Topnotch Medical Board Prep Pathology Main Handout - October 2024 PLE - PDF

TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ This handout is only valid for the October 2024 PL...

TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly. IMPORTANT LEGAL INFORMATION PATHOLOGY By Kevin A. Elomina, MD, DPSP The handouts, videos and other review materials, provided by Topnotch Medical Board Contributors: Mark Milan, MD, Frinz Moey C. Rubio, MD,FPSP Preparation Incorporated are duly protected by RA 8293 otherwise known as the Intellectual Property Code of the Philippines, and shall only be for the sole use of the person: Juan Lorenzo D. Santos, MD, & Bradley Ashley G. Ong, MD a) whose name appear on the handout or review material, b) person subscribed to Topnotch Medical Board Preparation Incorporated Program or c) is the recipient of this electronic communication. No part of the handout, video or other review material may be reproduced, TOPIC PAGE shared, sold and distributed through any printed form, audio or video recording, electronic medium or machine-readable form, in whole or in part without the written consent of 1. Cellular Responses to Stress 1 Topnotch Medical Board Preparation Incorporated. Any violation and or infringement, 2. Inflammation and Repair 3 whether intended or otherwise shall be subject to legal action and prosecution to the full extent guaranteed by law. 3. Hemodynamic Disorders 7 4. Genetic Disorders 10 DISCLOSURE 5. Diseases of the Immune System 14 The handouts/review materials must be treated with utmost confidentiality. It shall be the 6. Neoplasia 20 responsibility of the person, whose name appears therein, that the handouts/review materials 7. Infectious Diseases 24 are not photocopied or in any way reproduced, shared or lent to any person or disposed in any manner. Any handout/review material found in the possession of another person whose name 8. Environmental and Nutritional Pathology 30 does not appear therein shall be prima facie evidence of violation of RA 8293. Topnotch review 9. Diseases of Infancy and Childhood 33 materials are updated every six (6) months based on the current trends and feedback. Please buy all recommended review books and other materials listed below. 10. Blood Vessels 36 THIS HANDOUT IS NOT FOR SALE! 11. Heart 40 12. WBCs, LNs, Spleen, and Thymus 46 This handout is only valid for the October 2024 PLE batch. 13. Red Blood Cell and Bleeding Disorders 50 This will be rendered obsolete for the next batch 14. Lung and Pleura 56 since we update our handouts regularly. 15. Head and Neck 60 16. Gastrointestinal Tract 63 FOREWORD FOR TOPNOTCH PATHOLOGY 17. Liver, Gallbladder, and Pancreas 69 Pathology has evolved to be one of the “hardest” subjects in the PLE for the following 18. Kidney 75 reasons: o Topics from other subjects frequently appear 19. Lower Urinary Tract and Male Genital Tract 80 o Topics not mentioned in Robbins sometimes appear 20. Female Genital Tract 85 o Different focus on systems per season 21. Breast 89 o Different focus on information per season o Rare diseases are sometimes asked 22. Endocrine System 91 Basically, it’s hard because it is UNPREDICTABLE! And that’s not our fault (me, the 23. Skin 96 program, and the students). 24. Bones, Joints, and Soft Tissue 99 The only solution to an unpredictable opponent is to know everything there is to 25. Peripheral Nervous System and Skeletal Muscles 103 know about it, hence the sheer length of the main material and the lecture video. 26. Central Nervous System 104 Please understand that we are doing this not to overwhelm you. If you are going to fault me or the program for anything, better be it because of overpreparing you rather 27. Eye 110 than the other way around. BUT Please DO NOT expect for the program to cover everything there is to know about Pathology. It is taught for a year in medical school, trained for 4 years in residency, 1. CELLULAR RESPONSES TO STRESS and practiced for a lifetime, but we still know so little about it. The goal is to know CELLULAR RESPONSES TO STRESS AND INJURIOUS enough to pass the boards and become a competent general practitioner. These are my recommendations in studying Pathology for the PLE: STIMULI o Stick to one or few materials and master them. Around 80-85% of the seasonal feedback are in the handouts, and seasonal updates ensure coverage of those topics previously not covered. I always see Pathoma as your favorite, and if it works for you, then go. But if you don’t have the time, then I recommend sticking to our materials. o Memorize sometimes (only if needed), understand always. o Pictures help you memorize lesions. This material comes with a separate Atlas handout containing pictures from the lecture. If you want more, use Robbins atlas or the Internet. o Integrate and DO NOT forget what you learned in other subjects. Pathology is anything under the sun (including the other subjects). Be prepared to get answers from other subjects when necessary. Integration also reinforces information retention because it is processed in a higher order manner. o Manage your time wisely so that you can completely consume both the main handout and the lecture video. The lecture video will be helpful for visual and auditory learners. Do your best for the things you can control and pray to God (if you believe in Him) or rely on fate for the things that you cannot. At the end of the day, it’s all about giving it our all and then hoping that it will be enough. Best of luck, Topnotch students! See you on the other side soon. CELL INJURY AND CELL DEATH Figure 2.1. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 “Success is not final; failure is not fatal: It is the courage to continue that counts." - Winston Churchill CELL INJURY MAIN REFERENCE: CAUSES Kumar V. Abbas AK. Aster JC. Turner JR. Robbins and Cotran Pathologic Basis of Oxygen deprivation Immunologic reactions Disease.10th ed. Philadelphia: Elsevier; 2020 Physical agents Genetic derangements CONFORME: By proceeding, the user acknowledges the limitations of the Topnotch Chemical agents and drugs Nutritional imbalances Pathology Program in consideration of the broad nature of Pathology as a discipline and Infectious agents Cellular senescence the limited time for review. The user also acknowledges that enriching his/her learning experience as well as his/her performance in Pathology and in the PLE in general, is his/her SOLE RESPONSIBILITY. REVERSIBLE CELL INJURY Functional and structural alterations in early stages or mild forms of injury, which are correctable if the damaging stimulus is removed 2 Consistent features: Cellular swelling, Fatty change (1) CELLULAR SWELLING First manifestation of almost all forms of injury to cells Pathogenesis: Influx of ions (and water) due to failure of energy-dependent ion pumps (Na+-K+-ATPase) Morphology o Gross: Pallor, increased organ turgor and weight TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA Page 1 of 113 For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly.  TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly. o Microscopic: o Nuclear changes § Hydropic change/Vacuolar degeneration: Small clear § Karyolysis: Decreased basophilia of chromatin vacuoles in cytoplasm (distended and pinched off segments Due to DNA loss from enzymatic degradation by of endoplasmic reticulum) endonucleases § Eosinophilia (due to loss of RNA) Nuclear membrane is intact in karyolysis § Pyknosis: Nuclear shrinkage with increased basophilia (2) FATTY CHANGE § Karyorrhexis: Fragmentation of pyknotic nucleus Pathogenesis: Toxic injury disrupts metabolic pathways and Disintegration of nuclear membrane occurs leads to rapid accumulation of triglyceride-filled lipid vacuoles § Eventual loss of nucleus Seen in cells dependent on fat metabolism (liver, heart) Eosinophilia means it stains pink. Basophilia means it stains blue. Nucleic Morphology: Cytoplasmic lipid vacuoles acids are basophilic; hence when they are degraded or destroyed, eosinophilia occurs. It is just the balance of the colors. :) Dr. Rubio CELLULAR ADAPTATIONS HYPERTROPHY PATTERNS OF NECROSIS Increase in cell size à Increase in organ size COAGULATIVE NECROSIS Stimuli: Setting: Ischemic necrosis of all organs except the brain o Increased workload Pathogenesis: Slow protein denaturation o Hormonal stimulation Morphology: Mechanism: Increase in protein synthesis o Infarct: Localized area of coagulative necrosis Examples: o Acidophilic tombstone: Tissue and cell architecture o Physiologic: preserved, intense eosinophilia, and loss of nuclear details § Myometrial hypertrophy in gravid uterus (hormonal LIQUEFACTIVE NECROSIS stimulation) § Muscle of bodybuilders (functional demand) Setting: Bacterial/Fungal infections, Ischemic necrosis of the o Pathologic: Left ventricular hypertrophy in hypertensive brain heart disease (increased workload) Pathogenesis: Neutrophilic enzymes destroy cellular components Morphology: HYPERPLASIA o Pus: Creamy yellow necrotic material composed of leukocytes, fluid, necrotic debris Increase in cell number Stimuli: GANGRENOUS NECROSIS o Hormonal stimulation Setting: Loss of blood supply of a limb o Compensatory response (to decreased cell mass) Pathogenesis: Same as coagulative necrosis Mechanisms: Morphology: o Growth factor-driven proliferation of mature cells o Dry gangrene: Coagulative necrosis involving multiple o Increased output of new cells from tissue stem cells tissue planes Examples: o Wet gangrene: Superimposed liquefactive necrosis (due to o Physiologic: superimposed bacterial infection) § Pubertal breast changes (hormonal) § Liver regeneration (compensatory) CASEOUS NECROSIS o Pathologic: Endometrial hyperplasia (hormonal) Setting: Tuberculous infections Pathogenesis: Tissue destruction secondary to cell-mediated ATROPHY immune response Decrease in cell size and number Morphology: Stimuli: o Gross: White, cheese-like, friable foci of necrosis o Decreased workload o Malnutrition o Microscopic: o Loss of innervation o Loss of endocrine stimulation § Structureless collection of fragmented or lysed cells and o Loss of blood supply o Pressure amorphous granular debris Mechanisms: § Granuloma: Inflammatory border surrounding caseous necrosis o Decreased protein synthesis ENZYMATIC FAT NECROSIS o Increased protein degradation o Autophagy Setting: Acute pancreatitis, Breast fat necrosis Examples: Pathogenesis: Lipases break down triglycerides to fatty acids o Physiologic: Embryonic atrophy (notochord and thyroglossal that combine with calcium ions to form soap (saponification) duct) Morphology: o Pathologic: Brain cortical atrophy (Alzheimer disease) o Gross: Chalky-white areas of fat saponification o Microscopic: Shadowy outlines of necrotic fat cells, basophilic calcium deposits, inflammatory reaction METAPLASIA Differentiated cell type replaced by another cell type FIBRINOID NECROSIS Stimuli: Stress Setting: Immunologically mediated vasculitis Mechanisms: Reprogramming of stem cells Pathogenesis: Complexes of antigens and antibodies (immune Examples: complexes) are deposited in the walls of arteries o Squamous metaplasia: Columnar to squamous Morphology: Bright pink, amorphous material deposited in § Most common metaplasia the walls of arteries o Intestinal metaplasia § In Barrett esophagus FORMS OF CELL DEATH NECROSIS Pathologic process that is the consequence of severe cell injury General morphologic changes o Cytoplasmic changes § Increased eosinophilia: More pink appearance § Others: Glassy appearance, myelin figures, moth-eaten PATTERNS OF NECROSIS cytoplasm Clockwise from left: coagulative, liquefactive, caseous, fibrinoid, enzymatic fat Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA Page 2 of 113 For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly.  TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly. (2) APOPTOSIS METASTATIC CALCIFICATION Programmed cell death Pathologic calcification that occurs in viable tissue in the General morphologic changes setting of increased calcium levels o Decreased cell size Causes: Any condition that can cause hypercalcemia o Chromatin condensation: Chromatin aggregates under the Usually does not cause organ dysfunction except in massive nuclear membrane organ involvement § Most characteristic feature of apoptosis o Cytoplasmic blebs and apoptotic bodies 2. INFLAMMATION AND REPAIR o Macrophages that phagocytize apoptotic bodies INFLAMMATION o No inflammation § No release of cytosolic contents that can trigger Response of vascularized tissues to infections and damaged tissues that inflammation brings cells and molecules of host defense from the circulation to the § Macrophages inhibit proinflammatory cytokine production sites where they are needed, in order to eliminate the offending agents in apoptosis -itis: Suffix that connotes an inflammatory process Please remember that accumulation of damaged DNA (usually due to CAUSES viral infections) and misfolded proteins (as seen in enzyme deficiencies) Infections Presence of foreign bodies are triggers of apoptosis. Dr. Rubio Tissue necrosis Immune reactions KEY DIFFERENCES BETWEEN MAIN FORMS OF CELL DEATH FIVE CARDINAL SIGNS FEATURE NECROSIS APOPTOSIS SIGN PATHOPHYSIOLOGY Enlarged Rubor (Redness) Increased blood flow to inflamed Cell size Reduced (shrinkage) (swelling) Calor (Warmth) tissue (Vasodilation) Pyknosis, Fragmentation into Increased production of pain Nucleus Karyorrhexis, nucleosome-sized Dolor (Pain) substances in inflamed tissue Karyolysis fragments Increased vascular permeability Intact; altered Tumor (Swelling) Plasma leading to edema Disrupted structure, especially Functio laesa Tissue damage because of membrane orientation of lipids (Loss of function) inflammation Enzymatic Intact; may be Cellular digestion; may released in apoptotic GENERAL STEPS OF INFLAMMATION contents leak out of cell bodies Adjacent Recognition of the injurious agent Frequent None Recruitment of leukocytes inflammation Physiologic or Invariably Often physiologic; Removal of the agent pathologic role pathologic may be pathologic Regulation (control) of the response Table 2.1. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 Resolution (and repair) Remember: The apoptotic bodies are intact. There are no leaked cellular contents, thus inflammation is not initiated. Moreover, RECOGNITION OF THE INJURIOUS AGENT phosphatidylserine is switched from the inner leaflet of the plasma The immune system can recognize the presence of an injurious agent membrane to the outer leaflet – this process is a marker for apoptosis. or its effect (cellular damage) that triggers the inflammatory response Dr. Rubio Examples: AUTOPHAGY o Toll-like receptors (TLRs): Cellular receptors for extracellular Cell eats its own contents microbes Purpose: o Damage-associated molecular patterns (DAMPs): Uric acid, o Survival in times of nutrient deprivation ATP, K+, DNA o Removal of unwanted/dysfunctional cellular components o Fragment crystallizable (Fc) receptor in leukocytes: Impaired autophagic response can be a basis of diseases Recognizes microbes coated by antibodies o Example: Alzheimer Disease (Neurodegenerative disease) o Complement system: Circulating proteins activated by § Main pathology: Accumulation of abnormal proteins due to immune complexes or microbial surface molecules impaired autophagy à Abnormal proteins cause unfolded protein response + inflammation à neuronal injury RECRUITMENT OF LEUKOCYTES Inflamed tissues are infiltrated by leukocytes because of INTRACELLULAR ACCUMULATIONS leukocyte recruitment HYALINE CHANGE Homogeneous, glassy, pink appearance in Hematoxylin-Eosin (H&E) stain Location: Intracellular or extracellular Composition: Glycogen or non-glycogen Periodic Acid-Schiff-Diastase (PAS-D): Stain that differentiates glycogen from non-glycogen hyaline HYALINE PAS POST-DIASTASE Glycogen (+) (-) (Sensitive) Non-glycogen (+) (+) (Resistant) Glycogen stains rose-to-violet color in Periodic acid – Schiff (PAS) stain. Mnemonic: PASS the SUGAR. Dr. Rubio PATHOLOGIC CALCIFICATION Abnormal tissue deposition of calcium salts together with smaller amounts of other mineral salts Morphology o Basophilic, amorphous granular, sometimes clumped appearance STEPS IN LEUKOCYTE RECRUITMENT o Heterotopic bone may form in time Figure 3.4. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 202 Peripheral positioning of the leukocytes along DYSTROPHIC CALCIFICATION Margination the endothelial surface Pathologic calcification that occurs in necrotic tissue in the Results from slower blood flow due to vessel dilation setting of normal serum calcium levels Transient, weak binding and detachment of Psammoma bodies: Sand-like lamellated calcifications seen in Rolling leukocytes to the endothelium papillary tumors Mediated by selectins Often causes organ dysfunction TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA Page 3 of 113 For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly.  TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly. Permanent, firm adhesion of leukocytes to CYTOKINES AND CHEMOKINES Adhesion endothelium Cytokines: Mediate and regulate immune and inflammatory reactions Mediated by integrins Chemokines: Chemoattractants for specific types of leukocytes Transmigration of leukocytes across the Sources: Different types of cells endothelium CYTOKINE PRINCIPAL ACTION(S) Diapedesis Postcapillary venules – site of diapedesis Tumor Stimulates expression of endothelial adhesion Mediated by CD31/PECAM-1 necrosis molecules, and secretion of other cytokines Movement towards a chemotactic signal factor (TNF) Has systemic effects Most common exogenous product: N- IL-1 Similar to TNF; has a greater role in fever Chemotaxis formylmethionine T-cell growth factor IL-2 Endogenous chemotactic signals: IL-8, C5a, Proliferation of activated T cells leukotriene B4 (an arachidonic acid metabolite) Promotes hematopoiesis (Multicolony colony IL-3 N-formylmethionine is a prominent protein used in protein synthesis among stimulating factor) bacterial microbes. Th2 differentiation IL-4 Dr. Rubio IgE production CELLULAR INFILTRATES IN INFLAMMATION IL-5 Activates eosinophils TYPE INFILTRATE IL-6 Systemic effects (acute-phase response) Neutrophils (usually replaced by IL-7 Stimulates lymphoid progenitors Acute monocytes after 24-48 hours) IL-8 Neutrophilic chemotactic factor Prolonged Monocytes IL-10 Anti-inflammatory cytokine Pseudomonas Neutrophils (for several days) IL-12 Increased production of IFN-γ Viral Lymphocytes (usually first to arrive) IL-13 Mucus production in airway epithelial cells Allergic Eosinophils (main infiltrate) IL-17 Recruitment of neutrophils and monocytes Cell-mediated Interferon γ Activation of macrophages (increased ability Lymphocytes (main infiltrate) hypersensitivity (IFN-γ) to kill microbes and tumor cells) Memory Devices: REMOVAL OF THE AGENT Holy trinity of cytokines: IL-1, IL-6, TNF Leukocyte activation → phagocytosis → intracellular killing IL-1: Single root cause of all evil (physiologic consequence) IL-2 (Two): T-cells (T.T) o Reactive oxygen species (ROS) and nitric oxide (NO) (intracellular) IL-3: Trilineage hematopoiesis o Lysosomal enzymes (through phagolysosome formation) IL-6: Six pack (Increase in acute phase proteins) o Neutrophil extracellular traps (NETs) – extracellular fibrillar IL-8: Cheightmokine (Neutrophil) Dr. Elomina networks that trap microbes and concentrate antimicrobial substances, helping to prevent their spread. COMPLEMENT SYSTEM Killing mechanisms can also damage normal tissues (pathologic consequence) REGULATION OF RESPONSE Inflammatory mediators have generally short half-lives Neutrophils have short half-lives and die by apoptosis Anti-inflammatory cytokines: lipoxin, transforming growth factor-beta (TGF-β), interleukin-10 (IL-10) MEDIATORS OF INFLAMMATION Substances that initiate or regulate inflammatory reactions Can be cell-derived or plasma-derived Active mediators are produced only in response to various stimuli Most mediators are short-lived VASOACTIVE AMINES HISTAMINE Parent amino acid: Histidine Sources: Mast cells (richest), platelets, basophils Function: Arteriolar dilation, increase in venular permeability SEROTONIN Parent amino acid: Tryptophan Sources: Platelets, neuroendocrine cells Function: Vasoconstriction ARACHIDONIC ACID METABOLITES/EICOSANOIDS Parent molecule: Arachidonic acid: (20:4(ω-6)) o That’s why foods containing omega-6 are pro-inflammatory Two pathways o Cyclooxygenase (COX) pathway: Produces prostaglandins (PG), prostacyclins, and thromboxane (TX) o Lipooxygenase pathway: Produces leukotrienes and lipoxins ACTION EICOSANOIDS Vasodilation PGI2 (Prostacyclin), PGE1, PGE2, PGD2 Vasoconstriction TXA2, LTC4, D4, E4 ↑ Vascular LTC4, D4, E4 permeability Chemotaxis, LTB4, Hydroxyeicosatetraenoic acid THE COMPLEMENT SYSTEM leukocyte adhesion (HETE) Fig 5-1 and 5-2. Immunology and Serology in Laboratory Medicine, 5th ed. 2014 TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA Page 4 of 113 For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly.  TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly. COMPLEMENT SYSTEM TYPES OF INFLAMMATION Collection of soluble proteins and their membrane receptors that GENERAL TYPES function mainly in host defense against microbes and in FEATURE ACUTE CHRONIC pathologic inflammatory reaction Fast: minutes or General steps: Initiation à Cleavage of C3 à Cleavage of C5 à Onset Slow: days hours Membrane attack complex o Initiation Pathways: Monocytes/ Mainly § Classical pathway: Activated by antibodies Cellular infiltrate macrophages, neutrophils § Alternative pathway: Activated by microbial products lymphocytes § Mannose-binding lectin pathway: Activated by mannose Tissue injury, Usually mild and Often severe and residues in target cells fibrosis self-limited progressive Local and Prominent Less KEY COMPLEMENT PROTEINS AND THEIR FUNCTIONS systemic signs Adapted from Table 3.2. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 PROTEIN FEATURE C1* Activates classical pathway Remember: Chronic inflammation is married to fibrosis! Dr. Elomina Mannose-associated serine protease MASP ACUTE INFLAMMATION Counterpart of C1 in Lectin pathway In classical and Mannose-binding lectin Components: C4*, C2* pathways o Dilation of small vessels Cleaved to produce C3 convertase o Increased microvascular permeability Most abundant complement o Emigration of leukocytes and their activation C3 Gives rise to C3a (anaphylatoxin) and C3b (opsonin) through the action of C3 convertase VASCULAR RESPONSE IN ACUTE INFLAMMATION Gives rise to C5a (anaphylatoxin) and C5b DILATION OF SMALL VESSELS C5 (part of membrane attack complex) through Increase in caliber of blood vessels the action of C5 convertase o Results in increased blood flow and stasis of blood → Late components of the complement system erythema C6-C9 o Stasis → accumulation of leukocytes along endothelium (part of MAC) * Early complement components Histamine: most notable mediator that produces vasodilation OUTCOMES OF THE COMPLEMENT CASCADE INCREASED MICROVASCULAR PERMEABILITY OUTCOME INVOLVED PROTEINS Mechanisms: Anaphylatoxins: C3a, C4a, C5a o Endothelial cell contraction (Most common mechanism) o Promote histamine release from mast § Caused by exposure to inflammatory mediators (histamine, Inflammation cells bradykinin, leukotrienes, etc.) Chemotaxis: C5a § Rapid onset, transient duration o Leukocyte recruitment o Endothelial injury Promotion of phagocytosis o Increased transport of substances across endothelial cells Opsonization C3b (transcytosis) Via Membrane attack complex (MAC) Results in edema Cell lysis C5b, C6-C9 Sunburns: Caused by endothelial cell contraction and mild Opsonization is the process of making a microbe more palatable to the endothelial injury, delayed onset, slightly prolonged duration phagocytes for engulfment. Basically, opsonins make microbes “yummy”. Dr. Rubio Burns, Severe infection: Caused by endothelial cell necrosis and detachment (endothelial injury), rapid onset, prolonged duration COMPLEMENT-RELATED DISEASES Dr. Elomina DEFICIENCY DISEASE LYMPHATIC VESSEL RESPONSE Most common complement Increased proliferation and lymph flow to handle excess edema C2 deficiency fluid Pyogenic infections Lymphangitis: secondary inflammation of lymph vessels due to C3 Immune complex-mediated the primary source glomerulonephritis Lymphadenitis: lymph node inflammation C1 inhibitor Hereditary angioedema Decay accelerating MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION Paroxysmal nocturnal factor (DAF) and Hallmark: dilation of small blood vessels and accumulation of hemoglobinuria (PNH) CD59 deficiency leukocytes and fluid in the extravascular tissue Early components SLE-like syndrome (C1, C2, and C4) PATTERN FEATURE Increased risk to Neisseria infections Exudation of cell-poor fluid Late complements due to inability to form MAC Serous Seen in viral infections, burns, and OTHER MEDIATORS transudations MEDIATOR ACTION Exudation of fibrinogen and fibrin deposition Platelet aggregation Fibrinous in extracellular fluid (ECF) Platelet- Seen in fibrinous pericarditis High concentration: vasoconstriction & activating Exudation consisting of PMNs, and necrotic bronchoconstriction factor (PAF) Purulent debris Low concentration: vasodilation Increased vascular permeability Seen in abscess formation (collection of pus) Bradykinin Smooth muscle contraction Excavation of the surface on an organ or tissue Ulcers Vasodilation and pain when injected due to shedding of inflamed necrotic tissue Substance P Pain modulation OUTCOMES OF ACUTE INFLAMMATION The vasodilatory effect of bradykinin is not related to its smooth muscle- contracting effect. It is because of its interaction with endothelial Resolution receptors that leads to release of prostaglandins and NO that cause Abscess formation vasodilation. Bradykinin therefore is an endothelium-dependent Progression to chronic inflammation vasodilator. The difference in its effect on blood vessels and on other Healing by fibrosis smooth muscles is because the blood vessel has endothelium while the other has not. Situations where healing by fibrosis occurs: 1. Chronic inflammation, 2. Dr. Elomina Severe tissue injury i.e., Abscess formation Dr. Elomina TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA Page 5 of 113 For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly.  TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly. CHRONIC INFLAMMATION LEUKOCYTOSIS Response of prolonged duration in which inflammation, tissue Increased number of circulating white blood cells in peripheral injury, and attempts at repair coexist, in varying degrees blood Causes: Pathophysiology: o Persistent infection o Accelerated release of granulocytes in bone marrow o Hypersensitivity diseases (autoimmune diseases) o Increased production of colony-stimulating factors (CSF) à o Prolonged exposure to potentially toxic agents proliferation of leukocyte precursors General morphologic features: o Mononuclear cell inflammatory infiltrate: lymphocytes, SEPTIC SHOCK macrophages, plasma cells See Chapter 3, Hemodynamic disorders o Tissue destruction o Attempts at healing: angiogenesis, fibrosis REPAIR Cells involved: Restoration of tissue architecture and function after an injury CELL FUNCTION General types: Phagocytosis and antigen presentation o Regeneration: happens in labile and stable tissues; influenced Macrophages Secretion of inflammatory mediators by growth factors Initiation of tissue repair o Connective tissue deposition: happens in chronic, severe CD4+ T cells: Cytokine secretion promotes inflammation, and in permanent tissues inflammation Important cells and mediators: Lymphocytes B cells: Differentiate into plasma cells that o Macrophage: Most important source of growth factors during produce antibodies repair o Other cells involved: Eosinophils, Mast cells, and Neutrophils § TGF-β, Platelet-derived growth factor (PDGF), Fibroblast growth factor 2 (FGF-2)) o TGF-β: Most important cytokine for the synthesis and deposition of connective tissue proteins CLASSIFICATION OF TISSUES BY REGENERATIVE CAPACITY LABILE TISSUES Continuously lost and replaced either by proliferation of residual cells or maturation of stem cells Examples: Surface epithelium, Hematopoietic stem cells PATHWAYS OF MACROPHAGE ACTIVATION Adapted from Figure 3.20. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 STABLE TISSUES GRANULOMATOUS INFLAMMATION Cells by quiescent but with limited capacity to proliferate in response to tissue injury and loss Granuloma: collections of activated macrophages, often with Examples: Liver, Kidney, Pancreas, Endothelium, Fibroblasts, peripheral T-lymphocytes, and sometimes associated with Smooth muscle central necrosis Activated macrophages à epithelioid cells and/or giant cells PERMANENT TISSUES o Epithelioid cells: Hallmark of granuloma Terminally differentiated and non-proliferative o Giant cells: Foreign body or Immune (e.g., Langhans type in TB) Caseation necrosis may be present or absent IMPORTANT EVENTS IN REPAIR BY CONNECTIVE In tuberculosis (TB), Pattern of inflammation: Chronic granulomatous TISSUE DEPOSITION Pattern of necrosis: Caseation Dr. Elomina ANGIOGENESIS Formation of new blood vessels from existing ones SYSTEMIC EFFECTS OF INFLAMMATION Mediator: Vascular endothelial growth factor (VEGF) FEVER Elevation of body temperature FORMATION OF GRANULATION TISSUE Pyrogens: substances that induce fever Granulation tissue: Hallmark of repair o Exogenous: Bacterial products e.g., Lipopolysaccharide (LPS) o Components: Fibroblasts, loose connective tissue, à induces production of endogenous pyrogens angiogenesis, inflammatory cells o Endogenous: Cytokines (IL-1, TNF) Scaffolding for the eventual fibrous scar Pathophysiology: Pyrogens induce production of prostaglandins i.e., PGE2 à elevation of temperature set point REMODELING OF SCARS ACUTE PHASE RESPONSE Balance between extracellular matrix (ECM) degradation Increased production of plasma proteins in response to (matrix metalloproteinases – MMPs) and synthesis (tissue inflammation (acute phase proteins) inhibitor of metalloproteinases – TIMPs) Pathophysiology Imbalance can cause abnormalities in tissue repair o IL-1 and TNF: Causes production of Serum Amyloid A (SAA) o IL-6: Causes production of C-reactive protein (CRP) and Fibrinogen WOUND CONTRACTION PROTEIN FUNCTION Process in wound healing mediated by myofibroblasts Binds to microbial cell walls, may act as opsonins, and fix complement FACTORS THAT IMPEDE REPAIR CRP Marker of increased risk of myocardial Infections Pressure infarction in patients with coronary Diabetes mellitus Poor perfusion artery disease Vitamin C deficiency Foreign bodies Causes red cells to form stacks Glucocorticoids (inhibit TGF-β) Location of injury Fibrinogen (rouleaux) à increased erythrocyte Anything that promotes infections impedes repair because for the sedimentation rate (ESR) repair process to be complete, the inflammation should subside. Vitamin Binds to microbial cell walls, may act as C deficiency impedes collagen synthesis, which is essential for repair. SAA opsonins, and fix complement DM and pressure may cause inadequate perfusion, which is also Can cause secondary amyloidosis important for repair. Foreign bodies are harder to eliminate, which means longer duration of inflammation. Reduces availability of iron to erythroid Dr. Elomina Hepcidin precursors in marrow Causes anemia of chronic inflammation Thrombopoietin Can cause thrombocytosis TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA Page 6 of 113 For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly.  TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly. ABNORMALITIES IN TISSUE REPAIR Morphology CONDITION CAUSE o Most common sites: Subcutaneous tissues, lungs, and brain Wound o Gross: Inadequate granulation tissue Dependent edema: Location of edema dehiscence Proud flesh Excessive granulation tissue is influenced by gravity Contracture Excessive wound contraction Pitting edema: Depression on pressure Subcutaneous due to displacement of interstitial fluid Excessive collagen formation tissue Periorbital edema: occurs in renal Keloid: Scar tissue grows beyond the failure (area has a lot of loose Keloid and boundaries of the original wound connective tissue) hypertrophic o More common in African Americans Heavy (2-3x normal weight), frothy scars Hypertrophic scar: Scar tissue does not Lung blood-tinged fluid on sectioning grow beyond the boundaries of the Brain Narrowed sulci, flattened gyri original wound Pleura (hydrothorax), peritoneum Body cavities (ascites), pericardium 3. HEMODYNAMIC DISORDERS (hydropericardium) EDEMA AND EFFUSION o Microscopic: Clearing and separation of extracellular matrix Accumulation of fluid in tissues (edema) or body cavities (ECM), subtle cell swelling (effusion) Mechanisms and examples: HYPEREMIA AND CONGESTION o ↑ Hydrostatic pressure: Heart failure Increase in blood volume in tissues o ↓ Oncotic pressure: Nephrotic syndrome, liver cirrhosis FEATURE HYPEREMIA CONGESTION § Nephrotic syndrome: ↓ albumin due to renal losses Process Active Passive (proteinuria) § Liver cirrhosis: ↓ albumin due to ↓ hepatic synthesis Arteriolar dilation Reduced outflow of o ↑ Vascular permeability: Burns, infections (in inflammation Mechanism blood in a tissue o Lymphatic obstruction: Tumors, Filariasis, Post-radiation fibrosis, and ↑ oxygen (localized/systemic) Post-lymphadenectomy in breast cancer demand) § Impairs clearance of interstitial fluid Gross tissue Red Dusky o Sodium and water retention: Renal diseases, renal hypoperfusion color § ↑ Hydrostatic pressure: Increased intravascular volume Hemoglobin Oxygenated Deoxygenated § ↓ Oncotic pressure: Dilution decreases albumin concentration Morphology o Pulmonary congestion Engorged alveolar capillaries Acute Alveolar septal edema Focal intra-alveolar hemorrhage Thickened and fibrotic septa Chronic Hemosiderin-laden macrophages (heart failure cells) o Hepatic congestion Distended central vein and sinusoids Centrilobular ischemic necrosis (distal end of Acute blood supply) Periportal fatty change (better oxygenated, hence not necrotic) Centrilobular regions are grossly red-brown and slightly depressed contrasted with tan FACTORS INFLUENCING FLUID MOVEMENT ACROSS CAPILLARY surface (Nutmeg liver) WALLS Chronic Centrilobular hemorrhage Figure 4.2. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 Determinants of Starling forces: Hemosiderin-laden macrophages Hydrostatic pressure: Volume Variable degrees of hepatocyte dropout and Oncotic pressure: Albumin necrosis Dr. Elomina Summary of morphologic findings in congestion: Types of effusions: Acute congestion FEATURE TRANSUDATE EXUDATE o Edema: ↑ Hydrostatic pressure Abnormalities in ↑ Vascular (↑ Blood volume in vessels) Pathophysiology Starling forces permeability o Hemorrhage: Rupture of small vessels Vascular Chronic congestion Normal Increased permeability o Hemosiderin-laden macrophages: Marker of “old hemorrhage” Plasma protein leak Absent Present o Fibrosis and organ damage (decrease in area of viable tissue) Dr. Elomina Protein content of Low High fluid Specific gravity < 1.012 > 1.012 Fibrin Absent Present Inflammatory cells Absent Present Serous, Fibrinous (granular), Gross appearance Serous (clear) Purulent, Hemorrhagic Light criteria for exudative effusion: At least any of the following: CHRONIC PASSIVE CONGESTION, LIVER (NUTMEG LIVER) Figure 4.3. Robbins and Cotran Pathologic Basis of Disease, 10th ed. 2020 1. Fluid/Serum protein ratio: ≥ 0.5 2. Fluid/Serum LDH ratio: ≥ 0.6 3. Fluid LDH ≥ 2/3 upper limit of normal serum LDH Dr. Elomina TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA Page 7 of 113 For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly.  TOPNOTCH MEDICAL BOARD PREP PATHOLOGY MAIN HANDOUT BY DR. KEVIN ELOMINA For inquiries visit www.topnotchboardprep.com.ph or https://www.facebook.com/topnotchmedicalboardprep/ This handout is only valid for the October 2024 PLE batch. This will be rendered obsolete for the next batch since we update our handouts regularly. HEMOSTASIS AND THROMBOSIS Arterial and venous thrombosis ARTERIAL VENOUS HEMOSTASIS Turbulence or Formation of blood clots at sites of endothelial injury Sites Stasis endothelial injury Elements: Endothelium, Platelets, Coagulation factors Propagation Retrograde Anterograde STEPS IN HEMOSTASIS Composition Platelets > RBCs RBCs > platelets Arteriolar vasoconstriction: Occurs immediately to reduce blood Superficial leg veins: flow to the injury site Common Saphenous veins in Coronary > o Mediators: Reflex neurogenic mechanisms, endothelin sites of varicose veins cerebral > femoral (endothelium-derived vasoconstrictor) involvement Deep leg veins: Primary hemostasis: Formation of platelet plug (primary Popliteal, Femoral, Iliac hemostatic plug) Postmortem thrombosis o Sequence of events: Platelet adhesion à Shape change (into flat, o Gelatinous with dark-red dependent portion and yellow “chicken spiky shape) à Granule release à Recruitment à and Platelet fat” upper portion aggregation o Not attached to vessel wall Secondary hemostasis: Consolidation of initial platelet plug Mural thrombi: in heart chambers or aortic lumen o Sequence of events: Exposed tissue factor (Factor VII) initiates Vegetations: Thrombi in heart valves coagulation cascade à fibrin formation à additional platelet Homan Sign: Pain behind the knee on forced dorsiflexion of foot. It is infamously aggregation associated with deep vein thrombosis (DVT), BUT it suffers from low sensitivity Clot stabilization and resorption and specificity. Dr. Elomina o Stabilization: contraction into a solid, permanent plug o Resorption: counterregulatory mechanisms prevent further FATES OF THROMBUS clotting and eventual dissolution Propagation: Thrombi accumulate additional platelets and fibrin Embolization: Thrombi dislodge and travel to other sites in the INHIBITORS OF COAULATION AND FIBRINOLYTIC FACTORS vasculature FACTOR FUNCTION Dissolution: Rapid shrinkage and total disappearance of recent Inactivates Factors V and VIII thrombi Activated by thrombin bound to Organization and recanalization: Thrombi become incorporated in Protein C (PC) the vessel wall with formation of new capillary channels that restore thrombomodulin (an endothelial cell membrane protein) blood flow Protein S (PS) Cofactor of Protein C Antithrombin Inhibits Factors Xa, thrombin, XIIa, EMBOLISM kallikrein, XIa, IXa, and VIIa Detached intravascular solid, liquid, or gaseous mass that is carried Tissue factor by the blood from its point of origin to a distant site Inhibits VIIa and Xa pathway inhibitor Mechanisms of injury: Plasmin Main factor for fibrin degradation o Mechanical obstruction: Occlusion of vessels compromising Tissue plasminogen blood flow à Tissue infarction (after obstruction) and congestion Activates plasminogen to plasmin activator (tPA) (before obstruction) Reference: Henry’s Clinical Diagnosis and Management by Laboratory Methods, 24th ed. 2022 o Biochemical injury: Substances in embolus can cause inflammation and activation of coagulation cascade à Vascular THROMBOSIS injury, inflammation, organ damage, Disseminated intravascular Pathologic counterpart of hemostasis coagulation (DIC) Virchow triad of thrombosis: o Endothelial injury: Normal antithrombotic endothelium becomes PULMONARY EMBOLISM prothrombotic on injury Most common form of thromboembolic disease o Abnormal blood flow: Most common source: Deep vein thrombosis § Turbulent blood flow: Injures endothelium Sites of involvement: § Stasis: Maximizes platelet contact and retards washout of o Pulmonary vasculature activated clotting factors o Pulmonary artery bifurcation: Saddle embolus o Hypercoagulability: Genetic or acquired abnormality that o Paradoxical embolism: in systemic circulation through an predisposes to thrombosis interatrial/ventricular defect § Consider inherited causes of hypercoagulability in patients < 50 years old (even with acquired risk factors) Clinical presentation: o Clinically silent (60-80% of cases) § Common inherited thrombophilias o Pulmonary hemorrhage (more common due to dual blood supply) Factor V Leiden: Factor V becomes resistant to inactivation by o Acute right-sided heart failure (≥60% obstruction) Protein C o Sudden death: Saddle embolus o Most common inherited thrombophilia Prothrombin G20210A mutation Homozygous homocystinuria (deficiency of cystathionine β- SYSTEMIC THROMBOEMBOLISM synthetase) Most common source: Mural thrombi § Other conditions: Prolonged bed rest or immobilization, Tissue Sites of involvement: Lower extremities (75%), Brain (10%) injury (Surgery, Fracture, Burn), Disseminated cancer Clinical presentation: Silent or symptoms referable to end-organ ischemia Virchow Triad and type of thrombosis they primarily cause: Endothelial injury and turbulent blood flow: Arterial thrombosis Stasis: Venous thrombosis FAT EMBOLISM Hypercoagulable states: Both Fat globules (with red marrow) in vasculature Dr. Elomina