Pathology Flashcards
What is tissue hypertrophy?
- Increase in cellular size not number leading to overall organ/tissue size increase.
- Cell size increased by more structural components and increased synthesis of cellular proteins.
- Triggered by increased functional demand or stimulation by hormones or growth factors.
- Can be selective hypertrophy of specific sub-organelles.
What are examples of hypertrophy?
Physiological
- skeletal muscle enhancement through training
- uterus under influence of hormones such as oestrogen
Pathological
- cardiomegaly in hypertension and CCF (has an upper limit after which regression occurs -> call injury -> apoptosis/necrosis)
How is hyperplasia different from hypertrophy?
Hyperplasia involves an increase in the number of cells, hypertrophy is an increase in the size of cells.
How do leucocytes get to an area of acute inflammation?
- Margination of WCC in vessels, rolling and adhesion to endothelium (pavementing, selectins).
- Migration and diapedesis across endothelium (PECAM1, CD31, integrins)
- Migration towards chemotactic stimulus in tissue (bacterial products, cytokines, IL8, C5A)
What is the role of leucocytes in acute inflammation?
- Recognition and attachment to materials (opsonins) mediated by receptors).
- Killing of microbes: phagocytosis / engulfment / killing and degradation (H2O2-MPO-Halide).
- Release of products: amplify the inflamatory reaction (lysosomal enzymes, reactive oxygen/ntrogen)
What is reperfusion injury?
Further cell death in ischaemic tissues following restoration of blood flow.
What are the proposed mechanisms of reperfusion injury?
1. Generation of oxygen free radicals - formed from incomplete reduction of in-coming O2 by damaged mitochondria in affected tissue & action of oxidases (generated from ischaemic cells & leucocytes).
2. Associated inflammation - cytokines, adhesion molecules generated by hypoxic cells -> recruit neutrophils etc in reperfused tissue -> ensuing inflammation causes additonal injury.
3. Activation of complement system - IgM Ab deposit in ischaemic tissue -> restored blood flow brings complement proteins that bind Ab and are activated -> further cell injury & inflammation.
4. Mitochondrial permeability transition - via reactive O2 species -> effects mitochondrial function -> precludes recovery of ATP/energy supplies for the cell.
What is metaplasia and give some examples?
- Reversible change among differentiated cells such as epithelial or mesenchymal.
- One cell type is replaced by another by reprogramming of precursor stem cells or undifferentiated mesenchymal cells.
- Resp tract: trachea & bronchi, chronic irritation from smoking, ciliated columnar to stratified squamous.
- GIT: oesophagus, chronic gastric acid reflux, squamous to intestinal-like columnar “Barrett’s oesophagus”.
How may metaplasia progress?
- Cells lose normal protective function.
- Persistence of influence that initiated the metaplasia initiates malignant transformation.
- Eg squamous cell lung ca, oesophageal adenocarcinoma.
What is hypertrophy?
- Increase in the size of cells due to synthesis of more structural components.
- Resulting in an increase in the size of the organ.
- Caused by increased functional demand or by hormonal stimulation.
- May be pathological or physiological.
Give examples of physiological and pathological hypertrophy.
Physiological
- Skeletal mm (inc workload), uterus in pregnancy (hormonal).
Pathological
- Myocardial (due to HTN, AS, workload), BPH.
Describe the process of skin wound healing by first intention.
- 24 hrs: scab, neutrophils, clot.
- 3 to 7 days: mitoses, granulation tissue, macrophaged, fibroblasts, new capillaries.
- Weeks: fibrous union.
- <24 hrs: neutrophils at the margins of the incision.
- 24-48hrs: epithelial cells move from the wound edges & fuse in the midline beneath the surface scab, producing a continuous but thin epithelial layer that closes the wound.
- By day 3: neutrophils replaced by macrophages. Granulation tissue progressively invades the incision space. Collagen fibres in the margins of incision. Epithelial cell proliferation thickens the epidermal layer.
- By day 5: the incision is filled with granulation tissue. Neovascularisation is maximal. Collagen bridges the incision. The epidermis recovers its normal thickness.
- During the second week: continued accumulation of collagen & proliferation of fibroblasts. The leukocytic infiltrate, oedema, and inc vascularity have largely disappeared.
- By the end of the first month: the scar is made up of a cellular connective tissue devoid of inflammatory infiltrate, covered now by intact epidermis.
What are the morphological & chemical changes associated with early cell injury?
- Decreased generation of ATP
- Loss of cell membrane integrity
- Defects in protein synthesis
- Cytoskeletal damage
- DNA damage
What are the phenomena that characterise irreversible cell injury?
- Inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation & ATP generation) even after resolution of the original injury.
- Development of profound disturbances in membrane function.
Give an example of a protein that leaks across degraded cell membranes.
- Cardiac muscle: contains a specific isoform of the enzyme creatine kinase and of the contractile protein troponin.
- Liver (and specifically bile duct epithelium): contains a temperature resistant isoform of the enzyme alkaline phosphatase.
- Hepatocytes: contain transaminases.
What is the difference between ischaemic and hypoxic injury?
- Ischaemic involves disruption or reduction in blood supply resulting in reduced oxygen delivery, reduced delivery of substrate, and reduced removal of metabolic products.
- Hypoxic involves reduced oxygen delivery only. Hypoxic, anaerobic (glycolytic) metabolism can continue as new substrate being delivered.
- As a result cellular, & tissue, injury is much more rapid in ischaemic injury.
Describe the morphologic intracellular changes that occur in ischaemic injury.
Reversible
- cell swelling, ultrastructural changes including loss of microvilli & cell surface ‘bleb’ formation, swelling of ER & mitochondria, myelin figure formation, and clumping of nuclear chromatin
Irreversible
- severe mitochondrial swelling, plasma membrane damage, swelling of lysosomes
What is the complement system?
Plasma protein system involved in immunity against microbes.
Complement proteins numbered C1-9 are present in plasma in inactive forms.
Describe the main pathways by which complement activation occurs.
- Classical pathway: involving an antigen-antibody complex.
- Alternate pathway: triggered by microbial surface molecules (eg endotoxin). No antibody involvement.
- Lectin pathway: plasma mannose-binding lectin binds to carbohydrate on microbe.
- All pathways result in cleavage and activation of C3 (most important and abundant complement component).
How do activated complement products mediate acute inflammation?
- Vascular effects: increased permeability, vasodilation (via C3a, C5a mediated histamine release from mast cells)
- Leucocyte adhesion, chemotaxis, & activation: via C5a
- Phagocytosis: C3b acts as opsonin on microbe & leads to phagocytosis
- Cell lysis by the membrane attach complex (MAC) - composed of multiple C9 molecules
Describe the sequence of cellular events in acute inflammation.
- Leucocytes are the major cell type involved. In the first 6-24 hrs neutrophils, and monocytes/macrophages in 24-48 hrs. Leucocytes line endothelial wall - margination.
- First stasis of blood flow leading to inc leucocytes along endothelial wall
- Then leucocyte adhesion to endothelial wall & diapedesis or transmigration across into interstitium - extravasation. Adhesion & transmigration & recruitment are mediated by various mediators such as histamine, PAF, cytokines, & various attraction molecules - variously called immunoglobulins, integrins, selectins, mucin-like glycoproteins.
- Then leucocytes migrate to site of injury - chemotaxis. Chemotaxis & activation is mediated through various bacterial products, cytokines, chemical factors, Ag-Ab complexes, & products of necrosis.
- Then leucocyte activation to enable phagocytosis & enzyme release.
- Phagocytosis & release of various enzymes from leucocytes.
What are the differences between hyperplasia & hypertrophy?
Hyperplasia (can co-exist)
- increase in number of cells in organ/tissue
- usually resultng in increase in volume
- occurs if cellular population capable of synthesising DNA thus permitting mitotic division
Hypertrophy
- increase in size of cells
- causes increase in size of organs
Describe the different types of hyperplasia & give an example of each.
-
Physiologic:
- Hormonal
- Compensatory -
Pathological:
- Hormonal stimulation excessive eg oestrofen & effect on uterus, BPH caused by androgens
- Growth factors eg proliferation of connective tissue cells & blood vessels in aiding wound repair
What is apoptosis?
- Pathway of cell death
- Induced by tightly regulated intracellular programme
- Cells that are destined to die activate enzymes that degrade the cells’ own nuclear DNA & nuclear/cytoplasmic proteins
- The cell’s plasma membrane remains intact
- Apoptotic cell becomes target for phagocytosis
- Dead cell rapidly cleared before contents leak out so no inflammatory reaction illicited.
- Cell shrinks
Describe the physiologic situations where apoptosis occurs.
- Programmed destruction of cells during embryogenesis.
- Hormone dependent involution in adult, such as endometrial breakdown.
- Cell deletion in proliferating cell populations eg intestinal crypt cells.
- Death of host cells that have served their purpose eg neutrophils in acute inflammation.
- Elimination of potentially harmful self-reactive lymphcytes.
- Cell death induced by cytotoxic T cells.
What are the phases involved in scar formation?
1. Fibroblast migration & proliferation.
2. Extracellular matrix (ECM) deposition.
3. Tissue remodelling.
- What are the local triggers of fibroblast migration and proliferation (at the site of injury)?
- What are the sources of these local triggers?
1. Growth factors - TGF-beta, PDGF, EGF, FGF
Cytokines - IL-1, TNF
2. Platelets
Macrophages & other inflamm cells such as mast cells, eosinophils, lymphocyte
Endothelium
What is atrophy?
Give some examples of atrophy.
- Shrinkage in the size of the cell by loss of cell substance.
Eg
- Fracture disuse
- Damage to nerves causing muscle atrophy
- Breast/reproductive organs from oestrogen lack
What are the pathological types of atrophy?
- disuse
- denervation
- diminished blood supply
- inadequate nutrition
- loss of endocrine stimulation
- ageing
- pressure
What is hypertrophy?
- Increase in the size of the cells, due to synthesis of more structural components, resulting in an increase in the size of the organ (no new cells, just larger cells).
- Physiological or pathological in response to increased functional demand or specific hormonal stimulation.
- Can occur in both dividing & non-dividing cells.
What are the types of hypertrophy and give examples?
Physiologic
- Enlarged skeletal mm in labourers (workload). Enlarged uterus in pregnancy (hormonal). Enlarged breasts in lactation.
Pathological
- Enlarged prostate in BPH (hormonal). Enlarged heart in valve disease or chronic HTN (workload).
What is reperfusion injury?
What are the proposed mechanisms?
Further injury to ischaemic tissue that occurs after restoration of blood flow.
Mechanisms
- Oxygen free radicals
- Mitochondrial permeability transition
- Inflammation: cytokine production & inc expression of adhesion molecules, recruitment polymorphs
- Complement pathway activation
What is apoptosis? Under what conditions may it occur?
Programmed cell death
- Physiological: embryogenesis, hormone-dependent involution in adult, cell deletion, elimination of potentially harmful self-reactive lymphocytes, cell death induced by cytotoxic T cells.
- Pathological: cell death secondary to radiation injury or cytotoxins, viral hepatitis, pathologic atrophy after duct obstruction in pancreas/parotid/kidney, cell death in tumours.
What happens at a cellular level in apoptosis?
- cell shrinkage
- chromatin condensation
- formation of cytoplasmic blebs and apoptotic bodies
- phagocytosis of apoptotic cells or cell bodies, usually by macrophages
Describe the morphological changes seen in cells in reversible ischaemia.
Cellular swelling: failure to maintain ionic & fluid homeostasis; organelles become swollen
- plasma membrane alterations
- mitochondrial changes
- distended segments of ER; ‘vacuolar’ degeneration
- nuclear alterations
- fatty change; lipid vacuoles in cytoplasm
What metabolic changes occur in reversible ischaemia?
- Depletion of ATP -> sodium pump reduction -> swelling. Na into cells. Inc catabolites in cells -> inc osmotic load -> swelling.
- Anaerobic metabolism -> lactic acidosis, decreased pH.
- Detachment of ribosomes from ER -> dec protein synthesis.
How is the primary haemostatic plug formed?
After vascular injury, platelets contact exposed ECM eg collagen, adhesive glycoprotein, vWF.
- Adhesion - via glycoprotein 1b (GpIb) receptor to vWF forming bridge between plat & ECM collagen -> necessary to overcome high shear force of blood flow, deficient in vW disease or Bernard-Soulier syndrome.
- Activation resulting in shape change and secretion - granule release (ADP, TxA2).
- Aggregation - ADP potent activator of platelet aggregation and +ve feedback for more ADP release. Agonist binding causes intracellular protein phosphorylation cascade -> degranulation, including dense body content release of Ca++, required for coagulation cascade. Platelet activation causes appearance of negatively charged phospholipids on surface -> bind Ca++, critical nucleation sites for assembly of coagulation factor complexes.
- TxA2 amplifies platelet aggregation -> leads to formation of primary haemostatic plug.
- Aggregation reversible at this stage but not after next stage of stabilisation.
What are the steps involved in angiogenesis from pre-existing vessels?
Steps in angiogenesis
- vasodilation
- proteolytic degradation of basement membrane
- endothelial cells migrate to angiogenic stimuli
- maturation
- capillary formation
- recruitment of periendothelial cells for support structure & formation
Inhibitors such as endostatin are released by proteinases (this is a small fragment of collagen that inhibits endothelial proliferation & also angiogenesis)
In the normal coagulation cascade, what happens after factor X is acitvated?
- Conversion of prothrombin (2) to thrombin (2a) requiring Ca++ and activated factor 5 (5a) as cofactors. Occurs on surface of damaged endothelium or activated platelets.
- Thrombin (2a) catalyses fibrinogen (1) to fibrin (1a) in presence of Ca++
- Thrombin (2a) catalyses factor 8 to 8a in presence of Ca++ leading to cross-linking of fibrin
Describe the process of normal fibrinolysis.
- Plasmin is produced from circulating plasma protein plasminogen, either by factor 12a (dependent pathway), or by plasminogen activators
- Plasmin breaks down fibrin to FDPs (eg D-dimer) and disrupts polymerisation (fibrin degredation products)
- a) t-PA from endothelial cells most important plasminogen activator, and most active when att to fibrin
b) urokinase - like t-PA, circulating protein - Free plasmin inactivated by alpha 2 plasmin inhibitor
Describe how angiogenesis occurs.
- Mobilisation of endothelial precursor cells (EPC) from the bone marrow & from pre-existing vessels
- EPC migrate to a site of injury or tumour growth
- EPC differentiate & form a mature network by linking with existing vessels
- Stabilisation: endothelial cells from pre-existing vessels become motile & proliferate to form capillary sprouts
- Vessels mature involving pericytes & smooth muscle cells to form periendothelial layer
What are the factors involved in angiogenesis at a cellular level?
- Haemangioblast generates haemopoietic stem cells & angioblasts
- angioblasts like EPC are stored in adult bone marrow initiate angiogenesis
- participate in replacing lost endothelial cells, in vascular implant endothelization and in neovascularising ischaemic organs, cutaneous wounds & tumours
- Vasodilation of pre-existing vessels
- increased permeability, degradation of basement membrane, disruption of endothelial cell to cell contact, proliferation & migration towards angiogenic stimulus, & endothelial cell maturation/growth inhibition/remodelling capillary beds
- Factors: VEFG, angioproteins 1 & 2, PDGF, TGFB
- Receptors: VEGFR-2, FGF-2, EC receptor Tie 2
Describe the role of platelets in haemostasis.
Central role
Adhesion
- vWF acts as bridge b/w platelet surface receptors and exposed collagen. Platelets adhere and become activated.
Secretion (release reaction)
- Platelet granules (alpha granules + dense bodies). Factors released: Ca++, ADP, ATP, histamine, serotonin, adrenaline, fibrinogen, factors 5 & 8, TxA2). Ca++ required for coagulation cascade & ADP & TxA2, potent mediator of aggregation. Activation leads to surface expression of phospholipid complexes, critical binding Ca++, & clotting factors for intrinsic clotting pathway. Injured or activated endothelial cells expose tissue factor which activates extrinsic clotting pathway.
Aggregation
- Stimulated by ADP & vasoconstrictor TxA2. Enlarging platelet aggregate = primary haemostatic plug (reversible). coagulation cascase activated. Thrombin causes further aggregation. Platelet contraction creates the irreversible secondary haemostatic plug. Thrombin converts fibrinogen to fibrin which cements platelets n place
Describe the factors that inhibit activation of the coagulation cascade.
1. Antiplatelet: intact endothelium, endothelial PG12, NO, adenosine diphosphatase degrades ADP
2. Anticoagulant: membrane associated heparins allow antithrombin to inactivate factors, thrombomodulin allows thrombin to activate protein C, which requires protein S to be anticoagulant.
3. Fibrinolytic: endothelial cells snthesize t-PA
What mechanisms restrict the activity of the coagulation cascade?
Restriction of factor activation to sites of exposed phospholipids
3 types of natural anticoagulants
-
Antithrombins (eg AT3):
- Inhibit the activity of thrombin & other serine proteases (9a, 10a, 11a, 12a)
- AT3 activated by binding to heparin like molecules on endothelium ?utility of heparin in thrombosis
-
Proteins C & S
- Vit K dependant proteins characterised by ability to inactivate factors 5a and 8a
-
Plasmin (fibrinolytic system)
- plasminogen to plasmin by factor 12 dependent pathway or 2 groups of plasminogen activators (u-PA or t-PA)
- Breaks down fibrin & interferes with polymerisation
- Resulting fibrin split products (fibrin degredation products) also act as weak anticoagulants
- Endothelial cells modulate the coagulation/anticoagulation cascade balance by releasing PAI
- Block fibrinolysis by inhibiting t-PA binding to fibrin
- Tissue Factor Pathway Inhibitor (TFPI)
Describe the pathogenesis of tuberculosis in a previously unexposed immunocompetent person.
-
Infection by M. tuberculosis airborne
- Usually person to person droplet spread
-
M tuberculosis enters alveolar macrophages & replicates
- Replicates by blocking phagosome/lysosome fusion leading to bacteraemia (person generally asymptomatic or mild flu like illness)
-
Immunity through T cell mediated delayed type hypersensitivity (type 4), that also causes hypersensitivity & tissue destruction - in paticular granuloma formation & caseation
- About 3 weeks later T cell activation via MHC antigens on macrophages & IL-2 leading to macrophage becoming bactericidal (through IFN-gamma)
- This macrophage response also causes tuberculin positivity & formation of granuloma & caseation by recruiting monocytes (‘epithelioid histiocytes’)
-
Re-exposure or reactivation causes heightened immune reaction as well as tissue destruction
- Infection may be contained or may progress & may reactivate with immunosuppression from any cause.
How does Plasmodium falciparum malaria infection differ from other forms of malaria?
- All: sporozoite -> liver -> merozoites formed -> release & bind to RBC -> Hb hydrolysed -> trophozoite -> schizont -> merozoite/gametocyte
- P.falciparum
- infects RBCs of any age, causing clumping/rosetting -> ischaemia
- high cytokine production
- high level parasitaemia
- severe anaemia, cerebral symp, renal failure, pulm oedema, death
- Others:
- infect only new or old RBCs
- P vivax & ovale form latent hypnozoites (relapses)
- low parasitaemia, mild anaemia, rarely splenic rupture, nephrotic syndrome
How do the serological markers change with time in Hep A infection?
- IgM anti HAV appears at the onset of symptoms
- Faecal shedding of the virus ends as IgM titre rises (2-12 weeks)
- IgM Ab (months)
- Replace by IgG anti HAV (years)
How does the serology for Hep C infection change in the case of resolution?
- Incubation period (2-26 weeks)
- HCV-RNA (detectable for 1-3 weeks co-incident with transaminitis)
- Anti-HCV antibodies emerge. Only about 50% detectable during symptomatic acute infection. Remainder after 3-6 weeks. IgG/IgM, IgG persists
