USMLE STEP 1 – Pathology Exam 2023 Solved 100%

Characteristics of Dysplasia - ANSWER-Loss of uniformity of cell size and shape = pleomorphism, Loss of tissue orientation, Nuclear changes - increase nuclear:cytoplasmic ratio and clumped chromatin Reversible cell changes to injury - ANSWER-Cellular and mitochondrial swelling due to reduce ATP leading to reduce activity of Na/K and Ca pumps, Membrane blebbing, Nuclear chromatin clumping, Ribosomal / polysomal detachment (reduced protein synthesis). Irreversible cell changes to injury - ANSWER-Rupture of Lysosomes and autolysis, Nuclear changes - Pyknosis (condensation), Karyorrhexis (fragmentation), karyolysis (fading), Plasma membrane damage -> leakage of cytosolic enzymes into serum and influx of calcium activating lysozomal enzymes, Increase mitochondrial permeability. What is apoptosis? - ANSWER-ATP dependent programmed cell death What happens to the cell in apoptosis induced cellular breakdown? - ANSWER-Cell shrinkage, chromatin condensation, membrane blebbing, formation of apoptotic bodies (these are phagocytosed) What are the microscopic features of an apoptotic cell? - ANSWER-Deeply eosinophilic cytoplasm, basophilic nucleus, pyknosis = nuclear shrinkage, karyorrhexis = DNA fragmentation caused by endonuclease mediated cleavage, *intact* cell membrane What is DNA laddering? - ANSWER-Fragments of DNA in multiples of 180bp in gel electrophoresis - sensitive indicator of apoptosis What is the intrinsic apoptotic pathway involved in? - ANSWER-Tissue remodelling in embryogenesis When does intrinsic apoptotic pathway occur? - ANSWER-1) When a regulating factor is withdrawn from a proliferating cell population e.g. reduced IL2 after a completed immunologic reaction leads to apoptosis of proliferating effector cells 2) After exposure to injurious stimuli e.g. radiation, toxins, hypoxia, misfolded proteins What family of protein regulates the intrinsic pathway of apoptosis? - ANSWER-Bcl-2 family. BAX and BAK are proapoptotic. Bcl-2 and Bcl-xL are antiapoptotic. How do pro-apoptotic proteins cause apoptosis? - ANSWER-BAX and BAK form pores in the mitochondrial membrane - release of cytochrome C from inner mitochondrial membrane into cytoplasm - activation of caspases How do anti-apoptotic proteins prevent apoptosis? - ANSWER-Bcl-2 keeps mitochondrial membrane impermeable, so prevent cytochrome C release. A specific example of disregulation of antiapoptotic factors leading to malignancy - ANSWER-Bcl-2 overexpression - reduced caspase activation - tumorigenesis e.g. follicular lymphoma t[14;18] What are the 2 extrinsic pathways? - ANSWER-1) Ligand receptor interaction - FasL binding to Fas [CD95] or TNF α bind to its receptor 2) Immune cell - cytotoxic T cell release of perforin and granzyme B What is Fas-FasL interaction necessary for? - ANSWER-Thymic medullary negative selection Mutation in Fas increases the numbers of circulating self-reacting lymphocytes due to failure of clonal deletion Defective Fas-FasL interactions cause autoimmune lymphoproliferative syndrome What is necrosis? - ANSWER-Enzymatic degradation and protein denaturation of cells due to exogenous injury leading to intracellular component leak, an inflammatory process What are the 6 different kinds of necrosis? - ANSWER-Coagulative Liquefactive Caseous Fat Fibrinoid Gangrenous Coagulative necrosis: Examples? Caused by? Histology? - ANSWER-Ischaemia / infarcts in most tissue (except brain) Due to ischemia / infarction, injury denatures enzymes Preserved cellular architecture, but nuclei disappear, increase cytoplasmic binding of eosin stain = increase eosinophilia, red / pink colour Liquefactive necrosis: Examples? Caused by? Histology? - ANSWER-Examples: Bacterial abscesses, brain infarcts. Caused by: Neutrophils release lysosomal enzymes, digesting tissue. Histology: Early - cellular debris and macrophage, Late - cystic spaces and cavitations. Neutrophils and cell debris seen with bacterial infection Caseous necrosis: Examples? Caused by? Histology? - ANSWER-Examples: TB, systemic fungi (histo), Nocardia Caused by: macrophages wall off the infecting microorganism --> granular debris Histology: Fragmented cells and debris surrounded by lymphocytes and macrophages (granuloma) Fat necrosis: Examples? Caused by? Histology? - ANSWER-Examples: Enzymatic = acute pancreatitis (saponification of peripancreatic fat). Non-enzymatic = traumatic (injury to breast tissue) Caused by: damaged cells release lipase, breaks down triglycerides, liberated fatty acid bind calcium --> saponification Histology: Outlines of dead fat cells without peripheral nuclei; saponification of fat (combined with Ca2+) appears dark blue on H&E stains Fibrinoid necrosis: Examples? Caused by? Histology? - ANSWER-Examples: Immune reactions in vessels (e.g. polyarteritis nodosa). preeclampsia., hypertensive emergency Caused by: immune complexes combine with fibrin --> vessel wall damage (type III hypersensitivity reaction) Histology: Vessel walls are thick and pink Gangrenous necrosis: Examples? Caused by? Histology? - ANSWER-Examples: Distal extremity, GI tract, after chronic ischemia Caused by: Dry - ischaemia, wet - superinfection Histology: coagulative in dry, liquefactive superimposed on coagulative in wet Which areas in the brain are most vulnerable to hypoxia / ischaemia? - ANSWER-ACA / MCA / PCA boundary areas Neurons most vulnerable to hypoxic ischaemic insults include - Purkinje cells of the cerebellum and pyramidal cells of hippocampus Which area in the heart is most vulnerable to hypoxia / ischaemia? - ANSWER-subendocardium (LV) Which areas in the Kidney are most vulnerable to hypoxia / ischaemia? - ANSWER-Medulla - straight segment of proximal tubule, thick ascending limb Which area in the liver is most vulnerable to hypoxia / ischaemia? - ANSWER-Area around central vein - zone III Which areas in the Colon are most vulnerable to hypoxia / ischaemia? - ANSWER-Splenic flexure, rectum What are the inflammatory mediators that cause vasodilation? - ANSWER-Histamine, prostaglandins, bradykinin what are the inflammatory mediators that cause endothelial contraction? - ANSWER-leukotrienes (C4, D4, E4), histamine, serotonin What are the inflammatory mediators that sensitizes sensory nerve endings? - ANSWER-Bradykinin, PGE2 Mechanism that induces fever in inflammation - ANSWER-Pyrogens (such as LPS) induce macrophages to release *IL1 and TNF* --> increase COX activity in perivascular cells of hypothalamus --> increase PGE2 --> increase temperature set point What is the mediator that induces the increase in plasma acute phase proteins? - ANSWER-Notably induced by IL6 Mnemonic to remember acute phase reactants - ANSWER-*More FFiSH* in the *C* (sea) More - upregulated *F*erritin *Fi*brinogen *S*erum amyloid A *H*epcidin *C* reactive protein What is the function of Ferritin (as an acute phase reactant)? - ANSWER-Binds and sequesters iron to inhibit microbial iron scavenging What is the function of Fibrinogen (as an acute phase reactant)? - ANSWER-Coagulation factor - promotes endothelial repair, correlates with ESR What is the function of Serum amyloid A (as an acute phase reactant)? - ANSWER-Prolonged elevation can lead to amyloidosis What is the function of Hepcidin (as an acute phase reactant)? - ANSWER-Reduced iron absorption (by degrading ferroportin) and reduce iron release (from macrophages) - leads to anaemia of chronic disease What is the function of CRP (as an acute phase reactant)? - ANSWER-Opsonin - fixes complement and facilitates phagocytosis What proteins are downregulated in inflammation> - ANSWER-Albumin - reduction conserves AA for positive reactants Transferrin - internalised by macrophages to sequester iron What is the mechanism that lead to increase ESR? - ANSWER-Products of inflammation coat RBC and cause aggregation, denser RBC aggregates fall at a faster rate within a pippette tube --> increase ESR Causes of increased ESR - ANSWER-Most anaemias infection Inflammation - temporal arteritis, polymyalgia rheumatica Cancer Renal disease Pregnancy Causes of low ESR - ANSWER-Sickle cell anaemia - altered shape Polycythemia (RBC dilutes aggregation factors) HF Microcytosis Hypofibrinogenemia Name some of the mediators of acute inflammation - ANSWER-Toll-like receptors, Arachidonic acid metabolites, Neutrophils, Eosinophils, Antibodies (pre-existing), M<ast cells, Basophils, Complement, Hageman factor (Factor VII) What is an inflammasome? - ANSWER-Cytoplasmic protein complex that recognizes products of dead cells, microbial products and crystals (e.g. uric acid crystals), leads to activation of IL1 and inflammatory respone discuss the vascular and cellular components of acute inflammation - ANSWER-Vascular - vasodilation and increase endothelial permeability to bring more cells and proteins to site of injury. Cellular - extravasation of leukocytes from post-capillary venules and accumulate in the focus of injury. What cytokines mediate resolution and healing following inflammation? - ANSWER-Macrophages predominate in the late stages of acute inflammation (peak 2-3 days after onset) and influence the outcome of acute inflammation by secreting cytokines: IL10 and TGF- β What cytokine mediate persistent acute inflammation - ANSWER-IL8 Where does leukocyte extravasation occur? - ANSWER-Postcapillary venules What are the steps of leukocyte extravasation? - ANSWER-1) Margination and rolling 2) Adhesion 3) Diapedesis = transmigration - WBC travels between endothelial cells and exits blood vessel 4) Migration - WBC tracels through interstitium to the site of injury, following chemotactic signals What are the cell surface proteins that mediate margination and rolling? - ANSWER-E- and P-selectin on endothelium bind with Sialyl-Lewis X on leukocyte. GlyCAM-1, CD34 on endothelium bind with L-selectin. A defect in margination and rolling of leukocytes causes...? - ANSWER-Leukocyte adhesion deficiency type 2 - reduced Sialyl-Lewis X What are the cell surface proteins that mediate adhesion of leukocyte to endothelium? - ANSWER-ICAM-1 (CD54) on endothelium bind to CD11/18 integrins (LFA-1, Mac-1) on leukocytes. VCAM-1 (CD106) on endothelium bind to VLA-4 integrin. A defect in adhesion of leukocytes causes...? - ANSWER-Leukocyte adhesion deficiency type 1 - reduced CD18 integrin subunit. What cell surface molecules are involved in mediating transmigration of leukocytes? - ANSWER-PECAM-1 (CD31) on Endothelial cells and leukocytes bind together What are some examples of chemotactic products that are released in response to bacteria that can help the migration of WBCs? - ANSWER-C5a, IL8, LTB4, Kallikrein, Platelet-activating factor Characteristics of chronic inflammation - ANSWER-Infiltration of tissue by mononuclear cells (macrophages, lymphocytes, plasma cells). Tissue destruction and repair (including angiogenesis and fibrosis) occur simultaneously. Stimuli that leads to chronic inflammation - ANSWER-Persistent infection (TB, syphilis, fungi and viruses) --> type IV hypersensitivity, Autoimmune diseases, Prolonged exposure to toxic agents and foreign material (e.g. silica). Cellular mediators of chronic inflammation - ANSWER-Chronic inflammation is the result of the interaction between macrophages (the dominant cells) and T lymphocytes. How do T cells regulate chronic inflammation? - ANSWER-Th1 cells secrete IFNγ - leads to macrophage classical activation and is proinflammatory. Th2 cell secrete IL4 and IL13 - leads to macrophage alternative activation, results in repair and is anti-inflammatory. Examples of outcomes of chronic inflammation - ANSWER-Scarring, Amyloidosis, Neoplastic transformation - HCV --> hepatocellular carcinoma, H pylori --> gastric adenocarcinoma. What are granulomas? - ANSWER-Granulomas are made up of epithelioid cells (macrophages with abundant pink cytoplasm), with surrounding multinucleated giant cells and lymphocytes. Th1 cells secrete IFNγ, activating macrophages Name the organisms that cause granulomatous disease - ANSWER-Bacterial: Mycobacteria - tuberculisis, leprosy, Bartonella henselae, Listeria monocytogenes - granulomatosis infantiseptica, Treponema pallidum - tertiary syphillis. Fungal: endemic mycoses like histoplasmosis. Parasitic: schistosomiasis. Autoimmune conditions that cause granulomatous disease - ANSWER-Sarcoidosis, Crohns, Primary biliary cholangitis, Subacute (deQuervain / granulomatous) thyroiditis, Granulomatosis with polyangiitis (wegener), Eosinophilic granulomatosis with polyangiitis (Churg-Strauss), Giant cell (temporal) arteritis, Takayasu arteritis. Foreign materials causing granulomatous disease? - ANSWER-Berylliosis, talcosis, hypersensitivity pneumonitis What is an important consideration of granulomatous disease and TNF α? - ANSWER-TNF α from macrophages induces and maintains granuloma formation. Anti-TNF drugs can cause sequestering granulomas to break down --> disseminated disease. Always test for latent TB before starting anti-TNF therapy/ Granulomatous disease is associated with a metabolic change...? - ANSWER-Hypercalcemia due to calcitriol [1,25-OH2 vitamin D] production What is lipofuscin? - ANSWER-a yellow-brown wear and tear pigment associated with normal ageing. Formed by oxidation and polymerisaton of autophagocytosed organellar membranes. What is the difference between dystrophic calcification and metastatic calcification? - ANSWER-Dystrophic calcification = calcium deposition in abnormal tissues. Metastatic = deposit in normal tissues Dystrophic Vs Metastatic calcification: Extent / location - ANSWER-D - Localized and shows dystrophic calcification and thick fibrotic walls. Eg calcific aortic stenosis. M - Widespread, diffuse. e.g. metastatic calcifications of alveolar walls in acute pneumonitis Dystrophic Vs Metastatic calcification: Associated conditions - ANSWER-D: TB and other granulomatous infections, Liquifactive necrosis of chronic abscesses, fat necrosis, Infarcts, Thrombi, Schistosomiasis, congenital CMV, Toxoplasmosis, Rubella, CREST syndrome, Psammoma bodies M: Interstitial tissues of kidney, lung and gastric mucosa. Nephrocalcinosis of collecting duct may lead to nephrogenic diabetes insipidus and renal failure. Dystrophic Vs Metastatic calcification: Etiology - ANSWER-D: secondary to injury or necrosis. M: secondary to hypercalcaemia, e.g. primary hyperparathyroidism, sarcoidosis, hypervitaminosis D. High calcium-phosphate product levels, e.g. CRF with secondary hyperparathyroidism, long term dialysis, calciphylaxis, multiple myeloma. Hypertrophic scars - Collagen - Extent - ANSWER-Increase collagen synthesis - Type III collagen in parallel organisation. Confined to borders of original wound - infrequent recurrence. Keloid scars - Collagen - Extent - ANSWER-Significant increase collagen synthesis - Type I and III collagen that are disorganised. Extends beyond the borders of original wound with claw like projections typically on ear lobe, face, upper extremities. Frequently recur and has increase incidence in groups with darker skin. What is the role of this wound healing tissue mediator - FGF? - ANSWER-Stimulates angiogenesis What is the role of this wound healing tissue mediator - TGF β? - ANSWER-Angiogenesis, fibrosis What is the role of this wound healing tissue mediator - VEGF? - ANSWER-Simulates angiogenesis What is the role of this wound healing tissue mediator - PDGF? - ANSWER-Secreted by activated platelets and macrophages. Induces vascular remodeling and smooth muscle cell migration. Stimulates fibroblast growth for collagen synthesis. What is the role of this wound healing tissue mediator - metalloprpoteinases? - ANSWER-Tissue remodelling What is the role of this wound healing tissue mediator - ECF? - ANSWER-Stimulates cell growth via tyrosine kinase e.g. EGFR / ErbB1 Phases of wound healing - ANSWER-Inflammatory - up to 3 days after wound. Proliferative - day 3 to weeks after wound. Remodelling - 1 week to 6+ months after wound. Effector cells involved in the inflammatory phase of wound healing - ANSWER-Platelets, neutrophils, macrophages. Clot formation, increase vessel permeability, neutrophil migration into tissue, macrophages clear debris 2 days later Effector cells involved in the proliferative phase of wound healing - ANSWER-Fibroblasts, myofibroblasts, endothelial cells, keratinocytes, macrophages. Deposition of granulation tissue and type III collagen, angiogenesis, epithelial cell proliferation, dissolution of cloth and wound contraction (mediated by myofibroblasts). What deficiency causes delay in would healing? - ANSWER-Vitamin C, copper, zinc Effector cells involved in the remodelling phase of wound healing - ANSWER-Fibroblasts. Type III collagen replaced by type I collagen, increase tensile strength of tissue. Collagenase (require zinc to function) break down type III collagen. therefore Zinc deficiency leads to delayed wound healing. Exudate - protein concentration - ANSWER-> 2.9 g/fL Transudate - protein concentration - ANSWER-< 2.5 g/dL Lights criteria - ANSWER-Fluid is exudative if 1 or more of the criteria is met: Pleural effusion protein / serum protein ration > 0.5 Pleural effusion LDH / serum protein LDH ration > 0.6 Pleural effusion LDH > 2/3 of the upper limit of normal of serum LDH Amyloidosis - pathophysiology - ANSWER-Abnormal aggregation of protein into β-pleated linear sheets --> insoluble fibrils --> cellular damage and apoptosis. How can you identify amyloid deposits in the lab? - ANSWER-Congo red stain. Polarized light (apple green birefringence). H+E stain Primary amyloidosis - protein - disease - ANSWER-Protein - AL (from Ig Light chains). Seen in plasma cell disorders and multiple myeloma. Secondary amyloidosis: - Protein - Disease - ANSWER-Protein - Serum Amyloid A (AA). Seen in chronic inflammatory conditions such as rheumatoid arthritis, IBD, familial mediterranean fever, protracted infections. Dialysis related amyloidosis: