Pathophysiology Cycle 1 Summary PDF

Thugica Jeyabalan PATHOPHYSIOLOGY CYCLE 1 – SUMMARY IMMUNODEFICIENCY Causes of insufficient immune response Causes of secondary immunodeficiencies Inappropriate nutrition...

Thugica Jeyabalan PATHOPHYSIOLOGY CYCLE 1 – SUMMARY IMMUNODEFICIENCY Causes of insufficient immune response Causes of secondary immunodeficiencies Inappropriate nutrition Infections Lack of exercise Malnutrition (biggest) Deficiency of sleep Medical intervention: Exhaustion chemotheraphy, surgery, Stress (physical and emotional) antibiotics, immunosuppression Pathogen type B-cells T-cells Granulocytes Complement Bacteria + + + + Viruses + + Fungi and parasite + + + Combined (T and B cells) B-cell origin Phagocytic deficiencies Reticular dysgenesis Bruton Congenital agranulocytosis SCIDs Wiskott-Aldrich Lazy leukocyte syndrome syndrome Chronic granulomatous disease Isolated IgA deficiency Leukocyte – adhesion deficiency CVID T-cell origin DiGeorge syndrome CHEMOTHERAPHY Targets proliferating cells/cells active in metabolism à cancer cells, blood cells, epithelial cells, hair follicles HYPERSENSITIVITY Type I Type II Type III Type IV Aka Atopic allergies Organ-specific Immune-complex Delayed type autoaggression mediated Antigen Soluble Fixed Soluble Soluble Mediator IgE IgG IgG Th cells, macrophages Time Mins Mins – hours 3 – 8 hours 48 – 72 hours Basic problem Vastisity of reaction. Inappropriate target Vastisity of reaction. Overproduction of IgE for reaction. (1) Immune complex against limited number Complement deposited in tissues. of allergens à activation through excessive release of classical pathway (2) histamine Cytotoxic/ADCC Tissue Tissue hyperreactivity Destruction of cells Depsition of complexes consequence (acute process) and causes functional in the tissues leads to fibrotic consequences insufficiency and exarcerbation of chronic (chronic process) other consequences inflammation, fibrosis and consequently destruction of the functional tissue over years Example Anaphylaxis, Hay Hemolytic anemia. Serum sickness. Arthus Contact Fever, Food allergy, M.gravis. reaction. SLE dermatitis. Drug allergy, Asthma Goodpasture Tuberculosis.  Thugica Jeyabalan AUTOIMMUNE DISEASES Usually unknown etiology Usually lead to destruction of tissue by prolonged/chronic inflammation Can be related to antigen cross reactivity and autoreactive B cell faulty antigen presentation Treatment: anti-inflammatory drugs, Bone-marrow graft, cyclosporins, plasmapheresis, metabolic control, immunosuppression Organ-specific à Hypersensitivity type II Non-organ specific à Hypersensitivity type III Hashimoto thyroiditis Rheumatoid arthritis Pernicous anemia Scleroderma Addision disease Dermatomyositis Insulin-dependent diabetes mellitus Ulcerative colitis Goodpastures syndrome SLE Myastenia Gravis Sjogren syndrome Primary myxoedema Polymyositis Thyroxicosis Rheumatoid arthritis SLE Begins in synovial membrane of joints leading to Multi-organ and multi-system set of destruction, deformation and loss of function symptoms with exacerbation and remission Etiology – unknown. Probably EBV, CMV, rosacea, periods mycoplasms Etiology – unknown. Probably virus, UV Pathogenesis: production of Ab against own IgGs, Pathogenesis: production of anti-nuclear depostion of immune complexes in joints, autoantibodies, formation of immune deposition of collagen, formation of granulation, complexes which induce chronic angiogenesis, formation pannus by fibroblasts, inflammatory process, destruction of tissues overgrowth of synovial membrane, destruction of Morphologic changes: deposition of immune cartilage, bone and ligaments complexes in BV and organs involed. Morphologic changes: Butterfly rash on face. Inflammation of joints - Primary à Hand joints and muscles, pericardium, heart muscle, - Secondary à Hip, knee, jaw, feet joints endocardium, renal glomerulus. Interstitial Rheumatoid nodules formation in subcutaneous pneumonia. Anemia. Leukopenia tissue and internal organs (heart, BV, lungs) Dermatomyositis Celiac disease Inflammation of the skeletal muscle and the Gluten + genes (DQ2/8) + LGS heart muscle with skin changes symptoms: joint pain, osteoporosis, Etiology – unknown. Probably CMV, influenza diarrhea, steatorrhoea or coxachie virus Coexisting: Downs syndrome, diabetes Morphology – inflammatory infiltrates between type I, Duhring disease/dermamititis muscle fibers along blood vessels herpetiforms LEAKY GUT SYNDROME Based on 4 elements 1. Damage/relaxation of tight junctions à Zonulin 2. Inappropriate absorption of large molecules into the intestinal mucous membrane and then into the blood 3. Abnormal activation of immune system 4. Inflammation in the wall of the intestine One cause à many effects : GIT, skin, muscle, bones, joints, respiratory system, circulatory system, nervous system, genitourinary system Attributed to following types of developing pathologies: Immunodeficiency, allergic reactions, autoaggression, abnormal absorption, Metabolic disorders, direct toxicity Function of GIT Traditionally – almost exclusively in the context of digestion and absorption of food Recently – another key function is development and regulation of immune phenomena serving for the benefit of the whole organism Intestine – the immune organ. Immunization develops most intensely and systematically in the intestine.  Thugica Jeyabalan INFLAMMATION universal reaction of the organism to the potentially harmful stimulus Local event but depends on both local and generalized mechanism Features à calor (heat), dolor (pain), rubor (redness), tumor (swelling), functio laesa (loss of function) Course of reaction depends on type of inflamed tissue + type of inflammatory agent Defense reaction but may lead to destruction of tissues with subsequent loss of function Acute inflammation Chronic inflammation Rapid onset (mins to hours), short duration, quickness proceed gradually (days), long duration (years but Painful and localized may stop at any time) Usually mild tissue injury and self-limited painless/can live comfortable with it Stimuli: infections, trauma, tissue necrosis, foreign generalized in the organ/tissue bodies, immune reactions (hypersensitivity reactions) Often severe and progressive tissue injury Consequences: resolution/healing/chronic May arise from: persistent infections, immune- inflammation/abscess formation mediated inflammatory diseases, prolonged exposure to potentially toxic agents 1. Vascular events Main reactions: Vasodilation à increased blood flow 1. Infiltration with mononuclear cells – Increased permeability of microvasculature à exudate macrophages, lymphocytes, plasma cells fluid/edema 2. Tissue destruction Activation of endothelial cells à increased adhesion 3. Repair and migration Consequences: healing/regeneration/scar formation w/fibrosis 2. Cellular events Agents bound to cause chronic inflammation à Margination mycoplasma tuberculosis, allergens, autoimmunity Rolling à Selectin Adhesion à Integrins Transmigration à CD31/PECAM1 Chemotaxis Leukocyte activation (neutrophils) à chemokines Important tissue structures Macrophages Mast cells Capillary blood vessels: endothelial Blood derived, phagocytic, slow but move Bone marrow derived cells cells, base membrane (collagen, easily in the tissues located along BV (skin, digestive, laminin, fibronectin, proteoglycans) Main role in resolution phase of acute inf, RT) Connective tissue: cells (mast, subacute and chronic infl Need SCF stimulation provided fibrorblast, macrophages, professional APC: present extracellular Ag in tissues by fibroblasts lymphocytes), matrix (fibers – to Th cells in context of MHC-II First cells to react in protein, glycoproteins, proteoglycans Synthesize cytokines (IL1, INFy,TNF), inflammation proteolytic agents, complement components Atypical APCs: phagocyte bacteria à present Ag in MHC-II to Th cells Cells not recognizing specifically the agent Lymphocytes Release: biogenic amines, Macrophages, mast cells, platelets B: specialized APC. Extracellular heparin, plasminogen activator, Endothelial cells, neutrophils Ag – MHC-II to Th cells. Produce Ab chemotactic agents, arachidonic Eosinophils, NK cells of only one specificity. Possess BCR. acid derivatives, SRS-A Become plasma cells Preformed: histamine, Tc: cellular immune response. protease, hydrolase, Cells specifically recognizing the agent Recognize intracellular Ag – MHC-I proteoglycans, chemotactic f. Th lymphocytes, Tc lymphocytes Th: Regulation of immune De-novo: prostaglandin, B lymphocytes, plasmatic cells response leukotrienes, PAF, cytokine (IL4- 6, TNFa), chemokines (IL13, TGF-b, GM-CSF) Endothelial cells Neutrophils Induction by: opening of active role in stopping and transporting mobile cells, phagocytic calcium channels, bacterial lectin blood derived inflammatory cells to tissues, lysosomes contain enzymes binding, bridging of FcR for Ig, obtained through adhesion molecules first cell from blood coming to the activation of C3a/C4a/C5a Synthesize clotting factors, anticoagulants inflammation site receptors, phagocytosis of (AT III, prostacyclin), fibrinolytic agents and secrete factors promoting bacteria locally active catecholamines inflammation  Thugica Jeyabalan Humoral factor Source Function Elastase and collagenase Granulocytes Belong to metalloproteinase. Lysis of elastine and collagen. Complement system activation à MAC Histamine Mast cells, basophils, Increase inflammatory vascular dilation ( contraction of platelets postcapillary smooth muscles à loosening of tight junction) Increase permeability of microcirculation. Eosinophils chemotaxis Serotonin Platelets Increase inflammatory vascular dilation Increase permeability of microcirculation Prostaglandins Leukocytes, Increase inflammatory vascular dilation endothelial cells, Increase permeability of microcirculation platelets Increase sensation of pain Stimulation of granulocytes and lymphocytes Bradykinin Tissues Increase inflammatory vascular dilation Increase permeability of microcirculation Increase sensation of pain Complement components Plasma, occurs in Increase inflammatory vascular dilation blood. Activation of mast cells and BV: C3a, C5a Opsonization: C3b, C4b MAC à cell lysis Neutrophils chemotaxis: C3a, C5a, C5b67 Platelets Adhesion, aggregation, production of eicosanoids and clotting process Can substitute the mast cell in activation of inflammatory vascular reaction Store and release: serotonin, vWf, plasminogen, fibrinogen, PDF, adhesion molecules (integrins, selectins) Leukotriens Leukocytes Increased permeability of microcirculation Increased vasoconstriction Chemotaxis Thromboxane Platelets Increased aggregation of platelets Increased vasoconstriction Prostacyclin Endothelial cells Decreased aggregation of platelets Decreased vasoconstriction Cytokines Macrophages, T cells Activation of endothelial cells (increase expression of adhesion molecules) Activation of macrophages and granulocytes Chemotaxis Activation of generalized acute phase reaction PAF Mast, neutrophils, Increased permeability of microcirculation macrophages Increased adhesion of granulocytes to endothelium Increased aggregation and degranulation of platelets Complement activation (1) Classical pathway: C1 binds to AgAb Integrins > Immunoglobulin family (2) Alternative pathway: bacterial pathogens. Selectins > Mucin-like glycoproteins Spontanous hydrolysis of C3 activates. (3) Lectin pathway: Plasma lectin binds to mannose MHC-II à Th cells CD4+ à Extracellular Ag MHC-I à Tc cells CD8+ à Intracellular Ag Factors increasing vascular permeability Histamine – mast cells, basophils, platelets Bradykinin – tissues Prostaglandins – leukocytes, endothelial cells, platelets Leukotrienes – leukocytes Platelet activating factor – mast cell, neutrophils, macrophages APP (-) APP (+) Albumin, transferrin, a2-HS glycoprotein Ceruloplasmin, C3, C4 à increased by 50% ACT, API, haptoglobin, fibrinogen à increased 2-5 times CRP, SAA à increased up to 1000 times  Thugica Jeyabalan PATHOPHYSIOLOGY CYCLE 2 – SUMMARY NEOPLASM Carcinogenic agents: chemicals, ioninizing radiation (physical), oncogenic microbes (HTLV1, HPV, EBV, HBV, HCV, H. pylori) Increased risk: immunosuppressed patients, AIDS Changes leading to neoplasm transformation Mandatory condition for neoplastic growth Impairment of DNA repair mechanism Adaptation to certain cytokine enviroment - Mutations: p53 (50%), RB, cyclin D, CDK4, CDKIs (p21, Adhesion à to each other + tissue they grow on p27, p57, p16, p15, p18, p19) Appropriate blood supply à angiogenesis - protoncogene à oncogene Lack of recognition by the immune system - Decreased MHC-I expression (if they decrease too Increased proliferation potential much, they become target to NK cells) - Change function of certain proteins (changing their Defence from apoptosis structure would lead to recognition by T cells) Immortalisation (can proliferate endlessly) - Telomerases increase length of telomers which are crucial for mitoses Tumor Ag recognized by our immune cells Immune surveillance Products of mutated oncogenes and tumor suppressor genes Selective outgrowth of Ag-negative variants (strongly - Oncogene products: mutated RAS, BCR/ABL immunogenic subclones may be eliminated) - Tumor suppressor gene products: mutated p53 Loss or reduced expression of HLA-antigens (fail to express Products of other mutated genes normal levels of HLA-I à escape attack by CTLs. Such cells, Overexpressed/aberrantly expressed cellular proteins however, may trigger NK cells) - Overexpressed: tyrosinase, gp100, MART Immunosuppression mediated by secretion of factors from - Aberrantly: MAGE, BAGE the tumor Tumor Ag produced by oncogenic viruses: HPV E6 and E7. EBV- Antigen masking (by producing thick coat) induced EBNA Downregulation of co-stimulatory molecules needed for Oncofetal antigens antigen-presentation. Altered glycolipids and glycoproteins Cell-type specific differentiation Ag Staging Grading Features Based on Based on degree of well differentiated à undifferentiated 1) Size of primary lesion 1) Differentiation of tumor cells Grows much faster than benign 2) Spread to regional lymph nodes 2) Frequency of mitotic figures Spread locally and distant 3) Presence of distant metastases I to IV, less clinical value than staging Most prevalent: prostate in men, breast in women, lung and bronchus in both (2010) FLOW CYTOMETRY Method used to assess the statical arrangement of a heterogenous cell population Do not need staining, cells run naked through the machine Specimen: blood, bone marrow (not solid tissues) Detects 5 parameters: FSC, SSC, 2 polarized angles and electrical potential (Seperate detectors for scc and fsc) Basic use: apoptosis and cell death, phenotyping, cell cycle, functional analysis, classification of leukemias and lymphomas Forward scattered pattern Side scattered pattern Fluorescent dyes Detect size of the cell (tells only if the Detect shape and internal complexity; unstable, expensive, toxin in contact cell is large or small, does not measure granulation Tend to emit the light in a different color than the cell) More complicate structure of the cell what they absorb More scattering = larger size = more deflection Can be conjugated with Ab used to visualize unusual and small particles Disadvantage Possible to overcome: using large number of fluorescent Advantages channels, need to hire experienced cytometrists, fragility of the Can run more than 10,000 cells method Can analyze large samples Difficult to overcome: best obtained from blood/body fluids (not Can test several samples almost simultaneously solid tissue), expensive equipments Can test several parameters  Thugica Jeyabalan WATER, ELECTROLYTES AND ACID BASE BALANCE Water compartments Water distribution Ion movement between compartments ICF: 40% (2/3) of TBW. K+, phosphate 45-75% of body weight Electrolytes movement controlled by ECF: 20% (1/3) of TBW. Na+ and Cl- - 75% in newborns 1. Concentration: higher à lower 1. ISF: 15% of TBW - 45% in elderly 2. Electrical gradient: towards area of 2. IVF: 5% of TBW - 60% in men reverse potential - 50% in women 3. Hydrostatic pressure: increase diffusion rate across capillary membrane in the circulation Water movement between compartments Freely crosses all body membranes Water movement between ICF and ISF RBC in solution Distribution of water is controlled by: Osmotic forces determined mainly by the Isotonic à shape maintained 1. Osmotic pressure: holds water within concentration of Hypotonic à swelling due to compartment. Depends on concentration 1. Albumin in ISF (90%) gain of water of solutes 2. Potassium in ICF Hypertonic à shrinkage due 2. Hydrostatic pressure: pushes water Desired distribution of Na+ and K+ cations to escape of water outisde. Depends on compression force on both sides is obtained by sodium in compartment. potassium pump Sodium-potassium pump pulls the water as it exchange ions (energy dependent process) Water movement between IVF and ISF Sodium Osmotic imbalance Starling law of capillaires – movement of water between most abundant in ECF Liver disease, decreased albumin capillaries and interstitial space (= ultrafiltration) Nearly equal Protein malnutrition, burns Hydrostatic pressure in capillaries – produced by the concentration in IVF Hemorrhage, cirrhosis of liver pumping action of the heart. 35 mm Hg at the arterial end and ISF Inflammation and 15 mm Hg at the venous. Accounts for >90% of Glomerular disease of kidney Osmotic pressure in IVF – depends on colloid osmotic entire osmotic pressure pressure produced by serum albumin. Does not depend on in ECF sodium concentration. COP is 25 mm Hg at both ends. Disorder Cause 20:1 Compensation Respiratory acidosis Hypoventilation. Retained Co2 < Renal retention of HCO3. Excretion of acid salt. Increased ammonia formation Respiratory alkalosis Hyperventilation. Excessive > Renal excretion of HCO3. Retention of acid loss of Co2 salts. Decreased ammonia formation Metabolic acidosis Retention of fixed acids. Loss < Lungs: hyperventilation. Renal: as in of bicarbonate respiratory acidosis Metabolic alkalosis Loss of fixed acids. Gain of > Lungs: hypoventilation. Renal: as in base bicarbonate. K+ respirtory alkalosis depletion Metabolic acidosis Normal anion gap: Bicarbonate loss: diarrhea, ileostomy, pancreatic, biliary or intestinal fistulas, uretosigmoldostomy, RTA, carbonic anhydrase inhibitor (acetozolamide), hypoaldosteronism Increased acid load: ammonium chloride, hyperalimentaiton fluids Other: rapid administration of IV saline Increased anion gap Increased acid production: lactic acidosis, diabetic ketoacidosis, starvaiton, alcohol intoxication ingestion of toxic substances: salicylate overdose (salicylate, lactate, ketones), methanol or formaldehyde (formate), ethyle glycol (car antifreeze; ocylate, glycolate) Failure of acid excretion: diminished NH4+ excretion, retention of sulfuric or phosphoric acids; renal failure Metabolic alkalosis Net loss of H+ from ECF: vomitting, nasogastric suction, chloride-losing diarrhea. Loop or thiazide diuertics. Hyperaldosteronism. Cushing syndrome. Excess licorice ingestion. High dose carbenicillin/penicillin- Hypokalemia. Retention of HC03-: excess administration of sodium bicarbonate. Milk-alkali syndrome. Massive >8 unit bank blood. Posthypercapnia metabolic alkalosis; mechanical ventilation – rapid decrease in Paco2. Chloride-responsive metabolic acidosis: vomitting, NS suction, diuretics, posthypercapnia Chloride-resistant: mineralocorticoid excess, edematous states (congestive heart failure, cirrhosis, nephrotic syndrome) Respiratory acidosis Basic – hypoventilation. Inhibition of medullary respiratory center: drugs (opiates, sedetives, anesthetics overdose), oxygen theraphy in chronic hypercapnia, cardiac arrest, sleep apnea. Disorder of respiratory muscles and chest wall: myasthenia gravis, Gullan-barre syndrome, poliomyelitis, amytrophic lateral sclerosis, kyphoscoliosis, pickwickian syndrome, fractured ribs. Disorders of gas exchange: COPD (empysema, bronchitis). End-stage diffuse intrinsic pulmonary disease. Severe pneumonia or asthma. Acute pulmonary edema. Pneumothorax. Acute airway obstruction: aspiration of foreign body or vomittus. Laryngospasm of larngeal edema, severe bronchospasm. Respiratory alkalosis Basic – hyperventilation. Central stimulation of respiration: emotional stress, fever, thyrotoxicosis, CNS disorder, head trauma, vascular accidents, brain tumors, salicylate intoxication. Hypoxia: pneumonia, asthma, pulmonary edema, congestive heart failure, pulmonary fibrosis, high-altitude residence. Excessive mechanical ventilation. Uncertain mechanism: gram-negative sepsis, hepatic cirrhosis. Exercise.  Thugica Jeyabalan Definition Causes Clinical features Laboratory Hypovolemia ECF volume deficit Extrarenal loses: vomitting, gastrointestinal suction, Lassitude, weakness, fatigue. Increased can be defined as an diarrhea, ileostomies, bleeding, diaphoresis, extensive burns Anorexia, thirst, tachycardia. hematocrit. isotonic loss of body (evaporation), intestinal obstruction, peritonitis, severe Orthostatic hypotension. Dizziness, Increased serum fluids with relatively burns, ascites, pancreatitis, pleural effusion, crush injury or syncope, altered level of protein level. equal loss of water fractured hip, hypoalbuminemia consciousness. Decreased body Normal serum and sodium which Renal loses (polyuria): salt-wasting nephritis, diuretic phase temperature. Cold extremities. Na+ usually. causes mainly the of acute renal failure, diuretic excess, diabetic glycosuria, Prolonged filling time of hand veins. BUN/serum deficit of plasma hyperalimentation (urea excess), mannitol theraphy, addision Flat jugular veins in supine postion. creatinine rartion volume disease, hypoaldosteronism (aldosterone deficiency) Decreased CVP. Sticky oral mucosa. > 20:1. Urine Dry furrowed tongue. Poor skin specific gravity turgor and oliguria. high. Urine osmalality >450 Rapid loss of weight mOsm/kg. Urine 2% - mild Na+ 20 mEq/l (renal or adrenal cause) Hypervolemia ECF volume excess Altered regulatory mechanism: congestive heart failure, Jugular venous distention. Elevated Decreased is caused by the cirrhosis of liver, nephrotic syndrome. CVP. Full, bounding pulse. Slow symptoms. Low retention of water Renal failure, cushing syndrome, corticosteroid theraphy, emptying of hand veins. Peripheral serum proteins. and sodium in starvation (hypoalbuminemia), rapid infusion of IV saline. and periorbital edema. Ascites. Normal serum roughtly equal Pleural effusion. Acute pulmonary Na+. Low urinary proportions. edema: dyspnea, tachypnea, moist Na+ Excessive isotonic rales over lung fields. (200 mg/dL (11.1 Obesity: BMI >25 kg/m2 mmol/L) Diabetes in the family Fasting glucose >126 mg/dL (7 mmol/L) Low physical activity or sudden cessation of examined twice at distinct times physical activity Oral glucose tolerance test > 200 mg/dL environmental or ethnic conditions Previously identified IGT or IFG Diagnosis of prediabetes gestational diabetes in the past Women who have givenbirth of child with IFG – fasting glucose level within 100-125 weight > 4kg mg/dL (5.6-6.9). Indication to perform OGTT HT, polycystic ovary syndrome, CVD IGT – OGTT within 140-199 mg/dL (7.8-11) People >45y (once in 3 years) HDL 250 (2.85)  Thugica Jeyabalan PATHOPHYSIOLOGY OF LIPIDS Familial hypercholesterolemia Familial hypertriglyceridemia Familial hyperchylomicronemia 2-3x R of CVD and IHD (at 30-40 age) Autosomal dominant Autosomal recessive, rare Autosomal dominant pattern 1% of population Mutations in lipoprotein lipase Mutations in LDLr or ApoB (most Excess VLDL production in liver High levels of chylomicron and TG common in monogenic FH) Premature coronary disease Recurrent abdominal pain and acute Most frequent – polygenic FH Risk of pancreatitis pancreatitis High levels of Ch total >270 ald LDL >200 Tendon xanthomas Familial dysbetalipoproteinemia Secondary hyperlipoproteinemia Lipid profile (Causes) Increased Ch total and TG, decreased HDL Nutritional: high-fat foods, excessive TG < 150 mg/dL Premature atherosclerosis intake of carbohydrates, alcohol abuse Ch total 40 mg/dL Accumulation of: chylomicrons, IDL, VLDL hypothyroidism, glycogen storage dis Ch-LDL 135/85) polyphagia à obesity Retinal lipid infiltration (lipemia retinalis - Hyperglycemia (100mg/dL) Premature atherosclerosis (esp. Coronary) - Dyslipoproteinemia (TG >150) - Gene of leptin receptor Visceral steatosis - Low HDL (94 in overexpression of mRNA for M and 80 in F NPY à increased apetite à polyphagia à obesity Hypolipoproteinemias Tangier disease (hypoalphalipoproteinemia) Autosomal recessive Reduced HDL Cholesterol depositions Hypobetalipoproteinemia Autosomal recessive ApoB recessive Low Ch total, chylomicrons, LDL and VLDL Greasy stool Low A, D, E vitamins RETINAL VESSEL ANALYSER non-invasive, in vivo Dynamic vessel analysis (DVA) Limitations of analysis without any mechanical contact to the examination procedure f.eks with problems w/fixation, nystagmus vessels flicker stimulation (dilate pupil, adjust changes in vitrous body, cornea very high precission (up to -+ 1um) retina image, mark vessel area) Significnat myopia, astigmatism easy to use start of measurement, automatic eye procedures between measurements retinal vessels reflect systemic vessel start of flicker periods, flicker vessel Other: AMD, ADPKD, cataract, changes of the whole body repsonse is recorded, automatic astigmatism, myopia, glaucoma, possibility of silmutanous examination both analysis of records and present. Of synchysis scintillans arteries and veins results Static vessel analysis (SVA) AVR strongly reduced Reduced flicker response Increase of RR up to 3x presence Hypertension, DM standardizied retina picture of HT, atherosclerosis, systemic Acute coronayr syndrome measurement of all relevant vessels inflammation, metabolic Heart failure inside of circular measuring area syndrome, HF, cardiovascular calculations of: CRAE, CRVE mortality, future heart infarction, Arterio-venous ratio: CRAE/CRVE future stroke  Thugica Jeyabalan ISCHEMIC HEART DISEASE Pathophys of IHD Angina pectoris Stable angina pectoris different forms of chest discomfort High LDL , low HDL, smoking, most common manifestation of IHD and symptoms precipitated by some HT or DM disturb normal 16% in M and 11% in F (65-74y) activity with minimalor non-existent function of endothelium of 50-60% attacks are silent symptoms at rest/after admin of coronary arteries producing à quality: sensation of pain/discomfort, oppression, NTG endothelial dysfunction and pressure, burning, tightness, curshing or squeezing symptoms typically abate several atherogenesis Location: usually substernal, also jaw and mins after acitivty and recur epigastrium other precipitants: cold, heavy Radiation: left or right arm, shoulder, jaw or meals, emothial stress Risk factors for IHD epigastrium Symptoms: dyspnea, diaphoresis, weakness, nausea, Unstable angina pectoris Age (>55y for M, >65y for F) vomitting, and/or feeling of anxiety AP that changes or worsens Cigarette smoking, DM duration: 2min – 30min. (even to several hours) 1/3 features: Dyslipidemia, family history Relieved by NTG in 1-10 min or rest *Occurs unpredictably at rest HT, obesity and physical Related to: exercise, cold, meals, emotion, coitus, rest *Severe and of new onset inactivity Physical signs: S3, S4, apical systolic murmur, *Occurs w/crescendo pattern Medications, kidney disease pulmonary congestion 64% occurs between 10PM-8AM Atherogenesis Myocardial infarction (MI) Arterial injury pathomechanism: smoke, HT, irreversible necrosis of heart muscle secondary to prolonged ischemia due cholesterol, glycated substances, vasoconstriction, to the occlusion of the coronary vessel homocysteine or infectious agents Causes: ATHEROSCLEROSIS, vascular spasm, vascular infections, thrombo- Endothelial dysfunction and inflammatory embolus, congenital anomalies, cardiomyopathies, CO intoxication, cocaine response and amphetamine intoxication Platelet aggregation Location: retrosternal LDL oxidation Heaviness, pressure, squeezing, choking Fibromuscular plaque Gradual intensification of symptoms over a period of several minutes Remodeling of the plaque Lasts more than 30 min typically Vulnerable atherosclerotic plaque radiation: shoulder, both arms, back, interscapular region, root of neck, jaw, Plaque rupture, thrombus formation teeth, epigastrium Not relieved by rest or NTG Diagnosis à 2/3 criteria Acute theraphies of IHD - Chest pain >30 min - ECG: pathologic Q, ST elevation, T inversion Angioplasty (balloon) - CK-MB and Tropinin T increased Stenting (expandable metal mesh stens that dilate Complication: arrhythmias, heart insufficiency, mechanical injuries (mitral reduces diameter of artery) regurgitation, ventricle break, septal break), right ventricle infarct, infarct Coronary artery bypass grafting augmentation, thrombi in LV, thrombo-embolic complications, pericardial effusion HYPERTENSION 600 million in the worl, 3 million die Primary hypertension Secondary hypertension annually Pathogenesis Negative family history, sudden onset of 50% not diagnoses. 50% diagnoses; *Kidney – imbalance between vasoconstrictors HT, very high values of BP (>180/120), 50% treated; 50% controlled and dilators, B1-stimulation, increased renin, presence of additional symptoms adequaely (12.5% overall controlled) resistance ot natriuretic factors Renal – chronic, polycystic, Primary (essential) – 90-95%, high *Vascular – impaired synthesis of endothelial glomerulonephritis, renal artery stenosis, BP for which genetical cause can be vasodilators, increased catecholamines, vascular renin-producing tumors found wall stiffness Endocrine – primary Secondary – 5-10%, caused by *Neural – increased symp, improper response to hyperaldosteronism, Cushing, abnormal conditions of other organs baroreceptor stimuli acromegaly, hypothyroidism, Genetic: in family increased Rx4. Monogenic hyperthyroidism, pheochromocytoma, HTN less than 1% of population. Polygenic hypercalcemia Classification Environmental: obesity, physical inactivity Other: coarctation of aorta, sleep apnea, Optimal: 140/than 5drinks/d), drug addiction, cigarette - Inflammatory diseases of the arteries - Physical inactivity, sedentary lifestyle, stress - Cerebral cortical venous thrombosis - Postmenopausal hormone theraphy, carotid stenosis - Sickle cell anemias, snakebites, insect bites - Aspirin – acetylsalicylic acid Risk factors unable to control - Streptokinase – fibrinolytic drug - Age: more elderly than young - Polycthemia vera, DIC, oral contreceptives - Gender: more women than men - Drugs which increase BP: amphetamine, cocaine, - Race: African american high risk sympathomimetics - History of prior strokes - Hereditary vascular and metabolic disorders Signs and symptoms - Sickle cell disease: causes clot formation and strokes even - Sudden and dramatic, neck stifness/rigidity in children - Violent explosive headache - Visual disturbances: flashing lights, aura Signs and symptoms - Nausea and vomitting. Neck and back pains - Harder to be detected - Sensitivity to light, weakness on one side - Weakness in one side - Can present like a migraine headache - Facial drooping - Numbness and tingling Stroke warning signs - Language disturbances - Visual disturbances Sudden weakness or numbness of face, arm or leg, especially on one side of the body Left brain stroke Sudden confusion, trouble speaking or understanding - Right side paralysis Sudden trouble seeing in one or both eyes - Speech and language disturbances Sudden trouble walking, dizziness/vertigo, loss of balance or - Behavioral changes coordination - Swallowing problems Sudden, severe headache with no known cause (for hemorrhagic) Right brain damage - Left side paralysis - Spatial perception (location of limbs in relation to room) Transient ischemic attack - Coordination problems - Perception (recognition of familiar objects?) Temporary disruption of blood flow to the brain risk of cardiac events is also elevated aftet TIA Short-term risk: Age (>60y), HT, focal weakness with spell or Ischemic peumbra speech impairment without weakness, duration (>60min) or area of reduced perfusion sufficient to cause potentially 10-59mins, diabetes reversible clinical deficits, but insufficient to cause disrupted ionic homeostasis 20-8 ml/100g/min  Thugica Jeyabalan DISORDERS OF HEMATOPOIESIS Sickle cell anemia Iron deficiency anemia Etiology Hemoglobinopathy Blood loss B-globin mutations - Menstrual loss Homozygotes – all HbA replaced by Hbs - Stomach: hiatal hernia, esophageal varices, peptic ulcers, acute gastritis, drugs, Heterozygotes – 40% of Hb is Hbs carcinoma Multiple sickling weakens cell membrane - Large bowel: carcinoma, benign polyps, angiodysplasia, diverticular disease, Mean lifespan of RBCs: 20 days ulcerative colitis Elongated, spindle cells - Small bowel: hookworms, Crohns disease Hypoxia-induced fatty changes in heart, - Other: epistaxis, hematuria, coagulopathy, blood donation liver and renal tubules Malabsorption: achlorhydria, total gastrectomy, gastrojejunostomy, celiac disease prominent cheekbones and skull changes Inadequate intake or increased requirements: dietary (vegans), pregnancy and lactation, Vaso-occlusive pain crisis episodes growth and development Proliferative sickle cell retinopathy, autosplenectomy Symptoms Irritability, poor attention to other people, lack of interest in surroundings Pernicus anemia poor work performance, behavioural disturbances, pica increased frequency of infection, defective structure and function of epithelial tissue Most common cause of B12 malabsorption Stages in development of iron deficiency Often occurs together with other autoimmune disorders 1. Prelatent: reduction in iron stores without reduced serum iron levels 3 types of Ab Hb (N), MCV (N), transferin saturation (N), serum ferritin (D), Marrow iron stores 1. Binding to parietal cells 2. Blocking Ab – disrupts binding of (D) B12 to IF 3. IF-B12 complex Ab – prevent the 2. Latent: iron stores exhausted but blood Hg level remains normal complex from binding to cubulin Hb (N), MCV (N), transferrin saturation (D), TIBC (I), serum ferittin (D), marrow iron stores (absent) Hereditary spherocytosis 3. Iron deficiency anemia: blood Hg falls below the lower limit of normal Hb (D), MCV (D), transferrin saturation (D), TIBC (I), serum ferritin (D), marrow Autosomal dominant (rare AR cases) iron stores (absent) Mutations of RBCs membrane skeleton proteins (spectrin, ankyrin and others) Megaloblastic anemia Spherocytes are sequestered in spleen Dark RBC without central pallor B12 deficiency: gastrectomy, atrophic gastritis, caustic soda ingestion, pernicuous anemia, Hyperplasia of erythroblasts in BM absence of intrinsic factor, resection/irradiation of ileum, regional enteritis, small intestinal Clinical tests diverticula, blind loop syndrome, tapeworm, congenital absorpton defect (lmerslund - Blood smear: spherocytes syndrome), drugs (para-aminosalicylic acid, neomycin), chronic pancreatic insufficiency, - Increased osmotic fragility: congenital transcobalamin deficiency measures RBC resistance to hemolysis when exposed to a series Folate acid deficiency: inadequate diet of increasingly dilute saline - Impaired absorption:intrinsic disease of small intestine, blind loop syndrome solutions - Impaired utilization:excessive ethanol ingestion, B12 deficiency, drugs (methotrexate, trimethoprim, pyrimethamine) Physiologic response to anemia - Increased utilization: pregnancy, hemolysis, hemodialysis, exfoliative dermatitis, myeloproliferative disorders Increased heart rate Increased stroke volume Blood abnormalities: macrocytosis, anisocytosis, poikilocytosis, reticulocytopenia, Vasodilation hypersegmented neutrophils Decreased oxygen affinity Marrow abnormalities: hypercellularity, erythroid hyperplasia, megaloblasts Classification of anemia Anemia of chronic disease Thalassemia Acute infections: bacterial, fungal or viral Hemoglobinopathies Microcytic: iron deficiency, copper Chronic infections: tuberculosis, infective Mutation in a or b-globin gene deficiency, thalassemia, chronic disease endocarditis, chronic urinary tract infections B-thalassemia: hemosiderosis Noninfectious inflammatory: osteoarthritis, Normocytic: chronic disease, acute blood rheumatoid, collagen vascular disease loss, hemolytic disorders, malignancy Acute and chronic hepatitis Malignancy: Metastatic carcinoma, lymphoma, Macrocytic: folate deficiency, B12 leukemia, myeloma deficiency, drug-induced, inherited bone marrow failure Aplastic anemia Suppression of mulitpotent myeloid stem cell Normal values >50% idiopathic, Require transfusions (hemosiderosis) RBC: 4,7-6 (M) 4,2-5,5 (F) Thrombocytopenia, reticulocytopenia, granulocytopenia, No splenomegaly, hypocellular BM HCT: 42-54% (M) 37-47% (F) Immunosuppressive theraphy aimed at T cells is effective in 70-80% of cases HGB: 14-16 (M) 12-15 (F) Causes - Benzene, benzene-containing solvents Lab definition of anemia - Insecticides including DDT RBC: