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ACP > General Pathology > Flashcards

General Pathology Flashcards

1
Q

Main features of reversible cell injury (4)

A

Cellular swelling (hydropic change), blebbing of cell membrane, clumping of chromatin, fatty changes in hypoxic injury

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2
Q

Events in necrosis

A

Unprogrammed cell death
Lysozymes cause loss of membrane integrity and leakage of cellular contents –> digestion and denature proteins –> inflammation –> healing and repair (with architectural changes)

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3
Q

Microscopic changes in necrosis (6)

A

Nuclear: karyorrhexis, karyolysis, pyknosis
Cytoplasmic: eosinophilia, glassy homogenous
Necrotic cells disappear and replaced by myelin figures and then fatty acids

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4
Q

Coagulative Necrosis cause, tissue changes, complications (5)

A

Most common type
Wedge-shaped yellow area due to infarct (except of the brain)
Tissue architecture preserved
Gangrenous necrosis due to ischemia
Wet necrosis due to superimposed bacterial infection

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5
Q

Liquefactive Necrosis cause, manifestation (2)

A

Leukocyte enzymes digest tissue into liquid viscous e.g. in hypoxic brain injury
Formation of pus in acute inflammation –> abscess and cavitation

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6
Q

Caseous Necrosis cause, appearance (2)

A

Chronic granulomatous inflammation

Creamy-cheese appearance

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7
Q

Fat Necrosis causes, outcomes (2)

A

Fat digestion by lipase e.g. acute pancreatitis, breast trauma
Fatty acid combines with Ca2+ –> saponification (visible white chalky areas)

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8
Q

Fibrinoid Necrosis pathology (1)

A

Immune complex deposited in vessel wall (microscopic)

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9
Q

Apoptosis definition, features, mechanisms (2), physiological stimuli (3), pathological stimuli (3)

A

Programmed Cell Death through dedicated set of genes
No inflammation induced
Mitochondrial pathway (Bcl-2 pathway) and Death receptor pathway (TNF + FAS) –> cascade activation of DNA fragmentation
Physiologic: embryological development, withdrawal of hormones, death of immune cells (ageing, deletion of proliferative cell population)
Pathologic: DNA damage, misfolding of proteins, immune reactions

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10
Q

Apoptosis microscopic changes (3)

A

Shrinking cell, DNA fragmentation with formation of apoptotic bodies (that are engulfed by macrophages)

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11
Q

Autophagy

A

“Self-eating” as a survival mechanism during stress

Autophagic vacuoles –> autophagolysosome –> lysosomal enzyme digestion

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12
Q

Types of cellular adaptation and examples of each (4)

A

Hyperplasia – e.g. hormonal during pregnancy or puberty; BPH or endometrial
- controlled process, disappears once proliferative signals subside

Hypertrophy – e.g. muscle training, hormonal during pregnancy (gravid uterus or lactating breast); LVH

Metaplasia (increases risk of dysplasia but potentially reversible) – e.g. cervix transformation zone; Barrett’s oesophagus (squamous –> glandular) , Smoking (columnar –> squamous)

Atrophy – e.g. senile due to intracellular accumulation of lipofuscin; disuse muscle, denervating, pressure, ischemia, malnutrition

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13
Q

Pathways of intracellular accumulation (3)

A

Increased production/ decreased metabolism, genetic defect in metabolism, abnormal exogenous substance

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14
Q

Examples of intracellular accumulations (4)

A

Lipid –> TGs in fatty liver due to alcohol, DM, starvation; cholesterol esters e.g. atherosclerosis, xanthoma, cholesterolosis

Protein –> Reabsorption droplets in PCT in severe proteinuria, Russell bodies (excess Ig) in plasma cells, alpha-1 antitrypsin deficiency

Glycogen –> glycogen storage diseases, mucopolysaccharidoses, gaucher (glucocerebrosidase deficiency)

Pigments –> carbon, lipofuscin (brown atrophy; repeated free radical injury), melanin, hemosiderin (from Hb, frequent blood transfusion, metabolic diseases)

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15
Q

Subcellular changes (4)

A

Intracellular accumulations, pathologic calcification, hyaline changes, fatty infiltration

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16
Q

Pathological calcification, appearance (1), types (2)

A

Basophilic deposits
Dystrophic: normal Ca2+, in necrotic or injured tissues e.g. atheroma, TB granuloma, damages valves

Metastatic: high Ca2+ (hyperPTH, Vit-D related disorders, CKD, bone destruction, sarcoidosis), at normal tissues

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17
Q

Hyaline Changes morphology (1), examples (2)

A

Homogenous, glassy pink material on H&E
Intracellular: Mallory Denk bodies, Russell Bodies
Extracellular: Hyalinised arteriosclerosis, amyloid in AD

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18
Q

Fatty infiltration associations (1), morphology (1)

A

Associated with myopathy

Tissue infiltrated and replaced with fat cells

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19
Q

Mechanism of acute inflammation (5)

A
  1. Increase in blood flow (vasodilation induced by cytokines and histamines) –> produce heat and erythema
  2. Increase vascular permeability due to contraction endothelial cells - short-lived - (mediated by cytokines) or by direct endothelial injury –> form exudate and cause swelling

1+2 –> decrease in local blood flow leading to stasis –> facilitating margination of leukocytes

  1. Neutrophil recruitment: margination –> rolling (selectin, low affinity) –> adhesion (beta integrin, high affinity) –> transmigration –> chemotaxis (along gradient of chemokine, complements, LTB4)
    (6-24 hrs neutrophils; 24-48 hrs macrophages)
  2. Neutrophil action at site of injury – phagocytosis (ROS and NO in phagolysosome)
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20
Q

Complement System pathways (3)

A

Complements are soluble proteins circulating in blood
Classical Pathway – Ag-Ab complex fixes C1
Lectin Pathway – MBL or Ficolins on microbes activate C1
Alternative Pathway – bacterial polysaccharides or other cell wall components trigger, involves properdin, factor B and D

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21
Q

Complement System effects (3)

A

Inflammation: C3a and C5a (induced histamine release and assist chemotaxis)
Opsonisation: C3b (coats cell wall)
Lysis: C5b trigger formation of MAC

22
Q

Vasoactive amines examples (2), properties and actions (2), when released (3)

A

Histamine and Serotonin
Preformed, released mainly by mast cells – fast action (vasodilation and permeability)

Released when:

  • physical injury
  • binding of IgE to Fc receptors on mast cells (type I hypersensitivity)
  • C3a and C5a
23
Q

Arachidonic acids metabolites examples (2), released by (2), actions (5)

A

PGs and LTs, released by mast cells and leukocytes

Vasodilation, increase permeability, bronchospasm, chemotaxis, inhibition of inflammation

24
Q

Cytokines, Chemokines examples (2), produced by (2), effects (4)

A

TNF, IL-1, IL-6, produced by inflammatory cells e.g. macrophages, lymphocytes

Local effects: activation of endothelial cells for migration and attract leukocytes
Systemic effects: fever, leukocyte production, insulin resistance

25
Q

Manifestations of acute inflammation grossly (4), types of inflammation and their morphology (3)

A

Redness, heat, swelling and pain

Suppurative inflammation: purulent exudate with neutrophils, necrotic debris, oedema fluid (pus); abscess is focal collection of pus

  • morphology: necrotic focus + neutrophils + surrounding dilated vessels and fibroblasts
  • replaced by connective tissue and scarring

Serous inflammation: irritation of serous lining causing filling of potential spaces e.g. pleural, pericardial, peritoneal (not infected)

Fibrinous inflammation: more severe injuries causing increased permeability –> extravasation of fibrinogen –> form fibrin deposits in EC space
- resolution or organisation (exudates replaced by ingrowth of fibroblasts and BV)

26
Q

Outcomes of acute inflammation (3)

A

Complete resolution (limited injury, macrophages remove debris and microbes with lymphatics resorbing fluid)

Healing by connective tissue replacement (scarring and fibrosis)

Progress to chronic inflammation (persistent or interrupted healing)

27
Q

Chronic inflammation causes (3), morphologic features (3)

A

Persistent infections (TB, syphilis), Immune-mediated inflammatory diseases, Prolonged exposure to offending agent (silicosis, atherosclerosis)

Morphology:

  • mononuclear cells (macrophages, lymphocytes, plasma cells)
  • tissue destruction
  • attempts at healing (angiogenesis and fibrosis)
28
Q

Main differences between acute and chronic inflammation (4)

A

Onset, Inflammatory cells involved, Vascular changes, Signs (chronic inflammation: scar, fibrosis, necrosis, low grade fever, weight loss, anaemia)

29
Q

Macrophages in chronic inflammation, activation pathways (2), functions (4), fate (2)

A

Classically activated macrophage (M1)

  • induced by T cell derived signals e.g. IFN-gamma or endotoxins from microbes (ROS and NO increase phagocytic activities)
  • microbicidal and inflammation

Alternatively activated macrophage (M2)

  • other cytokines e.g. IL-4, IL-13
  • may inhibit M1
  • tissue repair, fibrosis and anti-inflammatory effects (IL-10, TGF-beta)

Functions:

  • phagocytosis (ROS, NO and proteases)
  • secrete inflammatory mediators (initiate and propagate inflammation e.g. IL-12, IL-23 to activate T cells)
  • antigen presentation to T cells (and respond to signals from T cells)
  • initiate tissue repair

Fate:

  • die or cleared into lymphatics
  • persist with local proliferation and tissue destruction (+/- giant cell formation)
30
Q

Macrophages vs Monocytes, lifespan, site of residence,

A

Tissue macrophages e.g. Kupffer cells, microglia, sinus histiocytes, alveolar macrophages – larger with longer lifespan
Monocytes - in blood, t1/2 = 1 day, extravasate into tissue within 24 hrs

31
Q

Lymphocytes in chronic inflammation, mechanism of actions (4)

A

Dominant in autoimmune and hypersensitivity
CD4 cells secrete cytokines to promote inflammation

Th1 –> IFN-gamma activate M1
Th17 –> IL-17 recruit neutrophils (by inducing secretion of other chemokine)
Th2 –> IL-4,IL-5, IL-13 activate eosinophils, M2

Th1 and 17 –> bacterial and viral diseases, autoimmune
Th2 –> allergic reactions, helminthic parasitic infection

Bidirectional interaction between macrophages and lymphocytes (macrophage activate T cells which recruit more macrophages)

32
Q

Plasma cells function (1), morphology (3)

A

Secretion of Ab against specific Ag after B cell contact with Ag at tissues
Morphology: clock-face, off centre nucleus, basophilic

33
Q

Other cell types in chronic inflammation (3)

A

Neutrophils (persist from acute inflammation)
Eosinophils (parasitic or IgE mediated inflammation, recruited by eotaxin, release MBP, very eosinophilic)
Mast cells (plethora of cytokines can promote or limit infl reactions)

34
Q

Histology of chronic inflammation (3)

A

Lymphocytes and Collagen
Necrosis
Granulation tissue and scarring (no dilated vessels)

35
Q

Granulomatous Inflammaton, cause (1), definition (1), macroscopic features (2), microscopic types and how to differentiate (2)

A

Presence of cellular agent that is difficult to eradicate

Focal accumulation of epithelioid histiocytes and giant cells with a rim of lymphocytes (+/- central necrosis)

Grossly, caveating (TB, syphilis) vs non-caseating (leprosy, Crohn’s - cobblestone mucosa, sarcoidosis)

Microscopic differentiation: foreign body granuloma (no inflammation, foreign body type giant cell with nuclei dispersed in cytoplasm) vs immune granuloma (cell-mediated immune response to pathogen, langerhans type giant cell with horseshoe nuclei)

36
Q

Types of chronic inflammation (2)

A

Recurrent acute (incomplete healing and repair) and primary chronic (e.g. UC, granulomatous, transplant rejection)

37
Q

Outcomes of chronic inflammation (5)

A

Abscess
Chronic regeneration leading to derangement of tissue architecture
Metaplasia as a protective mechanism
Fibrosis of serosal surfaces - fibrinous adhesions –> granulation tissue –> fibrous adhesions (symphysis) –> loss of mobility
Scarring - increased collagen deposition –> cause loss of function, contractures, adhesions

38
Q

Regeneration vs Repair, definition (1), tissue type (1)

A

Regeneration is replacement of damaged cells by undamaged cells and stem cells, in tissue with high proliferative capacity e.g. GI, skin, haematopoietic

Repair is regeneration + scar formation, in tissues incapable of regeneration or tissues that have damaged ECM –> leads to some functional loss

39
Q

Factors affecting healing (4)

A

Tissue proliferative capacity

  • labile e.g. epithelium
  • stable e.g. parenchyma of liver, kidney or pancreas/ mesenchymal cells, endothelial cells
  • permanent e.g. neurons, skeletal or cardiac muscles

Stem cells

  • self-renewal capacity, asymmetric replication
  • embryonic (pluripotent, inner cell mass) vs adult (multipotent?, organ or tissue e.g. BM, GI, Skin)
  • stem cell niches

Growth factors

  • polypeptides that drive cell proliferation and gene transcription e.g. EGF, TNF
  • from macrophages, lymphocytes, stromal cells
  • EGF mitogenic for keratinocytes and fibroblasts and stimulates granulation tissue formation

Extracellular matrix

  • basement membrane and interstitial matrix
  • repair only by scar formation once damaged
  • functions: tissue microenv, scaffold for tissue renewal, control cell proliferation, cell anchorage and migration
40
Q

Scar formation steps (5)

A

Clotting and chemotaxis
Inflammation and phagocytosis to remove destroyed tissue (M1 and M2)
Formation of granulation tissue (up to 10 days) – angiogenesis (VEGF, FGF - migration of endothelial cells and degrade ECM to permit vessels) and migration of fibroblasts
Scar formation by deposition of ECM from fibroblasts (TGF-beta, PDGF)
Connective tissue remodelling from 2-3 weeks (MMPs)

41
Q

Factors that influence tissue repair, systemic (4), local (4)

A

Systemic: nutrition (e.g. Vit C), metabolic e.g. DM, blood supply, glucocorticoids (weak scars)
Local: infection, mechanical (e.g. constant pressure), foreign body, size/location/type of wound

42
Q

Healing of skin wounds, stages (3), types of wound and different ways of healing (2)

A

Inflammation (24h) –> Proliferation i.e. fibroblast migration and re-epithelialisation (3-7 days) –> maturation i.e. ECM deposition and remodelling (weeks)

Primary intention: clean, uninfected wound with well apposed edges –> re-epithelialisation closes wound with thin scar formation (off stitches at stage 2)

Secondary intention: larger wound with complication e.g. abscess, ulcer –> wound left open with more inflammation, granulation tissue and collage deposition –> bigger scar
(wound contraction at stage 3)

43
Q

Pathological aspects of wound healing (4)

A

Inadequate scar formation – dehiscence and rupture, ulceration
Excessive repair – hypertrophic scar, keloid scar
Wound contracture – usually at palm, soles, anterior thorax –> deformities of wound and surrounding tissues
Fibrosis in parenchymal organs –> excessive collagen and ECM in chronic injurious stimuli e.g. liver cirrhosis – may cause organ dysfunction and failure

44
Q

Hallmarks of cancer (Growth and Immortality) - 6

A

Sustained proliferative signalling

  • mutation in genes involved in growth and proliferation
  • activation of oncogenes e.g. hyperactivation of RAS increasing transcription of MYC which increases cell cycle progression
  • EGFR, HER2, KRAS, Cyclin D1

Evading growth suppression

  • inactivation of tumour suppressor genes e.g. hyperphosphorlyation of RB (neg regulator of cell cycle) which decreases binding to E2F –> can promote cell to enter S phage
  • p53 mutation affecting ability to respond to DNA damage or cell stress –> decrease p21 transcription –> can’t prevent RB phosphorus –> no S phase block –> no cell cycle arrest for DNA repair or apoptosis

Aberrant apoptosis to resist cell death

  • increase antiapoptotic factors e.g. Bcl-2 over expression in leukaemia or follicular lymphoma
  • p53 mutations

Deregulating cellular genetics

  • Warburg effect
  • Oncometabolism –> e.g IDH mutation creating new enzymatic activity which leads to abnormal DNA methylation (hypomethylation increase activity of genes)

Replication immortality
- loss of p53 checkpoint activation in cell cycle after telomere shortening –> NHEJ mediated DNA double stranded repair –> chromosomal instability and mitotic crisis –> reactivation of telomerase leads to immortality

Angiogenesis

  • required for exponential growth of tumour cells (esp hypoxic areas)
  • controlled by angiogenic and anti-angiogenic factors –> hypoxia stimulates HIF-1 alpha –> increase VEGF transcription (also by RAS and MYC)
45
Q

Hallmarks of cancer (Progression) - 3

A

Invasion and Metastasis

  • invasion: loosen cell contacts (e-cadherin), degrade ECM (MMPs), attach to novel ECM components, migration of tumour cells
  • metastasis: intravasation after invasion, form tumour embolus, attach to basement membrane, extravasation – usually at first capillary bed encountered, may have organ tropism

Avoiding immune destruction
- expression of CTLA4 or PDL-1 which binds to T cells and induce T cell exhaustion

Malignancy enablers

  • genomic instability (defects in DNA repair e.g. MMR in MSH1 or MLH1 mutation, DSB repair in BRCA mutations; also DNA hypomethylation)
  • tumour promoting inflammation –> cytokines as GFs, M2 modify microenv to promote growth
46
Q

Carcinogenesis stages (3)

A

Multiple genetic changes involving 6-7 driver mutations accumulating over decades

Initiation (irreversible, constant DNA damage, normal phenotype)
Promotion (reversible, selective growth advantage for precursor cells – increase mutations, altered phenotype)
Progression (become more aggressive, proliferation of tumour cells leading to heterogeneity e.g. non-antigenic, metastatic, invasive)

47
Q

Carcinogens (3) and risk factors (4)

A

Smoking, Alcohol, Diet, Obesity

Oncogenic virus (15% cancers due to infection)
- HPV-16, 18 –> E6 binds and degrades p53 and activates telomerase; E7 binds to Rb and displaces E2F and activated cyclin E and A –> necessary but insufficient for CA cervix
- EBV –>failed immunoregulation leading to mutation of one clone and Burkitt’s lymphoma; also cause NPCA (40-100%), Hogdkin (30%)
HTLV-1 –> TAX protein increase cytokine expression to increase CD4 T cells, decrease TSG functions
- HBV –> HCC (80%)
- H. pylori –> produce CagA to activate NF-kB to cause inflammation –> CA stomach (80%)

Chemical carcinogens

  • direct acting e.g. chemotherapy
  • indirect acting e.g. polycyclic hydrocarbons (smoking), aromatic amines (rubber), aflatoxins (fungi)

Radiation

  • Non-ionising UV –> form thymidine dimer –> mutation in TSG and oncogenes (cumulative - SCC, BCC or intense intermittent exposure - melanoma)
  • Ionising Xray, Gamma ray, radioactive –> direct damage and chromosome breakage/ rearrangement or indirect from ROS
48
Q

Chronic inflammatory states associated with cancer (5)

A 
Hepatitis 
Reflux esophagitis
IBD
Asbestos or Silicosis
Gastritis, Ulcers
49
Q

Tumour suppressor genes, model of mutation (1), cancers associated

A 
Knudson's 2 hit model (acquired +/- germline mutations) --> higher risk in germline mutations 
APC - CA colon, FAP
RB1 - retinoblastoma
NF1/NF2 - neurofibromatosis type 1 and 2
BRCA1/2 - CA ovary, female breast (BRCA1)
p53 - Li-Fraumeni syndrome
PTEN - Cowden syndrome
MSH2/MLH1 - HNPCC
50
Q

Driver v Passenger mutation

A

Driver mutation causes functional loss and change in cellular behaviour e.g. at TSG or photo-oncogenes

Passenger mutation facilitates cancer development but does not affect cell fitness or behaviour

51
Q

Neoplasm, definition (1), components (2), terminology for different types of tumours (5)

A

Abnormal, uncoordinated excessive growth resulting in new tissue mass that is autonomous
Composing of parenchyma of neoplastic cells and supporting stroma

Epithelial - -oma/ -carcinoma
Mesenchymal - -oma/ -sarcoma
Haematolymphoid - -oma (malignant)
Germ cell - teratoma (only benign one is mature cystic teratoma of ovary); also seminoma, yolk sac tumour, embryonal carcinoma, choriocarcinoma
Precursor cells - -blastoma
52
Q

Benign vs Malignant Characteristics

A

Differentiation, Growth rate and morphological features (4), Invasiveness (3), Metastasis (3)

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