Pathology Flashcards
Inflammatory response - vascular
Transient vasoconstriction
-> Vasodilatation
- arterioles first, induced by histamine and NO, so ↑ blood flow and ↑ hydrostatic pressure
-> ↑ vascular permeability
- phase 1 - immediate transient response, mediated by histamine, leukotrienes, neuropeptide susbtance P, bradykinin, short lived (<30mins) and reversible
- phase 2 - prolonged response after direct endothelial injury affecting all levels of microcirculation
-> Exudation
- inflammatory extravascular fluid with high protein concentration and specific gravity >1.02
- ↓ intravascular osmotic pressure and ↑interstital osmotic pressure, oedema
-> increased blood viscosity
-> blood stasis
-> margination of leucocytes
Inflammatory response - cellular
Leukocyte extravasation
- margination
-> leukocyte adhesion to endothelium (regulated by endothelial binding receptors eg selectins, immunoglobulins, integrins, mucin-like glycoproteins)
-> leukocyte diapedesis (process of transmigration across endothelium, mainly in venules)
-> chemotaxis (elicited by exogeneous agents eg bacteria, and endogenous agents eg components of complement systems, leukotriene, cytokines)
Phagocytosis
- micobicidal substnaces released into extracellular space and phagolysosomes during phagocytosis by leukocytes
- eg lysosymal enxymes, reactive oxygen intermediates (H2O2), products of arachidonic acid metabolism (leukotrienes and prostaglandins)
- can cause endothelial and tissue damage including acute respiratory distress syndrome, acute transplant rejection, asthma, reperfusion injury
Chemical mediators of inflammation
MAIN ACUTE PHASE RESPONSE INDUCED BY TNF AND IL1
Haemogen factor activation - aka factor 12, from liver and plasma, works to activate kinin, clotting, fibrinolytic and complement systems
Complement system - from liver and plasma
Cytokines and NO - from endothelium and macrophages
Platelet activating factor - from endothelium and leukocytes
Serotonin - from platelets and mast cells, to increase vascular permeability
Histamine - from platelets and mast cells, assoc with IgE
Bradykinin - to increase vascular permeability, vasodilation, smooth muscle contraction, chemotaxis, activates Hageman factor. Formed by kallikrein, inactivated by ACE in lungs (protected by ACEi)
+ Prostaglandins, leukotrienes, platelet-activating factor, lysosomal enzymes
Signs of inflammation
Raised ESR (due to RBC clumping)
Leucocytosis - increased no of immature neutrophils
4 cardinal signs - rubour (red), calor (heat), dolor (pain), tumour (swelling)
Virchow sign = loss of function
Acute inflammation
Rapid onset and short duration
VASCULAR/CELLULAR CHANGES
- initial vasoconstriction then vasodilation, slowing of circulation (stasis), margination of leukocytes, central sludging of RBCs
- increased vascular permeability
- exudation of fluid - serous, fibrinous, purulent
- emigration of leukocytes (mostly neutrophils)
-> complete resolution / fibrosis / abscess / chronic inflammation
Chronic inflammation
From persistent infection, prolonged exposure to foreign agents, or autoimmune
Can start de novo without acute inflammation
Characterised by - infiltration by macrophages, tissue destruction, attempted repair by proliferation of new blood vessels, and fibrosis
Granulomatous inflammation
Pattern of chronic inflammation characterised by granulomas (focal) and epitheloid cells (activated macrophages) surrounded by mononuclear leukocytes
All can contain giant cells
TB - caseating granuloma, Langhans giant cell, mantoux test
Cat-scratch disease - stellate granuloma, contains neutrophils
Sarcoidosis - non-caseating granuloma, Schaumann’s body, raised ACE levels, Kveim’s test
Cellular adaptation
= cellular changes occuring in response to persistent physiological or pathological stress
ATROPHY - ↓cell size
- due to ↓ workload, loss of innervation/blood supply, inadequate nutrition, loss of endocrine stimulation, pressure
HYPERTROPHY - ↑cell size
HYPERPLASIA - ↑number of cells
- from increased cell mitosis, physiological (hormonal or compensatory) or pathological eg endometriosis
METAPLASIA - cell type replaced by another cell type, reversible but if stimuli persist then can -> cancer
DYSPLASIA - abnormal changes in cell shape and size, aka atypical hyperplasia
Cell injury
When limits of adaptive responses exceeded
Reversible or irreversible
See - ↓oxidative phosphorylation, ↓ATP, cellular swelling (aka hydropic degeneration)
Cell death
From irreversible cell injury
Necrosis = traumatic cell death
Apoptosis = programmed cell death
Autolysis = non-traumatic cell death occurring via action of own enzymes
See - mitochondrial damage, loss of membrane permeability
- pyknosis (condensation of chromatin), karyorrhexis (fragmentation of nuclear material), karyolysis (dissolution of nucleus)
Mechanisms of cell injury
- Depletion of ATP
→ anaerobic glycolysis → ↓pH and clumping of nuclear chromatin
→ ↓ protein synthesis → lipid deposition
→ failure of Na/K pump → influx of Ca and Na, loss of K, ER swelling, cellular swelling, loss of microvilli, bleb formation - Influx of Ca → increased cytosol Ca, activation of endonuclease → DNA damage, ATPase → decreased ATP, phospholipase → decreased phospholipids →membrane damage, protease → disruption of cell membrane)
- Oxygen-derived free radicals → DNA lesions, protein fragmentation, membrane lipid peroxidation
- can be neutralised by antioxidants (vitA/C/E, glutathione, superoxidase dismutase, iron+copper transport proteins)
Apoptosis
Programmed cell death
See - intact cell membrane, degradation of nuclear DNA. Cell shrinkage, chromatin condensation, formation of cytoplasmic blebs and apoptotic bodies, phagocytosis,
No proinflammatory markers
Extrinsic - via TNF receptor or Fas
Intrinsic (mitochondrial) - via release of pro-apoptotic molecules into cytoplasm via loss of Bcl-2 anti-apoptotic gene
PHYSIOLOGICAL
- during embryogenesis
- hormone-dependent involution
- elimination of harmful self-reactive lymphocytes
- induced by cytotoxic T-cells
PATHOLOGICAL
- in tumours
- atrophy after obstruction
- cytotoxic drugs and radiation
- cell injury in viral disease
B-cell lymphoma 2 gene
Family of oncogenes
Can be anti-apoptotic or pro-apoptotic
Live in mitochondria
Necrosis
Cell death in living tissues by enzymatic degradation
See - loss of membrane integrity, enzymatic digestion of cells, host reaction
Within 4-12h of insult
Gangrene is black necrotic tissue - wet (colliquative necrosis), dry (coagulative necrosis), gas (exotocin-producing clostridial species (usually C perfringens))
Patterns of necrosis determined by blood supply to organs
eg necrosis of striated tissue is rhabdomyolysis
Types of necrosis
COLLIQUATIVE = liquefaction
- due to action of tissue digestive enzymes
- mainly in CNS, kidney, pancreas
- caused by focal bacterial/fungal infections
COAGULATIVE
- hypoxic cell injury
- due to protein denaturation
- intracellular organelles disrupted, but shape of tissues maintained as proteins stick together
CASEOUS
- features between the two above
- tissues semi-solid/liquid
FIBRINOID
- due to immune-mediated vascular injury causing fibrin-like protein deposits in arterial walls
FAT
- due to lipase, tissues become chalky
- seen in breast, pancreas, omentum, skin
What mediates cell injury
Lipids
- TAG causing steatosis eg heart, liver, kidney
- cholesterol causing atherosclerosis, xanthoma, foamy macrophages
Proteins
Hyaline changes
Glycogen
Pigments
- lipofuscin (end product of free radical injury, brown), melanin (from tyrosine), haemosiderin
Cellular ageing process
Replicative senescence = cells have limited capacity for replication. After fixed no of divisions all cells arrest in terminally non-dividing state, caused by telomere shortening
Also influenced by free radical oxidate damage and genetic influence
Telomerase
Specialised enzyme made of RNA and protein, uses RNA as template for adding nucleotides to end of chromosomes
- maintains length of telomere
- prevents replicative sequence
- activity HIGH in germ cells, LOW in stem cells, absent in somatic cells, reactivated in cancer cells
Physiological response to injury
Immobility/rest
Loss of appetite
Catabolism
Minor - increased HR/RR/temp/WBC
Major - SIRS/hypermetabolism/catabolism/multiorgan dysfunction
Immunological and neuroendocrine responses
Ebb and flow phases in response to injury
Ebb = shock
- begins immediately from injury, lasts 24-48hrs
- hypovolaemia, reduced CO, decreased basal metabolic rate, hypothermia, lactic acidosis
- catecholamines, cortisol, aldosterone are main hormones
- functions to conserve circulating volume and energy stores
Flow
- hypermetabolic, like SIRS
- initial catabolic phase 3-4 days to mobilise energy stores (weight loss, urinary nitrogen excretion), later anabolic phase lasting weeks
- tissue oedema, vasodilating, increased CO, hypermetabolism, increased temp, leukocytosis, increased oxygen consumption, increased gluconeogenesis
Immunological response in injury
From proinflammatory to compensatory anti-inflammatory response CARS
Proinflammatory - mediated by innate immune system (interacts with adaptive immune system T and B cells) for pro-inflammatory cytokines (IL1, TNF, IL6, IL8) in first 24hrs, pyrexia due to action on hypothalamus, proteolysis in skeletal muscles, acute phase protein production in liver
- response followed by increased cytokine antagonists leading to CARS
Neuroendocrine response to injury
Biphasic:
ACUTE
- active secretion of pituitary and counter-regulatory hormones glucagon, cortisol, adrenaline
CHRONIC
- hypothalamic suppression and low serum levels of target hormone organs, so wasting
eg increased CRH from hypothalamus, increased secretion of ACTH from anterior pituitary, release of cortisol from adrenals
Counter-regulatory hormones to reduce insulin, increase metabolism, hepatic gluconeogenesis, adipocyte lipolysis, skeletal muscle protein catabolism, inactivate peripheral thyroid hormone, reduce testosterone, increase prolactin and GH
Energy expenditure in trauma
Increased by 25%
- central thermo-dysregulation
- increased sympathetic activity
- abnormalities in wound circulation - ischaemic areas produce lactate -> metabolised in Cori’s cycle, hyperaemic areas cause increased CO
- increased protein turnover
Protein metabolism in response to injury
SKELETAL MUSCLE
Protein degradation in peripheral tissues (skin, skeletal muscle, adipose tissue)
Muscle catabolism cannot be inhibited fully, so turnover rate 1-2%/day
HEPATIC
Liver protein turnover rate 20%/day - 1/2 for renewal of structural protein and 1/2 for synthesis of export protein
- during inflammation hepatic synthesis of acute phase proteins (fibrinogen, CRP), and serum albumin decreased due to transcapillary escape
Wound healing
INFLAMMATORY
- immediate until 2-3days
- local vasoconstriction
- thrombus formation and fibrin mesh
- platelets line damaged endothelium, release ADP/platelet derived growth factor/cytokines/histamine/serotonin/prostaglandins
- ADP causes thrombus aggregation
- cytokines attract lymphocytes and macrophages
- histamine causes increased capillary permeability
PROLIFERATIVE
- day 3-week 3
- fibroblast activity, producing collagen type 3 and ground substance using vitC
- angiogenesis, re-epithelialisation of wound surface, formulation of granulation tissue
REMODELLING
- maturation of collagen from type 3 to type 1
- decrease wound vascularity and wound contraction
Wound closure
Primary intention - NOT acute inflammatory reaction
- fibin-rich haematoma, then neutrophils at margin of wound within 24hrs and move towards clot
- epithelial cells move from wound edge and deposite basement membrane in 24-48hr
- macrophages replace neutrophils at day3
- granulation tissue invasion
- neovascularisation maximal at day5
- fibroblast proliferation at week 2
- scar devoid of inflammatory cells by week4
Secondary intention - where wound edges not opposed, heals from bottom upwards
- by granulation, contraction, epithelialisation
- requires myofibroblasts
Wound healing factors
At week 1, skin is 10% strength vs un-wounded, at 3months is 80%
Growth factors involved - EGF, TGF, VEGF, PDGF, FGF, IGF
Promoted by good blood supply, vitamin C, zinc, protein, insulin, UV light
Inhibited by glucocorticoids, infection, extreme temperatures
Scars
Matures over 2 years
- immature is pink, hard, raised, itchy
Mature - atrophic / hypertrophic (excess scar tissue not extending beyond boundaries of original wound, due to granulation tissue) / keloid (excess scar tissue beyond boundaries, due to persistant type 3 collagen)
Treatment of keloid/hypertrophic:
- excision of scar, laser, steroid injection, pressure, silicon gel sheeting, radiation, vitaminE
Reduce surgical scarring: monofilament sutures, removal of sutures at day3-5, tensionless suturing, fine sutures and steri-strips, subcuticular technique
Neoplasia
= abnormal, uncontrolled, uncoordinated growth, which persists after cessation of stimuli
Malignant neoplasia = invasion, rapid growth, metastases, poor differentiation
Tumour definitions
Carcinoma - epithelial origin
Sarcoma - mesenchymal origin
Teratoma - neoplasm with multiple germ cell layers (ovarian is benign, testicular is malignant)
Choristoma - non-malignant mass of normal tissue in ectopic location
Hamartoma - non-malignant mass of disorganised but mature tissue indigenous to site
Growth of tumour
Gompertzian - in early stages exponential growth, but slows as grows
Majority of growth occurs before clinically detectable
Radiologically needs to have - 10mm size, 10^9 cells
2^n = number of cells produced after n generations of division
2^45 is usually fatal (after 45 generations), but there is also concurrent tumour loss
Features of malignant transformation
- Establishment of autonomous lineage - resisting signals that inhibit growth, acquisition of independence from signal-stimulating growth, using oncogenes
- Obtaining immortality - normal cells have finite no of divisions (40-60) determined by progressive shortening of telomere, but ca cells do not undergo telomeric shortening
- Evasion of apoptosis (p53)
- Angiogenic competence
- Ability to invade
- Ability to disseminate and implant
- Evading detection and elimination
- Genomic instability
Differentiation
Extent to which neoplastic cells resemble normal cells
Benign = well differentiated (morphologically and functionally similar to mature normal cells)
Anaplasia = lack of differentiation
High-grade tumour = poorly differentiaed
Metastasis
ONLY cancers that can’t are BCCs and gliomas
LYMPHATIC - most carcinomas, eg endometrial, cervical
BLOOD - most sarcomas, renal cell ca, choriocarcinoma
BODY CAVITY - ovarian ca, breast ca, pseudomyxoma peritonei
Inherited genetic predisposition to cancer
Inherited syndromes (all autosomal dominant)
- retinoblastoma, MEN, neurofibromatosis 1+2, von Hippel-Lau syndrome
Inherited autosomal recessive syndromes of defective DNA repair
- xeroderma pigmentosum, Fanconi’s anaemia
Familial cancers
- breast, ovarian, HNPCC
BRCA genes
BRCA-1
- on long arm of chrom 17
- 80% lifetime risk breast ca, 50% ovarian ca
BRCA-2
- on long arm of chrom 13
- 45% breast ca, 25% ovarian ca
- also predisposes to prostate and pancreatic ca
Other cancer genes - HNPCC, RB (retinoblastoma), p16 (melanoma)
HNPCC
Hereditary non-polyposis colonic cancer, aka Lynch syndrome
Autosomal dominant inheritance
5 genes
80% lifetime risk colonic ca, 30-50% endometrial ca, 10% ovarian ca
Non-genetic predisposing factors to cancer
Chronic inflammation - crohn’s, UC
Pre-cancerous conditions - leukoplakia, cervical dysplasia, pernicious anaemia
Carcinogenic agents
- asbestos - mesothelioma, GI tract ca
- diethylstilbestrol (synthetic oestrogen) - vaginal clear cell ca
- high fat/low fibre - colonic ca
- aniline dye - bladder ca
- HPV 16/18 - cervical ca
- anabolic steroids or HepB - hepatocellular ca
Tumour markers
hCG - trophoblastic (choriocarcinoma), non-seminomatous germ cell tumour
Calcitonin - medullary ca of thyroid
Catecholamines - phaeochromocytoma
AFP - hepatocellular ca, non-seminomatous germ cell tumour
CEA (carcinoembryonic antigen) - colonic, pancreatic, gastric, lung
PSA - prostate
Immunoglobulins - multiple myeloma
Ca125 - ovarian ca, primary peritoneal ca
Ca19-9 - colonic, pancreatic
Ca15-3 - breast
Paraneoplastic syndromes
Symptom complexes in ca patients - not due to spread of ca but due to endocrine function or immunological response
Cushing’s - small cell lung, pancreatic
SIADH - small cell lung, intracranial
Carcinoid syndrome - bronchial adenoma, pancreatic, gastric
Polycythaemia - renal cell, cerebellar haemangioma, hepatocellular ca, fibroid
Myasthenia - bronchogenic ca
Acanthosis nigrans - lung, uterine ca
Dermatomyositis - bronchogenic, breast
Trousseau’s - pancreatic
p53
Transcription factor that regulates cell cycle - activates DNA repair, initiates apoptosis
Tumour suppressor
On chrom17
Li-Fraumeni syndrome - AD disorder linked to p53 mutation, 25x greater chance of malignancy by age 50
Anti-thrombotic agents
Anti-platelet
- prostacyclin
- NO
- ADPase
Anti-coagulant
- thrombomodulin
- anti-thrombin III
- tissue factor pathway inhibitor
Fibrinolytic
- tissue-type plasminogen activator (t-PA)
Pro-thrombotic agents
Pro-platelet
- von Willebrand factor
Pro-coagulant
- thromboplastin
Anti-fibrinolytic
- plasminogen activator inhibitor
Platelets -> haemostatic plug
Platelets contain fibrinogen, fibronectin, PDGF, histamine, serotonin, factor V and VIII
Platelet aggregation induced by vWF, ADP, thromboxane A2
PRIMARY HAEMOSTATIC PLUG
- platelet aggregation, reversible
SECONDARY HAEMOSTATIC PLUG
- thrombin binds to platelets, irreversible
FIBRIN BINDS TO PLUG
- ADP mediated activation of platelets, causes changes to their surface receptor for fibrinogen, so fibrin can form and bind to the plug
Coagulation cascade
INTRINSIC:
- from contact activation (surface damage)
- using factors XII XI IX VIII (12, 11, 9, 8)
- both activate factor X
(test using PTT - play table tennis inside, 25-29s)
EXTRINSIC:
- from tissue factor (III) released in trauma and inflammation
- using factors III (TF), VII (3 +7 = 10)
- both activate factor X
(test using PT - play tennis outside, 12s)
COMMON:
- activated factor X, causes prothrombin -> thrombin (II) (Ca and factor V (co-factor) are needed here)
- which then cleaves fibrinogen -> fibrin (I)
(factors 2, 7, 9, 10 are vitamin K dependent)
Proteins C and S
Protein C
- physiological anticoagulant
- degrades factor Va and VIIIa
- activated by thrombin
Protein S
- anticoagulant
- cofactor with activated protein C for the degradation of factor Va and VIIIa
- binds to complement factors
Factor V Leiden
Variant of factor V that cannot be inactivated by protein C
-> hypercoagulant state
Autosomal dominant
5% prevalence in caucasians
30% of patients with DVT or PE have
Fibrinolytic cascade
By generation of plasmin
Plasminogen -> plasmin via Hageman dependent pathway, plasminogen activators (tissue-type PA and urokinase-like PA)
