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)
Changes to coagulation in pregnancy
Physiological ↓ in platelet levels - due to haemodilution
Hypercoagulant - ↑levels of coagulant factors
↑ fibrinogen
↑ ESR
Fibrinolytic system - placenta secretes PAI-2 which inhibits fibrinolytic system, ↑ anti-thrombin III, ↑ FDPs
- activity remains low in labour but returns to normal 1hr after delivery of placenta
Virchow’s triad
Endothelial injury
Stasis
Hypercoagulability
Hypercoagulability states
PRIMARY (genetic) disorders
- protein C or S deficiency
- anti-thrombin III deficiency
- factor V Leiden
SECONDARY (acquired)
- pregnancy
- COCP
- antiphospholipid antibodies
- nephrotic syndrome
- Trousseau’s syndrome
- heparin induced thrombocytopenia syndrome
Thrombosis
Venous, arterial or cardiac
Based on Virchow’s triad - endothelial injury, stasis, hypercoagulability
Fate - propagation / embolisation / dissolution / organisation and recanalization
Antiphospholipid syndrome
= Hughes’ syndrome
Triad for definition - thrombosis (arterial or venous), recurrent miscarriage (>3 consecutive at <10 weeks), antiphospholipid antibodies
Autoimmune
Also see PET, preterm deliveries, thrombocytopenia, livedo reticularis
Primary if no other autoimmune conditions, secondary if also eg SLE
Fetal loss due to pro-coagulant state, and decreased level of annexin-V (anticoagulant on normal placental villi)
Treat - aspirin, and anticoagulants LMWH
Antiphospholipid antibodies
Heterogenous antibodies directed against anionic phospholipids or their binding proteins (prothrombin, factor V, protein C and S, annexin V)
Lupus anticoagulant and anticardiolipin antibodies
2-5% of normal obstetric population, 15% of those with recurrent miscarriage, 30% if SLE
Heparin-induced thrombocytopenia syndrome
Formation of antibodies that bind to heparin-platelet complex
So activates platelets -> low platelet count, thrombosis
Treat with lepirudin (thrombin inhibitor)
Disseminated intravascular coagulation
= consumptive coagulopathy
Causes - cancer, massive tissue injury, massive haemorrhage, infection, liver disease, placental abruption, pre-eclampsia, amniotic fluid embolism
Features - ↑PT, ↑APTT, high levels FDPs, ↑ soluble fibrin complex, ↓ fibrinogen, high D-dimer, thrombocytopenia, fragmented RBCs (schistocytes) on blood film
Embolism
eg pulmonary thromboembolism
- 60% silent, -> cor pulmonale (RV failure)
Fat embolism
- neurological symptoms, pulmonary insufficiency, anaemia, thrombocytopenia
Air embolism
- eg decompression sickness
Amniotic fluid embolism
- 1 in 8000 - 80,000 deliveries
- 60% mortality rate
Thrombocytopenia
5-10% term pregnancies
Gestational TP - benign, no treatment, will return to normal post delivery
TTP = thrombotic thrombocytopenic purpura
- thrombocytopenia with microangiopathic haemolytic anaemia and renal impairment
- platelet consumption disorder
- treatment is plasma exchange (NOT platelet transfusion)
If PLT >80 - regional anaesthesia safe
if >50 - LMWH is safe
Causes of thrombocytopenia
Immune thrombocytopenic purpura
Haemolytic uraemic syndrome
Thrombotic thrombocytopenic purpura
Bone marrow suppression
Gestational thrombocytopenia
HELLP syndrome
SLE and antiphospholipid syndrome
DIC
HIV
ITP
Due to antibodies against platelet surface glycoproteins
1-2:10,000 pregnancies
Antiplatelet IgG - can cross placenta and cause fetal thrombocytopenia
Treatment - corticosteroids, immunoglobulins, splenectomy, azathioprine, platelet transfusion
Infarction
Area of ischaemic necrosis caused by occlusion of either arterial supply or venous drainage to tissue
Causes - thrombosis, embolism, vasospasm, expansion of atheroma, extrinsic compression of vessel
Red (haemorrhagic) - due to venous obstruction
White (anaemic) - due to arterial obstruction
Septic ladder
SIRS = 2 of:
- temp <36 or >38
- tachycardia >90
- tachypnoea >20
- WBC <4 or >12
Sepsis is SIRS if result of infection
Severe sepsis is if also evidence of failure of >1 organ system
MODS = 2 or more failed organ systems, 60% mortality
Abscess
= collection of pus (dead and dying WBCs) surrounded by acute inflammatory response and pyogenic membrane
Contains hyperosmolar material that draws fluid in and increases pressure, causing pain
If related to surgical wound, usually takes 7-10 days to form
Outcome - resolution by I+D, antibiotics, chronic abscess (with plasma cells and lymphocytes), fistula, sinus
Determinants of wound infection
Host response
Virulence and inoculums of infective agent
Vascularity and tissue health
Presence of foreign body
Presence of antibiotics during decisive period
Categories of surgery according to infection risk
Clean (if +abx prophylaxis infection rate is 2%)
Clean-contaminated (“ 10%)
Contaminated (“ 20%)
Dirty (“ 40%)
Shock
Systemic state of low tissue perfusion, inadequate for normal cellular respiration
Pathogenesis:
- lack of O2 -> anaerobic respiration -> lactic acid -> metabolic acidosis
- consumption of cellular glucose stores -> cessation of anaerobic respiration -> cell lysis -> hyperkalaemia
- hypoxia and acidosis activate immune and coagulation systems -> increased capillary permeability
Cardio - decreased preload and afterload cause reflex tachycardia and vasoconstriction, reduced perfusion -> hypothermia
Resp - metabolic acidosis so increased RR and minute ventilation (to excrete CO2), -> compensatory respiratory alkalosis
Renal - reduced glomerular filtration, oliguria, activation of renin-angiotensin system, vasoconstriction
Hormonal - ADH and cortisol release
Ischaemia-reperfusion injury
Metabolites (H and K) that build up during tissue hypoperfusion are flushed back into systemic circulation
-> acute lung injury
-> acute renal injury
-> MODS
Causes of shock
HYPOVOLAEMIC - haemorrhoagic, non-haemorrhagic, 3rd spacing
CARDIOGENIC - MI, arrhythmia without output
OBSTRUCTIVE - tamponade, PE, pneumothorax
DISTRIBUTIVE - septic, anaphylactic, neurogenic
ENDOCRINE - adrenal insufficicency, hypo/hyperthyroidism
Occult hypoperfusion
When normal vital signs but continued tissue hypoperfusion
Due to low mixed venous oxygen saturation, persistent lactic acidosis
Or global hypoperfusion - see base deficit, lactate
Dynamic fluid response
Based on response to 250-500ml IV fluid challenge:
RESPONDER - sustained improvement, no active bleeding or fluid loss
TRANSIENT RESPONDER - improve but then revert back to previous state over 20 mins (have ongoing fluid loss)
NON-RESPONDER - show no improvement
Central venous pressure
Normal CVP = 5-15cm H2O
After IV fluid challenge - should get CVP rise of 2-5, then drifting back over 20 mins
- if no response then underfilled
- large sustained response then overfilled
Mixed venous oxygen saturation
From RA
Measure of O2 delivery and extraction by tissues
Normal value 50-70%
If <50% - inadequate oxygen delivery, or increased oxygen extraction
If >70% - in sepsis due to decreased utilisation of O2 at cellular level
Haemorrhage
Leads to acidosis, hypothermia, coagulopathy
Degree of haemorrhage - <15% is within limits of compensatory mechanism (at expense of GI tract, muscle, skin)
15-30% decompensation starts
30-40% BP falls
>40% severe
Types of haemorrhage (primary/reactionary/secondary)
Primary - immediate
Reactionary - delayed but within 24hr of event, can be due to dislodgement of clot/vasodilation/normalisation of BP
Secondary - within 7-14 days of primary event, caused by sloughing of vessel wall
Blood transfusion
Packed red cells - 330ml RBC, 250mg iron, stored at 2-6 degrees, 5 week shelf life
Fresh frozen plasma - stored at -40degrees, shelf life 2 years
Cryoprecipitate - rich in factor VIII and fibrinogen
Platelets - stored at 20-24degrees, shelf like 5 days
Complications of transfusion
Single transfusion
- haemolytic (ABO incompatibility)
- febrile (graft vs host response from residual leukocytes in blood)
- allergic
- infection
- air embolism
- thrombophlebitis
- transfusion-related acute lung injury (from FFP)
Massive transfusion
- coagulopathy
- hypocalcaemia, hyper/hypokalaemia, hypothermia, iron overload
Management of transfusion induced coagulopathy
FFP if PT>1.5x normal
Cryoprecipitate if fibrinogen <0.8
Platelets if <50
TXA
Aprotinin
Recombinant factor VIIa
Cervical screening
Every 3 years in 25-49yo
Every 5 years in 50-65yo
False negative 10%
Borderline/mild dyskariosis 10%
Moderate/severe dyskariosis 2%
Inadequate 10%
Cervical intraepithelial neoplasia
Form of cervical dysplasia, premalignant
Major aetiology HPV 16 and 18
Most spontaneously regress, or progression to cancer takes 15years
Cytology - nuclear enlargement, increased nuclear:cytoplasmic ratio, nuclear pleomorphism, hypochromasia, increased mitotic activity
Cervical glandular intraepithelial neoplasia
Usually coexists with squamous disease
Multifocal in 15%
Cervical cancer
9:100,000, commonest gynae ca worldwide
Mean age presentation is 52yo, but bimodal distribution with peaks in late 30s and early 60s
99.7% of cervical ca due to all types of HPV (70% due to 16 and 18)
Squamous cell 80%
Adenocarcinoma 15%
<1% small cell ca (neuroendocrine, poor pronosis as early spread), clear cell ca, glassy cell ca
Classification of cervical cancers
Stage 0 - ca in situ
Stage 1
- 1A - limited to cervix, micro-invasive - treat with LLETZ/trachelectomy/hysterectomy
- 1B - visible lesion - need radical hysterectomy and lymphadenectomy
Stage 2 - invades beyond uterus but not to pelvic floor or lower 1/3 vagina
- 2A without parametrial
- 2B with parametrial
- treat with radiation, cisplatin-based chemotherapy, and hysterectomy
Stage 3 - extends to pelvic side wall or lower 1/3 vagina or hydronephrosis
- 3A - no side wall
- 3B - side wall or hydronephrosis
- treat with radiation therapy and cisplatin-based chemo
Stage 4 - extends beyond true pelvis
- 4A - bladder and rectum
- 4B - distant mets
- radiation + chemo
Uterine fibroids
= leiomyomas
Oestrogen dependent benign tumours
Arise from uterine smooth muscle
No evidence that can become malignant, risk to leiomyosarcoma 0.25%
Microscopically, tumor cells resemble normal cells (elongated, spindle-shaped, with a cigar-shaped nucleus) and form bundles with different directions (whorled). These cells are uniform in size and shape, with scarce mitoses.
Degeneration due to outgrowing blood supply - hyaline most common, or red in pregnancy
Intravenous leiomyomatosis is variant fibroid - can metastasize via haematological spread, in any organ
Endometriosis
Ectopic endometrium (stroma + glands)
Frequently in POD and ovaries
In women of fertile age, 1-2%
Unknown aetiology - theories oestrogen dependent, genetic, transplantation, retrograde implantation from menstruation
Can be associated with cancers eg clear cell carcinoma
Dysmenorrhoea, dyspareunia, dyschezia, dysuria, chronic pelvic pain, infertility in 40%
Ca125 elevated
Histologically see haemosiderin-laden macrophages
Staging of endometriosis
1 - superficial lesions and filmy adhesions
2 - deep lesions at cul-de-sac
3 - all above + endometriomas on ovaries
4 - all above + extensive adhesions
Adenomyosis
Presence of endometrial glands in myometrium
20%
Endometrial hyperplasia
Related to prolonged oestrogen stimulation of endometrium
Simple, complex or atypical
(atypical highest rate of progression to malignancy endometrial adenocarcinoma, 25-50%)
Treatment - progestogens for simple/complex
- TAH + BSO for atypical
Endometrial cancer risk factors
Endometrial hyperplasia
Hypertension
Ovarian ca, breast ca
Diabetes
Tamoxifen, oestrogen
Late menopause
Early menarche
Obesity
Nulliparity
Endometrial cancer types
Carcinoma
- non-endometroid (papillary serous or clear cell, both poorly differentiated with poorer prognosis)
- or endometroid
Sarcoma
From pluripotent stem cells in endometrium
HOMOLOGOUS if contain endometrial tissue only - stromal or glandular, HETEROLOGOUS if they contain extra-uterine tissue such as skeletal muscle or cartilage, PURE if differentiation occurs along one cellular pathway only - for instance, an endometrial stromal sarcoma, MIXED if differentiation occurs along more than one cellular pathway - for instance containing both endometrial stromal sarcoma and endometrial adenocarcinoma
Poor prognosis
Staging of endometrial cancer
1 - limited to uterus, 85-90% 5 year survival
1A - invasion <1/2 myometrium
1B - invasion >1/2 myometrium
2 - cervical stromal invasion, 65% 5yr survival
3 - extension beyond uterus but confined to pelvis, 45-60% 5yr survival
3A - invasion of serosa, adnexa, peritoneal fluid
3B - vaginal invasion
3C - nodal involvement
4 - distant mets, 15% 5yr survival
4A - mucosa of rectum and bladder
4B - distant mets including abdominal and/or inguinal lymph
PCOS
5% prevalence
Based on Rotterdam criteria, need 2/3 of:
- oligo-ovulation
- excess androgen activity
- polycystic ovaries on imaging (>12 follicles in each ovary measuring 2-9mm in diameter, or ovarian volume >10ml)
High androgen activity due to - high LH, decreased SHBG, increased insulin, extra-ovarian production of androgens (eg Cushing’s, CAH)
High LH:FSH ratio 2:1 or more
Higher risk of endometrial hyperplasia/neoplasia, insulin, resistance, dyslipidaemia
Primary ovarian cancers
EPITHELIAL 85%
- serous (75%), mucinous, Brenner’s (transitional cells, secrete oestrogen, mostly benign, can be bilateral), clear cell, differentiated, endometroid (assoc with endometriosis), fibroma
STROMAL 5%
- sertoli-leydig (testosterone secreting, usually benign), thecofibroma, granulosa (oestrogen secreting, see Kall-Exner bodies)
GERM CELL 5% (or 70% in under 20s)
- germinoma, endodermal sinus tumour (secretes AFP and a-antitrypsin), choriocarcinoma (secretes hCG), teratoma, embryonal (secretes LDH)
Secondary ovarian cancers
From peritoneal, endometrium, breast, and GI tract cancers
Krukenberg cancer = secondary ovarian from GI primary, characterised by mucin-secreting signet-ring cells, usually affects both ovaries
Teratomas
Includes dermoid cysts (from all 3 germ cell layers), mature teratomas, struma ovarii (mostly thyroid tissue, can cause hyperthyroidism), carcinoid component
Benign teratoma is the commonest ovarian tumour (40%)
- bilateral in 10-15%
- 1% undergo malignant transformation
5 year survival rate for all stages of ovarian cancer
45%
Ovarian cancer tumour markers
Biochemical:
- ca125 (elevated in 50% with early disease, 80% with late)
- ca119 or CEA in mucinous
- AFP in germ cell
- B-HCG in choriocarcinoma
- LDH in dysgerminoma
Cytokeratins
- CK 7 positive
- CK 20 negative
Risk of malignancy index (RMI) = CA125 x menopausal status x ultrasound features
- premenopausal = 1, post = 3
- >1 USS feature seen = 3
- RMI>200 highly indicative of malignancy
Lichen sclerosus
aka chronic atrophic vulvitis
Autoimmune
All ages but common after menopause
See - narrowed introitus, labial atrophy, epidermal atrophy, hydropic degeneration of basal layer, dermal inflammation, sclerotic stroma
5% have association with squamous vulval carcinoma
Staging of ovarian carcinoma
1 - limited to 1 or both ovaries
1A - 1 ovary, peritoneal washings -ve
1B - both ovaries, peritoneal washings -ve
1C - capsule ruptures, peritoneal washings +ve
2 - pelvic extensions
2A - implants on uterus
2B - implants on pelvic structure
2C - peritoneal washings +ve
3 - peritoneal implants beyond pelvis or with extension to small bowel/omentum
3A - microscopic implants
3B - macroscopic <2cm
3C - macroscopic >2cm
4 - distant metastasis
Lichen simplex chronicus
aka hyperdysplastic dystrophy
Secondary to pruritus
See - acanthosis of vulval squamous epithelium, hyperkeratosis, thickened epithelium, increased mitotic activity in basal and prickle cell layer
Vulval intraepithelial neoplasia
See - epithelial nuclear atypia, increased mitosis, lack of surface differentiation
90% associated with HPV
10-30% assoc with another primary squamous neoplasm in vagina or cervix
Extramammary Paget’s
Non-invasive intraepithelial adenocarcinoma
Not usually associated with underlying invasive malignancy
Can be assoc with adenocarcinoma arising from urethra, rectum or Bartholin’s gland
Lesion - sharp demarcation, erythematous, pruritic
Vulval cancer
4% of gynae cancers, 3/100,000 women, median age 74yo
Usually presents with itching
Types - SCC 85%, melanoma 5%, BCC, adenocarcinoma, sarcoma
Vulval cancer staging
1 - confined to vulva
1A - lesions <2cm with stromal invasion <1mm
1B - lesions >2cm, stromal invasion >1mm
2 - extension to adjacent perineal structures, eg 1/3 lower vagina, 1/3 lower urethra, anus
3 - positive inguino-femoral nodes
3A - <2 lymph node mets
3B - >2 lymph node mets
3C - with extracapsular spread
4 - extension to upper urethra and vagina
4A - upper vagina, upper urethra, bladder, rectum
4B - distant mets including pelvic lymph nodes
Vaginal cancer
1% of gynae cancer
Primary carcinoma uncommon
Associated with HPV
Types - 90% SCC, adenocarcinoma, germ cell, sarcoma Botryoides
Pre-eclampsia
BP >140/90 with proteinuria, after 20w gestation
2-3% of pregnancies (HTN in 10-15%)
2% of those with PET -> eclampsia
Unknown aetiology
Pathophysiology ?due to poor placentation -> utero-placental resistance and abnormal placental function
- vasoconstricted
- plasma contracted
- intravascular coagulation
- endothelial dysfunction (↑ capillary permeability, ↑ vascular tone, ↑ fibronectin, platelet thrombosis)
- biochemical - ↓NO, ↓ thromboxane A2, angiotensin and endothelin, ↓prostacyclin
Classification and features of PET
Mild
- BP >140/90
- proteinuria 300mg/24hr
Severe
- BP >160/110
- proteinuria >5g/24hr
Features
- headache, visual disturbance, epigastric/RUQ pain, vomiting, ankle swelling, seizures
- hyper-reflexia, clonus, oliguria
- deranged LFTs, low platelets, abnormal renal function, deranged clotting, elevated urinary protein
Risk factors for PET
Age >40
BMI >30
Family hx
Primip
Multiple pregnancy
Previous hx
Hydatidiform mole
Pre-existing HTN
Renal disease
Diabetes
Antiphospholipid syndrome
Complications of PET
Haemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome
Placental abruption
FGR
Eclampsia
Pulmonary oedema
DIC
Commonest causes of death in PET - cerebral haemorrhage, ARDS
Obstetric cholestasis
Features - pruritus of limbs and trunk (palms and soles especially), no rash, abnormal LFTs, rare to have jaundice
Multifactorial poorly understood pathogenesis
Complications - vitK deficiency, PPH, pre-term delivery, intrapartum fetal distress, intrauterine fetal death 1-4%, fetal intracranial haemorrhage
Risk of recurrence 90% in future pregnancies
Acute fatty liver of pregnancy
Usually after 30w gestation
RFs - primigravida, obesity, male fetus, multiple pregnancy
10-20% maternal mortality, 20-30% fetal mortality
Features - vomiting, abdo pain, jaundice, abnormal LFTs, profound hypoglycaemia, hyperuricaemia, coagulopathy
Complications - fulminant hepatic failure, encephalopathy
HELLP syndrome
Haemolysis, elevated liver enzymes, low platelets
20% of those with severe PET
Pathogenesis - endothelial cell injury, microanngiopathic platelet activation and consumption
Effects on pregnancy - abruption, acute renal failure, hepatic necrosis, liver rupture, subcapsular liver haematoma
Perinatal mortality 10-60%, maternal 1%
Risk of recurrence in future pregnancies low, but risk of PET high (75%)
Peripartum cardiomyopathy
Dilated cardiomyopathy
From 8mo gestation to 5mo postpartum
Assoc with congestive HF, ↓LVEF, cardiac arrhythmias, thromboembolism
Cause unknown, diagnosis of exclusion
Maternal mortality 25-50%
Management - diuretics, B-blockers, ACEi, anticoagulation, or if refractory then LV assist device or heart transplant
Coombs’ test
Positive if agglutination occurs
Indirect - detects antibodies against RBCs present in patient’s serum, used for antibody screening (cross-matching and antenatal screening)
Direct - detects antibodies bound to RBC surface antigens, indicates immune-mediated attack o RBCs
- alloimmune haemolysis (haem disease of newborn)
- autoimmune haemolysis (SLE, idiopathic, secondary to lymphoproliferative disease or infection)
- drug-induced immune-mediated haemolysis (methyldopa, penicillin, quinidine)
Kleihauer’s test
To measure fetal RBCs in maternal circulation
Normally fetal maternal haemorrhage is <4ml at delivery
Anti-D immunoglobulin
- 500IU neutralizes 4ml of RH+ve RBC
- should be given within 72hr of sensitisation in non-sensitised Rh-ve women
- provides protection for 6 weeks
Sheehan’s syndrome
Hypopituitarism
- caused by ischaemic necrosis due to blood loss and hypovolemic shock during and after childbirth
Signs - absence or difficulty with lactation, amenorrhea / oligomenorrhea and features of hypothyroidism (tiredness, weight gain etc) due to reduced TSH.
Arias-Stella reaction
Due to direct effect of progesterone on the endometrium
- endometrial epithelial cells become increasingly vacuolated and thrown into pseudo-papillary folds giving a hyper-secretory impression, evidence of decidualisation around spiral arteries and under the surface of the epithelium
- glandular hyperplasia, intra-nuclear cytoplasmic invaginations which may resemble viral inclusions
- in normal intra-uterine pregnancy, ectopic pregnancy, progestogen therapy and can also occur in the endocervix
Endometrial appearance with contraceptives
COCP - glandular atrophy
Copper IUD - mononuclear cell infiltration, irregular polymorphs near the surface, foci of haemorrhage and squamous metaplasia may be present, cyclical changes persist
Progesterone IUS - progestogenic effects including decidual change and inactive or weakly secretory glands with thinning of the endometrial lining
Endodermal sinus tumour
= yolk sac
Rapidly growing
Intraperitoneal spread
Germ cell tumours
Typically produce AFP
Occur in young women
See Schiller-duval bodies
Dysgerminoma
= the seminoma in males
- commonest malignant germ cell tumour; occur in young women between the ages of 13 - 30 years
- 10-15% are bilateral; solid tumours which typically present with abdominal mass or pressure symptoms
- lymphatic spread to the para-aortic nodes
- very radio-sensitive
- no reliable serum marker but commonly see elevated LDH, occasionally hCG
- karyotyping recommended
Ovarian choriocarcinoma
- usually a secondary from a uterine tumour
- primary ovarian choriocarcinoma is rare and develops from germ cells
- solid tumours, typically unilateral with cytotrophoblasts and syncytiotrophoblasts on histological examination
- produce HCG
Meig’s syndrome
Triad of benign ovarian tumour (typically thecoma/fibroma), ascites and pleural effusion
Thecomas may produce oestrogen with a presentation similar to that described for granulosa tumours. Less likely to rupture
Fibromas with > 3 mitoses per 10 high power fields are considered fibrosarcomas
Psammoma bodies
Concentric lamellated calcified structures, most commonly in papillary thyroid carcinoma (PTC), meningioma, and papillary serous cystadenocarcinoma of ovary
Contain calcium
