) ABL aay yee ease Canceas > t (4:22) +» CML > ALL — Oncogene Addictions + Targeted therapy > Imatinib B a a hese (iil) BRAF~> MAPK + Cell Replication t Associated with - ~ Hairy cell leukemia - 100% - Benign Nevi - 80% - Melanoma - 60% (iv) Beta-catenin -» + MyC activity 4 1 Cell Proliferation] APC gene 3 ‘beta-catenin activity E - CADHERIN — t colon cancer 4. Nuclear Transcription Factors: MyC Gene - t cyclin activity ~ t Telomerase L DR.SPARSH GUPTA- Reprogram —+ "Stemness”” [MyC gene are called "Master Regulator’] Subtypes -» C-MyC - Burkitt's Lymphoma -» fastest rate > N-MyC - Neuroblastoma + L-MyC - Lung Cancer seall cell 5. Cyclins » CDKs Off 7 On 4 Phoshphorylation D+46 E42 Aw2 Boa Cell Cycle ae p)coune WOK, / * \epinslne? a wo Mes,” adhe acre.) a DKL G,S ~ Rb gene; P,, gene GS > Pr gene CDK activity ~ + (cyclins) 4 (CDK inhibitors) CDK inhibitors P, Py Pay P., Por P. P. All eyelins DK con [BpreptadderGENETIC BASIS OF CARCINOGENESIS - 2 2. insensitivity to Inhibitors: Tumors supp. Genes +1 any hallmark of cancers beelR “Double Hit" concept -» KNUDSON discovered it 2-HIT 1 Retinoblastoma Functions of Tumors supp. Genes 1. Regulate G1/S Transition + Rb / PSB gene 2. DNA repair + P53 / BRCA +4. / 2 gene 3. Mitogenic Pathway - + APC gene NF - 1/2 gene PTEN gene 4. Angiogenesis - VHL gene Rb gene = located on chromosome 13 & 14 ~ Discovered by scientist named Knudson — Retinoblastoma SPORADIC + 1-2 U/L Familial + 4+ 2 B/L Rb - Recessive in nature aperi AD — loss of heterozygosity . aU (Autosomal Dominant) \ v cee Rb - Governor of cell proliferation nome (also called) sivion EBV + E7 + 1Rb ~ t cells on ge ; in 1 Ca cervix 4 2:P., Gene — Guardian of Genoma N cell + MDM destroys P., DNA damage — P,, activity P., + GADDYS ~ @ 1 > 1 BAX Cell arrest Wild type +@- Chr. 17P Germline P,, Gene mutation Li Fraumeni Syndrome - 1 cancers Sporadic -+ w/e - human cancer 3. BRCA 1. = Chr. 17 q @ Breast / Ovary BRCA 2 ~+ Chr. 13 q @ Breast / Prostate 4..NE 4 Chr. £7 q > Neurofibromatosis NF 2+ Chr. 22 q+ 1 AC Neuromas S.WT, = Chr. 23 p + Wilms tumor6 VHL Gene -+ N+ 1 HIF +1 VEGE Che. 3 p+ VHL Synd. Kidney cancer / brain cancer / PHEO 7. APC Gene 1 beta ~ catenin activity 1 Adenomas Mutation -+ 11 ADENOMAS FAM ADEN. Polyposis + 1 COLON Cancer > Called -+ "Gatekeeper of colonic Neuplasia’ 3GENES REGULATING APOPTOSIS - Intrinsic Pathway affected ~ BCL - 2 over activity 1 APOP = 1 Cancer Follicular Lymphoma 4. DNA REPAIR GENE / DEFECTS + Nucleotide Excision Repair Defect by UV - xeroderma Pigmentosa + Mismatch Repair defect + LYNCH Syndrome AD Homologous Recombination Repair -+ Seen in + BLOOM Syndrome + FANCONT'S Aneraia + ATAXIA TELANGIECTASIA BRCA 2 /2 gene defects + Only in familial Breast cancer Tsporadie- Do not have any role in sporadic breast cancer. 3. Altered Metabolism- WARBURG EFFECT ~ AEROBIC glycolysis 4 @ 4. Inamortality : @®- only germ cells have Telomerase 5. Sustained Angiogenesis: VEGF|T Angiostatin | 1 FUF ENDOSTATIN| (-) BEVACIZUMAB SNVASION & METASTASIS: Twist / Snail + EMT 4 DR.SPARSH GUPT6.ESCAPE IMMUNE SURVEILLANCE: _- LEWIS THOMAS — Sm surnerr Advance concepts of Genetic Deficiency: + ChromoThyrypsis -_——_ GLIOMA OSTEOSARCOMA, 4 ob BE + Epigenetic Changes: DNA Hypermethylation Acetylation of Histone + mi-RNA + microRNA 10 MRNA Translation 1 Cancer + ONCO mai RNAS + Mi R155 B- cell lymphoma 1 Cancer = tumor Supp. miRNA -+ miR 15 miR 16 = Dicer + For functional MIRNA ~ Defect - CLL 1 1 Cancer preiadEtiological Factors of Neoplasia Etiological factor:- 2. Chemical: (N) 4 tnitiators + Mutated DNA < 4 Promoters -» Increase cells Directly + DNA damage without alteration wien Indirectly -- DNA damage with alteration Eg: - PAH - — Adenocarcinomas ‘ Pancreas Sq cell cancer Transitional cancer 4 4 Lungs Urinary Bladder (fp - naphthylamine) Larynx ~ Nitrosamines -» Stommach| esophageal carcinomas 4 Japan = Azo dyes - GIT cancer ~ Vinyl chloride > Angiosarcoma + 4 Arsenic Thorotrast + Increase Skin cancer - Asbestos + 1+ P ‘ 25-35 Years Mesothelioma - most specific < 15-20 Years Broncho cancer -» most common ~ Drugs ~ Alkylating agents + 2° leukemia + Topo(-) 2. Cyclophosphamide -» t bladder cancer AMES test / carcinogenicity test SS 0 @ chenkal. © pe pre LaddTwo petri dishes taken ~ 1" without chemical 2° with chemical ~ $ typhimurium is taken te inoculated - 2" = growth is not there = 2° = mutation - histidine produced - prominent growth Percival Pott: ~ Chimney sweepers -+ scrotal skin cancer 4 Bath daily 2. Radiation exposure ;~ A Non ionizing - UV Rays<<————__ B -+ Bad < cca tonising DNA damage Dimers Xeroderma Pigmentosum NEF Genes ~ defect -+ increase cancer = lonising radiation - X || [) -» OH + DNA Damage 4 Radiology | Atomic Bombs s,|[M 1 Lead Aprons = 1 Increase leukemia» AML, CML, ALL CLL- is not associated with radiation exposure ~ t increase papillary thyroid cancer ~ Thorotrast -» Angiosarcoma ~ Skin | GIT | Bone - Resistant to lonizing radiation exposure 3, Microorganisms: 1. H. Pylori: Cytotoxins - CAG 'A' -» Gastric Adenocarcinoma ~ Beell (+) > ¢ (32:48) Maltoma 2. Fungi Aspergillus Flavus 4 Aflatoxin Hepatocellular Carcinoma 3. Viruses -» = RNA DNA Eg. HTLV-1. — RNA virus - Adult T cell leukemia L_-TAx protein — t cyclins 4 DR SPARSH GUPTA(4-6 decades) | DNA repair genes = CD, T cell > Caribean islands - HCV ~» liver cancer - RNA viruses - HPV -» DNA virus -» 6,11 - low risk -» development of viral warts » Condyloraa Acuminata 4 Higher risk + 16,18 (t Cancer) Development of cancer 4 4 E> (-) p gene > Cervix E, + (-) Rb gene + Anal canal + (-)phsp” > Oral cavity > (+) cyclin AVE KSHV - DNA virus - HHV - 8 + (1 immunity) > Kaposi's sarcoma + 3! effusion lymphoma L_ Body cavities ~ HBV virus + liver cancer integration + Insertional mutagenesis 4 1 Cancer —» t Regeneration ~ EBV +B cell Immortalisation + t cancer > LMP - 4 gene + 1 IHC - KB L1BeL-2 “+ EBNA protein + T cyclin D VIL - 10+ 1 T cell activity = Hodgkin's lymphorna = non ~ Hodgkin's lymphoma = Burkitt's Lymphoma (African endemic) + Nasopharyngeal carcinoma T cell cancer 1 [CHINA 4. Parasitic infection ~ Clonorchis sinensis + Cholangiocarcinoma = Schistosomiasis + t Bladder cancer eprsoma, —> * larcet, uTeGRATION cell cancerDiagnosis of Tumors Diagnosis of cancers 3. FLOW CYTOMETRY = Using cells in form of a Flowing stream ~ One of the best technique to detect presence or absence of certain molecules on the cell surface ~ For diagnosis of - Hematological Malignancies ~ Nucleic Acid content of a cell 2 Cytological Methods (A) FNAC. - 22-26 quage needle -> inserted at the examination site = It’s OPD procedure ~ Disadvantage 4. Contraindicated in patients with bleeding disorders 2. Sometimes USG.Radiograph assistance is required 3. Limitation on vascular lesions ‘Adenoma TF Follicular grid Carcinoma (B) EXFOLIATIVE CYTOLOGY hy Shed cells are studied. 59, Columnar. Toretion These are— shed spontaneously = L2 ‘ ae sy ettod Scraping / Brushing a 8s Used in case of lungs, oral cavity, cervical tissue examination pommstEN Cervical tissue -> PAP Smear Forcervieal cancer-Best screening method -VIA(Visual Inspection after application of Acetic acid) Other method ~ PAP Smear yen spotele 3. Histological methods - most common method ~ Microscopie Examination fixed tissue after performing a biopsy ~ In case of solid cancers» Cervical cancer (High Risk of contamination) ~ Therefore-> Not reliable for diagnosis of such solid cancers Light microscope -» Formalin Electron Microscope -> Glutaraldehyde Routine stains-> Eosin, Hematoxylin stain Special stains (to pick up cancer much more rapidly) 4. Immuno cyto chemistry (a) surface markers detection using presence of Hlouroscent antibodies ~ Particularly used -» for diagnosis of undifferentiated tumors Eg. Keratin-> carcinoma Desmin -» Myogenic tumors Vimmentin->Sarcoma GFAP-> Glial tumor a PrepLadder(b) Detection of Primary in case of metastasis (6) for prognosis / deciding therapy Eg, Breast cancer -> ER(+) -> good prognosis HER 2./ Neu(+) -> poor prognosis 5. Tumor markers Surrogate markers ~ Never useful for definitive diagnosis of cancer — 2 —_® » 2 Co rane 1 : Phase |. - elevated level of tumor markers Phase Il. — response of therapy Phase Ill. Normal levels / cancer free duration (stage of Remission) Phase IV. Stage of Recurrance PSA -> Prostate cancer Ig-> Multiple Myeloma HCG-> Chriocarcinoma Calcitorain -> Medullary thyroid cancer Catecholamines -> Pheochromocytorna CEA-> Increased in patient of colon / pancreatic cancer AFP -> Increased hepatocarcinoma / Non Semino Elevation of CALS-3 -> Breast cancer CAL49-4 ~> Pancreatic cancer CA125 -> Ovarian cancer NSE-> Neuroblastoma 4 DR. SPARSH GUPT:OO OO Paraneoplastic Syndromes Cannot be explained on the basis of - Direct spread ~ Distant Metastasis ~ Indigenous Hormones Significance 2. May be initial Manifestations 2. May mimic metastasis 3. May Indicate worsening condition 1. Endocrinopathies -»Hyperealcemia (MC Paraneoplastic Syndrome) In lung cancer, kidney cancer, Breast cancer Cause -> due to presence of 4 Pgs/ PTHrP. (squamous cell carcinonna) ~ Cushing syndrome-> Lung cancer, Carcinoid tumor 1 (Sraall cell variant) = SIADH -> 11} Antidiuretic Hormone secretion -> may result in hyponatrenaia ~ In lung cancer, CNS 1 (swaall cell variant) = Hypoglycemia -> fibrosarcoma (MC), Hepatocellular carcinoma ~ Polyeythemia ~> erothropoetin secretion ~> In hepatocellular carcinornia , kidney cancer, firromyoma, cerebellar Hemangioblastoma it) Vascular / Hematological - venous Thrombophlebitis / migratory thrombophlebitis Tumor cells 4 raucin 4 formation of throrbophlebitis ~ trousseau sign seen in Ca Pancreas, AML-ym3, Broncogenic carcinoma Marantic endocarditis (NBTE) ~ Non bacterical thrombotic endocarditis ~ seen in Ca Pancreas, AML-1m3 Anemia — Thymoma iti.) Dermatological Acanthosis nigricans ~> skin thickening and hyperpigmentation -? seen in stomach, lung, uterine cancer Dermatomyositis -» Presence of anti p140 Ab, ant piss Ab in these patients (In auto Immuno dermatomyositis - ant Jor Ab (+), so it is Different) Examples — Breast & lung cancer Seborrheic Keratosis ( Sign of leser Trelat ) = In stomach cancer (MC), colon cancer, breast cancer (Eypreptadderiv) Neuro Muscular iy Myasthenia Gravis~ post synaptic problem ~ Thymoma patients ©6 ~ Formation of abnormal antibodies against Ach receptors Lambert eaton Syndrome = Lung cancer (small cell variant) Due to antibodies ~ Muscle weakness against Ca’* = Pre synaptic problem Opsoclonus- ie. random eye movements = Neuroblastoma eg. of tumor arising from adrenal medulla. Limbie Encephalitis - Presence of anti-Hu Ab ~ Lung cancer ( small cell variant) Sub Acute Cerebellar Degeneration — anti Yo Ab -> Uterus / ovary/ Breast cancer ~ More common in females v) Osseus, soft tissue changes Hypertrophic osteoarthropathy C/E ~ Clubbing of fingers = Seen in lung cancerVASCULITIS - Inflammation of blood vessels ~ Non infectious = Immunological C/E ~ 4. Ischernic Symptorns Classification 2) Large vessel vasculitis - AORTA or Major Branches €g- 1) Temporal Arteritis - M/C ~ Adults External carotid Internal carotid ‘ Superficial temporal (A) (terminal Branch) ~ Characteristically affected C/F — M/C Headache (Localised Headache) ~ Jaw claudication- most specific symptom ~ Fever / Malaise / Joint pain / Muscle pain (poly myalgia Rheumatica) - Shoulder girdle >> pelvic girdle involvernent Ds-ttt TC = tt ESR (>SOmm / 1" hr) loc - BIOPSY GRANULOMA Formation ~ Giant cells (+) (temporal arteritis is 2" example of Granulomatous Vasculitis) ~ ¢g of GIANT CELL ARTERITIS ~ ICA can also be involved ‘ Opthal mic (A) 4 4 Blood Flow to eyes 4 Sudden onset of Blindness R, —- DOC - STEROIDS (may preserve vision if given timely) ~ Intermediate R, — patient asked to inhale & exhale in same polythene bag B PrepLadder(when steroids not available) inhalation of greater amount of Co, 4 Act as vasodilator 4 Preserve vision for some amount of time 2. TAKAYASU ARTERITIS ~ HTN (RENOVASCULAR HTN) Elderly individual Young Individual ‘ + Atherosclerosis India Non specific Aortic Inflarnation (TAKAYASU Arteritis) I Medium sized vessel vascultits ¢g-Renal (A) / Popliteal (A) / coronary (A) involvement ¢g- (2,) Poly arteritis Nodosa = Young adults ~ Vessels involved-multiple = Immune complxes (+) —» Fibrinoid necrosis (+) ~ HBs Ag + Anti-Hbs Ab +ve + deposition in multiple organs 4 DR. SPARSH GUPT~ Small vessels are spared (Lungs not involved) Organs involved 2) Renal (A) 4 Micro aneurysms formation 4 Less blood — kidney 4 RAAS (+) 4 HTN - Glomerulo nephritis (~) coz small vessels are spared 1 H/L-RBC cast (-) 2) GIT — pain / blood in stools (melena) 3) Skin — Nodules / papules / ulcerations 4) Nerves - mononeuritis multiplex z 6) Joints — arthralgia f {i TONS ~ risk of seizures =) BME Nopucar oppose 4» NODD. ~ Early phase ~ Fibrinoid Necrosis (+) AtrenRance = transmural inflammation ~ Late phase — fibrosis (+) R, — steroids ~ cyclophosphamide 2. Burger's Disease ~ Necrotising Inflammation (+) -> (A) > (V) >(N) ~ Lymphaties are never affected (mc) ‘Aka — THROMBO-ANGIITIS OBLITERANS - TIBIAL (A) - me involved 1 4 Blood to lower limb - No symptoms — at rest 4 - On walking - pain (+) SJ — Ciieoumo- Anqiris OpLiTeRANS) K /A Intermittent claudication ~ Young ° Neeys tin® No Uke - H/O smoking ° (Hyper sensitivity Rn to (+) of nicoting R, = Quit smoking ~ Vasodilators -s, IW (K)AWASAKI'S Disease = (Kids <4 yrs (Bppreptadcercre Fever + C-conjunctivitis — Non exudative R-Rash ~ extensor surfaces of body Hands Enedema Feet A-Adenopathy ~ cervical LN M-Mucosal ulcers + Strawberry tongue = Thrombocytosis > 4 Blood to heart ~ Coronary Vasculitis. 1 MI (me cause of MI in child is Kawasaki's disease) Ds- Tet - ESRt - Platelet count t R, ~ IVIg + Aspirin ~ (avoided in febrile child) 4 Cause Mitochondrial damage 4 Rays Syndrome ~ Steroids - avoided 4 May develop coronary (A) Aneurysm (itt) Small vessel Vasulitis ~ Arterioles, venules, capillaries ~ (+) ANCA auto antibody Meo <~ 4 »Proteinase-3 (Cytoplasmic-ANCA) r 4 P-ANCA ( peri nuclear PR-3 ANCA 4 MPO-ANCA 6g- wegener's granulomatosis ¢g ~ Microscopie polyangitis ~ Churg-strauss syndrom = Good pasture syndrome P-ANCA -» a/w GIT - ulcerative colitis = produced against nuclear enveloped protein /Ag (3) WEGENER'S GRANULOMATOSIS ~ Granulomotis with polyangitis © = Necrotizing granulomas present + 4 DR.SPARSH GUPTARule of involvement R-renal U-upper respiratory tract, ENT L- Lungs Renal involvement = erescentic GN 4 RPGN ~ RBC cast present@ E- otitis Media N <— septal perforation Saddle nosa T- Strawberry gums = Subglottic stenosis Lungs ~ cough/blood - ex R- cavitation lesions@) Ds - 1) C-ANCA present - PR -3 ANCA present 2) biopsy - Crescentic glomerulonephritis present Re ~ cyclophosphamide - DOC ~ Steroids Death - due to Renal involvement / Renal failure 2. Microscopie poly Angitis = Small vessel involved ~ Lungs affected ~ Renal involvement present = GN present ~ Pp -ANCA present - P-ANCA present = No nasopharyngeal involvement M/E some stage of inflammation present Granuloma absent * Associated with i) Infections ii) Penicillin (drugs) ii)SLE PAN (Poly Arteritis Nodosa Absent Absent present Absent Absent + C- ANCA (PR-3 ANCA) ~ Kidney involved lungs involved URT involvedRx- Steroids 3. HENOCH- SCHONLEIN PURPURA = Children (rac affected) PATHOGENESIS URT: + gAtt eg of Type IHS uc. prelent Kidneys skin Gir joints 4 4 1 4 GN present — purpura ~ Abdominal pain = pain - Microscopic 4 ~ Malena ~ Arthralgia yr Hematuria RASH (d/t vasculitis) —* he L— Lower limbs Byttocks * -msemee ed og - Aka- NON- Thrombocytopenic purpura Cal = Aka ~Anaphylactoid purpura ios 4. CHURG — STRAUSS Syndrome ascul Greruloma formation Eosinophilia present “*L Bronchial Asthma Drugs- Montelukast FINDINGS 1. Multiple organ involvernent — lungs /Dermatological / Cardiac 2. P- ANCA present 4 DR. SPARSEANGINA ISCHEMIC HEART DISEASE 1) ANGINA ~ Reversible decrease in blood supply to cardiac ts. 2) MI ~ Prolong decrease in blood supply to cardiac ts 3) Chronic IHD - Prolong decrease in blood supply + cardiac failure 4) Sudden cardiac Death - Death within 3 hr of onset of any kind of cardiac symptom. e ~~ Ventricular fibrillation ANGINA —__}?—_—__ TSE, 1) STABLE ANGINA ~ (+) ce of fixed coronary (A) obstruction = No physical Activity - No clinical manifestations (Gis — exeae) = Exertion — Clinical symptoms appear ~ Level of obstruction > 75% -> Heavyness of chest or other symptoms develops. ~ Level of obstruction > 80-40%. -> Symptoms appear oven at rest. 2) PRINZ METAL ANGINA = + ce of coronary A spasm = Blood to cardiac tissue compromised Se ‘ ws —+> ® Ofex ERCISE Development of clinical symptoms ~ Spasms occurs at rest /exercise (unrelated with physical activity) R, — Nitrates (very effective) ~ B ~ Blockers contraindicated Because pt already has spasm 4 B ~ Blockers if given + Spasms aggravates 3) UNSTABLE ANGINA ao Cas ~ Pathogenesis — == = Ulceration & rupture of plaque + Increased attachment of platelets &e fibrin 4 cause spasm c/s - New pain / worsening of pain / Severe pain in known pt of coronary Artery obstruction is suggestive for ulceration = Increased platelets 4 Blood supply severely cormpromised to heart ()prepadder4 Cardiac ts — irreversible injury Most dangerous type = Unstable Angina a/w MI 4 aka — Pre — infarction Angina R, - Nitrates - Anti platelet drugsMYOCARDICAL INFARCTION ~ Irveversible Cardiac tissue injury ~ Ulceration / rupture / hemorrhage of plaque +nt 4 Exposure to Collagen 4 Platelet aggregation 4 Thrombus / coronary artery spasm 4 Infarction Types - Transmural MI Subendocardial MI Clinical Symptoms = Chest pain Radiates — Inner arma ~ Jaw ~ Epigastrie region Levine Sign MI -> No chest pain — [ Diabetes Mellitus, Elderly patients ] + Silent MI - Diaphoresis - increased pulse rate ~ Dyspnea ~ Nausea / Vomiting Blood vessel -» Left anterior desending vessel gets affected by atheroscleorotic Obstruction LAD vessel Apex of heart Anterior wall (LV) ‘Ant I/V Septum 1 Ant. Wall MI (MC type) D. 1) ECG / EKG - Hyperacute 'T’ waves ST segment elevation Old MI -> ‘8 Wave 2) Estimation of cardiac enzymes i) Myoglobin (1° Increased) ii) CK -> CK - MM / —€&-MB_ 7 cx - BB (BPreptadder useful for Dxiit) Tropinin T/t -> Elevated for 7-10 days, best enzyme for Dx, specific, sensitive Re-infraction => Increased Troponin Cardiac Troponin T ~ Most important iv) LDH -> Normal individual LDH, >» LDH, Mr LDH, >>> LDH, (Flipping of LDH ratio) LDH is last enzyme to increased in MI. LDH -E4CtSTripheny! Tetrazolium Chloride (TTC) 4 Brick red color -> Normal tissue MI > LDH ““" -> TTC -> Pale color / yellow 3) Echocardiography = Hypokinesia ~ Akinesia 4) Thalliunn Sean -> K’ infarcted area -> (pickedup against viable ) 5) Biopsy SA. hours ----> no change o ~ 4224 hours -> Intercellular edema -> Waviness of fibres Cardiac tissue pale -» (TTC) ~ £23 days -> Coagulative necrosis ~ Neutrophillic infiltaration ~ Infarct -> Yellow border ~ 3-7 days ---> Infiltration of monocytes & macrophages ~ Decreased Neutrophils = Hypermaic border 4 DR.SPARSH GUPT=.7-40 days --> Granulation tissue - Red / Brown margins = Sear depression ~ 4-6 weeks -> Collagenous Sear Grey / white Sear Repurfusion injury Thrombolytic therapy (Stk) => worsening of manifestations in patients M/E -> Ca’ -> contraction bands 1. Arrythmia -> Decreased Heart rate, ventricular fibrillation (with in 2 hr)\g 4 Moratlity in 25% cases Lignocaine is helpful 2. Cardiac failure -> Decreased pumping ability 3. Cardiac rupture syndrorae 3-7 days after Mi = Free wall rupture - MC observed -> cardiac Temponade ~ interventricular Septum damage = Mitral regurgitation 4, Auto-inmmune pericarditis Neo antigens -> 2-3 weeks after MI 4 activation of immune system -> Inflammatory response aka Dressler syndrome R,- NSAIDS 5. Ventricular Aneurysm ~ Clot / thrombus ~ Mortality (Bppreptadder—_ Left Ventricular Failure Right Ventricular Failure ~ Systemic hypoperfusion of vital organs - MC precipitated because of LVF 2) Renal tissue-RAAS(+) ~ Pulmonary hypertension-> cor 2) Brain - Hypoxic ischemic Pulmonale Encephalopathy ~ Involvement of -liver 3) Pulmonary system-lungs are ~ splenic tissue the 1" organ to be affected in LVF - Congestive splenomegaly(Gandy gamma body) = Pulmonary edema = Congestive hepatomegaly (Nutmeg liver) ~ Dyspnea - Chroni¢ involvement -> Heart failure cells ‘ Macrophages ‘ Hemosiderin ~> Pedal edema -> Generalized edema ~> Anasarca fprepadderRheumatic Fever Associated:~ * Seen in children (5-45 yrs) + Immunological + Sore throat -> By group ABHS 4 Ab ——+ 'm protein’ (100) = glycoproteins (Cross-Antigenecity) [ heart / CNS / Joints] < Diagnosis: + Evidence of ® strep-infection @ [2 major or 3 major, 2 minor] Molecular Mimicry Minor criteria : ->fever ~> Arthralgia > tESR ->t PR interval >t C-RP large joints- have migratory arthritis - Joints - Non-Erosive Arthritis-> R, / Aspirin (0)] (Most common C/F) (N) ~ Pt has $/C Nodules -> Painless, Extilocation (E) - Erythema Marginatum (S) - SYDENHAM's CHOREA (seen in late stage-> CNS-> Cause basal ganglia) (C) - CARDITIS -> Pancarditis Pericarditis-> Fibrindeposition present t {known as "Bread N BUTTER" Pericarditis} [Also called "Pericardial Rub] Myocardium» Aschoff Body -> present around BV s-@ “@® ‘ ry Plasma cell / F-cell / (M) Anreseatuo + Antischkow cell<> Aschoff Body — seen in any layer of heart = Most common in myocardium ' [Acute (RHD)] Myocarditis > (—» © (ex failure Endocarditis-> Mitral Valves => (M) >A >T > (P) (Most common involve) Mitral Regurgitation ‘ Atrial valve 4 MC Callum Plaque Acute RHD Chronic RUD ---> (F) ----> Mitral stenosis Gradual deposition vegetations S Vegetations RHD ----> Small (a) step buvis Commonly involve valve HACEK Negative cle Fever; MURMURS (+) We. Loss; R.TH SPOTS; OSLER NODES painful Janeway Lesions Painful (less) Diagnosis- = Duke's Criteria - Blood Culture - Echo cardio findings —-O - Fever / Predisposition \@ features t she : ta eno (L)| Multiple| Friable Loc 4 Small Evnbolisnn (+) Sterile firm ~ Ring abscess presentSLE (SLE) BE - BSmall] sterile Marantic endocarditis ~ Lower surf/ Firm LO¢| small | < © Sterile, embolism (+) o Marantic Endocarditis seen in ~ Ca Pancreas - AML-MB 4 DR.SPARSHGCARDIAC TUMOURS ‘Tumours Primary Secondary = Malignant 1 €.g -> Angiosarcoma (seen in adults) Most common de orign from lungs Rhabdomyosarcoma (seen in child) = Benign ~ Adult children, (Myxoma) (Rhabomyoma) Myxoma:- Site- ATRIUM -> ( MC-left atrium) Types :-> oral > (5) - 90% Familiar -> B/L - 10 to 20% Associated with-» Carney's syndrome ->(M) / skin /increased Endocrine activity Histo :- Myxoma is an example of tumor characterised by lepidic cells -> seen in Myxoid Matrix RHABDOMYOMA :- seen in children Site :~ ventricles (Right or left) Associated :- TSC 1/2 gene Histo :- Have Spider cells -»BASIC CONCEPTS KIDNEY NORMAL ANATOMY Anteriorly to posteriorly Gr Pouns 4. Renal vein 2. Renal artery 3. Renal pelvis -» to be approached posteriorly or Frora back Function of kidney -+ Excretion of nitrogenous waste + Acid base balance + Erythropoietin ; Renin (blood pressure) 4 ‘ (peritubular cells) juxtaglomerular cell of kidney ~ 2 alpha hydroxylase enzyme Active from vitamin D GLOMERULAR DISORDERS ~ Afferent arteriole (brings blood) ~ Efferent arteriole (exit of blood) = Glomerular tuft of capillaries -» (Filtration of blood) ors S ey, > Formation of urine + 7 Pow ri we 4 sehea jy Afferent arterioles ~ Directly under control of PGs, cause vasodilatation Efferent arterioles — Angiotensin Il. -+ vasoconstriction 2. GER ~ normal 125 mi/min Glomerulus Layer 4 - endothelial cells Layer 2 - Basement membrane layer Layer 3 - Visceral epithelial cells (Finger like projections) Layer 4 - parietal epithelial cells Layer 5 - Mesangial cells - connective tissue cells supporting the tuft of capillaries ULTRA FILTRATION OF BLOOD = Blood flows in downward direction - Glomerular filtration barrier is composed of (2preptadder2. Endothelial cells (layer ) 2. Basement membrane (layer ) 3. Visceral epithelial cells (layer) Or PODOCYTE LAYER Urine collected in bowman's space lined by parietal and visceral layer aka URINARY SPACE ULTRA STRUCTURE OF GLOMERULUS ee Factors affecting filtration CC rari Size of molecule / charge of the molecule J PODOCYTES = meget charg a (collagen, connective tissue material) + Bonmtel 518 coe el Ifa molecule is an anion (negatively charged) - Does not get filtered easily (repulsion) If it is cationic in nature — filtered easily Electrolytes : glucose, amino acids, Na’, K’ (get filtered easily) Proteins : Albumin < Globulin < Fibrinogen (small (bigger molecules) molecule) 4 4 unfavourable filtration Favourable filtration 4 Sian (negative Charge gets Plasma proteins + negatively charged Wocsraus het repelled) Hyatne ~ Thus these proteins do not appear in the urine of a normal individual Owes, + TAMM HORSFALL PROTEIN (tubular protein) is present in urine of normal individual secreted by ascending limb of loop Henle cells = € 150 ma/I in 24 hours ~ Acquires shape of tubule known as hyaline cast(amorphous appearance) aka physiological cast = In some disease, deposition of antigen antibody (immune) complexes in the glomerulus we E a 7 J neremelae Podocyte Layer ~ Subepithelial deposits oe Basement membrane + Intramembranous deposits we PE oe Endothelial cells = Subendothelial deposits Usenaiore Ere =a 5 ee er ed Subendothelial immune complex seen in disorders deposits fc 4 Membranoproliferative glomerulopathy Type | (MPGN 1) Intramembranous immune complexes - MPGN II Subepithelial immune complexes + Membranous glomerulopathy ~ Post streptococcal glomerulonephritis L DR. SPARSH GUPTANEPHRITIC SYNDROME: POST STREPTOCOCCAL GLOMERULONEPHRITIS NEPHRITIC SYNDROME: Pathogenesis: Immune complex mediated OR complement activation mediated inflammation resulting glomerulonephritis Ag + AB - Immune complex formation 1 ©system activation 4 C., (Influx of WBC) ‘ Glomerulonephritis Glomerulonephritis = Syndrome having 4 classical components ~ Proteinuria - Oliguria ~ Hypertension - Hematuria Glomerulonephritis 4GFR Proteinuria Damage to blood vessels & endothelial cells urine output RAAS activation 4 4 + Development of RBC in urine Oliguria | Aldosterone 4 (€ 400 ml in 4 Angiotensin I! Hematuria 24 hours) 4 (at least > 3 RBC per High yield) + BP (HTN) (in 3 samples 2 week apart) Isomorphie RBC - seen in glorserular cause of hematuria Eg: kidney stones Dysmorphie RBC - Disease of glomerulus POST STREPTOCOCCUS GLOMERULONEPHRITIS: ~ Pediatric age group = AW type Ill HR. - MW 10-34 days ~ H/0 skin infection or Sore Throat 1 (due to group A Beta HS + strains 4, 22, 2) 4 Ab ~ Bacteria 4 VC formation 4 Trap in glomeruli ‘ (BpprepLadder Complement activation‘ Development of glomerular inflammation (Diffuse, WBC +) C/E -» HTN / Hematuria / Oliguria / Proteinuria + + Headache Cola colored urine Diagnosis - = Urine investigation » RBC Cast © = Blood investigation -» Anti DNAase Ab - higher diagnosis specificity + Anti streptolysin O Ab (ASLO) +46, - level of complementary protein going to reduce only Temporary 3. Renal Biopsy (/C formation + Subendothelial Membrane Subepithelial (MC) 4 Subepithelial HUMPS @ [Through immunofluorescence] + Starry sky appearance + Flea-Bitten kidney + PSGN + Vasculitis LE + Malignant hypertension + Leukernia + PSGN + 92-95% recovery Diffuse Proliferative Glomerulonephritis + A/K Acute Glomerulonephritis A/W Infection (post) (Non-tnfectious) 4 4 M4 PSGN SLE - kidney > MC affecting organ {RPGN AND BERGER'S DISEASE RPGN ( Rapidly progressive Glormerulo nephritis) - Onset of S/s -» Kidney failure (within few weeks to months) Pathogenesis ~ Severe glornerular inflammation 1 Leakage of fibrinogens, thrombin 4 Crescent formation - deposition of fibrin = WBC infiltration ~ Proliferation of Parietal cell present 44. GFR > Renal failure ~ Biopsy shows RPFN - aka — crescentic GN ©) @ ReGn (cesses) ‘Subtypes of RPGN Type ~ | - Anti - GBM Disease = Good pasture syndrome = on immunoflourescence — linear IF present ret Artteny Being tne Carmine Arm heel (ANCA) ~ Plasma pheresis — remove the abnorraal antibodies Type tl = immune complex deposition ~ seen in pt of - SLE - IgA Nephropathy - HSP ~Characterised by granular IF present (BPreptadderRx = Treat primary cause Type Ill No GBM Antibody present “Nec pritnt = aka PAUC! - Irmune RPGN mn x x x *. a 4 ANCA present = 2 types C- ANCA present — Pt with wegener’s granuloma P= ANCA present ~ microscopic polyarteritis Clinical feature — H/o Disease ‘ 14d renal function - | urine output (oliguria) ~ Hematuria Diagnosis = hematuria (altered color ) = RBC cast - Reduced UO in = Abnormal antibodies ~ finding suggesting H/O any etiological disorder Kidney biopsy - lmmunoflorescence Blood investigati BERGER'S DISEASE ‘Aka ~ IgA nephropathy ~ Adults (Big people - Berger) -MC GN present - H/O mucosal infection ‘ (Respiratory / urinary /gastro intestinal mucosa) + 11 IgA Antibody (Reduced clearance ) + Immune Complex formation (Mesangiura) 4 Glornerular injury Time taken from the develo; ~ Pediatric - H/O pharyngitis after 10-14 days - ISerum C, levels (Transient Hypo complementernia) Clinical Features - Hematuria (majority Pt- Gross Hematuria > Microscopic ~ Recurrent Hematuria Fae 9 ~ Mucosal infection present Diagnois~ Kidney Biopsy - Mesangiurm 1. t cells present =< 72 brs ~ Normal complement protein levelsNEPHROTIC SYNDROME: BASIC CONCEPTS T eell injury ~~ = Imumune complex mediate injury Cytokine releases 4 Podocyte Damage (Podocytopathy) Podocyte Loss of ve charge Liver produces ve lipids 4 4 Massive proteinuria + Lipids (blood) + Albumin 4 * JANP Lipids (urine) AT IIL 7 + Protein C/S_| Clot formation ug Edema I omponsnts of Nobo sendrame 1 Massive proteinuria Hypo albunimea Edema Hyperlipidinnea ~ Loss of protein ~ Less than 39/dl plasma More than 3.5 protein concentration 9/24 hours 4 Albumin - 4 oncotic protein + edema LANP - | Atrial natriuretic peptide + edema Na’ / water excretion (1 Na’ water in body) + Loss of Tranferrin -» Fe deficiency anemia (Iron resistant) © Loss of Thyroid binding globulin + Hypothyroidisnn * Loss of Lipids + hyaline cast -> lipid cast or oval fat body (on m/E maltese cross present) —_______Podecytopathy Mild severe 4 ‘ Loss of albumin loss of albumin Ig protein C/s, AT- Ill 1 + Selective proteinuria Non selective proteinuria 4 4 Excellent response Steroids not helpful with steroidswr Structure of podocyte SSS eee >" Povocins NerHnin Genes ~ NPHS 3 gene associated with Nephrin defect -+ (Finnish subtype) congenital Nephrotic syndrome NPHS 2 gene associated with Podocin defect 4 FSGS 4 DR. SPARSH GUP"eae NEPHROTIC SYNDROME : MINIMAL CHANGE DISEASE MC cause of Nephrotie syndrome -» Children Cause = Idiopathic ~ Drugs NSAIDS ~ Hodgkin's lymphoma ~ Respiratory tract infections ~ Atopy Clinical features Podocyte damage child -» Frothiness in urine ~ Swelling Components of nephritic syndrome Massive proteinuria Hypoalbuminemia Edema Hyperlipidemia + lipidemia Dx = 1. Blood -» hypoalburinemia 1 Lipids 2. Urine 24 hours urine sample — Massive proteinurea 3.5 g of protein /24 hour ~ oval fat bodies / Lipid Cost Kidney biopsy . oO EFFACEMENT OF Poooone LM (low magnification) > Normal glomeruli — minimal change disease EM (Electron microscope) -» Effacement of podocyte IF (Immuno Alurosence) -» No immune complexes Nil — deposit disease Lipoid nephrosis Rx Steroid therapy -» Excellent response (prepLadderFOCAL SEGMENTAL GLOMERULO SCLEROSIS Primary Secondary = Reflux nephropathy ~ Hypertension ~ Sickle cell disease -HIV = Heroin abusers (IV) = Unilateral renal agenesis FSG in adults -» Nephrotic syndrome Minimal change disease in children -» Nephrotic Syndrome Adults + Non selective Proteinuria (Excessive frothiness, edema) ‘ FSG Focal segmental Few/ Fraction of glomeruli are affected (Focal) ~ Affected glomeruli + (Sclerosis only in 1 particular part ) (segmental) ME Effacement of podocytes Variant HIV + (Kidney problem) HIV associated nephropathy Variant Glomerular Tip Collapsing type ‘ 1 Good prognosis Extensive glomerular damage Tubular cystic lesions + Visceral Epithelial cell hypertrophy 1 Poor Prognosis (non selective proteinuria) t Poor response with SteriodsMEMBRANOUS GLOMERULOPATHY AND MEMBRANO PROLIFERATIVE GLUMERULOPATHY MEMBRANOUS GLOMERULOPATHY - MC cause of Nepthrotie Syndrome in elderly Etiology 3- idiopathic 2 ~ Drugs (NSAIDS /Penicillamine) - infections (Hepatitis B Virus/ Malaria) = SLE, Auto-immune thyroiditis = Cancer (Colon cancer/ Melanoma) = Autoimmune ds ~ Auto Ab present = (HLA - DQ Al) + 1 Phosphor lipase A, Receptor 1 Podocytes 1 Damage 1 C/F — Non selective Protein urea HEYMANN NEPHRITIS MODEL ~ for animals (Rat kidney) 4 Ab against Rat kidney Fa 7 MEGALIN NE oh cen Reveal about 2 causes d [7 kidney Biopsy = Low magnification - Thickened glomeruli present ~ Electron microscopy = Immunoflorescence Memb. Glom ~ Effacement of Podocyte present = Subepithelial 1/C (On IF) - BM deposition - DOME app. BM deposition - Spike App. In BAW /C MEMBRANO — PROLIFERATIVE GLOMERULOPATHY (MPGN) AKA MESANGIO- CAPILLARY GLOMERULOPATHY = Pt. have mixed picture of manifestations of Nephrotic and Nephritic syndrome but predominant is Nephrotic Syndrome Etiology 1. - Idiopathic 2- Hep. C/ Leprosy / Hep. B Partial Lipo dystrophy syndrome cue 2 Antitrypsin deficiency / SLE (PreptadderSYSTEMIC DISORDERS AFFECTING GLOMERULUS NEPHROTIC SYNDROME 2MCD 2FSGS 3 Memb Glom 4MPGN Systemic disorders a/w Nephrotic syndrome 12DM = (MC) 2 Amyloidosis 3SLE Pathophysiology of Renal Ds ~ in pt suffering from DM DM -1 1 Thyperglycemia (Absolute insulin deficiency) 4 Non Enzymatic Glycosylation aN = (NE) 1 Advanced Glycation End Products 1 Deposited in efferent vessels 1 (earliest change) Exit of Blood reduced 1 High pressure at filtration site L Hyper filtration injury 1 Deposition of materials in ECM 1 PAS +ve Nodules deposit K/A NODULAR GLOMERULO SCLEROSIS (Most Characteristic lesion) ‘Aka ~ KW lesion J Diffused Glomerulo sclerosis 1 LiGFR + DM is commonest cause of CKD globally Condition arised d/t 211 Glucose 21 Filtration injuryDiameter of efferent vessel depends on ~ Ang Il 1 ve Action of Ang II sed by [a | 1 risk of Diabetic Nephropathy + ARB 1 1 Ang Il + V. d (eff) RENAL PAPILLARY NECROSIS. + Coagulative Necrosis of tips of Renal Papillae * Etiology *DM - 1 infection risk a PAPILLARY + Obstruction of urinary tract — Back pressure change Mecams *Sickle cell Disease - Reduced Blood supply #1 Analgesics intake - absent Co x enz@I Pgs Amyloidosis Amyloid protein —tepesits kidney 4 > 2° Amyloidosis (deposition in rnesangium) 1 Involvement of complete glomerulous 1 Nephrotie Syndrome SLE Ly Membrancus glomerulopatha >> MPGN 1 Most conmnon cause of nephrotic syndrome Nephritic syndrome ~ Diffuse proliferative GN (wire loop lesions) D msnessoumRENAL TUMORS ; RENAL CELL CARCINOMA RENAL TUMORS aN Benign Malignant Benign 2. Angiomyolipoma = Spontaneous hemorrhage ~ Associated with tuberous sclerosis = CNS involvement - t risk of epileptic attacks = increase risk of renal tumor - angiomyolipoma = Cardiac involvement -» Rhabdormyoma ~ Skin manifestation» Macules 4 Shagreen patch 2. Oncocytoma = Large Eosinophilic cells + Mitochondria +++ lalignan\ 4. Renal Cell Carcinoma / Hypernephroma / Grawitz tumor - 6th - 7th decade -M>F - Upper pole of kidney affected 1. Tobacco (mn. inp.) 2. Asbestos 3. Hypertension / obesity 4. Estrogen 5: Sickle cell trait 6. End stage renal disease -+ Dialysis Farilial RCC * VHL Syndrome VHL gene > Chromosome 3p + Tumor suppressor gene 1 4 Hypoxia inducable factor (HIF) 4 4 Vascular growth factor Renal Cancer Pheochromocytoma Cerebellar Hemangioblastoma* Hereditary Leiomyomatosis —) + FH gene rec _}] — mutation * Birt - Hogg - Dube Syndrome = Kidney Cancer = Skin Cancer | S/R/P = Pulmonary Cyst * Hereditary Papillary Cancer ~ MET gene mutation CLE of RCC - Hematuria - (painless) —] ~ Palpable mass Classical triad ~ Costovertebral pain I of ROC Fever / weight loss / malaise ox Kidney Biopsy + Histopathological examination 4 Subtypes of Kidney Cancer 2 Clear Call Carcinoma - M/C renal cancer ~ Origin ~ Proximal tubule ~ VHL gene mutation ~ Unifocal / Unilateral washed Glycogen + lipids» clear cytoplasm off (ID — cleor eepasm 2. Papillary Cancer Origin - distal tubular cells Multifocal / Bilateral Trisomy - 7/46/47 Associated with Sporadic variant Familial variant of OF P Cancer of P Cancer of kidney kidney © : ngs non et & 4 Boris —eblee DR. SPARSH GUPTA= Psammoma body + ~ Dialysis associated cystic disease 3. Chromophobe Carcinoma - Perinuclear halo +nt ~ Hypoploidy = BHD syndrome = Best prognosis 4 Bellini duct cancer ~ Collecting duct (medulla) ~ t Anaplasia -» poorer prognosis 5. Medullary Carcinoma - Sickle cell trait ~ collecting duct 6. Xpil translocation gene ‘ TFE gene -» young patients Metastasis of Kidney cancer Lungs > Bones > Hepatic Tissue> Adrenal Glands ve mc) © © RCC ~ venous spread Right testicular vein = Inferior vena cava (IVC) © tele Left Gonadal vein -» Renal Vein > Tumor cells — left renal vein + IVC -+ Renal vein gets obstructed Blood from left sided testicular vein X drain into IVC ' High pressure in venous return in testicular tissue 1 Left sided varicocele (associated with tumor in left kidney) Paraneoplastic Syndrome (BjprepLadder-?tESR ~ Anemia - Polyeythemia - Leukemoid reaction 2! Amyloidosis Kidney cancer Hodgkin lymphoma ~ Hypercalcemia / feminisation / masculinisation = Cushing syndrome ~ Hepatic dysfunction (non metastatic) ‘ Stauffer SyndromeWILMS TUMOR «Malignancy seen in children (pediatrie malignancy) Risk factors: 2. WAGR syndrome * Wilms tumor / aniridia / genital anomalies / retardation sInvolvement of WT, WT2. gene (tumor suppressor genes chromosome 11p) ‘* Mutation of these genes +1 risk of WT 2. BECKWITH - WIEDEMANN SYNDROME * WT + Hemihypertrophy 3. DENYS - DRASH SYNDROME * WT + GONADAL DYSGENESIS ClF- Abdominal mass Fever Hematuria + Abdominal mass earliest and most common presentation Diagnosis + Renal biopsy + Histological exarnination + Triphasic Tumor (best) 1. Blastemal component 2. Epithelial component 3. Stromal component + Nephrogenie rest is present -+ precursor lesion / indicator of cancer +1 risk of cancer in opposite kidney Prognosis «Depends on degree of anaplasia #1 degree of anaplasia + poor prognosis + indicator of high degree anaplasia pS gene mutation, aneuploidy Poor prognosis * Better prognosis as compared to adult counterpart hypernephroma + Renal cell carcinoma in elderly ~+ poor prognosis WT + overall better prognosisHHLIRUSIN METABOLISM : GASIC CONCEPTS AND BILIARY TRACT DISORDERS BILIARY METASQRISM s destruction (qpteen) 4 Releave of MEME 4 (Albumin) = Unconjugated Bilirubin 4 ves up =» UGT (UDP Glucuronosyl transferase) xg Conjugated Bilirubin / 4 Biliary Ducts Gk — Intestine load ® / 4 Gut Bacteria 4 /_ Stereobitinagen (yellow in color stools) Kidneys —/ are Urcbilinagen YAUNDICE Jaundice (Bilirubin >> 2.5 mg/dl) Elastin OO truce 1B (> 50% Bilirubin) (Jaundice / Plewritis / Grey colored stools) ~ RBC destruction ~ Biliary duet obstruction stones / cancer / infection (Hemolytic anemia) ~ Biliary tract diseases = New born ~ Primary biliary cirrhosis ~ Genetic disorders ~ Primary sclerosing cholangitis (A UGT activity) ~ Genetic Disorders 2. GIBERT syndrome (b excretion of CB) 4 2. DUBIN JOHNSON syndrome Adults ~ Autosomal recessive condition 4 ~ MRP ~ 2 deficiency Stress 1 ~ Dark pigmented liver 2. Crigler Najjar Sire 4 tl (Thus of epinephrine) Type | - zero activity 2. ROTOR syndrome of enzyme = Normal liver appearance ‘Type ll ~ Reduced activity of enzyme UGT [Bjpreptadder~ Seen in new borns ~ Autosomal recessive ‘Type | - mortality of babies Type li - t concentration of UC Bilirubin ‘ ~ Phenobarbitone (anti epileptic drug) given in babies ~ Phototherapy given VIRAL HEPATITIS - 1 UCB =16B BILIARY TRACT DISORDERS 2) 1° Biliary Cirrhosis ~ Granulomatous damage -» I/H ducts - Females >> males + 40-50 years ~ Associated with autoimmune disorder Sjogren's syndrome ~ Antimicrobial antibodies + -» Pyruvate dehydrogenase complex -1CB + t Cirrhosis / + Cancer 2) 1° Selerosing Cholangitis * Males > females * Damage to I/H + E/H bile duets * Bile ducts » Concentric Periductal Fibrosis 1 Onion skin appearance * Beaded appearance on Cholangiograrn * Ulcerative colitis ++ * p-ANCA+ Toaey Citgnosls PScrerRos iG CHOLANGITIS 4 DR. SPARSH GUPTACIRRHOSIS Risk factors ~ Alcohol - Non-Alcoholic Fatty liver Disease = Viral hepatitis = Metabolie disorder of liver Characterized by = Damage to liver - Bridging fibrous septa = Regen. Par. Nodule present = Stellate A Myofibrobalst 170 cell TGF -B Features of cirrhosis = Portal Hypertension (HTN ) -+ Congestive Spleenomegaly / Ascites / P- S Shunts. = 4 protein synthesis -» 4 Albumin — Ascites 4 clotting factor, t Bleeding TPT / aPTT 4 Metabolisnn + Estrogen t + ‘ Causes - PE / Spider Angios/ Gyne 4 Gonads functions 1 NH, + Neurotransmitter activity» HE LK LH tNa’/ 10. (All) It leads to 4 Hepato - Renal/ Hepato -Pulm Syndrome Alcoholic liver Disease 2) Alcohol steatosis :~ Also called "Fatty liver" Micro ~vesicular (Reyes syndrome / AFL preg. / CHR. HEP V/ Drugs Macrovesieular Seen in - PEM / TPN / J-1 By pass/ DM / Lipodystrophy2) Alcoholic hepatitis :- Acetaldehyde - Perivenular / Perisinusoidal Fibrosis ~ (MALLORY Denk Body -+ Cytokeratin (CK) Filament Mallory Dank Body New + NAFLD Indian + ICC + Cu W + Wilson's Disease > ALD, a-1 AT def. + Tumour (HCC) — CHR. Cholestasis (primary Bil Cirrhosis) > Fin. Hyperplasia ra4> Mallory Denk body not seen in :-> Secondary Biliary Cirrhosis 3. Cirrhosis -» Called laennec cirrhosis Non- Alcoholic Fatty Liver Disease ~ Idiopathic/ Cryptogenie = Obesity / Dyslipidemia/ Insulin resistance = Asymptomatic + Diagnosis of Exclusion Most Common cause > Cardiovascular cause Microscopically — Steatosis / NASH - AST ALD (Alcoholic liver Disease)» —~ >2 ALT NAFLD (NON Alcoholic liver Disease) » “21 <2 ALT Hepatitis Hep A - transmit by Feco- oral route -+ most common hepatitis in ( Child) Hep B > Transfusion Associated . HEP Carrier / t HCC Hep C -» CHRonic/ Most common to cause " Cirrhosis" Hep D ~ Hep. B > Co-infection > Super — infection Hep E ~ FO. + M/C — Adults) (Most common in) > Fulminant — Pregnant fernale 4 DR. SPARSH GUPTAHep. B :~ PlmZ Allele Panacinar EMPH Diagnosis — PAS positive / Diast © granules 4 Hepatocytes Hemochromotosis > Hepcidin present IRON overload (CHR. 6p.23) (D-HFE gene Las - Multiple blood transfusion j—» hemosiderosis Africans 4 Liver + Cirrhosis Skin (1 melanin) Pancreas ----» diabetes mellitus (DM) = Cardiac + Arrhythmia / RCM\ = GONADS -» Male -» Gonadal. Dysfunction ~ Pseudo- Gout Diagnosis -> - tron overload = 1S. iron/ t %T)/ 1S. Ferritin - Liver Bx - Prussian Blue Bronze diabetesRe -+ tron chelation Phlebotomy ~ Wilson's Disease -» C4 Ceruloplasmin 4 APO@ Bile = AR + Chr. 13 -» ATPTB gene ~ Cu + Organs Pt have- (Associated with) 4. (Liver) Damage + Cirrhosis / Increase Cancer 2.CNS Cu - basal ganglia -» PARKINSONISM + Abheimer Il Cells 3. Eyes -» Cornea -+ DE SCEMET (M) C KF Ring Sunflower © (This type of cataract have sunflower appearance ) Diagnosis “L. t Urinary . Cu -» Most specific 2. Liver + Cu > 250 yg Cu 3. Serum Cul/N/T (Serum cu level is not reliable) Re DMT , + Zine 4 DR. SPARSH GUPLIVER TUMORS HEPATIC TUMORS Benign Malignant * Cavernous aa Hemangioma (we) Primary Secondary tumors * Hepatic adenoma tumors 4 METASTASIS (M/C) Pancreas / colon / Breast (w/c) 4 t size of liver 4 Nodular edges (smooth) Cirrhosis + Rough surface On palpation Hepatic Adenoma = Young female - H/O OCPs ~ Subcapsular + Pregnancy -+ rupture t t intraperitoneal hemorrhage ~ B catenin mutation +» 10% hepatocellular carcinoma (malignant) Primary malignant tumors 2) Hepatoblastoma - children (me) 2) Angiosarcoma - T/A/P [Thorotrast / Arsenic / polyvinyl chloride] 3) HEPATOCELLULAR CARCINOMA - Adults (vac) HEPATOCELLULAR CARCINOMA Risk Factor 1. Chronic hepatitis (B>>C) 2. Alcohol intake 3. Aflatoxins (Aspergillus Flavus) - fungal contarainated peanuts 4. Hemochromatosis /WILSON'S disease 5. Hereditary Tyrosinenia Pathogenesis 1. B catenin activation 2.4 p™ gene activity 3. tIL-6 - t multiplication / | differentiation 4. B Dysplastic nodule -» Low grade + > High grade +++ (worst outcome) B PrepLadder- Chronic liver disease - cellular change 4 ‘ Small cell change ttt progression To malignancy 5. Hepatitis B virus -» HBx protein + Oncogenic ~+ Mutation of infected cell C/E - Male > female (3:1) - Elderly = Malaise = Abdominal pain (m/e symptom) - Weight loss, fatigue Physical examination - Hepatomegaly (ra/c sign) Diagnosis ~ Tumor markers 1. a-fetoprotein (AFP) tt 2. ARGINASE - 37] more sensitive, specific Hep - far 4 ] Gilypican 3 Variants of HCC * Fibrolamellar variant = Young adults (20-40 yrs) - Male = females ~ In south east asia (INDIA) = F >> M = Not associated with hepatitis B / Cirrhosis ~ Arises from left lobe = indolent, slow growth ~ BETTER PROGNOSIS = Normal AFP levels ~ Neurotensin (marker) Microscopically, prominent mitochondria ONCOCYTES present, lots of collagen Metastasis of HCC = Expanding cancer - Multifocal = Infiltrating cancer - SATELLITE NODULES - central umbilication = Involvement of lungs ~ Involvement of lymph nodes ~ peri-hilar ~ peri-pancreatic > peri-aortic Prognosis + poor Treatment - SORAFENIB.—- Surgery - Transplant large cell change + 7 SATELLNE NepuLes wel? 4 DR.SPARSH GUPTATESTIS : CRYPTORCHIDISM AND ORCHITIS Cryptorchidisrn swe genitourinary disorder in male child + Failure of testicular descent + Exposure to high temperature + Sparing of leydig cells Complications 2. Atrophy (exposure to high temp.) - | fertility 2. Tumor ~ 1 seminoma 3. Torsion Treatment Surgery * ORCHIOPEXY (6 months - 2 years) + Risk not reduced Orchitis Inflammatory disorder Testicular tissue Epididymis ec 35 years or > 35 years + Organisnas 1. E. coli 2. Chlamydia 3. Mumps (+ parotid gland + pancreas) 4. TB + granulomatous orchitis 1" - epididymis, subsequently involvement of testicular tissue ‘ Syphilis Fesris 1" involvement of testis then involvement of epididymis ‘Pain in groin, scrotal sac Scrotum elevation u tt (Prehn sign) Cremasteric reflex | present absent (stroking of inner thighs)cfr - TESTICULAR TUMORS + Adult pt. + Painless enlargement Tsed scrotal mass + Associated finding of secretion of hormones sometimes Spread - Lymphatic + Para - Aortic LN = Hematogenous + Lungs (MC) > CNS > Liver > Bone Biopsy - C/I in testicular tra Painless enlargement of testis ~ taken to be malignancy unless proved otherwise - remove testis in Toto 1 Then do H/P examination Risk factors 1. Gonadal dysgenesis 2. Genetic Defects 3. Opposite testis 4. Temp. (Cryptorchidism) S. Intratubular Germ Cell Neoplasia (ITGCN) CLASSIFICATION Germ cell tm (Gonads) Seminoma — NSGCT ~ Slow growth ¢g - Chorio Ca / Embryonal Ca / ~ Sparing of Tunica Tunica Albuginea ~ Radio - sensitive ~ Spread - Lyrphaties Teratorna / Yolk Sac tr Clery ~ Hemorrhage / Necrosis + ~ Hematogenous spread ~ Better prognosis Mnemoni¢e GOTT G ~ Klinefelter syndrome ~ Testicular feminisation 0 - it2p ; NANOG OCT 3/4 iT: 1 - tse risk of all testicular tra except Teratorna Spermatocytic Seminoma rm cell tm - Stromal tm ~ Leydig cell tom ~ Sertoli cell ~ Lymphoma (EppreptadderMC site - Gonads MC extragonadal site - Mediastinuna SEMINOMA Variants ~ classical + Anaplastic + Spermatocytic Classical ewe - Adults © Genes - OST 3/4 - NANOG -C-KIT Gross + Grey tm “ec hemorrhage [ Necrosis \ M/E - Sheets of cells with clear cytoplasm - contain glycogen *V infiltration lymphocytic - (stroma) Anaplastic Variant #1 Anaplasia + oT mitosis Spermatocytic Seminoma + Elderly ‘*Characterised - by app of 2° spermatocyte cells + Excellent prognosis «No LN metastasis *No lymphocytic infiltration NsacT Subtypes 4. Embryonal Ca *.20-30 years +ce of primitive cells / embryonal cells “1 BHCG/1 AFP 2. Teratoma «tm arising from > 1. germ cell layer Ectoderm + Meso + Endo (mc) ZD msnssicurnSS [—— ja * Origin from Totipotent cells Seen in [~ Pediatric - Pure teratoma - rare = Mixed (embryonal) Adults ~ Malignant (unless proved otherwise) M/E ~ Ecto / Meso / Endo origin 1 Has chances of malignant transformation 1 sce Markers ~ 1 AFP = 18 -HCG YOLK SAC TM / ENDODERMAL SINUS TUMOR * Children - <4 yr “TARP eta, -AT M/E - Schiller - Duval Body® aka Glomeruloid body o0 Glomenvioib BoP’ CHORIOCARCINOMA + CYTOTROPHOBLAST “+ SYNCYTIOTROPHOBLAST 1B -HCG sheilar to TSH Hyperthyroidism 1 FSH / LH activity - Gynecomastia + Small palpable mass (usually missed) + Aggressive, spread easily * Poor prognosis [BPreptadderNON GERM CELL TUMOR Stromal tumors * LEYDIG CELL TUMOR * Hormonal secretion androgen - precocious puberty Estrogen- Gynecomastia M/E - Lipid droplets LR/ES INS wot Eosinophilic shaped * GERTOLI CELL TUMOR Gilent tm T estrogen synthesis * LYMPHOMA + Elderly - me in elderly +B *DLBCL Malignant tra * Poor prognosis KE erystals@ Inclusions DiagramPROSTATE GLAND Periurethral zone U. BLADDER ‘ Benign hyperplasia of prostate ® 1 -- Compression of urethra 1 ‘Symptoms - early presentation Peripheral zone t Ca of prostate arise : LN L>> cnnintinpipnve GS Lor 1 Pers vertnant Compression of urethra - late 1 [ee) Symptoms - late (BHP) BENIGN HYPERPLASIA PROSTATE - MC region of enlarged prostate (> SO yr) ~ Hormone dependent Androgen - modified Testosterone 1 tT —S4_» pyr ete | Estrogen eels Findings - Nodularity® M/E ~ Hyperplasia + Stromal cells + Glands 2 layers > Basal layer - cuboidal > Coluranar cells layer (BppreptadderC/F~ = Urethral compression ~ Urine retention - 1 risk of UTI ~1 Frequency - Difficulty in starting / stopping of stream M/C complication ~ obstructive uropathy -+ MC - Median lobe hypertrophy ~ Bladder Diverticula ~ Hydronephrosis Risk of cancer - NO Rx - Drug therapy (improve urinary flow) 1 OS a reductase Definitive Rx ~ Surgery PROSTATE CANCER - Elderly male pt. (MC) Risk Factors = Age - wimp. - Die®- 11 (lipid consumption), 11 (Vit. A, carotene, soya food) ~ Androgens ~ 11 Androgen - | Ca risk ~ Genes - BRCA - 2 gene mutation = 1st degree relatives of pt. Genetic markers ~ Hyper methylation of Glu - S - transferase = WE - cadherin gene - TMPRSS2 - ERG fusion C/E - Asyraptomatic ~ Pain - Back / Pelvis (bone involved) Metastasis + LN - obturator LN ~ Blood ~ Bones (rae - Lumbar spine) + Lungs/ responsible for (Pelvis, Femur) Hepatic involvement ~ Prostate Ca + Osteoblastic Metastasis 4: Core Biopsy FD enssunoncuraM/E ~ Adenocarcinoma ~ Single layer cells ~ Basal cells Grading - GLEASON SCORING Serum PSA parameters (Prostate Specific Antigen) ~ 5. PSA levels - > 10 ng/ml (suggestive of cancer) @< 4 ng/ml) = PSA density - S. PSA / volume of gland - PSA velocity - > 0.75 ng/ml (associated with increased risk of cancer) = Subtype + Free form - a/w BHP +@ound form - cancer development 1 Gad for pt. New Biomarkers = Urinary PCA - 3 1, in case of cancer ~ TMPRSS2. - ERG fusion DNAFEMALE GENITAL TRACT : CERVIX FEMALE GENITAL TRACT ° ovary CERVIX oo + Ukerus Endocervix Exocervix — Corvin (Cervical 05) 1 (Colunmnar Cells) Squamous cells Transformation zone / squarous columnar area 1 MC site for squamous dysplasia 1 Pap Smear Cervical intraepithelial Neoplasia (CIN) * Dysplasia changes + 1 N:C T mitosis Progression to malignancy Most important risk factor 4 HPV infection Low risk High Risk Subtypes Subtypes 6,44 16,48 31,33 eg 4 1 Condyloma Cancer Accuminater or Viral wartsHistological -+ Kilocytosis 1 Pyknotie nucleus Perinuclear Halo Markers for High rate replication - Ki - 67 / ple HPV + E, protein + | ps3 /1 telomerase + E, protein + 1 Rb gene 1 HPV infection - Early age of intercourse ~ Multiple partners ~ High isk partners ~ Multiparity Cervical intraepithelial Neoplasia Low grade SIL + Mild dysplasia High grade SIL + Moderate / severe 10% LSIL Tygougn? HSIL Im 10 yrs 10% HSIL Tr 40 yrs” Cancer Dx of dysplasia Colposcopy examination -+ acetic acid ) 1 Visual inspection after . ignewal vaneularn application of acetic acid M0saie pattern Or Abnormal vascularity Cervical Cancer Risk Factors 2. HPV infection = Most important 16/18/31/33 2. Smoking + Polycyclic aromatic hydrocarbons 1 1 exposure 3 Immune deficiency -» inadequate removal of viruses BD onsouncsourn4. OCPs + Oral contraceptive pills 4 Alteration in cervical tissue & vagina pH C/F - Post - coital bleeding Extension ~+ ~+ Vagina ~+ Bladder -+ obstruction at level of ureter + Renal dysfunction 4 Kidney failure 4 Death = Pulmonary systen M/E * Most common variant $q. cell carcinonna + Adenocarcinoma * Mixed adenocarcinoma Screening 2. VIA (visual inspection after acetic acid) ~ Colposcopy > Th ~ best method } 2. PAP smear Iyers spatula. Tissue is taken from TZ -> fixed on on slide -> dysplasia features are observed Female + H/O vaccination ~+ screening required Adenocarcinorna ~ X screening Vagina + Embryonal Rhabdomyosarcoma Child + ¢ 5 yrs + H/O grape like mass 1 Sarcoma botryoidesM/E Tennis ~ racket cells 1 Also seen in case of - Birbeck granules (A/W langerhans cell) ~ Clostridium tetani Muscle Markers ~ Myoglobin@ ~ Desmin@ ~ Clear Cell Adenocarcinoma Precursor lesion ~ vaginal adenosis Example of condition ——_l Female ~ intra urine exposure to ~+ diethylstilbestrol t Causes of inhibition of Mullerian duct differentiation = Incomp. Cervix ~ Abnormal uterine shape > Squamous Cell Cancer * Associated with HPV 16 © Extension of Ca cervix BD onsonsioursUTERUS Uterus Disorders Myometrium — Endometrium Physiology Endometrium undergoes cyclic changes L esti and per (proliferation phase) plantation of zygote 1 progesterone : shedding of lining ENDOMETRIAL DISORDERS 3. ENDOMETRIOSIS + Ectopic endometrial tissue SITES - Ovary >> uterine ligament Recto uterine pouch Bladder / bowel Mucosa of fallopian tube Cyclic change -+ also in ectopic endometrial tissue + hemorrhage inside ovaries + cystic lesions |, enlarged ovary L, chocolate cyst Uterine ligament involvement + pelvic pain, dysmenorrhea Commonest symptorn Recto - uterine pouch or Pouch of douglas + pain during defecation Bladder / Bowel -+ pain on urination, Abdorninal pain Endometrial tissue in mucosal lining of fallopian tube ~ 4 fertility Pathogenesis of Endometriosis «Regurgitation Theory «During menstruation, endometrial cells migrate and deposit in ovary + Estrogen availability required, survival of cells aromatase, PgE, Complications * Dysmenorrhea, | fertilitye 11 ovarian cancer * Chocolate cyst * Burn - powder appearance or Gun powder appearance (pelvic peritoneum) Il ADENOMYoSIS + Endometrial tissue in myometrium *Gland present > 2.5 mm below endo / myometrial junctionIll ENDOMETRIAL HYPERPLASIA Excessive estrogenic stimulation <--> Endometrial glands + Number of glands 11 + Manifests as heavy bleeding «Associated with PTEN mutation WHO Classification, 1.Non - atypical EH 1-5 % risk of development of cancer 2. Atypical EH ~+ Presence of atypical cells (1 N/C), mitosis 1, dysplastic cells + 11 risk of cancer (23-48 %) ~+ Aka endometrial intraepithelial neoplasia (EIN) Malignany: Endometrical carainoma IV ENDOMETRIAL CARCINOMA *M/c invasive cancer in female genital tract cr Post menopausal bleeding (w/c) Prevalence of cancer 1 - AWARENESS t * Metastasis : lungs Subtypes 55-65 yrs = 65-75 yrs CI/ setting - Unopposed estrogen ~ Atrophy Exposure ~ Thin physique - Obesity -HTN -DM Genetic factor - PTEN mutation ~ pS3 mutation (aneuploidy) * INDOLENT I" AGGRESSIVE Spread through lymphatics Intra peritoneal spread * Good Prognosis * Bad Prognosis MVE Normal englometrial glands | Poorly differentiated ENDOMETRIOID PAPILLARY SEROUS CANCER BH vasmssscurnMYOMETRIAL DISORDERS LEIOMYOMA * Higher prevalence © Aka FIBROID + Arises from smooth muscle mass * Benign + Commonest in reproductive age group females Locations ev + Subrmucosal ie * Intramural + Subserosal C/E - Asymptomatic ~ Subraucosal -> heavy bleeding/ menorrhagia Mertility compression of bladder / bowel Grossly: multiple, well circumscribed, whorled mass, no hemorrhage (GREY WHITE) M/E- Smooth muscle cells 1 Whorled appearance Advanced info «MED 12 mutation Il LEIOMYOSARCOMA + Malignant counterpart of leiomyoma *M/c sarcoma of uterus *Arises spontaneously, DE - NOVO origin Grossly - Single tumors, brown (hemorrhage, necrosis) M/E [ Hemorrhage, necrosis Atypical mitosis > 10 mitosis HpfOVARIES OVARIAN TUMORS a NN Primary Secondary (inside ovary) (metastasis) Normal Histology * Cells lining the surface - SURFACE EPITHELIAL CELLS - COELOMIC EPITHELIAL CELLS Tumor arising tromit k/as Surface epithelial cell tumor (m/c) Sex-conp Sunsnee STROMAL COLL ‘temeLiom, Geameere © Germ cell - GERM CELL TUMORS *Sex cord stromal cells - theca cells, granulosa cells, fibrosa cells SEX CORD STROMAL TUMORS Risk Factors Genetic Non-Genetic = BRCA 4/2 (serous, surface ~ nulliparity ~ asbestos Epithelial tumor) K - RAS mutation LYNCH / TURNER / PEUTZ JEGHERS syndrome ~ Sex cord stromal tumors 1 Dysgerminoma Protective Factors + Pregnaney +00Ps I SURFACE EPITHELIAL TUMORS °M/e * Usually cystic mass + May be Benign / Borderline / malignant * Benign : younger female, normal epithelial lining (BpPreptadder+ Malignant : elderly, atypia (1 N/C ratio, necrosis, hemorrhage) Subtypes My Servant Began Experiencing Cancer + Mucinous tumor + Serous tunor + Brenner tumor + Endometrioid tumor Clear cell tumor Mucinous Ovarian Tumor + Cystic ovarian tumor, epithelial lining + COLUMNAR NON CILIA CELLS *Secretion of mucus * BENIGN ~+ Mucinous cystadenoma + MALIGNANT — Mucinous Cystadenocarcinoma cr * Unilateral ; mono-ovarian turnor «Massive enlargement + Multiple eysts + Mucin secretion + in peritoneal cavity (PSEUDOMYXOMA PERITONE!) Risk Factors = Smoking *K-RAS gene mutation Mt Serous Ovarian Tumors * Cystic mass *Ciliated epithelium (Fallopian tube) * BENIGN ~ Genign serous ovarian tumor (most common) * MALIGNANT + SEROUS CYSTADENOCARCINOMA + M/C, B/L 2. BRCA 4 gene mutation 2. Concentric signs of caleification (PSAMMOMA BODY) ll. Brenner Tumor * Unilateral + Mostly benign+ Histological finding, WALTHARD NESTS ‘ Presence of transitional epithelium *Similar to urinary bladder ( presence of transitional epitheliurn) Endometroid Cancer ‘*PTEN gene mutation #Cells resembling endometrial adenocarcinoma © H/0 endometriosis (ectopic presence of endometrial tissue) V Clear Cell Cancer * Clear appearance, glycogen inside cell C/E of Surface Epithelial Tumors +» Abdominal enlargement ~ Because of t ovary size ~ Ascites (malignant) Abdominal pain, weight loss *Palpable ovaries (post menopause) «Malignant pleural effusion ~ Hepatic metastasis = Pulmonary metastasis Diagnosis Tumor Markers 1. CA 125 ~ determination of progression of disease ~ Elevated 2. Osteopontin ll GERM CELL TUMORS + Dysgerminoma + Endodermal sinus tumor *Teratoma * Ovarian Choriocarcimoma 'DETOL' 1. Dysgerminoma ‘= Malignant tumor, m/e GCT + Female counterpart of seminoma * Radio sensitive eU/L+M/c ovarian tumor in patient who is going to having STREAK GONADS, TURNER SYNDROME * Tumor marker : Serum LDH 11 * Microscopic finding : clear appearing cells, lymphocytic infiltration in fibrous septa, over expression of OCT 3/4 Nanog, C-KIT mutation + Prognosis : Good Teratoma + Arises from totipotent cells +> 1 germ cell (mesoderm, ectoderm, endoderm) + Subtypes «Mature bmmature «Specialised Mature Teratoma + Well differentiated tissue Cystic mass * DERMOID CYST (presence of skin / hair / cartilage / sebaceous glands / adipose tissue) #Seen in reproductive age group of female sAssociated with 46XX genotype Malignant transformation - Squamous cell carcinoma (1%) immature Teratoma #Seen in prepubertal females / adolescent female Poorly differentiated tissue + Malignant teratoma Specialised Teratoma * Functional tissue Thyroid tissue 1 k/as STRUMA OVARIL |, hyperthyroidism * Secretion of serotonin, S-HT 1 Ovarian Carcinoid tissue * Carcinoid tumor arising in ovarian tissue because of specialised teratoma v/s carcinoid tumor present jin ovary because of metastasis 4 — ‘DR SPARE GUPTA# Specialised carcinoid tissue (ovarian teratorsa) : U/L * Serotonin secreting carcinoid tissue in ovaries : B / L (complication or metastasis) Endodermal Sinus / Yolk Sac Tumor and m/e malignant GCT + m/e malignant ovarian tumor in CHILD (< 4 year) ‘= Microscopie examination + SCHILLER DUVAL BODY # Central body vessel surrounded by 2 layers of tumor cells * Aka Glomeruloid body + Tumor marker - AFP / a, - Antitrypsin Ovarian Choriocarcinoma * Coexist with other GCT «Placental origin (trophoblastic cells) s Tumor marker ~ 11 hCG = Non responsive chemotherapy * Poor prognosis Ill SEX CORD STROMAL TUMORS Tumor arising from theca cells, granulosa cells, and fibroma cells Hormone secreting tumors - FUNCTIONAL TUMOR | Thecoma Fibroma #Theca and fibroma cells + SPINDLE CELLS + Theea cells + estrogen, positive staining with oil red ‘o' ‘+ Fibroma - estrogen (absent), negative staining with oil red ‘o" Fibroma has 2 important associations Pa “. MEIG syndrome Basal cell nevus syndrome (> 6 cm) 4 scores Classical triad A\ 6—oO I. Granulosa - Theca Cell Tumor + Associated with FOX L2 mutationestrogen ‘Hormone secretion Precocious Endometrial Endometrial Puberty Hyperplasia Carcinoma M/E 1. CALL EXNER BODY Centre + acidophilic inclusion surrounded by turnor cells 2. COFFEE BEAN NUCLEUS ~ cleared nucleus STAIN : inhibin (positive) Ill SERTOLI - LEYDIG CELL TUMOR «Secretion of androgens (over activity of leydig cells) + Muscularization (atrophy of breast tissue in females, heaviness of voice, clitoral enlargement, development of hirsutism, 4 fertility «© PURE LEYDIG CELL TUMOR : no increase in number of sertoli cells L M/E : Reinke crystals Rod like eosinophilic inclusions IV Gonadoblastoma *Rare malignancy Mixed tumor (stroma + germ cell) Abnormal sexual development * Majority - females (80%), males (20%) + Surgical resection on time Very good prognosis SECONDARY OVARIAN TUMORS + M/c metastasis : mullerian origin (uterus, fallopian tube, opposite ovary, pelvic peritoneum) *NON / EXTRA MULLERIAN ORIGIN + Stomach / colon / breast cancer Borencicirn| KRUKENBERG TUMOR += D/L (lymphatic spread) + Origin from stomach, breast, colon, pancreas * Stomach Cancer -+ m/e primary ~+ diffused variant Breast Cancer + Lobular carcinoma M/E-mucinous vacuoles inside tumor cells nuclei -+ periphery [ERO nae Bertie! = k/as SIGNET RING APPEARANCE Il PSEUDOMYXOMA PERITONEI +» Mucus in peritoneurn 1. Arises in appendix -- APPENDICEAL TUMOR (w/c) 2. Surface epithelial tumor -+ Mucinous Ovarian Tumor 4 Responsible for spread of mucus in peritoneuraTHYROID BASIC CONCEPT THYROID REGULATION Pituitary ¢. 1 TSH 1 Thyroid Gland Inhibitory effect 1 4 wT NX (Produced more) Active form THYROID HORMONES: ‘Bi 1 BMR *Bone growth * Beta Adrenergic Receptors + Cvs *Brain growth Thyroid function Tests 2 S.TSH + t (Hypothyroidism) 1 (Hyperthyroidism) ~ Subclinical diseases - 1 TSH (Best investigation) -QTs, T4 mo Free protein bound (Thyroid binding globulin) tsed TBG in 1. OCPs (oral contraceptive pills) 2. pregnancy 3. hormone replacement therapy 4 sed TBG in 1. Nephrotie syndronne 2. Anabolic steroids ~ Best test 2Serum T4 levels 3 Radioactive | uptakeuptake a Ya , 3 az 1 synthesis 4 synthesis rage tobe: 4 1 Wer Hot Nodule L * Graves Disease * Toxie Nodular Goitre Cold Nodule t + Thyroiditis + Excessive thyroid hormone consuraption (External) 4. Serum Thyroglobulin test 1 Marker for thyroid cancerTHYROIDITIS ‘*Tes in secretion of T,, T, Tes in secretion of T,, T. ACUTE THYROIDITIS '* Bacterial infection Clinical feature fever / Thyroid / cervical LN present 1 (Tender ) 7ST S.TSHL iy ~ Reduced uptake of radioactive iodine HASHIMOTO'S THYROIDITIS :- (chronic lymphocytic thyroiditis) * Auto-immune disorder ~ PTPN -22/ CTLA - 4 Mutation 1 CD, T cell/ CD, T cell Auto - Ab® '* Most coramonly seen in females ‘* Associated with HLA D, / DR,@ + Frequently seen in patients of = Tklinefelter/ Down / Turner Syndrome «Pts. Have high risk of suffering from 1 PA/ SLE/ Type | DM/ MG/ RA cre: middle aged ———> Hashi toxicosis female 4 Painless / Hypothyroidism Diagnosis + + Follicular darnage present *L Infiltration °G.C present + Hurthle cells present 4 Askanazy cells present @) / Granular (Oncocytic metaplasia) — Cytoplasrn * Patients have high risk of development of B- cell cancer. * Developrnent of marginal zone lymphoma (BpPreptadderREIDEL'S THYROIDITIS:~ |g C,, related disease - young females 1 (fibrosis of thyroid gland + extra present structures) eg. Trachea, esophagus “Hard rock like thyroid—+Hypothydoidism «Dysphagia + Dyspnea/ stridor Re © Rituximab + Tamoxifen DEQUERVAIN'S THYROIDITIS * Gramulomatous thyroid + Female pt-s who have history of viral infection - fever/ malaise/ pain in neck. Most common cause offtender thyroid | L ‘Transient hyperthyroid Cervical LN + Microscopic Examination Granuloma -gaint cell On routine examination: ~ Sut SSH! 1 uptake | Reo * Self limiting condition * NSAIDS elt doesn't cause permanent hypothyroidism. SUB-ACUTE LYMPHOCYTIC THYROIDITIS Painless Acute immune disease ™ Females (post-partum) © Painless * Transient hyper + hypothyroidisen *No fibrosis present * No hurthle cells _ 4 OR SPARSH GUPTAHYPERTHYROIDISM AND GOITRE Thyrotoxicosis Increase in amount of thyroid hormone due to any cause can be due to :- +1 gland activity <— Graves dente Texie multinodular goitre «Normal gland activity 1 - External supplementation (Iatrogenic) ~ Stress -Struma ovarii GRAVES DISEASE «Most common cause of hyperthyroidism and thyrotoxicosis + Auto-immune disease + Male > > > Female + 20-40 years * Associated with HLA DR3 | B-8 ‘+ High risk of suffering from SLE / Type IDM| Pernicious anemia | Addison disease + Formation of Auto-Antibodies ( Thyroid stimulating !g) 1 Causes Overactivity of TSH receptors 1 Hyperthyroidism Thyroid dysfunction ‘Skin manifestations Eye manifestations (pre-Tibial myxedema) * proptosis * Skin * Infiltration of * Non-Pitting Edema Extra-occular muscles weakness Clinical features: + Weight loss * Heat intolerance + Diarrhea * Oligomenorrhea * Osteoporosis + Systolic hypertension —+ Sinus tachycardia ‘+ Higher risk of Atrial Fibrillation Thyroid Acropachy + Swelling of digits as well as clubbing seen in patients of hyperthyroidism Elderly patients - Apathetic hyperthyroidism ‘*More prominent CVS manifestation * Less prominent Hyperthyroidism manifestation Diagnosis Routine tests:~ 2.5.7. (11) 2. S. TSH (11) 3. 1" uptake (1 1) mtS.T, i ‘Thyroiditis 41S. TSH < External Microscope examination:= Diffuse 11 size * Follicular hypertrophy | hyperplasia Papillae formation (No fibrovascular core) '*$ calloping of Colloid Management Thioamides | GOITRE + Enlargement of thyroid gland 1@ = = t sie Decrease in hormonal synthesis can be due to:~ Hinalyan sEndemic + > 10% population affected < Andes belt * Sporadic -+ «More in case of females (2) «Seen at puberty/ pregnancy«Goitrogens + Drugs (Li, / Amiodarone/ Para amino salicylic acid) +Pendred syndrome Pendrin -+ Sensory Neural Heaving loss + | Thyroid function Endemic sporadie 4 IT/T. 1 Tt TSH 4 Follicular hyperplasia (Diffuse goitre) 4 Ural) Multinodular goitre 1 TtT/T, 4 Autonomous 4 Toxic Multinodular Goitre Simple goiter/ colloid goiter/ diffuse goiter/ multinodular goitre — non Toxie goitre Complications:— *# Cystie lesion (cyst formation) + Hemorrhage + Jugular venous compression 1 Compression of face 1 PEMBERTON SIGN + Hoarseness + Dyspnea (because of compression of trachea) Toxic multinodular goitre:~ Plummer syndrome Plummer — Vinson syndrom 9 + * Iron deficiency anemia * Atrophic glossitis Toxie MNG * No skin involvement * No eye involvement Microscopically Hyperplastic stage involution * Esophageal websTHYROID TUMORS THYROID TUMORS Benign ‘malignant Follicular Adenoma ra) Risk factors Malignant. genetic - RET gene - Medullary ~ RAS gene ~ Follicular - RET / PTC gene ~ Papillary - P53 gene - Anaplastic Environmental Radiation TSH +++ ~ t Papillary ~ Follicular cancer PAPILLARY THYROID CANER = M/C thyroid cancer = Post radiation RET ~ PTC gene mutation - Young patients (20-40 years) ~ Lymphatic spread present @ -+ Palpable LN present @ epi b Diagnosis ¢ M/E - 1 Papillae formation present Fibro-vascular present core 2 Psammona body present 3 Nuclear findings * Hallmark Feature | Orphan-Annie eye nuclei present ii Pseudo inclusions Present iii Nuclear groovingSUBTYPES OF PAPILLARY THYROID CANCER 2 Follicular type +» MC 2 Diffuse sclerosing 3 Tall cell variant + BRAF present -» Metastasis present 4 Papillary microcarcinoma ( < 4 em) FOLLICULAR THYROID CANCER = RAS mutation = Seen in Endemic goitre ~ 40-50 years females ~ Blood vessels present (Hematogenous spread) 1 1 1 Lungs bones liver DIAGNOSIS 1 FNAC + not useful ~ Follicular adenoma and follicular carcinoma cannot be diagnosed by this 2 Biopsy - Metastasis present ~ Follicular carcinoma metastasis present x capsule present Vascular present ~ Best technique 3 Serum thyroglobulin + ~ Marker of receurence ~ Hurthle cell present ~ Seen in - follicular adenoma - Follicular carcinoma ~ Hashimotos disease = IF more than 50% hurhtle cells 4 Hurthle cell tumor + Poorer prognosis MEDULLARY THYROID CANCER ~ Arises from 'C’ cells -» secretion of ~ Calcitonin - ACTH / S- HT/ VIP - Amyloid deposition present = RET gene mutation present SUBTYPES OF MEDULLARY THYROID CANCER 4 Sporadic MTC = Unilateral = Unicentrie = 60-70 years b DR SPARSHGUPTA2 Familial MTC ~ Bilateral - Multicentric ~ indolent ~ slow rate of growth ~ Better prognosis * MEN syndrome ~ (multiple endocrine neoplasia) MEN Men 2A 26 ~ Aggressive cancer - Younger pts ~ Poorer prognosis - MEN 2B more aggressive than MEN 2A * Prophylactic thyroidectomy indicated in Pts RET gene mutation DIAGNOSIS. 3. FNAC polygonal cells present ME + + sten in amyloid stroma 2. CALCITONIN 3. Carcino embryonic antigen (CET) Calcitonin absent Tumor Burden MCT ANAPLASTIC THYROID CANCER - P53 gene mutation ~ Metastasis present ~ Elderly pts <= thyroid Extra-thyroid structures (Esophagus/ Trachea/ Laryngeal Nerve) = Firm, non- tender gland ~ Thyroglobulin negative ~ Cytokeratin positive PRIMARY B CELL LYMPHOMA ~ Classically e.g, of marginal zone lymphoma = Seen in Hashimoto's thyroiditis ([BppreptadderParathyroid 2 superior (derived from 4* pharyngeal pouch) #4 inno. 2 inferior (3 pharyngeal pouch) + Responsible for secretion of PTH which acts on kidney -+ 1 Ca’ Facilitate activity of 1 « OH ase which is required formation of active form of Vitamin D Bones ~ osteoblasts +Osteoclast 1 1 Ca’) © PTH is responsible for tS. Ca’, 1 S. PO,” *When Hypocalcaemia, there is 1 Ca” sensed by CaS R (Calcium sensing Receptor) CaS Ris present on parathyroid gland which t PTH and results in normalization of serum calcium Hyperparathyroidism -» 24 PTHT 1-4 T'S. Ca (Asymptomatic) 1S. Po,” * Can be (Seen in females; Incidental finding) ™ 2/3 Primary Hyperparathyroidism+ A/W overactivity of Parathyroid gland which is caused by 3 factors # Parathyroid adenoma + MC cause of 2° hyper PTH + Parathyroid Hyperplasia + Parathyroid carcinoma P. Adenoma -+ arising from © inferior parathyroid gland -+ atrophy of other glands. oM/E Z sheets of cells present @ No adipose tissue «Mutation of 4. Cyclin D, overactivity 2. MEN 1 gene underactivity -May be sporadic in nature as well. C/F of 2 Hyper PTH * Kidney + 1 stones; polyuria #GIT + Nausea / Constipation; t peptic ulcer disease, pancreatitis = CNS ~ confusion / Anxiety / psychosis [EpPreptadder+ Bones -» Osteoporosis Coneavity on vais Skull Phalanges 1 (Salt and pepper appearance) ea es * Cyst Present + Hemorrhage present + OFC (Brown tumor) * Joints + Pseudo-gout Investigations + 1.S. PTH ttt S.Ca tt S. Po ht * Findings in glands which helps in distinguishing between pts. Suffering from adenoma and parathyroid hyperplasia 1 1 2. Only 4 gland t 11 2.4 gland 1 Tin size 2. All other 14 2. WASSERHELLE cell Hyperplasia because of increase in no. of chief cell Other conditions having Hypercaleaemia (1 1 Ca) D ~ Drugs (Thiazidey Vit D Toxicity 1+ lmamobilization S - Sarcoidosis (1 1 a OHase) C+ Cancers (Multiple myelorna, Metastasis) Squamous cell lung cancer [ Renal cell carcinoma Breast cancer + Symptomatic Hypercalcemia is most commonly associated with Malignancies Secondary hyper PTH ~ associated with: * Renal failure (MC) + Vit D deficiency © GIT (Steatorrhea) Li Ca 41 PTH BD me smsescuonHypoparathyroidism -» causes: «Surgical Removal (Thyroid surgery ) MC + Auto - immune disease (APS 1) {~~ Due to defect in AIRE gene Addr. Insufficiency 1Candida (chronie mucocutaneous candidiasis) #1Mg* seen in Diuretic Alcohol Amino glycosides Diarrhoea *# Di-George syndrome Clinicel feature ~ 1 Ca"; 11 PO,"; 1S. PTH + Tetany + Carpo-pedal Spas 1. chvostek sign 2. trousseau sign *CVC +1 QT interval * Calcification (Basal Ganglia) * Caries (Dental defects) * Cataract 4. pseudo-hypoparathyroidism + S. Ca” 4 S. Po? t S.PTHTT + Associated with maternal Imprinting of gene End organ Resistance + Pt have mental retardation, calcification in basal ganglia, short stature, small 4 and 5* metacarpals of hand (Archibald sign) 2. Pseudo- pseudo hypoparathyroidism — S. Ca” 1) s. Po. 1) S. PTHT CA) + Pts. Have mental retardation, obesity, skeletal defects «Associated with paternal imprinting of gene [BpPreptadderZona Zona Reticulata Glomerulosa Fasciculata 4 ‘ Aldosterone Cortisol Sex - steroids G F R Cushing Syndrome 1 Cortisol CE + Central obesity + Moon faces + Hypertension + Muscle wasting + Skin atrophy + osteoporosis Factors 1. External (Iatrogenic) -» MC cause t Inhibition of ACTH secretion 4 Bilateral adrenal atrophy 2. Endogenous (0 Pituitary adenoma + cushing disease 1 ACTH - B/L adrenal hyperplasia M/E ~ Basophilic granular cytoplasm 4 Intermediate filaments ‘ Crook Hyaline change(ii) Ectopic ACTH Secretion + Small cell cancer in lang ) -+ | ACTH -» Bilateral adrenal + Medullary thyroid cancer hyperplasia Dexamethasone supp. Test -+ Differentiation b/w pituitary adenoma & Ectopic ACTH High dose — inhibit pituitary does not work in ectopic ACTH secretion G pr LACTH 4? Centison (ii) Adrenal Cause + Hyperplasia / adenoma / cancer Cancer - left A gland -» 1 cortisol + | ACTH ~ 4 right sided t size adrenal glands Asymmetric appearance of adrenal gland ADRENOCORTICAL INSUFFICIENCY a Primary Secondary 4 Acute disease Chronic disease (adrenal crisis) (addison's disease) Acute Crisis + Abrupt withdrawal of steroids (MC cause) - Stres (chronic adrenal insufficiency) + Adrenal gland hemorrhage + Anticoagulant therapy + Disseminated intravascular coagulation + Bacteria + Meningococcus (waterhouse - Fredrickson syndrome) Difficult deliveryChronic Insufficiency (Addison's disease) + Autoimmune disease ~ Autoimmune endocrinopathy syndrome 3 (Ab IL-27) - Adrenal insufficiency + Parathyroid + Chr. mucocutaneous candidiasis ~ Autoimmune endocrinopathy syndronne 2 (schmidt syndrome) 4 Thyroid / DM-1 MC cause in developed countries + Infections (TB / Histoplasmosis / AIDS) 4 (INDIA) + Metastasis (Lung, Breast) + Genetic cause (adrenogenital syndrome) + Child C/E + Progressive weakness t Fatigue 18 dna / tk Pro-opiomelanocortin + } ACTH ~ t Melanocyte stimulating hormone 4 t Pigmentation a Sun exposure Knuckle / Elbow / Knee Secondary Adrenal Insufficiency Problem -» Pituitary + Hypothalamus + Metastasis + Infection + Infarction - Post radiationcrr > | ACTH ~ No pigmentation 1 4 Cortisol / 4 androgen Aldosterone + normal nearly ADRENAL MEDULLA Neural Crest -» chromaffin cells 4 Adrenaline / Nor Adrenaline Location + adrenal medulla / mediastinum / bladder ~ organ of Zuckerkandl (aortic bifurcation) Adrenaline N-methyl — Nor Adrenaline Transferase [Preochromecytoma] “Adrenal medullary tumor Associated with VHL syndrome “ NF-2 gene mutation + MEN 2A / 2B syndrome + Sturfee weber syndrome + 5 DH isoenzyme mutation Aka - Rule of 10 tumor 10% - Bilateral 10% ~ Extra adrenal (Paraganglioma) 10% — Children 10% > W/O hypertension If metastasis +nt +» Malignant Pheochromocytoma IF metastasis -nt +» Benign 40% Familial + Now 25% germ line mutation ce + Headache - Episodic Hypotension - Palpitation Tachycardia + Sweating+ Anxiety + Postural hypotension (1 plasma volume) Different b/w essential hypotension & Pheochromocytoma Essential hypotension -+ Episodic HTN - not present Palpitation - not present Sweating —_- not present Anxiety = not present Postural hypotension ~ not present Adrenaline -COMT, Metanephrine MAO ‘VM acid Nor Adrenaline => Nor Metanephrine Dx - * 24 hr urinary metanephrines + t - Biopsy -» metastasis + malignant Zellballen ~» nest of sustentacular cells (5-200) Chief cells (Chromogranin Synaptophysin) Re + Surgery > TOC + Labetalol (a-B blocker) Alpha blocker first + then beta blocker + Phentolamine (shorter duration) Phenoxybenzamine (irreversible)INTROPUCTION TO CNS ‘Type of cells present - Neurons + glial cells Oligodendrocytes formation of myelin = Schwann cell ~ 3. axon = Oligodendrocytes - multiple axons - Astrocytes blood brain barrier Post Injury Most imp. Cell responsible for gliosis. + Ependymal cells ventricular lining + Meningothelial cells -» cover brain (formation of meninges) * Microglia -» phagocytosis 1 Gitter cell N/syphilis -» Rod cells @ (BPreptadder——_——_——_—_———— MENINGITIS CSF Findings (Meningitis) Normal Clear o-s/ul 15-40 40-70 115-120 1mg/dl mg/dl meq/l Bacterial | Turbid ttt ttt Ww + neutro 8 Cobweb tt tt 1 ut Coagulum | N+M Viral Clear oO t Normal 1 except maurnps/ Herpes Fungal Clear or + tt 4 4 mildly turbid | CSF pleocytosis + Tubercular meningitis (multiple types of cells)NEURO-DEGENERATIVE DISORDERS Characterised by Loss of neurons Intracellular protein aggregates ALZHEIMER'S DISEASE - Most common cause of memory loss aya , L lal Seene 3 Sporadic, < Age 5 4? 7 DHE ig ApoE, (1) ApoE, A ~~ht (Decrease the risk) alt pene Familial seach = Down syndrome (trisomy 23) salute a ~ Presenilin ~ 4- gene + Chr. 14 ~ Presenilin — 2 gene -+ Chr. 2 Tau -+ Migro-tubules ~» Tangles (Diffuse) 1. Cerebral atrophy F/P/T Occipital spared 2. Neurofibrillary tangles - tau: Pp “N P ~ Co-relates directly with severity ~ Best visualized with silver stains 3. Neuritic plaques Qo conle M a Tague 4. Cerebral amyloid angiopathy Affects the blood vessels of brain amyloid protein ~ blood vessel ~ Fragile 4 1 bleeding in brain Clinical feature = Memory loss (short term) = Loss of smell t Language/ behavioral defect Death = due to pneumonia Rez AChEO ‘Memantine @p LaddeFRONTO-TEMPORAL LOBE DEGENERATION Due to frontal invo. -» behavioral defect Early manifestations Due to temporal invol ~+ language deficit * Later on patient will have dementia 1. FTLD - tau 2. FILD - TDP 4 Pick's disease * Atrophy + F/T lobe * Parietal / occipital spared * knife-edge gyri carer Teo Turin * Pick cells + normal * pick'body (VC = 3R tau se) se PARKINSONISM ee Tees Factors involved * Age = Idiopathic + PD * MPTP ~ meperidine * Wilson's disease * Copper poisoning * Drugs responsible + antipsychotics Protective factors:~ * Caffeine * Nicotine Nigro- striatal pathway affected Clinical features:- Brady kinesia Rigidity —————. Tremors Pts. Will have ~ Mask like faces ~ Stooping pasture -1S. dem. Late manifestation + dementia b DR. SPARSH GUPTAFindings:= * Pallor in subs nigra * Lewy body + u synuclein in sub. Nigra Huntington's disease + Genetics -AD - CAG repeats 1 11 1 risk of early onset in next generation (Anticipation) * Chromosome 4 4 4° - 5" decade * Caudate atrophy Clinical feature * Chorea-athetosis Doc [ * Oculomotor abnormality * Depression Death = recurrent infectionsCNS TUMORS 1° tumors 2° tumors - metastasis 2° producing organs - Lungs, Breast ca, skin ca, (small cell ca) kidney ca Risk factors = Smoking ~ Radiation exposure = Familial syndronses = Turcot syndrome - APC gene rautation = t risk of colo-rectal ca ~ Li-Fraumeni syndrome — P,, mutation ~ Gorlin syndrome — PTCH gene mutation = Cowden syndrome - PTEN mutation Clinical feature ~ Headache = Vomiting ~ Seizures -ticT General principles ~ Majority of Tm in Adults - Supratentorial origin tent. ~ Majority of Tm in children — Below tentorium WHO latest classification Histology + molecular parameters - Atypia present / absent - Mitotic activity ~ Necrosis ~ Micro-vascular Invasion WHO grading Grade | Grade IV 4 + (Slow growth) (Aggressive) ADULT CNS TUMORS - Supra tentorial ~ Affect cerebral Hemispheres INFILTRATING ASTROCYTOMA Low grade - P,, gene / PDGFa tt High grade - Rb gene mutation / CDK, NA GLIOBLASTOMA PrepLadder ~ High grade tm (WHO Grade IV)_ |= No Grade! = MC 2° malignant tea — Adults = Aggressive tra 1 Cross corpus callosum R/G ~ Butter Fly Glioma / Tm 1° Gliobastoma —» Denovo = Wild (DH, + 90% cases, elderly Pt 2° Glioblastoma — low grade astrocytoma de differentiation - mutation IDH, - 10% cases = young Pt. M/E 1. PSEUDOPALISADING — Necrosis area Surrounded by Tm cells. 2. GLOMERULOID BODY - Endothelial cell proliferation Re- Drugs - Timozolamide Prognosis not very good 4 Improved Prognosis OLIGO DENDRO GLIOMA - Cerebral hemisphere origin 1 Frontal lobe - 4° -5* decade ~ Appear in the form of calcification M/E ~ Fried Egg Appearance ~ Perineuronal satellitosis inewronah 004 7 Point's og, _ 4 DR. SPARSH GUPGENETIC MUTATION ASSOCIATED = 1DH,, DH, - MC -1PQ ~} co-deletion -!9qo_) + tt response rate 4 Better prognosis MENINGIOMA - Origin - meningothelial cells of Arachnoid - MC # Brain tumor - Adults = Benign tm - female > > male ~ Progesterone receptor present - } size of tm at time of Pregnancy Risk factor ~ Radiation exposure - Gene mutation > MF - 2 gene - M/C > TRAF - 7 gene (TNF receptor associated factor -7 gene) = U/L tra usually If B/L menigioma or acoustic Neuroma + Meningioma ] suspect NF -2 gene mutation K/A Neurofibromatosis 2 M/E PSAMMOMA BODY Low grade High grade ~ Fibroblastie ~ Atypical Meningioma = Syncytial ~ Anaplastic (Most aggressive) ~ Secretory - Transitional SCHWANNOMA ~ Benign ten peripheral @ = Origin - Schwann cells ven Cranial @ IC ul CN ‘ C/F = Tinnitus arises from vestibular ~ SNHL part ya Acoustic NEUROMA ~ Sensory findings (BppreptadderLocation -C-P angle B/L. Acoustic Neuroma a/w - U/L tra Neurofibromatosis - 2 M/E 1) Antony ‘A’ Area = Hyper cellular area Ml) Antony 'B' Area ~ Hypocellular area VEROCAY BODY ~ Nuclei free area intermediatly ~ Associated with Antony ‘A! area = Immuno reactive for S-100 present PEDIATRIC CNS TUMORS 2) Pilocytic Astrocytoma CHILDREN - M/C £ Benign P53 mutation rare cystic Mass Cerebellum M/E 2. ROSENTHAL FIBRES ~ Red- pink fibres present 1 Cytoplasen MEDULLOBLASTOMA. = Malignant - Children - M/C £ malignant = Cerebellum origin ~ Not arising from medulla (not as named) ~ Origin - Newroectoderraal cells - Poor differentiation ~ Metastasis (CSF) 4 through A K/A 'DROP' metastasis JM/E ~ Atypical cells present ~ High rate of mitosis present ~ marker ~ Ki - 67 present ~ Horner wright Rosettes WHO classification 2) WNT type = monosomy & = Overactivity of [\- catinin- Best prognosis 2) SHH type 2) Group 3 medulloblastoma - worst prognosis 4) Group 4 medulloblastoma + Myc gene / i 27 4 ~ poor prognosis Dx- Radiosensitive Ske R/T EPENDYMOMA = Malignant = Origin~ Ependymal cella 4 veni spinal cord (Chitd) (Adults) 4 1 Obstruction to flow of CSF a/w neurofibromatosis 2 ‘ Hydrocephalus present CSF spread M/E 0820 2. Perivascular Pseudo Rosettes ° Oe 2. GFAP present S06! Glial fibrillary Acidic Protein) - Poor prognosis 2° CNS LYMPHOMA Risk factor + Immunosuppression < AIDS Post - Transplantation - B-cell tra (DL- BCL) ~ EBV associated Wf ~ Multifocal an rooting M/E ~ “HOOPING” — Characteristic finding 4 In £ CNS lymphoma not in 2 (preptadder