PATHOLOGIES Flashcards
(120 cards)
1
Q
Anaemia
A
Insufficient O2 carrying capacity due to decrease Hb concentrations
2
Q
Why is there not enough haemoglobin
A
Bone marrow doesn’t produce enough Hb - hypoproliferation - not enough ingredients or incorrect instructions.
Shortened survival - blood loss, haemolysis
3
Q
Iron absorption
A
Absorbed from duodenum.
Regulated by negative feedback of hepcidin - regulates ferroportin receptors on enterocytes, duodenum and proximal jejunum.
Transferred into plasma and bind to transferrin - transport protein.
Absorption depends on hepcidin, activity of ferroportin and type of iron available.
4
Q
Iron transport and storage
A
Iron transported from enterocytes to plasma or excess Iron stored as ferritin.
In plasma - attach to transferrin and transported to bone marrow or RBCs.
5
Q
Where is folate and B12 absrobed from
A
Folate = duodenum and jejunum B12 = ileum via intrinsic factor
6
Q
Function of folate and B12
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Folate = necessary for synthesis of DNA B12 = co-factor for methylation in DNA and cell metabolism - intracellular conversion to 2 active co-enzymes necessary for homeostasis of methylmalonic acid & homocysteine
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Q
Mechanism of absorbing B12
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Require intrinsic factors made in parietal cells of stomach
Transcobalamin II and transcobalamin I transport vit B12 to tissues
8
Q
Pernicious anaemia
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Autoimmune disorder - lack intrinsic factor - decrease B12 absorption.
Antibodies against gastric parietal cells or intrinsic factor
9
Q
Macrocytic anaemia
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Low Hb
High MCV
Norm. MCHC
10
Q
Haemolytic anaemia
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Anaemia due to shortened RBC survival
11
Q
Haemolysis
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- Shortened red cell survival
- Bone marrow compensates - increase RBC production
- increase young cells in circulation
12
Q
Compensated haemolysis
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RBC production able to compensate for decrease RBC life span = norm Hb
13
Q
Incompletely compensated haemolysis
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RBC production unable to keep up with decrease RBC life span = decrease Hb
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Q
Clinical findings of haemolytic anaemia
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Jaundice, pallor/fatigue, splenomegaly
Haemolytic crises - increase anaemia and jaundice with infections.
Aplastic crises - anaemia, reticulocytopenia
15
Q
Chronic clinical findings of haemolytic anaemia
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Gallstones - pigment due to bilirubin
Folate deficiency - increase synthesis for cells, increase demand because more broken down
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Q
Haemolytic anaemia - laboratory findings
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Increased reticulocyte count Increased unconjugated bilirubin Increased LDH Low serum haptoglobin proteins that binds free haemoglobin Increased urobilinogen Increased urinary haemosiderin Abnormal blood film
17
Q
Red cell membrane disorders examples
A
Hereditary spherocytosis
Hereditary elliptocytosis
18
Q
Red cell enzymopathies examples
A
G6PD deficiency
PK deficiency
19
Q
Hereditary spherocytosis
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Common haemolytic anaemia - inherited autosomal dominant fashion
defect in protein in vertical interaction between membrane skeleton and lipid bilayer
Decrease membrane deformability - membrane lose shape = RBC spherical
20
Q
Clinical features of Hereditary spherocytosis
A
Asymptomatic to severe haemolysis, neonatal jaundice, pigment gallstones.
Decrease eosin-5-maleimide (EMA) binding - binds to band 3
21
Q
Glucose 6 phosphate deficiency
A
hereditary, X-linked - protection from oxidative stress
22
Q
Effects of oxidative stress on Hb and membrane proteins
A
Hb - denatured Hb - heinz bodies - bind to membrane
Membrane proteins - decrease RBC deformability
23
Q
Pyruvate kinase deficiency
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Autosomal recessive
Required to generate ATP - essential for memrbane cation pumps.
Lose K+ and H2O = dehydrated and rigid
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Q
Thalassaemias
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Imbalanced alpha and beta chain production - excess unpaired globin chains = unstable.
Precipitate and adamage RBC - ineffective erythropoiesis in bone marrow
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Beta thalassaemia major - if transfusion does not occur
Failure to thrive, progressive hepatosplenomegaly, bone arrow expansion - skeletal abnormalities.
Side effects = Iron overload - heart failure, liver cirrhosis, endocrinopathoes
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Confirming diagnosis of sickle cell anaemia
Solubility test - expose blood to reducing agent - HbS precipitate = + trait and disease
Electrophoresis
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Steps for Primary haemostasis
1. Endothelium release small amount of von Willebrand factor
2. Collagen exposed to blood – von Willebrand factor binds to it
3. Platelets express receptors for both collagen and von Willebrand factor is then active when bound and then express functional fibrinogen receptors – NEEDED for aggregation
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Steps for secondary haemostasis
1. Platelet is activated
2. Tissue factor expressed by many sub-endothelial cells activate coagulation cascade to initiate increase of thrombin
- Factor FVIIa binds to tissue factor – prothrombin into thrombin
3. Thrombin activates receptors on platelets and endothelium - increase platelet aggregation and initiate release of stored von Willebrand factor from endothelial cells
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Steps for amplification stage in blood coagulation
1. Thrombin activates 2 cofactors - factor 8a and 5a
2. Form Ca2+ dependent complexes on surface of platelets with factor IXa and factor Xa - accelerate production of factor Xa and thrombin = amplification stage
3. Increase production of thrombin via tenase and prothrombinase - thrombin converts fibrinogen into fibrin mesh
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Steps of fibrinolysis
Plasminogen activated to plasmin by tissue plasminogen activator (t-PA)
Plasmin degrades the fibrin mesh to fibrin degradation products which can be cleared.
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What is antithrombin
Serpin = serine protease inhibitor
| Activity increases by binding to heparan binding sites on endothelial cells
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Protein C
Activated by thrombin + thrombomodulin on endothelial cells = APC
then works with protein S
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Protein S
APC cofactor
| Help bind to cell surface - APC degrades cofactor FVa and FVIIIa
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Molecular basis of Haemophlia
Failure to clot leading to haemorrhage.
Mutation in cogaultion factors - haemophilia A and B
Platelet disorder - von Willebrand disease
Collagen abnormalities - fragile blood vessels and bruising
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Molecular basis of thrombophilia
Excessive clotting leading to thrombosis
Inherited = mutation in coagulation factors (DVT)
Acquired = malignancy increase clotting factors (DVT)
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Molecular basis of DIC
Whole body clots
Infection - sepsis
Depletion of clotting factors and platelets leading to bleeding
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Aneuploid
Chromosome number is not an exact multiple of haploid number
| Extra or missing chromosomes - trisomy or monosomy
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How does aneuploid chromosomes occur
Error in segregation of pair of homologous chromosomes in meiosis I
Or when there is an error in segregation of chromatids - meiosis II = imbalance of chromosomes in zygote
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Trisomy 13
Pataus syndrome
| complications of heart abdominal wall and brain
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Trisomy 18
Edwards syndromes
| complex heart and brain abnormalities
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Trisomy 21
Down syndrome
High chance of health problems - congenital heart problems, disorders of digestive tract, visiom and increased risk of leukaemia
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Mitotic non-disjunction
Post zygotic non-disjunction - affect only a proportion of cells = mosaicism
Individual has a mixture of cell types
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Trisomy rescue/anaphase lag
Mechanism in cell recognise there is a wrong number of chromosomes and throws out one of the chromosomes to become disomic.
Could have both maternal chromosomes - clinical impact
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Philadelphia chromosome
Translocation between chromosome 9 and 22.
ABL on chromosome 9 = proto-oncogene
BCR on chromosome 22 = prone to ds DNA breaks.
Exchange material which can trigger oncogene potential in ABL. Can lead to types of leukaemia and myeloma
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What occurs in Robertsonian translocation
Involves acrocentric chromosomes
| Ds breaks p arm is cut off and lost - q arms stuck together around centromere
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Detecting chromosomal abnormalities - what is FISH
Hybridisation - single strand nucleic acid strand binds to new single stranded nucleic acid strand - use metaphase chromosome
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Detecting chromosomal abnormalities - steps in FISH
1. Fluorescent probe
2. Denature probe and target DNA
3. Mix probe and target DNA
4. Probe binds to target
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Steps for array CGH
1. Patient and control DNA labelled with fluorescent dyes and applied to microarray
2. Patients and control DNA compete to attach or hybridise to the microarray
3. The microarray scanner measures the dluorescent signals
4. Computer software analyses the data and generates a plot
Looks for microdeletions and duplications
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QF-PCR
Uses microsatellites - isolate DNA from patient and make primers
PCR amplification
Gel electrophoresis
Genotype size of fragments
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What are the effects of inborn errors of metabolism due to
Toxic accumulation of substrates
Intermediates from alternative metabolic pathways
Defects in energy production/use due to deficiency of products
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Example of disease with autosomal recessive inheritance
Inborn errors of Metabolism
PKU
Alkaptonuria
MCADD
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Example of disease with autosomal dominant inheritance
Inborn errors of Metabolism
Marfan's
| acute intermittent porphyria
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Example of disease with X-linked inheritance
Inborn errors of Metabolism
Fabry's disease
| Ornithine carbamoyl transferase deficiency
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Example of disease with Mitochondrial inheritance
Inborn errors of Metabolism
MERFF - deafness, dementia, seizures
| MELAS - lactic acidosis, stroke like episodes
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Heteroplasmy - mitochondrial inheritance
Cell contains varying amounts of mtDNA and mutated mtDNA
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Classification of IEM
Toxic accumulation
Deficiency in energy production
Disorders of complex molecules involving organelles
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Clinical scenarios of neonatal presentation of IEM
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Poor feeding, lethary, vomiting
Epileptic encephalopathy
Profound hypotonia
organomegaly
Sudden death in infancy
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Biochemical abnormalities of neonatal presentation of IEM
Hypoglycaemia
hyperammonaemia
unexplained metabolic acidosis/ketoacidosis
lactic acidosis
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Anencephaly
opening in anterior portion of neural tube
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Craniorachischisis
Complete opening of neural tube - 1st stage of closing foes not occur properly
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Spina bifida
Opening at caudal end of neural tube
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Steps for primary neurulation
1. Shaped - will narrow along mediolateral axis and extend along rostral caudal axis
2. Folding - occurs by establishing hinge points at different regions along neural plate
3. Elevation - folding of lateral wings of neural plate
4. Convergence - neural folds converge - form more hinge points in dorsal regions
5. Closure - fuse with each other and complete closure of neural plate
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How does Cell wedging occur
Change shape of cells in neural plate - apical side = narrow = work as hinge
Remodelling of microtubules and actin filaments - Wnt PCP - control actomyosin cytoskeleton at apical side - contracted along medial lateral axis
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Wnt PCP pathways association with neural tube formation
Controls the remodelling of actomyosin cytoskeleton at apical side of cell - becomes contracted along medial lateral axis = change shape of epithelium = hinge
Mutations in pathway = no hinge = craniorachischisis
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Proteinopathies involved in Alzheimer's disease
- Amyloid plaques - extracellular protein aggregates. Enriched in Aβ peptides
- Neurofibrillary tangles - paired helical filaments - intracellular protein aggregates. Enriched in Tau protein.
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How do amyloid plaques form
Aβ peptides cleaved from transmembrane protein called amyloid β precursor protein (APP) by proteases.
Cleavage by β secretase and then γ secretase – release Aβ fragment – accumulates leading to plaque
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How do neurofibrillary tangles form
Tau binds microtubules in axons - hyperphosphorylated tau = displaced leading to tangles, destabilised.
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Motor symptoms of parkinsons
Resting tremor
bradykinesia
rigidity
postural instability
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Non-motor symptoms of parkinsons
Depression and anxiety
Loss of smell
Sleep disorders
Constipation
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Proteinopathy involved in parkinsons
Lewy bodies - intracellular protein aggregates. Enriched in in α-synuclein protein – not pathogenic but high levels of α-synuclein is pathogenic.
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Causes of parkinson's
1. Early/juvenille onset recessive mitochondrial conditions
2. Late/later onset (usually) autosomal dominant PD
3. Mutations that cause 'PD plus' conditions
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How does early onset mitochondrial PD occur
Loss of function - mutations in 2 proteins central to activating mitophagy - PINK1 and Parkin = cause early onset PD (EO PD)
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Causes for late onset genetic PD
Mutation in SNCA (α-synuclein) gene amplification – confirm is pathogenic
Mutation in LRRK2 and VPS35 gain of function
GBA loss of function mutation
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GBA and α-synuclein
GBA encode GCase = α lysosomal enzyme – α-synuclein is degraded in the lysosome
Unhealthy = low GCase = lysosome impaired = accumulate α-synuclein
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Pathogenic feed forward loop of α-synuclein
Increase α-synuclein = decrease GCase = decrease lysosomal function
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The effect of Neuroinflammation and association with PD
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Neuroinflammation = activation of immune system within NS - microglia active
Activation = neurotoxic factors = neuronal damage/death - neurotoxic insult = microglial activators - α-synuclein & other proteins
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Neuroinflammation and association with Alzheimers
Many alzheimer's risk factors cause high levels of circulating inflammatory cytokines
Increase BP, CVS, diabetes, smoking - increase inflammation
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Major functional changes in cancers
1. Increase growth – loss of growth regulation, stimulation of environment promoting growth
2. Failure to undergo apoptosis or senescence
3. Loss of differentiation – including alterations in cell migration and adhesion
4. Failure to repair DNA damage – including chromosomal instability
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Capture of c-src by retrovirus
Reverse transcription - dsDNA provirus, accidental integration of v-src next to c-src = fusion - packaged into capsid = oncogenic
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4 types of proteins involved in transduction of growth signals
Growth factors – EGF
Growth factor receptors – ErbB
Intracellular signal transducers – Ras and Raf – activate the ERK MAP kinase pathway leading to induction of additional genes
Nuclear transcription factors – ERK from the kinase pathway
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Codon mutations for bladder carcinoma
Glycine into valine
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Codon mutation for lung cancer
Glycine into cysteine
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RAS oncogene mechanism
1. Binding of extracellular growth factor signal
2. Promotes recruitment of RAS proteins to the receptor complex
3. Recruitment promotes Ras to exchange GDP (inactive Ras) with GTP (active Ras)
4. Activated Ras then initiates the remained of the signalling cascade (mitogen activated protein kinases)
5. These kinases ultimately phosphorylate targets, such as transcription factor to promote expression of genes important for growth and survival
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Mutated RAS
Hyperactive RAS - loss of GTPase
| Activity of RAS protein no return to inactive RAS GDP - ALWAYS ON = TUMORIGENESIS
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MYC oncogene mechanism
Encode helix loop helix leucine zipper transcriptionfactor - dimerises with partner protein Max = transactivate gene expression
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MYC deregulation
chromosomal translocation
| Under control of foreign transcriptional promoters = deregulation of oncogene - drive relentless proliferation
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MYC activation in Burkitt's lymphoma
Associated with EBV
| Chromosomal translocation put mYC gene under regulation of Ig heavy chain - cmyc deregulated
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Retinoblastoma cancer
Rare childhood cancer – immature retinoblasts grow quickly and do not turn into mature retinal cells
Reflect light back in white = leukocoria
Hereditary mutation on chromosome 13, retinoblastoma 1 gene
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Retinoblastoma gene in cell cycle
Rb protein – regulate the cell cycle, inhibit G1 to S phase transition – regulate activity of E2F transcription factor
Cyclin D1 – 1st cyclin synthesised – drive progression into G1 with cdks4/6. Then arrest of cell cycle due to DNA damage
Substrate for cyclin D = RB protein – Cyclin D and E families phosphorylate RB – inactive
Active Rb = hypophosphorylated – bound to E2F – block progression to S phase
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Regulation of P53
Usually p53 levels low due to MDM2 protein – ubiquitin ligase – + ubiquitin to lysine residues of molecule and targeted for proteasomal degradation.
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Activation of P53
Stress signals can activate p53 - sensed by kinases = phosphorylate p53 - disrupt interaction with MDM2
ATM/ATR activate oncogenes - phosphorylate p53 directly/indirectly move back into nucleus to regulate process - DNA repair, apoptosis, cell cycle arrest
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Therapeutic strategies to increase P53s life/activation
Refold P53 into wild or regulate regulators of P53
wild type = increase 1/2 life
Nutlin = MDM2 antagonist
CRM1 - nuclear export inhibitor - accumulate P53 in nucleus
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Leukaemia
malignant disorders of haematopoietic stem cells characteristically associated with increased WBC in bone marrow or/and peripheral blood
Clonal disease - all malignant cells derive from single mutant SC
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Aetiology - genetic risk factors of leukaemia
Gene mutations involving oncogenes or tumour suppressors
Chromosome abberations - translocations and numerical disorders (BCR-ABL in CML)
Inherited immune system problems - ataxia telaniectasia, wiskott aldrich syndrome
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Environmental risk factors for leukaemia
* Radiation exposure – acute radiation accidents or atomic bomb survivors
* Exposure to chemicals and chemotherapy - Cancer chemotherapy with alkylating agents – industrial exposure to benzene
* Immune system suppression – e.g. after organ transplant
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Acute leukaemia
Undifferentiated leukaemia - characterised by uncontrolled clonal and accumulation of Immature WBC - lymphoblasts or myeloid blasts in bone marrow and blood
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Symptoms of acute leukaemia
Thrombocytopenia - purpura, epistaxis, bleeding from gums
Neutropenia - recurrent infections, fever
Anaemia - lassitude, weakness, tiredness, shortness of breath
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Acute lymphoblastic leukaemia
Commonest cancer of childhood - cancer of immature lymphocytes - B cell and T cell leukaemia
Treat with chemotherapy
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Acute myeoblastic leukaemia
Very rare cancer of immature myeloid WBC
| Treat = chemotherapy, monoclonal antibodies +/- allogeneic bone marrow transplant
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Chronic leukaemia
Differentiate leukaemia - characterised by uncontrolled clonal and accumulation of mature WBC - increase number of differentiated cells
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Chronic lymphocytic leukaemia symptoms
Large numbers of mature lymphocytes in bone marrow and peripheral blood.
Recurrent infections due to neutropenia, and suppression of normal lymphocyte function
Anaemia thrombocytopenia
Lymph node enlargement and hepatosplenomegaly
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Chronic myeloid/granulocytic leukaemia - symptoms and diagnosis
Often asymptomatic and discovered through routine blood test
Increase WBC count in blood and bone marrow, presence of Philadelphia chromosome
Treatment = targeted therapy - IMATINIB
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BCR-ABL unregulated tyrosine kinase effects
Proliferation of progenitor cell in absence of growth factors
decrease apoptosis
decrease adhesion to bone marrow stroma
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Imatinib mechanism for targeted therapy
Small molecule inhibitor
targets Abl-CML treatment - 95% of CML have detectable philadelphia chromosome
Imatinib competes with ATP - tyrosine is not phosphorylated and cannot phosphorylate substrate
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Lymphoma
Cancer of WBC - affect mature blood cells - B and T cells
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Lymph node functions
Blood filtration/purification
Absorption and transport of lipids
Removal of excess fluids from tissues
Immune system activation
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Hodgkin lymphoma
17% of lymphomas
Clonal B cell malignancy - presentation = non-painful enlarged lymph node
Risk = 50% cases due to EBV
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Diagnosis and treatment of hodgkin lymphoma
Diagnosis - Biopsy - find multinucleated reed sternberg cell
| Treatment - chemotherapy, +/- radiotherapy. SC transplant
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Non Hodgkin lymphoma
83% of lymphomas - incidence increases with age
Enlarged lymph nodes - some forms slow and the others fast - general lymphoma symptoms
Risk factors = virus infections, EBV in burkitt lymphoma. Human T cell leukaemia in adult T cell lymphoma
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Causes of non hodgkin lymphoma
Chromosomal translocations
Tissue specific enhancer = activate promoter of rearranged segment of chromosomes - cases of follicular lymphoma - start to regulate and enhance transcription of genes located on other chromosome.
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Example of chromosome translocation for non hodgkin lymphoma - follicular lymphoma
Chr 18 has BCL-2 gene
Enhancer in chr 14
BCL-2 = apoptosis inhibitor
Enhance transcription of apoptosis inhibitor = decreases apoptosis
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Low grade lymphoma
Normal tissue architecture partially preserved - normal cell of origin recognisable
divide slowly
May be present for many months before diagnosis
behave in indolent fashion
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High grade lymphoma
Loss of normal tissue architecture - normal cell of origin hard to determine
Divide rapidly
present for a matter of weeks before diagnosis
May be life threatening
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Diagnosis and treatment of non hodgkin lymphoma
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Diagnosis = immunophenotyping, cytogenetics, light chain restriction, PCR
Treatment = chemotherapy, radiotherapy, SC transplant, monoclonal Ab therapy - RITUXIMAB
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Multiple myeloma
Tumour of bone marrow that involves plasma cells
Presentation = absence of initial symptoms - later = bone pain, bleeding, freq infections and anaemia
Risk factors = obesity, radiation exposure, family history, and certain chemicals
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3 aspects of myeloma
1. Suppression of normal bone marrow, blood cell and immune cell function - anaemia, bleeding tendency and recurrent infections
2. Bone resorption and release calcium
3. Pathological effects of paraprotein
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Bone resorption and release of calcium effects in myeloma
Myeloma produce cytokines (IL6) to bone marrow stromal cells to release RANKL to osteoclast activation and suppress OPG.
Ca2+ released from bone leads to hypercalcaemia leading to mental disturbance and multiple symptoms
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Pathological effects of paraprotein
Single monoclonal Ig in serum - high levels - malignancy
Precipitate in kidney tubules leading to renal failure - deposited as amyloid in tissues.
2% of cases develop hypervisocosity syndrome
Increase viscosity of blood leading to stroke and heart failure
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Diagnosis of myeloma
Serum electrophoresis for paraprotein
Bone marrow biopsy fo rhigh levels of plasma cells
Flow cytometry and cytogenetics to detect cause
Urine electrophoresis
Erythrocyte sedimentation rate - increase staking RBC
Radiological investigation of skeleton for lytic lesions
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Treatment for myeloma
Radiotherapy – localised bone pain
chemotherapy combinations (thalidomide, lenalidomide and bortezomib) – when there is dissemination
targeted therapies, immunotherapy (CAR-T), and allogenic haemopoietic SC transplantation in young patients.
