PP Flashcards
Are pale cells or pink cells alive or dead?
Pale cells are alive, pink cells are dead (have taken up eosin stain)
Name free radicals and how they cause damage
Superoxide, OH-
Damage cell membranes by stealing electrons from neighbours
How do anti-oxidants work
vits ACE donate an electron
Name three things that can happen to a nucleus in necrosis
Pyknosis- nucleus shrinks and dark
Karyorrhexis- breaks into bits
Karyolysis- nucleus dissolves
Describe features of a dying cell
Swollen, chromatin clumps, blebs, ER and mito swell, ribosomes detach
Difference between oncosis and necrosis
Oncosis is process of dying, necrosis is changes after death 12-24hours
4 types of necrosis
Coagulative (e.g. heart, kidney), liquefactive (brain), caseous (TB), fat (breast)
Describe how to prepare slides
Add formalin to prevent auto lysis, put in casettes, processor adds water and paraffin wax, blocking, microtome cuts 3-4microns thick, float on warm water bath to remove creases, stain, mount on medium
Explain dystrophic and metastatic calcification
Dystrophic- localised calcium crystals from dying/damaged tissue e.g. athero plaques, TB LNs. Crunchy. Normal Ca metabolism
Metastatic- systemic abnormal Ca metabolism e.g. increased breakdown of bone from excess PTH or destruction of bone e.g. Paget’s disease of bone, immobilisation
What is mallory’s hyaline?
Keratin clumps in alcholic liver disease
What do HSPs do?
Fix misfolded proteins e.g. ubiquitin
Apoptosis definition and process
programmed cell death with shrinkage, membrane integrity maintained. p53 activated and outer membrane becomes leaky, cytochrome C released from mito which activates caspases (or TNFa from Tc binds to death R to activate caspases), apoptotic bodies made which express surface proteins, no inflam
Define gangrene (and dry, wet, gas)
Gangrene is visible necrosis. Dry is exposed to air, wet is infection, gas is infection with anaerobes (soil e.g. motorbike accident)
What are red and white infarcts?
White: in solid organs with occluded end artery
Red: in loose tissues with collateral circulation, or if re-perfused or haemorrhage
What’s ischaemia-reperfusion injury?
Reperfusion can make it worse as brings ROS, brings neuts (inflam and damage), and increases complement
Give examples of when K, enzymes, and myoglobin are released from damaged cells
K in MI, AST and ALT in liver damage, myoglobin in rhabdomyolysis
Stem cells show ____ replication and are __potent
Asymmetrical replication (one stays a stem cell) and unipotent
Describe process of repair/resolution
Healing by secondary intention
Haemostasis
Acute inflam
Chronic inflam
Granulation tissue (new capillaries from endo cell prolif, fibroblasts make ECM and myofibroblasts contract)
Early scar (can’t lay down elastin, no melanocyte regen)
Scar maturation
Compare healing by primary and secondary intention
Primary is incised, non-infected wound with minimal tissue loss, low granulation tissue, v minimal scar. Basal epidermal cells creep and deposit BM to undermine scab
Secondary is excisional, large tissue loss, or infected, lots of granulation tissue, leaves scar, takes longer, needs big contraction
Components of granulation tissue?
Fibroblasts, myofibroblasts, endothelial cells (angiogenesis), macrophages
What cell connecting molecules are there?
Cell:cell is cadherin, cell:ECM is integrins
What are the principles of haemostasis?
Vasoconstriction, platelet plug blocks, blood coag and fibrin clot (makes clot stable), fibrinolysis
Haemostasis =
stopping bleeding whilst maintaining fluidity of blood
What normally inhibits coagulation in blood
Endothelial prostacyclin and NO inhibit platelet aggregation
Plus nothing for platelets to bind to: vWF not expressed
How do platelets work?
Block the hole- have cytoskeleton proteins to change shape, have pseudopodia to help sealing. Release granules. Have a fibrin R to cross-link with other platelets
What granules do platelets have?
Dense: adrenaline, ATP, ADP, calcium, 5HT
Alpha: fibrinogen, thromboxane A2 (vasoconstricts and platelet aggregation)
Describe the fibrinolytic system
Plasminogen —TPA—> plasmin which breaks down fibrin. Protein C (protein S is a cofactor) decreases fibrin formation, antithrombin III and TFPI
What are PT and APTT?
PT is extrinsic, APTT intrinsic + common
What do D-dimers measure
Released from fibrin of clot as it hardens
What does thrombin time measure
Fibrinogen –> fibrin
What’s thrombocytopenia?
<150 x 10^9/L
Causes of thrombocytopenia
Increased destruction: Immune thrombyocytopenic purpura, thrombotic thrombocytopenic purpur, disseminated intravascular coagulation, haemolytic uremic syndrome, splenic pooling
Reduced production: from megakaryocyte- B12/folate def, cancer/fibrosis in BM, chemo/antibiotics
Either peripheral destruction or marrow failure
Name inherited bleeding disorders
Haemophilia A: deficient factor 8. Elevated APTT (intrinsic), normal PT, diagnosed prenatal/birth, muscle haematomas, haemarthoses, post op bleeds. X linked AR
Haemophilia B: deficient factor 9
vWD: AD, most common. vWF carries VIII & role in platelet adhesion so increased APTT and normal PT. Measure VIII cofactor binding. Skin, mucosal bleeding
Thrombophilia: loves to clot e.g. protein C or S deficiency, ATIII deficiency. Cause DVT, PE, stroke
What is DIC?
Widespread activation of clotting cascade following trigger e.g. virus (EBV,HCV,CMV), malignancy, ABO transfusion reaction, with microthrombi +++ formed in circulation, using up clotting factors and platelets to cause haemolytic anemia. RBC damage from moving through clots. Increased PT and APTT and D-dimers. Treatment is platelet infusions and LMWH
Name anti-coagulant and anti-platelet drugs
Anti-coagulant: heparin (binds to ATIII and increases its activity by x1000) and warfarin (inhibits vit K dep factors)
Anti-platelet: aspirin (inhibits COX which catalyses thromboxane which aggregates platelets), clopidogrel (inhibits ADP from binding to platelets so blocks aggregation)
What should you give for anticoagulant OD?
Vit K, FFP, RBCs
What protein drives the stages of the cell cycle?
Cyclins! Eg. G1 cyclin for G phase
What are CDKs?
Activated by cyclins to drive activity in a particular cell cycle stage
What is p53?
Tumour suppressor gene- can induce growth arrest, DNA repair and apoptosis
What is the R point?
Near end of G1 and is the point of no return where the cell is committed to completing the cell cycle and no longer requires growth factors. Activates p53
Give examples of physio and patho hyperplasia
Physio endometrium from oestrogen
Patho eczema
Give examples of physio and patho hypertrophy
Physio uterus in pregnancy
Patho LV hypertrophy
Give examples of physio and patho atrophy
Physio breast, muscle
Patho AD cerebral atrophy
Define atherosclerosis
Hardening and thickening of arteries as a result of the process of atheroma
Define arteriosclerosis
Hardening and thickening of arteries and arterioles NOT DUE to atheroma e.g. diabetes mellitus, HTN
Define atheroma
Deposit of lipid intracellularly and extracellularly in the tunica intima and media of medium and large sized arteries
Describe cellular events leading to atherosclerotic lesions
Chronic endothelial injury, platelet adhesion, monocytes accumulate, release of growth factors and cytokines
SM cells migrate from media to intima
Macrophages and and SM cells engulf lipid to form foam cells
SM cells proliferate, collagen and matrix deposited, extracellular lipid deposition, neovascularisation
Describe the macroscopic appearance of atherosclerosis
Fatty streak, simple plaque, complicated plaque (calcification, thrombosis, haemorrhage, aneurysm)
What’s a complicated plaque?
If it calcifies, thrombosis, aneurysm, haemorrhage
Describe microscopic appearance of atherosclerosis
Early changes are foam cells, extracellular lipid deposition, SM proliferation
Later changes are fibrosis, necrosis, disruption of elastic lamina, ingrowth of blood vessels, plaque fissuring (breaking), extension into media
Common sites for atherosclerosis
Aorta (esp. abdo aorta), carotid, cerebral, coronary, leg
Describe some severe effects of atherosclerosis
If in coronary arteries –> IHD –> MI, angina, cardiac arrest
If in carotid –> cerebral –> ischaemic stroke, TIA
If in abdo aorta –> AAA –> rupture –> death
If in leg –> PVD –> intermittent claudication, gangrene, DVT
If in SI –> mesenteric ischaemia –> necrosis/death, ischaemic colitis
Describe different theories of atherogenesis
Insudation: endothelial damage and inflam, vessel more permeable, lipid enters
Reaction to injury: endothelial damage cause plaques to form, vessel more permeable, platelet adhesion, monocytes penetrate endothelium, SM cells proliferate and migrate
Monoclonal: each plaque is monoclonal, SM proliferation is key, do they represent abnormal growth like a tumour?
Unifying: endothelial injury (from HTN, raised LDL, smoke) leads to platelet adhesion, SM proliferation, insudation, PDGF release, SM cells make matrix and collagen, SM and macrophages become foam cells, cytokines released
What cells are involved in atherogenesis?
SM cells, macrophages, endothelial, platelets, neutrophils, lymphocytes
Name risk factors for atherosclerosis
Age, sex, hyperlipidemia, exercise, diet (high fat bad),smoking, hypertension, apoE genotype (affects LDL levels), familial hyperlipidemia, DM doubles risk, >5 units/day alcohol, CMV and H.pylori
Why are platelets important in atherogenesis?
Adhesion plus they release PDGF which stimulates SM cell proliferation and migration
Which cells produce collagen in atherogenesis?
Endothelial and SM
Associated signs with familial hyperlipidemia?
Xanthelasma (hands), xanthoma (eyes), corneal arcus
Atherosclerosis prevention?
Stop smoking, decrease fat intake, treat HTN/DM, reduce alcohol intake, regular exercise, lipid lowering drugs if needed, aspirin anti-platelet
Define sepsis, severe sepsis and septic shock
Sepsis = SIRS (systemic inflammatory response syndrome) + suspected/confirmed infection. SIRS is RR >20/min, temp >38.5, HR >90bpm
Severe sepsis = sepsis + 1 organ failure
Septic shock = severe sepsis + MAP <60mmHg despite fluids, lactate >4mmol/L
Define neoplasia, dysplasia, anaplasia, metaplasia
Dysplasia = disordered tissue organisation, pre-neoplastic so still reversible Neoplastic = abnormal growth of cells persisting after initial stimulus removed, irreversible Anaplasia = no resemblance to any tissue Metaplasia = change of one cell to another cell type
Cancer =
malignant neoplasm
Atresia =
absence of normal opening
Pleomorphism =
Variation in size and shape of cells and their nuclei
Progression =
accumulation of mutations in a monoclonal population
Describe macro and micro and behavioural differences in benign and malignant tumours
Benign is well differentiated, confined to site of origin, edges well demarcated, regular appearance
Malignant is irregular appearance, have potential to metastasise, areas of necrosis and ulceration, dysplastic or anaplastic, pleomorphic, hyperchromatic, more mitotic figures, increasing nuclear size
Difference between in situ and invasive malignancy
In situ is before invasive carcinoma which is when it has gone through BM
What clonality are neoplasms?
Monoclonal. Neoplasm means mutations in a monoclonal population
What types of genes are involved in neoplasia?
TSGs e.g. p53
Proto-oncogenes are normal genes which if mutated could become oncogenes
Name types of benign neoplasms
Papilloma, adenoma, leiomyoma, lipoma, glioma, benign teratoma (dermoid cyst), osteoma, fibroma, chondroma, neuroma, neurofibroma, melanocytoma
Name types of malignant neoplasms:
Osteosarcoma, melanoma, chondrosarcoma, leukaemia, lymphoma, seminoma, malignant teratoma, myeloma, fibrosarcoma, nephroblastoma, carcinoma (breast, lung, prostate, colon), adenocarcinoma (stomach, SI, colon, PTH), leiomyosarcoma, lipsarcoma, sarcoma
Invasion =
Past the BM
How to histologically identify Hodgkin’s?
Reed-Sternberg cell (from B cells), pale cytoplasm, one/2 large nuclei, many eosinophils because RS cells release factors that trap them
Describe process leading to metastasis
Dysplasia (reversible), irreversible carcinoma in situ, invasive carcinoma though BM, can spread through lymph or blood or spaces (transcoelomic spread), grow in secondary site
What changes are needed for invasion
Altered adhesion: reduced E-cadherin expression (cell-cell), reduced integrin to detach from stroma
Altered proteolysis: MMPs
Altered motility: changes in actin expression
These changes in adhesion, proteolysis and motility is called epithelial-to-mesenchymal transition (EMT)
What are micrometastases?
Surviving deposits of failed colonisation that can be dormant
What is the seed and soil phenomenon?
Unpredictable mets because depends on cell-niche environment
What’s a sarcoma?
Malignant tumour of non-epi tissue
Common sites of blood-born mets?
Liver, brain, lungs, bone
Which neoplasms most frequently spread to bone?
Lung, breast, prostate, kidney
Which neoplasms that spread to bone cause sclerotic, and which cause lytic, bone lesions?
Sclerotic: breast and prostate carcinomas
Lytic: squamous cell carcinoma
Describe local effects of neoplasms
Pressure/compression, invasion, destruction, ulceration, bleeding, obstruction of tubes and orifices
Describe systemic effects of neoplasms
Paraneoplastic syndromes: Hypercoagulability Endocrine tumour hormone production Cachexia, malaise, anorexia, febrile, hypercalcemia DIC
Name extrinsic carcinogens and how they work
2-napthylamine is purple dye causing bladder carcinoma. Asbestos causes mesothelioma
Ionising radiation strips electron to damage directly e.g. DNA breaks or indirectly by making free radicals
HPV cervical carcinoma (expresses E6 and E7 which inhibit p53 and pRB
HBV/HCV chronic hepatocyte injury
H pylori chronic gastric inflam
HIV lowers immunity so allows carcinogenic infections
How much of cancer risk is environmental?
85%
What is a complete carcinogen?
Acts as a both an initiator (mutate) and promoter (proliferate). A carcinogen can only be one of those things
What are proto-oncogenes, oncogenes, TSGs and caretaker genes?
Proto-oncogenes could acquire a mutation to become oncogenes, oncogenes enhance neoplastic growth, TSGs inhibit neoplastic growth (have 2 alleles), caretaker genes promote genome stability
Name some oncogenes
RAS, c-myc, HER-2
What is the 2 hit hypothesis?
TSGs have two alelles so both need to be inactivated
Name some inherited tumours
HNPCC- AD germline mutation that causes DNA mismatch
Familial breast carcinoma- BRCA1/2 that repairs DSBs
Xeroderma pigmentosum- AR from NER problem so very sensitive to UV, early skin cancer
Retinoblastoma- AD two hit hypothesis
Familial adenomatous polyposis: colorectal cancer.
Describe stages in carcinogenesis:
Initiators initiate, promoters proliferate, progression occurs (accumulation of mutations in monoclonal population)
May involve adenoma to carcinoma sequence as in the colon, where intestinal epithelium acquires mutations to become an adenoma and further mutations such as p53 to become carcinoma
Hallmarks of cancer
Immortal (no limit to divisions), grow without growth factors, invasive, resistance to stop signals, angiogenesis, apoptosis resistant
What virus can cause Kaposi’s sarcoma?
HHV8
What virus and parasite causes Burkitt’s lymphoma?
EBV. Infects B cells, dysregulates c-myc, cell survives longer
Malaria also, because it reduces resistance to EBV
Commonest cancer in adults
Prostate, breast, lung, bowel
Commonest cancer in children
Retinoblastoma, leukaemia, lymphoma, neuroblastoma
Leading causes of cancer-related death
Lung 10%, , bowel, oesophageal 15%, breast and prostate
What’s TNM staging
Tumour size, LN involement, mets?
What staging system for lymphoma?
Hodgy podgy Ann Arbor. Stage for lymph involvement (III is both sides of diaphragm, IV extra-lymphatic) plus a B for B symptoms (weight loss, night sweats, fever)
What staging system for colorectal cancer?
Duke’s poop. A is into bowel, B is through bowel, C is LN, D is distant mets.
What does tumour grading tell you?
How well differentiated it is
What staging system for breast cancer?
Bloom Richardson. Assesses tubule formation (how much normal tubule is left versus cancer), nuclear pleomorphism (how uniform are nuclei), mitotic count (how much division)
How does radiotherapy work
Ionising radiation that damages cells to trigger apoptosis at checkpoints
Name mechanisms of chemotherapy
Alkylating- cross links DNA strands (cyclophosphamide)
Antimetabolites- mimic DNA substrates (5FU)
Antibiotics- e.g. bleomycin causes DSBs
Vincristine blocks microtubule assembly
Name an anticancer hormone therapy
SERM like tamoxifen binds to ER
Androgen blockade for prostate cancer
Name a targeted molecular cancer therapy
Herceptin binds to HER-2
What are neo-adjuvant and adjuvant treatments?
Neo-adjuvant: reduce tumour size prior to surgical excision
Adjuvant = after surgical removal to eliminate subclinical disease
Describe use of tumour markers
HCG from testicular tumour (testicles trying to be pregnant) CEA for CC AFP for hepatcellular (like AST) PSA for prostate CA125 ovarian (125 eggs)
Describe UK screening programmes for colorectal, breast, and cervix
Cervix is 25-64 every 3 years
Breast is 50-70 every 3 years
Colorectal is occult blood screening 60-74 every 2 years
What’s a struma ovarii?
Dermoid cyst (ovarian teratoma) that is mostly thyroid tissue
What are fibroids?
Uterine leiomyoma
For bone pain in a young person, what are your cancer differentials?
Osteosarcoma most likely if young. If older then myeloma.
Why in osteosarcoma would bone pain increase after exertion?
Periosteum containing the blood vessels is stretching by tumour so already a bit ischaemic, increases ischamia in exercise
Describe symptoms you might get from a neuroendocrine tumour in the SI
For symptoms to occur it must metastasise to liver too otherwise hormones will be metabolised. 5-HT produced by tumour can increase bowel transit to cause diarrhoea, vasodilation from bradykinin, thickened bowel wall causing intermittent ado pain.
What does an early first pregnancy do to rates of cancer?
Reduces breast cancer because earlier terminal differentiation of breast cells. Increases risk of cervical cancer due to early exposure to HPV
What infection can increase risk of bladder cancer?
Schistosomiasis because eggs embed into bladder wall
What makes asbestos dangerous?
Microscopic easily inhaled rigid fibres that aren’t easily metabolised, induces necrosis, generates free radicals, can cause mesothelioma, lung cancer, or asbestosis
What is mesothelioma?
Cancer of pleura/peritoneum
Describe the appearance of squamous cell and basal cell carcinomas
Squamous cell has irregular margin and crusted centre
Basal cell from UV exposure, volcano appearance, very rarely metastasises.
Name some small cell and non-small cell lung cancers
Non-small: large cell, adenocarcinoma, squamous cell carcinoma, neuroendocrine
Small: mesothelioma, carcinoid tumours (a type of neuroendocrine)
Which testicular cancers will affect boys at which ages
<20: non-seminomatous
20-30: teratoma (positive for AFP and HCG)
30-40: seminoma
What’s the difference between a teratoma and seminoma?
Teratoma- all 3 germ cell layers
Seminoma- uniform cell type of germ cell epithelium only
What cancers is Tamoxifen good and bad for?
Binds to ER and inhibits in breast cancer but activates in endometrium so increases risk of endometrial cancer
What grading system for prostate cancer?
Gleason (gleasy prostate)
When is PSA raised?
Prostate cancer, prostate hyperplasia, prostatitis,
What is cancer staging and grading?
Staging is size & spread (TNM, Ann Arbor, Duke,)
Grading is how well differentiated (Bloom Richardson, Gleason,
Name the three zones of the acinus
Furthest from central vein is periportal, then midzonal/transition zone, inner is centrilobular
What microscopic findings occur from paracetamol OD?
Coagulative necrosis (ghost outlines), karyorrhexis (breaking nucleus), neutrophil infiltrate
Describe effects of excessive alcohol intake
Cirrhosis, fatty liver (because breaking down acetaldehyde converts NAD to NADH, which is used in FA synthesis), alcoholic hepatitis, elevated AST, hypoalbuminemia
Which areas get liquefactive necrosis?
If low connective tissue (brain) or in areas of infection with neutrophils +++ (abscess)
What happens in hereditary haemochromatocytosis?
Body absorbs too much iron so deposited in skin, joints, bones, heart, liver. Fatigue, joint pain, arthritis, cirrhosis, diabetes, heart failure, osteoporosis.
What’s coal worker’s pneumoconiosis?
Coal dust inhaled, macrophages trap and transport to LNs, trigger immune response. Fibroblasts activated, can become ischaemic and necrotic and create lung cavities. Can cause COPD, chronic bronchitis, cor pulmonale
Causes of meningitis at different ages
Newborns: strep pneumoniae, e coli, listeria
Infants/children: strep pneumoniae, neisseria meningitidis
Adults: step, neisseria, listeria
Complications of meningitis
Hearing loss, vision loss, epilepsy, amputation if sepsis, DIC
What bugs often implicated in ascending cholangitis?
E.coli and klebsiella
Describe stages of lobar pneumonia
Day 1-2 is red/purple from dilation of blood vs
Day 3-4 red hepatisation (red/brown), accumulation of fibrin
Day 5-7 grey hepatisation, alveoli filled with exudate (neuts and MO)
Day 8-3 weeks: resolution, exudate drained via lymphatics and productive cough)
What’s hereditary angioedema?
Recurrent attacks of oedema (face, limbs, airway, GI) due to lack of C1 inhibitor
What’s CGD?
Chronic Granulomatous Disease, AR defective NADPH oxidase in neuts
What are rheumatoid nodules?
Granulomas with T & B cells, multinucleate giant cells, due to immune complexes deposition
What signs occur in RA
LESS: loss of joint space, erosion, soft tissue swelling, soft bones (osteopenia).
Complications of Crohn’s and UC
Crohn’s: bowel fistulas, anal lesions
UC: colon cancer
Tell me about sarcoidosis
Presents with tiredness, cough, CXR enlarged hillier LNs, biopsy iwht non caseating granulomas (can still see individual cells), raised calcium and ACE because granulomas secrete it
When might a foreign body giant cell arise?
After silicone implant rupture causing fibrosis
What is traumatic neuroma?
Following trauma to axon attempts to connect to distal axon, searches for place to go forming tangled mass –> nodule in that area (regeneration without a direction)
Describe Seddon’s classification of nerve injury
Neurapraxia: damage to myelin (loss of conduction)
Axonotmesis: damage to myelin and axon. Wallerian degeneration, will regenerate
Neurotmesis: damage to myelin, axon, endoneurium. Wallerian regeneration, will only regenerate with surgery
Alport syndrome
Defect with type IV collagen. Glomerulonephritis, haematuria and proteinuria
How do you treat proud flesh?
With cauterisation
Immune thrombocytopenic purpura
Autoantibodies to platelet membrane glycoproteins to target for destruction
Thrombophilia
At increased risk of VTE due to absence of anti-coagulation factors e.g. protein C, protein S, antithrombin III
DIC?
Systemic coagulation caused by trigger e.g. EBV, cancer, sepsis, transfusion reactions. Thrombosis leads to infarction (e.g. renal) but also using of coagulation factors leads to haemorrhagic damage too.
Why is an MI red and then white?
Red from inflammatory reaction and white from death/fibrosis
What’s a paradoxical embolism?
Passes from venous to arterial circulation through a defect e.g. patent foramen ovale, septal defect
How might fat embolism present?
Post surgery that has released fat from BM that has travelled to pulmonary circulation and caused dyspnea
PVD presentation
Intermittent claudication, gangrene, erectile dysfunction, pain at rest from chronic ischaemia
In an AAA, which parts of the wall become thicker and thinner?
Thicker- tunica intima
Thinner- tunica media
Causes of LV hypertrophy?
AV stenosis, aortic regurg, HTN,
What cell type changes occur in smoking?
Columnar bronchus epithelium changes to squamous to cope with smoke better. Risk of squamous cell carcinoma
What’s traumatic myositis ossificans?
When bone grows in muscle following trauma because fibroblasts become osteoblasts
