Case 14 Flashcards
What are component causes?
Factors that work together with the necessary cause to produce disease.
Overcrowding and TB
What is a necessary cause?
A factor that must be present for a disease to occur.
What is a sufficient cause?
A combination of factors that is sufficient to cause disease in at least some people
Levels of causation: upstream factors
Social - gender, race, SES
Population: income inequality, lack of social cohesion, inadequate medical services
Levels of causation: downstream factors
Physiological: genetics, sex, age
Behavioural: smoking, diet, exercise, alcohol
Ecological model: levels of causation
Biological
Behavioural
Societal
Structural
Evidence based practice
Assess your patient Ask the right question Access the evidence Appraise the evidence Apply the evidence Audit your clinical practice
Which study designs are best for evaluating potential harms?
Case reports can’t draw generalisable conclusions
Case control prone to bias and confounding
Trials not useful for long term effects
Cohort studies with a large representative sample, objective measures of exposure and outcome and good long term follow up are good
Systematic reviews of all the good evidence are best
Is an apparent association real?
Bias?
Confounding?
Chance?
Is the association causal? Bradford Hill
Bradford hill criteria
Does cause precede effect? What is the strength of the effect? Is there a dose-response effect? Is there biological plausibility? Has the effect been consistently shown in similar studies in different populations?
Acute leukaemia non-specific presenting features
Unwell Tired Aches and pains Fever Often little to find on exam but may have bleeding, sepsis, pallor
NB if symptoms persist/get worse
Acute leukaemia specific features
Bone marrow infiltration: anaemia, bleeding, infections
Tissue infiltration: gum hypertrophy, lymphadenopathy, splenomegaly, CNS disease (ALL)
Tests used toc lassify acute leukaemia
Morphology (peripheral blood and bone marrow) Cytochemistry Immunophenotype ( flow cytometry) Genetic abnormalities (FISH, PCR)
Leukaemia initial diagnosis
FBC
Differential count
Morphological review of peripheral blood slide
Leukaemia definitive diagnosis
Bone marrow aspirate/trephine biopsy
Aspirate provides cells for cytogentic/molecular studies
Leukaemia additional non-diagnostic tests
LP to exclude CNS disease
HIV test
DIC screen
Electrolytes and renal function
Supportive therapy
Packed red cell transfusion for anaemia
Platelet transfusion for thrombocytopaenia
Hydration and allopurinol for tumour lysis syndrome
Prevention and treatment of infections
Anti emetics to prevent chemo-associated nausea
Primary lymphoid organs
Bone marrow
Thymus
Main Th1 cytokines
IL-2, TNF beta, IFN gamma
Cell mediated response
Main Th2 cytokines
IL-4, IL-10
Antibody response
A chromosomal translocation may result in
Fusion protein product
Aberrant expression of normal protein
Karyotype analysis
Direct morphological observation of chromosomes under a microscope
Requires cells to be in metaphase
Therefore cell culture is performed before analysis
FISH
Uses fluorecent-labelled genetic probes which hybridize to different parts of the genome and allow visualization of karyotype abnormalities
How is acute leukaemia defined?
> 20% blasts in blood or BM at presentation
Abnormalities leading to build up of leukaemic cells
Increased rate of proliferation
Avoidance of apoptosis
Block in differentiation
Modes of action of antibodies
Neutralisation
Opsonisation
Agglutination
Activation of classical complement pathway
General properties of immunity
Specificity
Versatility
Memory
Tolerance
Secondary lymphoid tissues
Lymph nodes Spleen Tonsils MALT BALT
T cell mediated killing
Perforin release
Release of granzyme proteases
Fas ligand
NK cell killing
NK cells are inhibited by class 1 MHC which are not expressed at normal levels on cancer or virally infected cells
Perforin release
Macrophage activation
Structure of the lymph node
Dense connective tissue capsule pierced by afferent lymphatics with valves.
Fibrous trabeculae
Subcapsular space flows into paratrabecular sinuses - lined with macrophages.
Outer cortex with follicles, inner cortex, medulla
Medullary sinuses surrounded by medullary cords.
One efferent lymphatic vessel
Where do most lymphocytes enter the lymph node?
High endothelial venules in the inner cortex
Where in the lymph node are plasma cells found?
In the medullary cords where they can secret antibodies directly into the medullary sinusoids without leaving the lymph node
What is the function of follicular dendritic cells?
Mature activated B cells migrate to the germinal centre where they must interact strongly with whole antigen presented by FDCs in order to proliferate or else they accumulate in the mantle zone and undergo apoptosis and phagocytosis by macrophages.
Structure of the thymus
Fibrous capsule
Two lobes, divided into incomplete lobules by fibrous trabeculae containing trabecular arterioles
Cortex contains thymic epithelial cells organised in a 3D network supported by collagen fibres
Thymic epithelial cells populate the medulla. Some form Hassal’s corpuscles which produce thymic stromal lymphopoeitin which optimises negative selection
Blood thymus barrier
Double basal lamina
Endothelial cells linked by tight junctions
Thymic epithelial cells surround capillaries and are linked tightly by desmosomes
Macrophages engulf foreign antigen
General organisation of the spleen
Surrounded by a fibrous capsule. Capsule-derived trabeculae penetrate the stroma carrying trabecular arteries and veins
No cortex/medulla. No afferent lymphatics
Stroma consists of reticular fibres supporting the red and white pulp
Component of the splenic white pulp
Central arteriole
PALS
Corona containing B cells and APCs
Germinal centre
Red pulp
Interconnected network of splenic sinusoids lined by elongated endothelial cells.
Splenic cords separate splenic sinusoids.
Splenic cords contain plasma cells, macrophages and blood cells.
Vascularisation of the spleen
Splenic artery enters at the hilum Trabecular arteries Central arteriole + radial arterioles + marginal sinus Penicillar artery Macrophage sheathed capillaries Splenic sinusoids or red pulp stroma
How is the classical complement pathway activated?
Binding of C1 to an antigen bound antibody
B cell development
Occurs in bone marrow niche environment created by stromal nurse cells in the presence of IL-7
As the cell matures from pro-B to pre-B to immature B, heavy chain VDJ rearrangement occurs followed by light chain VJ rearrangement
As the cell matures it migrates from the subendosteum towards the central axis
Negative selection takes place in the BM and self-reactive cells undergo apoptosis
T cell development
Immature T cells must migrate from the BM to thymus to complete development
Arriving T cells are double negative.
They become double positive and express both CD4 and CD8
Positive selection allows cells that bind self MHC but not self antigen to continue and the rest undergo apoptosis
Negative selection eliminates self reactive cells and they are phagocytosed by macrophages
Single positive mature cells migrate to the periphery
5 periods of psychosocial support
At diagnosis At remission At relapse At terminal phase At death
Hypersplenism
Association between peripheral blood pancytopaenia and splenic enlargement
Primary idiopathic form causes massive splenomegaly requiring splenectomy
Causes of gross splenomegaly
Chronic myeloid leukaemia
Myelofibrosis
Malaria
Gaucher’s disease
Causes of moderate splenomegaly
Amyloidosis
Haemolytic anaemia
Chronic lymphocytic anaemia
Congestion
Causes of mild splenomegaly
Infection
Autoimmune disease
Felty’s disease
Anat path reader general causes of splenomegaly
Congestion Infection Immune disorders Red blood cell abnormalities Primary or metastatic neoplasms Storage disorders Amyloidosis
Reactive lymph node hyperplasia
Usually mixed response in nodes draining sites of infection
Granulomatous lymphadenitis
Mycobacterial: caseous necrosis with Langhans giant cells
Toxoplasma: follicular hyperplasia with adjacent granulomas and marginal zone B cell hyperplasia
Sarcoidosis
Crohn’s disease
Reaction to tumour antigen
Foreign body reaction
Necrotising lymphadenitis
Stellate abcesses within lymph nodes surrounded by pallisades histiocytes
Lymphogranuloma venereum and cats scratch disease
Kikuchi’s disease
SLE
Follicular hyperplasia
Syphilis, any stage
Marked follicular hyperplasia with many interfollicular plasma cells
Rheumatoid arthritis
Paracortical hyperplasia
EBV
Paracortical hyperplasia with numerous large transformed T cells
Dermatopathic lymphadenopathy. Brown yellow cut surface. Histiocytes contain melanin
HIV lymphadenopathy
AIDS related complex or persistant generalised lymphadenopathy syndrome
Initial hyperplasia
Mantle zone implosion/follicular lysis
Loss of germinal centre B cells and paracortical T cells
Hodgkins lymphoma distinguishing features
Almost never involves tonsils, skin, stomach, ileum
Reed-Sternberg cells
Classic Reed Sternberg cell
Large cell with large multilobated nucleus, very large eosinophilic nucleolus and slight acidophilic cytoplasm
Classifying HD
Use WHO classification
Divided into lymphocyte predominant and classic HD
Classic HD is further divided into 4 types. Lymphocyte rich, nodular sclerosing, mixed cellularity and lymphocyte depleted
Spread of disease in HD
Spreads predominantly through contiguous lymphatics
HD complications
Infection
Cachexia
Iatrogenic
Second malignancy
NHL risk factors
Viruses: EBV, HTLV1
Immunodeficiency: x-linked, AIDS, transplantation
NHL presentation
Painless rubbery nodes
More likely to be multicentric
May be no systemic symptoms
May involve extralymphoid tissue like skin, GIT etc
List the human herpes viruses
HSV 1 and 2 VZV CMV EBV HHV 6 and 7 HHV8
Herpes virus morphology
Double stranded RNA
Icosahedral capsid
Envelope
Which anatomical sites are affected by HSV 1 and 2?
1: orofacial
2: genital
How does HSV maintain latent infection?
Persists in episomal form in the sensory ganglia supplying the area of primary infection - generally the trigeminal or sacral ganglia.
Rare life threatening HSV syndromes
Acute necrotising encephalitis
Neonatal infection
Disseminated infection
HSV reactivation may be provoked by
Sunlight Stress Febrile illness Menstruation Immunosuppression
HSV primary infection syndromes
Gingivostomatitis Exzema herpeticum Traumatic inoculation Conjunctivitis, keratitis Genital herpes
Recurrent HSV syndromes
Cold sores
Recurrent genital herpes
Recurrent kertitis
HSV diagnosis
IgG indicates past infection. Igm unreliable
Microscopy
PCR
Culture
Progression of VZV lesions
Macule Papule Vesicle Pustule Scab
Chicken pox
Mild febrile illness
Generalised vesicular rash
Highly infectious via respiratory droplets and vesicle secretions
Chicken pox complications
Secondary skin infections Post infectious encephalomyelitis Stroke (vasculitis) Pneumonia Haemorrhagic varicella
Congenital VZV
Infection before 20 weeks teratogenic
Zoster complications
Post herpetic neuralgia
Encephalitis, myelitis
Stroke
Preciptating factors for zoster
Immunosuppression
HIV
Old age
Cancer
VZV diagnosis
Clinically apparent
IgG for past infection. IgM unreliable
PCR
Treatment of HSV and VZV
Acyclovir
PEP for varicella
Immunosuppressed, baby less than 6 months or pregnant: zoster immune globulin or avyclovir
Low risk patient: varicella vaccine or acyclovir
CMV transmission
70-90% of adults have antibodies. Infection in first few years of life
Spread in saliva, urine, breast milk, semen, blood. Therefore close contact, kissing, sexual contact, iatrogenic
CMV clinical syndromes
Primary infection in adulthood gives an infectious mononucleosis-like illness
Congenital: severe disease only follows primary infection in pregnancy
Immunosuppressed patients: interstitial pneumonia, retinitis, GIT ulceration neurological disorders
CMV treatment
Gancyclovir
CMV diagnosis
IgG
Viral antigen in diseased tissue
PCR
Viral load
EBV transmission
Saliva, kissing
As for CMV
90-100% of adults have antibodies
Infectious mononucleosis symptoms
Fever, malaise Rash Lymphadenopathy Sore throat HSM Atypical lymphocytosis
Self limiting
Infectious mononucleosis differential diagnosis
EBV
CMV
HIV
HHV6
EBV diagnosis
Mono spot heterophile antibodies
IgG and IgM to viral capsid antigen
Complications of EBV latency
Lymphoproliferative disorders
NHL
HD
Nasopharyngeal carcinoma
Neonatal HHV6 infection
Roseola infantum: febrile illness, rash, febrile convulsions
HHV8 disease associations
Kaposi’s sarcoma
Primary effusion lymphomas
Multicentric castleman’s disease
Gout
Recurrent inflamatory disorder caused by deposition of urate crystals in synovial fluid
Gout pathogenesis
Hyperuricaemia
Crystal deposition
Macrophage phagocytosis
Inflammatory cascade
Causes of hyperuricaemia
Overproduction: Inherited enzyme defects Ethanol Obesity Malignancy Myeloproliferative, lymphoproliferative, heamatological disorders
Underexcretion:
Clinical disease- renal insufficiency, ketoacidosis, hypothyroidism etc
Diuretics
Overconsumption of meat, seafood, beer
Gout prevention
Diet Drugs: Increase excretion- probenecid Decrease production - allopurinol Increase metabolism - rasburicase
Tumour lysis syndrome
Life threatening oncological emergency caused by rapid lysis of malignant cells.
Hyperuricaemia
Hyperkalaemia
Hypocalcaemia
Hyperphosphataemia
GIT disturbances Muscle weakness, cramps Parasthaesia Tetany Lethargy
Tumour lysis syndrome treatment
Kayexalate
Calcium replacement
Phosphate binders
Dialysis
Tumour lysis syndrome prevention
IV hydration
Urine alkalinisation
Hypouricaemic agents
Multiple myeloma clinical features
Bone marrow infiltration:
Bone pain, fractures, lytic lesions
Hypercalcaemia
Anaemia, infections
Monoclonal protein production:
Renal failure
Hyper viscosity syndrome
Peripheral neuropathy
Receptor mediated apoptotic pathway
Ligand binding to the Fas or TNF receptors triggers an intracellular caspase cascade resulting in cell shrinkage, DNA cleavage, nuclear fragmentation and phagocytosis of apoptotic bodies by macrophages
Mitochondrial apoptosis pathway
Damage to cellular components triggers release of cytochrome C from the mitochondria which then activates caspase proteases. Mitochondrial membrane permeability controlled by Bcl proteins. p53 activates apoptosis by raising the level of BAX which overrides Bcl2 and triggers Cytochrome c release
Specific treatment of acute leukaemia
Induction
Consolidation
High dose intesification (requires BM transplant)
Maintenance
Mechanisms of action of chemotherapeutic drugs
Damage to mitotic spindle Bind DNA and interfere with mitosis Deprive cells of asparaginine Lysis of lymphoblasts Cross-link DNA, impede RNA formation
