Pathology Flashcards
What are the key diagnostic tests for SLE, Sjögren’s syndrome and scleroderma respectively?
SLE - Anti-dsDNA antibody
Sjögren’s - anti-ribonucleoprotein antibodies (anti-SS-A and anti-SS-B)
Scleroderma -DNA topoisomerase I (Scl-70) antibody
All are characterised by ANA
Sjögren’s syndrome is associated with increased risk for which cancer?
B-cell lymphoma
What is CREST syndrome?
Calcinosis (plus anti-Centromere antibody)
Raynaud phenomenon
Esophageal dysmotility
Sclerodatyly
Telangiectasia
Describe the 3 tissue types relevant for tissue regeneration with examples
- Labile tissues: continuously cycle to regenerate tissue e.g bowel (stem cells in mucosal crypts); skin (stem cells in basal layer); bone marrow (haematopoietic stem cells)
- Stable tissues: quiescent but can reenter cell cycle e.g. hepatocytes (liver), proximal renal tubule (kidney)
- Permanent tissue: lack regenerative potential e.g. myocardium, skeletal muscle, neurons (damage to these tissues will be repaired via fibrous scar)
What is the marker of haematopoietic stem cells
CD34+
What are the 3 main components of granulation tissue?
Fibroblasts (deposit type III collagen), capillaries (provide nutrients), myofibroblasts (contract wound)
When granulation tissue is converted to scar, type X collagen is replaced by type Y collagen
X = III (3); Y = I (1)
Occurs via collagenase , which requires zinc as a cofactor . Type I collagen will give the tissue more strength
Where are each type of collagen typically located?
Type 1 = bONE; type 2 = cartilage (car-‘two’-lage); type III = blood vessels, granulation tissue, embryonic tissue; type 4 = basement membrane
Revise key growth factors involved in wound repair
TGF-alpha: epithelial & fibroblast growth factor
TGF-beta: important fibroblast growth factor; inhibits inflammation
PDGF: endothelium, smooth muscle, fibroblast growth factor
FGF: angiogenesis; skeletal development
VEGF: angiogenesis
What are the 2 ways cutaneous healing can occur?
Primary intention - wound edges approximated -> minimal scar formation
Secondary intention - wound edges NOT approximated -> granulation tissue fills the defect, contraction of myofibroblasts will contract the wound
Contrast hypertrophic scar vs keloid?
Hypertrophic scar - excess of type I collagen
Keloid - excess of type III collagen
What is Dubin-Johnson syndrome?
Deficiency of bilirubin canalicular transport protein causing elevated conjugated bilirubin. Autosomal recessive disorder. Characterised by very dark liver, but otherwise rarely clinically significant.
What is Crigler-Najjar syndrome?
Genetic disorder of bilirubin metabolism. Absent UGT (uridine glucuronosyltransferase) -> unable to breakdown bilirubin
It presents in baby, causes kernicterus and is usually fatal
Pruritus in obstructive jaundice is due to elevated plasma ___
Bile acids
List 4 groups of chemicals that mediate acute inflammation and list examples for each
1) Vasoactive amines: histamine, serotonin
2) Lipid products (metabolites of arachidonic acid, present in phospholipid membranes): prostaglandin, leukotrienes, TxA2
3) Cytokines: IL-1, IL-6, TNF
4) complement pathway
Histamine causes vaso(constriction/dilatation) and (increases/ decreases) vascular permeability
Vasodilatation, increases
Serotonin is produced in which cells?
Platelets, certain neuroendocrine cells (e.g. GIT)
Which enzymes produce prostaglandins and leukotrienes respectively?
Cyclooxygenase and lipooxygenases
Montelukast is a ____ used in _____
Leukotriene receptor antagonist; asthma
DiGeorge syndrome is the failure to form the 3rd and 4th ____ and is due to a ___ microdeletion. It causes __ cell deficiency
Pharyngeal pouches; 22q11; T cell deficiency (due to lack of thymus) - also hypocalcaemia (lack of parathyroids) and abnormalities of heart, great vessels and lower face
Low immunoglobulin levels (e.g. due to CVID) increases the risk for what types of infection? (Broad categories)
Bacterial, enterovirus, Giardia
C5-9 deficiency increases the risk for ____ infection
Neisseria
What are the 2 hallmarks of acute inflammation?
Oedema and neutrophils
Innate immunity is a broad, non-specific system that includes epithelium, mucous, complement and which types of cells?
Neutrophils, eosinophils, basophils, macrophages, mast cells
Toll-like receptors (TLRs) are found on which cells?
Macrophages & dendritic cells.
TLRs recognise PAMPs (pathogen associated molecular pattern) and binding results in R activation & gene upregulation e.g. including NF-kappa B -> immune mediation
Which molecules mediate vasodilation and increased vascular permeability
PGI2/ PGD2/ PGE2. Note that vasodilation occurs at arteriole, vascular permeability usually occurs at post-capillary venule
Leukotrione B4 (LTB4) is produced via the ____ pathway. It attracts and activates ____
5-lipooxygenase; neutrophils. LTs mediate vasoconstriction (increasing vascular permeability) and cause bronchospasm
Which complement proteins activate mast cell degranulation?
What are the other 2 mechanisms by which mast cells are activated?
C3a, C5a
Tissue trauma
Cross-linking of surface IgE with Ag
Describe the 3 pathways of complement activation:
Classical: C1 binds to IgG/ IgM bound to antigen (“GM makes classic cars”)
Alternative: microbial products directly activate complement
Mannose-binding lectin (MBL): MBL binds mannose on microorganisms and activates complement
Hageman factor (factor _____) is an inactive pro inflammatory protein produced in the liver. It is activated in the ___ clotting pathway upon exposure to sub endothelial or tissue collagen and plays an important role in ___
XII
Extrinsic pathway
DIC, especially in severe gram negative sepsis. Subsequently activates coagulation + fibrinolytic system, complement and Kinin system (bradykinin).
Pain in acute inflammation is mediated by ___ and ___
PGE2 and bradykinin (these sensitise sensory nerve endings)
What is the primary metastatic site for colorectal cancer?
Liver (due to venous drainage pathway via portal system)
Anal tissue above the pectinate line drains to ____ nodes , whereas that below the pectinate line drains to ____ nodes (include multiple stations)
ABOVE: internal iliac nodes;
BELOW: superficial inguinal nodes -> deep inguinal nodes + external iliac nodes
Metastatic calcification occurs due to ____ and typically affects interstitial tissues of gastric mucosa, kidneys, lungs, systemic arteries and pulmonary veins - these tissues all have an internal (ACIDIC/ ALKALINE) compartment in common
Hypercalcaemia; alkaline (they excrete acid)
What are the main chemotactic agents?
Leukotrienes (LTB4), activated complement C5a, cytokines (IL-8 family) and bacterial products
What are the two main opsonins and their respective receptors?
IgG (Fc fragment) - binds FcgR
C3b - binds CR 1-3 (also bound by fibronectin/ laminin)
Opsonisation is most effective when simultaneous C3 and Fc binding occurs
Another opsonin is collectins
The relevant gene for familial hypercholesterolaemia is located on which chromosome? What is the inheritance pattern?
Chromosome 19
Autosomal dominant
What are the most common types (3) of nonrandom structural chromosomal abnormalities in tumour cells?
Balanced translocation;
Deletions;
Gene amplification
True or false: streptococcus pneumoniae release toxins that cause necrosis of lung tissue in pneumonia
False
They induce chemotaxis but elicit no major toxins (therefore cause inflammation WITHOUT necrosis)
True or false: most antibiotics are lipid soluble
False! Most antibiotics are NOT lipid soluble. Therefore they have difficulty passively diffusing through gram NEGATIVE membrane (lipid bilayer)
Clostridium spp. are gram ____ bacterium
Positive
Gram ___ bacteria contain/ release endotoxins whereas gram ___ bacteria contain/ release exotoxins
Positive
Negative
Which gram negative bacterium is one of the few to excrete a clinically significant exotoxin?
Pseudomonas aeruginosa
What is the definitive treatment for synergistic bacterial gangrene?
Surgery - wide excision + drainage
(Antibiotics and hyperbaric O2 can be supplemental therapies)
What is the main virulence factor of streptococcus pneumoniae?
Its capsule
Allows it to escape phagocytosis & spread in lung/ bloodstream
What are the main sites of systemic miliary tuberculosis?
Liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes and epididymis
List 4 situations that delay/ inhibit wound contraction?
Steroids, burns, skin grafting, XRT
What does the autoclave process involve for sterilisation?
Pressured steam at 121 degrees for 15mins
What is SIRS criteria?
Any 2 of the following:
Tachycardia >90bpm
Temp <36 or >38
RR >20
WCC <4 or >12 or >10% immature band forms
What is qSOFA criteria?
RR ≥22
SBP ≤100
Altered mental status
What are the 4 types of healing?
1) Resolution
2) Regeneration
3) Fibrous repair
4) Remodelling
In graft rejection, CD4+ (TH) cells are stimulated by ____ on graft cells and CD8+ (Tc) cells by ____
CD4+ (TH) - class II HLA
CD8+ (Tc) - class I HLA
Ig classes are named according to their ____ chain
Heavy
IgM, IgG, IgE, IgA, IgD
Class switching is induced by binding of ____ to ______ and secretion of which cytokines?
TH2 TCR binding to Ag-MHC class II complex on B cell surface
(Also co-binding of CD40L/ with CD40)
IL-4,5,6,13, TGFß, TNFa, IFN
- IL-4,13: IgE, some IgG
- IL-5, TGFß: IgA , some IgG
- IFN: IgG
True or false: the Ab-Ag combination is determined by covalent linkage
False
It is shape-determined, and the combination is divalent
What does HLA stand for? Which chromosome are the genes located?
Human leukocyte antigen
Chromosome 6
MHC class I are found on _____ cells and recognise ____
MHC class II are found on _____ cells and recognise ____
Class I - all nucleated cells; recognise viral/ self Ag
Class II - antigen presenting cells; recognise foreign Ag (bacterial)
Which Ig can cross the placenta?
It does this by binding to placental Fc-Rs
IgG
Which of the following pairings is most antigenic?
Live or killed virus
Carbohydrate or protein
Dermal antigen or IM/Subcut antigen
Live
Protein
Dermal
Immunological tolerance (to ‘self’) begins in foetal development around ___ weeks
20
Which immunoglobulins can have J chains?
J chains are only found in immunoglobulin molecules that exist in ____ form
IgA, IgM
Polymeric form
What scenarios may allow for future antibody-mediated hyperacute graft rejection?
Prior sensitisation with preformed antigraft antibodies
E.g. multiparity; previous renal transplant; previous blood transfusions
Compare the pathological effects of hyperacute graft rejection with chronic humoral rejection
Hyperacute - acute necrotising vasculitis with fibrinoid necrosis & graft ischaemic necrosis
Chronic humoral - slower rate of acute necrotising (subacute) vasculitis with intimal fibroplasia & foam cell accumulation
List 3 common sites affected by graft versus host disease
Skin - exfoliative dermatitis
Intestine - ulcerative enteritis
Liver - destruction of small bile ducts
(as well as the immune system)
Atherosclerosis is primarily a disease of which arterial layer?
Intima
In the pathogenesis of atheroma , ____ & _____ cells are responsible for phagocytosis of lipids
Macrophages and myofibroblasts
What are the 4 major clinical complications of atherosclerosis?
1) Ischaemia, due to narrowing
2) Thrombosis causing infarction
3) Embolism
4) Aneurysm +/- rupture, due to weakened wall
What are AGE products?
Advanced glycation end products
Intact endothelium secretes ____ , which inactivates thrombin/ Xa/ IXa , and ______, which binds free thrombin and activates protein C, PGI2, NO and ADPase to inhibit platelet aggregation
Injured endothelium secretes ____, which adheres platelets to collagen, and ____ , which activates coagulation
Intact - Heparin & thrombomodulin
Injured - vWF, thromboplastin
____ are the major prothrombotic force
Platelets
What is Virchow’s triad?
1) endothelial injury
2) alterations in flow e.g. stasis, turbulence
3) hypercoagulability
Describe the evolution of thrombi (5 pathways)
- Proximal propagation
- Embolism
- recanalization
- fibrous organisation
- resolution
What are foam cells?
Macrophages that have ingested lipid (& fibrous tissue) in atherosclerosis formation
What are the pathological findings post-MI at day 1-3 and day 3-7? When is a mature scar formed?
Day 1-3: coagulative necrosis (anucleated eosinophilic cardiac cells, neutrophilic infiltrate)
Day 3-7: formation of fibrovascular granulation tissue, macrophage phagocytosis of necrotic myocytes
Mature dense collagenous scar complete >2months
What are the 3 main causes of infarction?
1) Thromboembolism
2) Vasospasm/ vessel torsion
3) External compression/ entrapment
Infarction of the lungs is always (RED/ WHITE), and why?
Red aka haemorrhagic
Due to dual blood supply & loose structure - reperfusion of infarcted tissue, with collection of blood
When is the highest risk of myocardial rupture following an acute MI?
The first 3 days, as this is when there is maximal necrosis
Tumours cells have surface Rs for ____ & ____ to enable attachment to the ECM
Laminin (basement membrane) & fibronectin (interstitial CT matrix)
Signet ring cells are representative of which type of cancer? Give 3 specific examples
Mucus-secreting carcinoma e.g. gastric, colorectal, ovary
Reed-sternberg cells are pathognomonic for ___
Hodgkin’s lymphoma
What histopathological feature is typical in thyroid, ovarian & breast carcinoma and meningioma
Psamomma bodies
Tumour regression is most common in which 3 cancers (include site where relevant)
Neuroblastoma, melanoma (uveal tract), renal carcinoma
What is a Philadelphia chromosome (genetic abnormality, relevant genes & chromosomes) and which cancer is it associated with?
Translocation of ABL gene on chromosome 9 to sit within BCR gene (forming BCR-ABL1) gene on chromosome 22
CML
List an example of a chemical carcinogen that acts through a) initiation , b) promoter
a) any of: alkylating agents (cyclophosphamide, chlorambucil, busulphan), polycyclic hydrocarbons (cigarettes, BBQ), natural (aflatoxin, nitrosamine, asbestos)
b) any of: saccharin, cyclamates, oestrogen
What is the cancer most strongly associated with ionising radiation?
Leukaemia
A normal p53 gene will bind damaged DNA & activate which possible pathways?
Cell cycle (G1) arrest via p21 to inhibit COX
DNA repair via GADD45
Apoptosis via bax gene
What are the stages in the metastatic cascade?
- Clonal expansion, growth, diversification & angiogenesis
- Metastatic subclone
- Adhesion to & invasion of BM, passage through ECM
- Intravasation
- Interaction with host lymphoid cells
- Tumour cell embolus
- Adhesion to basement membrane
- Extravasation
- Metastatic deposit
- Angiogenesis
- Growth
(Page 306 Robbins)
What is the commonest form of cancer in immunosuppressed hosts?
Malignant lymphoma, especially immunoblastic lymphoma
Medullary thyroid carcinoma and phaeochromocytoma are associated with with MEN syndrome
MEN 2A
MEN 1 syndrome is associated with neoplasms of the ____
Pancreas and pituitary (the latter usually adenomas)
Which is the most common thyroid carcinoma?
Papillary
What is the genetic inheritance of familial adenomatous polyposis (FAP)?
Autosomal dominant
Carcinomas typically spread via lymphatics. What are 5 exceptions to this?
Choriocarcinoma, RCC, HCC, thyroid follicular, colorectal cancer - these tend to spread haematogenously
Describe the tumour staging system for colorectal cancer
Stage I-IV
I: T1 (into submucosa) / T2 (into muscularis propria) N0M0
II: T3 (into serosa), T4 (past serosa) N0M0
III: N+
IV: M+
The HER2 gene is a(n) oncogene/ tumour suppressor gene
Oncogene
Cancer cachexia is thought to be mediated by ___
TNF-alpha
Which virus is nasopharyngeal cancer linked with?
EBV
What are the 2 most common causes of inherited hypercoagulability?
Factor V Leiden & prothrombin mutation
What is the mechanism of oestrogen-dependent hypercoagulability?
Likely increases hepatic synthesis of clotting factors
Arterial & cardiac thrombi usually occur at sites of ____ , whilst venous thrombi occur at sites of ____
Turbulence/ endothelial injury
Stasis
Which type of haemolytic transfusion (acute/ delayed) reaction is caused by
a) ABO incompatibility
b) rhesus incompatibility
a) Acute
b) Delayed
What are the 2 most common inherited bleeding disorders?
Haemophilia A & von Willebrand disease
Regarding coagulation, the ___ pathway is measured by PTT and ____ pathway measured by PT
Intrinsic - PTT
Extrinsic - PT
DIC is most likely associated with which 4 (general) conditions?
Obstetric complications, malignant neoplasms, sepsis & major trauma
Anti-A/B antibodies are Ig__ (do/do not cross placenta) and anti-D (rhesus) antibodies are Ig__ (do/do not cross placenta)
Anti-A/B - IgM, do not cross
Anti-D - IgG, do cross
Streptococcus is catalase ____, and staphylococcus is catalase ____
Strep - negative
Staph - positive (either coagulase positive e.g. S. aureus or negative e.g. S. epidermidis)
Clostridium is gram ____
Positive
List 4+ gram negative bacteria/ classes
E. coli
Klebsiella
Pseudomonas
H. influenzae
Neisseria
Moraxella
Gram ____ bacteria have a thin peptidoglycan layer and an outer membrane with LPS endotoxin
Negative
Which types of streptococcus exhibit ß-haemolysis (complete)
GAS - S. pyogenes
GBS - S. agalactiae
True or false: Mycobacterium has a thick cell wall
FALSE - it has NO cell wall
Glycopeptide antibiotics (e.g. ____) target the ____ of G____ bacteria
E.g. vancomycin
Target - cell wall
G+ve
Bind D-ala-D-ala residues
Which antibiotic classes affect protein synthesis?
Aminoglycosides
Tetracyclines
Chloramphenicol
Erythromycin
Lincosamides e.g. lincomycin
buy AT 30, CEL at 50
ß-lactam antibiotics are not active against ______
Intracellular pathogens or those lacking a cell wall
Aminoglycoside antibiotics demonstrate ____-dependent killing, whilst ß-lactams demonstrate ___-dependent
Concentration
Time
____ antibiotics (class) can cause serum sickness
Cephalosporins
____ antibiotics (class) can prolong QT
Macrolides
____ are not effective against enterococci
Cephalosporins
What is the mechanism/ target site of -azole fungal drugs ?
Inhibit cytochrome P450 enzyme involved in ergosterol pathway (key fungal cell membrane component)
Nystatin is a ____ (class) anti-fungal
Polyene
Reduces cell membrane ergosterol content
What is the MOA and side effects of methotrexate?
MOA: folate antagonist
AEs: bone marrow suppression, hepatotoxicity, pneumonitis
What drug class does cyclosporin belong to and what effect does it have on T cells?
Calcineurin inhibitor
Blocks transcription & release of IL-2 from Th1 cells (responsible for proliferation)
What is the MOA of azathioprine?
It is an anti-proliferative immunosuppressant, metabolised to mercaptopurine, which inhibits DNA synthesis
List 4 virulence factors of pseudomonas aeruginosa
- Exotoxin A: inhibits protein synthesis by ADP-ribosylating ribosomal protein
- Elastase
- Leukocidin: kill leukocytes
- Haemolysins: destroy cell membranes
Which are more toxic generally: endotoxins or exotoxins?
Which is more common in each gram type of bacterium?
Exotoxins
Endotoxins - more in G-ve
Exotoxins - more in G+ve
____ is the most important cytokine for synthesis & deposition of connective tissue proteins in the tissue repair process
TGFß
It also stimulates fibroblast migration & proliferation, collagen/ fibronectin synthesis and inhibits metalloproteinases, decreasing ECM degradation
Robbins p105
In tissue repair, collagen synthesis & granulation tissue formation starts around day ____ (range)
Day 3-5
Wound tensile strength reaches 70-80% of normal by _____
3 months
List the 4 main complications of wound healing
1) Dehiscence/ ulceration
2) Excess scar formation: hypertrophic or keloid
3) Excess granulation tissue
4) Contracture
Robins p109-110
Melanocytes are derived from the ____ , located in the ___ layer of epidermis and produce melanin from ____
Neural crest
Basal layer
Tyrosine
What is the most common subtype of melanoma?
Superficial spreading
The other types are lentigo maligna, nodular and acral lentiginous
What are the stages of bony fracture healing? When does the bone become weight-bearing
Haematoma
Soft (pro)callus
Hard (bony) callus
Remodelling
-> weight-bearing during this stage, ~4wks onwards
True or false: the procallus in fracture healing provides structural rigidity for weight-bearing
False
At this stage it anchors ends together, but does not provide structural rigidity
This comes with hard bony callus & remodelling
What are the 4 main mediators of neutrophil chemotaxis & activation?
C5a
LTB4
IL-8 family
Bacterial products
What are the key leucocyte adhesion molecules?
Integrins, P-selectins
Endothelial adhesion molecules mostly in immunoglobulin superfamily
What is the most powerful product from granulocytes in killing pyogenic bacteria?
List 4 other mediators
The peroxidase-myeloperoxidase halide system
Any 4 of:
- lysozyme
- lactoferrin
- Defensins
- bacterial permeability increasing protein
- Major basic protein
- Acid proteases
List 4 protection systems from free-radical cell injury
Antioxidants: cysteine, methionine
Superoxide dismutase
Catalase
Glutathione peroxidase
Give examples of granulomatous disease
Sarcoidosis: classic immune (epithelioid) granuloma
Berylliosis: focal granulomatous lesions
Crohn’s
Primary biliary cirrhosis
Cat scratch lymphadenitis
Clonality in neoplasia can be determined by ____ isoforms
G6PD (X-linked gene)
What are the 2 signals required for T cell activation?
Signal 1: MHC-Ag binding TCR
Signal 2: B7 binding CD28
TH1 cells are important in ___ whereas TH2 cells in __ (allergy/ autoimmunity)
TH1 - autoimmunity
TH2 - allergy
Which antibodies can perform neutralisation?
IgG, IgA
HIV infects ____ cells and has a ____ genome
CD4+ T cells
ssRNA
Corticosteroids inhibit prostaglandin/ thromboxane synthesis via _____
Binding nuclear receptors to reduce Annexin transcription and inhibit PLA2 activity
Lost 4+ features of cellular atypia
1) Mitotic figures
2) Cytoplasmic basophilia
3) Hyperchromatic nuclei
4) Loss of nuclear polarity
5) High nuclear:cytoplasmic ratio
6) Pleomorphism, Anisokaryosis, karyomegaly
