ICS Flashcards
what two categories do most autopsies fall under in most countries?
those performed under instruction of a legal authority
those performed with permission from deceased’s relatives to gather info on the nature and extent of the deceased’s disease
why are medico-legal autopsies performed?
to determine the cause of death and to collect evidence to use in prosecution of those responsible for the death
when are clinical autopsies performed?
on patients who die in hospital
why are clinical autopsies performed?
certified cause of death given by clinicians with primary responsibility for the patient shows a 30% discrepancy with cause found at autopsy
how can clinical autopsy be useful?
more accurate data about cause of death: clinical audit, education of clinicians and national allocation of health resources, determining extent of disease and response to treatment
what is an advantage of clinical autopsy?
simple and cost-effective compared to modern methods of in-vivo imaging
what is happening to the rate of hospital autopsies?
declining
what is the prevalence of types of autopsy in the UK?
hospital - less than 10%
medico-legal - more than 90%
when are deaths ‘presumed natural’?
cause of death not known
not seen by doctor in last illness (within 14 days)
when are deaths ‘presumed iatrogenic’?
peri/postoperative deaths
anaesthetic deaths
abortion
complications of therapy
when are deaths ‘presumed unnatural’?
accidents industrial death suicide unlawful killing neglect custody deaths war/industrial pensions
doctors and referrals for autopsy
have no statutory duty to refer
common law duty
GMC guidance
registrar of BDM and referrals for autopsy
have a statutory duty to refer
where do referrals for autopsy come from, other than doctors and registrars of BDM?
relatives
police
anatomical pathology technicians
other properly interested parties
what types of pathologists perform autopsies?
histopathologists and forensic pathologists
what types of autopsies do histopathologists perform?
hospital and coronial autopsies
when do histopathologists perform coronial autopsies?
natural deaths drowning suicide accidents road traffic deaths fire deaths industrial deaths peri/postoperative deaths
what types of autopsies do forensic pathologists perform?
coronial autopsies
when do forensic pathologists perform coronial autopsies?
homicide
death in custody
neglect
these if they may be due to action of a third party: drowning, suicide, accidents, road traffic deaths, fire deaths, industrial deaths, peri/postoperative deaths
what is the role of the coronial autopsy?
to answer:
who was the deceased?
when did they die?
where did they die?
how did they come about their death?
what year was the coroner’s act established?
1988
what is S19 of the Coroners Act (1988)?
allows coroner to order an autopsy where death is likely due to natural causes to obviate need for inquest. no power to authorise special investigations
what is S20 of the Coroners Act (1988)?
allows coroner to order an autopsy where death is clearly unnatural and inquest will be needed. can authorise special investigations
when were the Coroners Rules established?
1984
what is R5 of the Coroners Rules (1984)?
autopsy as soon as possible
what is R6 of the Coroners Rules (1984)?
by a pathologist of suitable qualification and experience
what is R10 of the Coroners Rules (1984)?
report findings promptly and only to coroner
what is R11 of the Coroners Rules (1984)?
autopsy only on appropriate premesis
when were the Amendment Rules established?
2005
what are the Amendment Rules (2005)?
pathologist must tell coroner what materials have been retained
coroner authorises retention and sets disposal date
coroner informs family of retention
family has choices
coroner informs pathologist of family’s decision
pathologist keeps record
autopsy report must declare retention and disposal
what choices do family have in the Amendment Rules (2005)?
return material to family
retain for research/teaching
respectful disposal
when was the Coroners and Justice Act established?
2009
what changes are in the Coroners and Justice Act (2009)?
affects S19/20 - coroner can defer opening the inquest and launch investigation instead
enshrines a system of medical examiners
little practical change to the pathologist
inquests have conclusions, not verdicts
when was the Human Tissue Act established?
2004
what does the Human Tissue Act (2004) require?
S16(2): autopsies only to be performed on licensed premises
license holder
consent from relatives for any use of tissue if not subject to coronial legislation or retained for criminal justice purposes
public display requires consent from deceased
what are the penalties of the Human Tissue Act (2004)?
3 years imprisonment and/or a fine
what are the stages of the autopsy?
history/scene external examination evisceration internal examination reconstruction
what is involved in external examination?
identification
disease and treatment
injuries
how is someone identified in an external examination in autopsy?
formal identifiers gender, age body habitus jewellery body modification clothing
what are the steps involved in evisceration?
Y shaped incision open all body cavities examine all organs in situ remove thoracic and abdominal organs remove brain
what is studied in internal examination in autopsy?
heart and great vessels lungs, trachea, bronchi liver, gallbladder, pancreas spleen, thymus, lymph nodes genitourinary tract endocrine organs central nervous system
what is inflammation?
local physiological response to tissue injury - usually a manifestation of disease
how can inflammation be classified?
time course (acute and chronic) and differences in cell types
what is acute inflammation?
initial tissue reaction to a wide range of injurious agents. often transient, it is similar whatever the causative agent
how long can acute inflammation last?
few hours to few days
what are the principal causes of acute inflammation?
- microbial infections (pyogenic bacteria, viruses)
- hypersensitivity reactions (parasites, tubercle bacilli)
- physical agents (trauma, ionising radiation, heat, cold)
- chemicals (corrosives, acids, alkalis, reducing agents)
- tissue necrosis
- bacterial toxins (ischaemic infarction)
how do microbial infections cause acute inflammation?
- viruses kill individual cells by intracellular multiplication
- bacteria release specific exotoxins and endotoxins
- hypersensitivity reactions e.g. parasitic infections and TB
when do hypersensitivity reactions occur?
- when an altered state of immunological responsiveness causes an inappropriate or excessive immune reaction that damages the tissues
- cellular/chemical mediators similar to inflammation
how do physical agents cause acute inflammation?
physical trauma, UV or other ionising radiation, burns or excessive cooling
what are the essential macroscopic appearances of acute inflammation?
- redness (rubor)
- heat (calor)
- swelling (tumor)
- pain (dolor)
- loss of function
what is rubor?
- redness
- due to dilation of small blood vessels within the damaged area
what is calor?
- heat
- due to hyperaemia, leading to vascular dilation and delivery of warm blood to the area and systemic fever (due to the chemical mediators of inflammation)
- only seen in peripheral parts of the body
what is tumor?
- swelling
- due to oedema and the physical mass of inflammatory cells migrating to the area and formation of new connective tissue
what is oedema?
accumulation of fluid in the extravascular space as part of the fluid exudate
what is dolor?
- pain
- due to stretching/distortion of tissues due to oedema and pus under pressure in an abscess cavity, and chemical mediators of acute inflammation
what chemical mediators of acute inflammation contribute to pain?
bradykinin, prostaglandins and serotonin
what is loss of function?
movement of an inflamed area is consciously and reflexly inhibited by pain
severe swelling may physically immobilise tissues
who added loss of function to the Celcus list?
Virchow (1821-1902)
what happens in the early stages of acute inflammation?
oedema fluid, fibrin and neutrophil polymorphs accumulate in the extracellular spaces of the damaged tissue
how is acute inflammation histologically diagnosed?
presence of the neutrophil polymorph
what three processes occur in the acute inflammatory response?
- changes in vessel calibre and flow
- increased vascular permeability and formation of fluid exudate
- formation of cellular exudate - emigration of neutrophil polymorphs into extravascular space
what feature of normal blood flow keeps blood cells away from the vessel wall?
in blood vessels larger than capillaries, blood cells flow in the centre of the lumen (axial flow) and the area near the vessel wall carries only plasma
what lines small blood vessels?
single layer of endothelial cells - may be uniform or have thinning areas (fenestrations)
how does ultrafiltration occur under normal conditions?
oxygen, CO2 and nutrients transfer across the wall by diffusion
high colloid osmotic pressure inside the vessel due to plasma proteins favours fluid return to vascular compartment
high hydrostatic pressure at the arteriolar end forces fluid into the extravascular space, which returns into the capillaries at the venous end due to low hydrostatic pressure
what happens to ultrafiltration in acute inflammation?
increased capillary hydrostatic pressure and escape of plasma proteins into the extravascular space leads to more fluid leaving the vessels than is returned to them
why does the blood flow through all of the capillaries in acute inflammation?
opening of precapillary sphincters
what is exudation?
the net escape of protein-rich fluid
what is the fluid exudate?
protein rich fluid that escapes from vessels in acute inflammation
what are features of the fluid exudate?
high protein content (up to 50g/L)
immunoglobulins, coagulation factors
what are immunoglobulins responsible for in fluid exudate?
destruction of invading microorganisms
what are coagulation factors responsible for in fluid exudate?
fibrinogen causes fibrin deposition on contact with extravascular tissues
acutely inflamed organ surfaces are completely covered with fibrin
what is the turnover of the fluid exudate?
large turnover - constantly drained away by local lymphatic channels to be replaced by new exudate
what are causes of immediate transient increased vascular permeability?
chemical mediators, e.g. histamine, bradykinin, nitric oxide, C5a, leucotriene B4, platelet activating factor
what are causes of immediate sustained increased vascular permeability?
severe direct vascular injury, e.g. trauma
what are causes of delayed prolonged increased vascular permeability?
endothelial cell injury, e.g. x rays, bacterial toxins
give examples of tissue sensitivity to chemical mediators
CNS vessels are insensitive to chemical mediators, but vessels in the skin, conjunctiva and bronchial mucosa are sensitive to them, e.g. histamine
what are the steps in neutrophil polymorph emigration?
- margination
- pavementing
- pass between endothelial cells
- pass through basal lamina and migrate into the adventitia
what is margination of neutrophils?
caused by loss of intravascular fluid and increase in plasma viscosity with slowing down of flow at the site of acute inflammation
neutrophils flow in plasmatic zone
what is pavementing of neutrophils?
adhesion of neutrophils to the vascular endothelium, occurring at sites of acute inflammation
where does pavementing occur?
only seen in venules
how does pavementing occur?
interaction between paired adhesion molecules on leukocyte and endothelial surfaces
how do neutrophils migrate through the vessel walls?
active amoeboid movement through the walls of venules and small veins
pseudopodia are inserted between endothelial cells, through the basal lamina and into the adventitia
why are endothelial cells not damaged by pseudopodia insertion?
the defect is self-sealing
what is diapedesis?
red cells escaping from vessels - this is passive and depends on hydrostatic pressure
what does large presence of red cells in the extravascular space imply?
severe vascular injury e.g. tear in vessel wall
what is chemotaxis?
neutrophil polymorphs being attracted towards certain chemical substances in solution
what compounds may be chemotactic for neutrophils?
complement components, cytokines and products produced by neutrophils
what causes up-regulation of adhesion molecules on the surface of endothelial cells?
histamine and thrombin released by the original inflammatory stimulus
what do endogenous chemical mediators cause?
vasodilation emigration of neutrophils chemotaxis increased vascular permeability itching and pain
what is the best-known chemical mediator in acute inflammation?
histamine
what does histamine cause?
vascular dilation
immediate transient phase of increased vascular permeability
how and where is histamine stored?
preformed granules
mast cells, and also basophils and eosinophils
what stimulates histamine release?
complement components C3a and C5a
lysosomal proteins released from neutrophils
what are other chemical mediators of acute inflammation, apart from histamine?
- lysosomal compounds
- eicosanoids
- 5-hydroxytryptamine (serotonin)
- chemokines
what are the 4 enzymatic cascade systems contained in the plasma?
- complement
- kinins
- coagulation factors
- fibrinolytic system
what are 4 features of the enzymatic cascade systems contained in the plasma?
- safer to have inactive precursors than active mediators
- each step results in amplification of the response
- larger number of regulators can modulate the response
- each step results in end products with different activities
what activates the kinin, fibrinolytic and coagulation systems?
coagulation factor XII (Hageman factor)
what does the coagulation system produce? what happens to it?
fibrin, which is degraded by plasmin into fibrin split products
what does the kinin and fibrinolytic system produce? what happens to them?
- kinin system produces kinins
- fibrinolytic system produces plasmin - both activate the complement system, which produces activated complement
what activates the complement system?
kinins and plasmin produced by the kinin and fibrinolytic system
what occurs in the kinin system?
- activated factor XII and plasmin activate the conversion of prekallikrein to kallikrein
- kallikrein stimulates the conversion of kininogens to kinins
what can activate prekallikrein?
- activated factor XII
- plasmin
- leukocyte proteases e.g. trypsin
how can the complement system be activated in acute inflammation?
enzymes that activate complement are released during tissue necrosis
classical and alternative pathways
what activates complement in the classical pathway?
formation of antigen-antibody complexes
what activates complement in the alternative pathway?
endotoxins of Gram-negative bacteria
what are the chemical mediators of vascular dilation?
histamine prostaglandins PGE2/I2 VIP nitric oxide PAF
what are the chemical mediators of increased vascular permeability?
transient phase - histamine
prolonged phase - bradykinin, nitric oxide, C5a, leukotriene B4 and PAF, prostaglandins
what are the chemical mediators of adhesion of leukocytes to endothelium?
IL-8, C5a, leukotriene B4, PAF, IL-1 and TNF-alpha up-regulate adhesion molecules on endothelium
what are the chemical mediators of neutrophil polymorph chemotaxis?
leukotriene B4, IL8, others
what chemical mediators do tissue macrophages secrete when stimulated by local infection or injury?
IL-1, TNF-alpha, E-selectin, IL-8 and neutrophil attractant 78
what is the role of the lymphatics in acute inflammation?
lymphatic channels become dilated as they drain away the oedema fluid of the inflammatory exudate
limits extent of oedema
carry large molecules and some particulate matter
what are terminal lymphatics?
blind-ended, endothelium lined tubes present in most tissues in similar numbers to capillaries
where do terminal lymphatics drain into? what is the pathway of lymph?
collecting lymphatics
terminal lymphatics -> collecting lymphatics -> lymph nodes
what is a feature of the lymphatic endothelium that is important in inflammation?
basal lamina is incomplete and junctions between cells are simpler and less robust than capillary endothelial cells
gaps open up passively and allow large protein molecules to enter
where are antigens carried to?
carried to regional lymph nodes for recognition by lymphocytes
what brings about amoeboid movement?
contraction of cytoplasmic microtubules and gel/sol changes in cytoplasmic fluidity
what is amoeboid movement dependent on?
- active mechanisms depend on calcium ions and are controlled by intracellular concentrations of cyclic nucleotides
what is chemotaxis?
directional movement of an organism in response to a chemical stimulus
what activates the complement alternative pathway? what does this produce?
- bacterial lipopolysaccharides
generates component C3b (opsonising properties)
what activates the classical complement pathway? what does this produce?
- antibodies binding to bacterial antigens
- component C3b
what is the role of neutrophil polymorphs in adhesion to microorganisms?
binding of immunoglobulins to microorganisms by their Fab component leaves the Fc component exposed
neutrophils bind to the Fc fragment of the immunoglobulins via their surface receptors
what is phagocytosis?
process of a cell using its plasma membrane to engulf a large solid particle to produce a phagosome
briefly describe phagocytosis
- adhesion of particle to the cell surface by opsonisation
- the phagocyte ingests the attached particle by sending pseudopodia around it
- pseudopodia meet and fuse, so particle is in a phagocytotic vacuole (phagosome)
- lysosomes fuse with phagosomes to form phagolysosomes
- intracellular killing of microorganisms occurs
how may the microbicidal agents in neutrophil polymorphs be classed?
- those that are oxygen-dependent
- those that are oxygen-independent
what are oxygen-dependent mechanisms in neutrophil polymorphs?
- neutrophils produce hydrogen peroxide, which reacts with myeloperoxidase in cytoplasmic granules in presence of a halide, e.g. Cl- to produce a potent microbicidal agent
- peroxide anions (O2-)
- hydroxyl radicals (OH)
- singlet oxygen (1O2)
what are oxygen-independent mechanisms in neutrophil polymorphs?
- lysozyme (muramidase)
- lactoferrin
- cationic proteins
- low pH in phagosomes
what does lactoferrin do in neutrophil polymorphs?
chelates iron required for bacterial growth
what does the release of lysosomal products do?
- damages local tissues by proteolysis by elastase, collagenase etc.
- activates coagulation factor XII
- attracts other leukocytes into area
what are pyrogens?
compunds that produce systemic fever by acting on the hypothalamus
what is the role of mast cells in acute inflammation?
- on stimulation by the C3a/C5a complement components, they release preformed inflammatory mediators stored in their granules
- metabolise arachidonic acid into newly synthesised inflammatory mediators e.g. leukotrienes, prostaglandins, thromboxanes
what are beneficial effects of the fluid exudate?
- dilation of toxins
- entry of antibodies
- transport of drugs
- fibrin formation
- delivery of nutrients and oxygen
- stimulation of immune response
why is fibrin formation in acute inflammation beneficial?
- may impede the movement of microorganisms, trapping them and facilitating phagocytosis
- matrix for the formation of granulation tissue
what is the lifespan of neutrophils? where may they die?
- 1-3 days, constantly replaced
- most die locally
- some leave site via lymphatics
- some are actively removed by apoptosis
what do monocytes transform into?
- upon leaving the blood vessel, they transform into macrophages
- become more metabolically active, motile, phagocytic
what is the proportion of neutrophils to macrophages during acute inflammtion?
- macrophages appear within a few hours of inflammation
- macrophages don’t predominate until later stages where neutrophils have diminished and macrophages have proliferated
what is the role of macrophages in acute inflammation?
clear away tissue debris and damaged cells
how do neutrophils and macrophages release their content?
- discharge lysosomal enzymes into ECF
- by exocytosis or entire cell contents are released when cells die
what are the harmful effects of the fluid exudate released in acute inflammation?
- digestion of normal tissues
- swelling
- inappropriate inflammatory response
what is an example of harmful swelling due to fluid exudate in children?
swelling of the epiglottis in acute epiglottitis due to haemophilus influenzae infection may obstruct the airway
what is an example of harmful swelling due to fluid exudate in an enclosed space?
- cranial cavity
- acute meningitis or a cerebral abcess may raise intracranial pressure
- raised pressure may impair blood flow into the brain
- leads to ischaemic damage or force the cerebral hemispheres against tentorial orifice and the cerebellum into the foramen magnum
what are the possible outcomes of acute inflammation?
- resolution
- suppuration
- repair and organisation
- chronic inflammation
what is resolution in relation to acute inflammation?
- complete restoration of the tissues to normal after an episode of acute inflammation
- usual outcome
what are conditions that favour resolution of acute inflammation?
- minimal cell death and tissue damage
- occurrence in an organ or tissue with regenerative capacity vs one that can’t
- rapid destruction of the causal agent
- rapid removal of fluid and debris by good local vascular drainage
what is an example of an acute inflammatory condition that usually resolves completely?
acute lobar pneumonia
what is the sequence of events leading to resolution?
- phagocytosis of bacteria by neutrophils and intracellular killing
- fibrinolysis
- phagocytosis of debris and carriage through lymphatics to lymph nodes
- disappearance of vascular dilation
what is suppuration? what causes it?
- formation of pus, a mixture of living, dying and dead neutrophils and bacteria, cellular debris and sometimes globules of lipid
- excessive exudate
what is usually the causative stimulus for suppuration?
- must be persistent
- infective agent, usually pyogenic bacteria
what are examples of pyogenic bacteria?
- staphylococcus aureus
- streptococcus pyogenes
- neisseria species
- coliform organisms
what can suppuration lead to?
- discharge of pus
- repair and organisation
what is an abscess?
- pus accumulates in a tissue
- surrounded by pyogenic membrane, consisting of sprouting capillaries, neutrophils and fibroblasts
how do abscesses die/get removed?
- often burst; abscess cavity collapses and is obliterated by organisation and fibrosis, leaving a small scar
- surgical incision and drainage
how is an empyema formed?
- pus accumulates inside a hollow viscus
- mucosal layers of outflow tract of the viscus may be fused together by fibrin
what is a sinus tract?
an abnormal connection lined by granulation tissue, between an abscess and the skin/mucosal surface
what is a fistula?
- formed when deep-seated abscesses discharge pus along a sinus tract
- it is an abnormal passage connecting two mucosal surfaces or one mucosal surfaces to the skin surface
what often causes sinuses?
foreign body materials (indigestible by macrophages)
what is the treatment of fistulas?
surgical elimination of foreign body material
how may fibrous walls of long-standing abscesses become complicated?
dystrophic calcification
what can cause organisation and repair in acute inflammation?
- excessive necrosis
- suppuration
what is an outcome of organisation and repair in acute inflammation?
fibrosis
what is organisation in acute inflammation?
organisation of tissues is their replacement by granulation tissue as part of the repair process
what are the circumstances favouring organisation and repair?
- large amounts of fibrin formed (which can’t be removed completely by fibrinolytic enzymes from plasma or neutrophil polymorphs)
- large amount of tissue becomes necrotic or dead tissue isn’t easily digested
- exudate and debris can’t be removed or discharged
what happens in organisation in acute inflammation?
- new capillaries grow into the inert material (inflammatory exudate)
- macrophages migrate into zone, fibroblasts proliferate, leading to fibrosis and possibly scar formation
what causes fibroblasts to proliferate?
TGF-beta
what is an example of organisation and repair in acute inflammation?
in pleural space following acute lobar pneumonia
what causes progression from acute to chronic inflammation?
persistent causal agent
what are some systemic effects of inflammation?
- pyrexia
- constitutional symptoms
- weight loss
- reactive hyperplasia of the reticuloendothelial system
- haemotological changes
- amyloidosis
what is pyrexia?
- polymorphs and macrophages produce endogenous pyrogens
- pyrogens act on the hypothalamus to set thermoregulatory mechanisms at a higher temp
what endogenous pyrogen has the greatest effect?
interleukin-2
what stimulates the release of endogenous pyrogen?
- phagocytosis
- endotoxins
- immune complexes
what are constitutional symptoms?
- malaise
- anorexia
- nausea
why does weight loss occur due to inflammation?
- negative nitrogen balance
what are examples of haemotological changes due to inflammation?
- increased erythrocyte sedimentation rate
- leukocytosis
- anaemia
what is increased erythrocyte sedimentation rate? why does it occur?
- non-specific finding in many types of inflammation
- due to alterations in plasma proteins leading to increased rouleaux formation of red cells
when does neutrophilia occur?
pyrogenic infections and tissue destruction
when does eosinophilia occur?
allergic disorders and parasitic infection
when does lymphocytosis occur?
chronic infection, viral infections, whooping cough
when does monocytosis occur?
infectious mononucleosis and certain bacterial infections, e.g. TB and typhoid
why may anaemia occur in inflammation?
- blood loss in the inflammatory exudate
- haemolysis
- anaemia of chronic disorders due to toxic depression of bone marrow
how may secondary amyloidosis occur?
long-standing chronic inflammation may cause amyloid to be deposited in tissues by elevating serum amyloid A protein
what is chronic inflammation?
- inflammation extended over a long period of time
- type of cellular reaction differs from acute inflammation
- lymphocytes, plasma cells and macrophages predominate
- granulation and scar tissue are formed
- usually primary
what cells predominate in chronic inflammation?
lymphocytes, plasma cells and macrophages
what are causes of chronic inflammation?
- primary chronic inflammation
- transplant rejection
- progression from acute inflammation
- recurrent episodes of acute inflammation
what is the most common type of acute inflammation to progress to chronic inflammation?
suppurative type
what are examples of chronic abscesses?
- osteomyelitis (abscess in the bone marrow cavity)
- empyema thoracis that has been inadequately drained
what causes a chronic abscess?
- pus forms abscess cavity that’s deep seated or drainage is delayed/inadequate
- abscess develops thick walls of granulation and fibrous tissues over time
- rigid walls fail to come together after drainage
- stagnating pus becomes organised by ingrowth of granulation tissue, then replaced by fibrous scar
what are examples of indigestible material?
- keratin from ruptured epidermal cyst
- fragments of necrotic bone in the sequestrum of chronic osteomyelitis
what are the most indigestible forms of material? give examples
- inert foreign body materials
- surgical suture, wood, metal, glass, prostheses
what type of chronic inflammation do foreign bodies provoke?
- granulomatous inflammation
- cause macrophages to form multinucleate giant cells
what is an example of recurrent episodes of acute inflammation becoming chronic inflammation? what happens in this?
- chronic cholecystitis, due to gallstones usually
- replacement of gallbladder wall muscle by fibrous tissue
- predominant cell type becomes the lymphocyte instead of the neutrophil polymorph
what are specific causes of chronic inflammation?
- resistance of infective agent to phagocytosis and intracellular killing
- endogenous materials
- exogenous materials
- some autoimmune diseases
- specific diseases of unknown aetiology
- primary granulamatous diseases
what are examples of resistance of infective agent to phagocytosis and intracellular killing causing inflammation?
TB, leprosy, brucellosis, viral infections
what are examples of endogenous materials causing inflammation?
necrotic adipose tissue, bone, uric acid crystals
what are examples of exogenous materials causing inflammation?
silica, asbestos fibres, suture materials, implanted prostheses
what are examples of some autoimmune diseases causing inflammation?
organ-specific disease, non-organ-specific autoimmune disease, contact hypersensitivity reactions
what are examples of organ-specific diseases causing inflammation?
Hashimoto’s thyroiditis, chronic gastritis of pernicious anaemia
what are examples of non-organ-specific diseases causing inflammation?
rheumatoid arthritis
what are examples of contact hypersensitivity reactions causing inflammation?
self-antigens altered by nickel
what are examples of specific diseases of unknown aetiology causing inflammation?
chronic inflammatory bowel disease, e.g. UC
what are examples of primary granulomatous diseases causing inflammation?
Crohn’s disease, sarcoidosis
what are macroscopic appearances of chronic inflammation?
- chronic ulcer
- chronic absess cavity
- thickening of the wall of a hollow viscus
- granulomatous inflammation
- fibrosis
what are microscopic features of chronic inflammation?
- cellular infiltrate consists of lymphocytes, plasma cells and macrophages
- some eosinophil polymorphs, neutrophil polymorphs are scarce
- production of new fibrous tissue from granulation tissue
- continuing destruction of tissue at same as regeneration
- tissue necrosis
what does tissue healing involve?
regeneration and migration of specialised cells
what are features of repair?
- angiogenesis
- fibroblast proliferation
- collagen synthesis -> granulation tissue
what regulates healing and repair? what do they do?
- low molecular weight proteins called growth factors
- bind to receptors on cell membranes, triggering series of events to lead to cell proliferation
what is the function of EGF?
- epidermal growth factor
- regeneration of epithelial cells
what is the function of TGF-alpha?
- transforming growth factor alpha
- regeneration of epithelial cells
what is the function of TGF-beta?
- transforming growth factor beta
- stimulates fibroblast proliferation and collagen synthesis
- controls epithelial regeneration
what is the function of PDGF?
- platelet derived growth factor
- mitogenic and chemotactic for fibroblasts and smooth muscle cells
what is the function of FGF?
- fibroblast growth factor
- stimulates fibroblast proliferation, angiogenesis and epithelial cell regeneration
what is the function of IGF-1?
- insulin-like growth factor-1
- synergistic effect with other growth factors
what is the function of TNF?
- tumour necrosis factor
- stimulates angiogenesis
what does the lymphocytic tissue infiltrate contain?
B and T lymphocytes
how do macrophages move through tissue?
amoeboid motion
what is a difference between macrophages and neutrophil polymorphs?
- macrophages are longer lived
- macrophages can ingest a wider range of materials
- macrophages can harbour viable organisms if they can’t kill them by lysosomal enzymes
what are examples of organisms that can survive inside macrophages?
- mycobacteria (Mycobacterium tuberculosis, M. leprae)
- Histoplasma capsulatum
where are macrophages derived from?
blood monocytes that have migrated out of vessels
what system are macrophages part of?
mononuclear phagocyte system/reticuloendothelial system
what is involved in the activation of macrophages?
- increased size
- protein synthesis
- mobility
- phagocytic activity
- increased content of lysosomal enzymes
what cytokines do macrophages produce?
- interferon alpha and beta
- interleukin-1
- interleukin-6
- interleukin-8
- TNF-alpha
what is a granuloma?
aggregate of epithelioid histiocytes
- may contain other cell types, e.g. lymphocytes and histiocytic giant cells
what are examples of granulomatous diseases?
TB and leprosy
what is the appearance and arrangement of epithelioid histiocytes?
- large vesicular nuclei
- plentiful eosinophilic cytoplasm
- elongated
- arranged in clusters
what is the function of epithelioid histiocytes?
- full purpose not known
- produce ACE
- measurement of ACE in blood can act as a marker for systemic granulomatous disease, e.g. sarcoidosis
how can the appearance of granulomas be augmented?
- caseous necrosis (e.g. TB)
- conversion of some histiocytes into multinucleate giant cells
what does the association of granulomas with eosinophils indicate?
parasitic infection, e.g. worms
what are effector T lymphocytes derived from?
- non-sensitised T lymphocytes by transfer factor
- T lymphocytes
what do effector T lymphocytes produce?
- lymphotoxins
- inflammatory mediators to produce increased vascular permeability
- migration inhibition factors to affect macrophages
what are memory cells derived from?
- effector T lymphocytes
- transformed B lymphocytes
what are transformed B lymphocytes derived from?
- B lymphocytes
what are antibodies derived from?
- transformed B lymphocytes
what are monocytes derived from? where?
haemopoietic stem cell -> promonocyte -> monocyte
what can monocytes differentiate into when they enter tissues?
- connective tissue histiocyte
- alveolar macrophages
- peritoneal macrophage
- Kupffer cell of liver
- melanophage of skin
- lipophage
- osteoclast in bone
- microglial cell in brain
- specialised histiocytes, e.g. epitheliod cell
- histiocytic giant cell
where/when do histiocytic giant cells tend to form?
- where particulate matter that’s indigestible accumulates
- foreign materials are too large to be ingested by just one macrophage
how many nuclei do histiocytic giant cells contain?
over 100
how do histiocytic giant cells form?
‘by accident’ when 2 or more macrophages attempt to engulf the same particle simultaneously - cell membranes fuse and cells unite
what is the activity of histiocytic giant cells like?
- little phagocytic activity
- no known function
how are Langhans giant cells arranged? where are they seen?
- horseshoe arrangement of peripheral nuclei at one pole of the cell
- seen in TB and other granulomatous conditions
what are foreign body giant cells? when are they seen?
- large cells with nuclei randomly scattered throughout cytoplasm
- particulate foreign body material
- often seen in granulomas
- don’t have a defining feature
what are causes of granulomatous disease?
- specific infections
- materials that resist digestion
- specific chemicals
- drugs
- unknown
what are examples of specific infections that cause granulomatous disease?
- mycobacteria
- fungi
- parasites, larvae, eggs, worms
- syphilis
what are examples of materials resisting digestion that cause granulomatous disease?
- endogenous (keratin, necrotic bone, cholesterol crystals, sodium urate)
- exogenous (talc, silica, suture materials, oils, silicone)
what are examples of specific chemicals that cause granulomatous disease?
beryllium
what are examples of drugs that cause granulomatous disease?
- hepatic granulomas due to allopurinol
- phenylbutazone
- suphonamides
what are examples of unknown factors causing granulomatous disease?
- Crohn’s disease
- sarcoidosis
- Wegener’s granulomatosis
exudate vs transudate
- exudate has a high protein content due to increased vascular permeability
- transudate has a low protein content due to vessels having normal permeability
acute vs chronic inflammation
- acute inflammation has a rapid onset and usually resolution, and neutrophil polymorphs are the most abundant cells
- chronic inflammation has an insidious onset, prolonged course and slow resolution, and lymphocytes, plasma cells and macrophages are the most abundant cells
granuloma vs granulation tissue
- a granuloma is an aggregate of epithelioid histiocytes
- granulation tissue is an important component of healing. comprises small blood vessels in a connective tissue matrix with myofibroblasts
fibrin vs fibrous
- fibrin is deposited in blood vessels and tissues or on surfaces due to action of thrombin on fibrinogen
- fibrous describes the texture of a non-mineralised tissue where the principal component is collagen
how do irritants and corrosive chemicals cause inflammation?
- corrosive chemicals (acids, alkalis, oxidising agents) provoke inflammation through gross tissue damage
- infecting agents may release specific chemical irritants leading directly to inflammation
how does tissue necrosis cause inflammation?
- death of tissues from lack of oxygen or nutrients due to inadequate blood flow (infarction)
- edge of recent infarcts often show acute inflammatory response, due to peptides released from dead tissue
what are time course mechanisms as causes of increased vascular permeability?
- immediate transient chemical mediators
- immediate sustained severe direct vascular injury
- delayed prolonged endothelial cell injury
what are immediate transient chemical mediators as causes of increased vascular permeability?
- histamine
- bradykinin
- nitric oxide
- C5a
- leucotriene B4
- platelet activating factor
what are causes of delayed endothelial cell injury?
- xrays
- bacterial toxins
how does the acute inflammatory response spread following injury to a small area of tissue?
chemical substances being released from injured tissues, spreading outwards towards uninjured areas
what chemical mediators of acute inflammation are released early in the response? what do they cause?
- histamine and thrombin
- up-regulation of adhesion molecules on surface of endothelial cells
- very firm neutrophil adhesion to the endothelial surface
what is the role of the neutrophil polymorph?
phagocytoses bacteria
what are terms used to describe macroscopic appearances of acute inflammation?
- serous
- suppurative (purulent) inflammation
- membranous inflammation
- pseudomembranous inflammation
- necrotising (gangrenous) inflammation
what is the function of B lymphocytes?
on contact with an antigen, they become progressively transformed into plasma cells (produce antibodies)
what is the function of T lymphocytes?
- cell mediated immunity
- on contact with an antigen, they produce a range of soluble factors called cytokines, which recruit and activate other cell types
what are Touton giant cells? when are they seen?
- central ring of nuclei, peripheral to which there is lipid material
- seen when macrophages attempt to ingest lipids
- seen in xanthomas/dermatofibromas of the skin
what is the role of acute inflammation in the CVS?
- response to acute myocardial infarction
- generation of some complications of MI e.g. cardiac rupture
what is the role of chronic inflammation in carcinogenesis?
- initiation and propogation of cancer
how is chronic inflammation involved in MIs?
- myocardial fibrosis
how does inflammation contribute to development of atheromas?
- macrophages adhere to endothelium
- migrate into arterial intima and with T lymphocytes, express cell adhesion molecules which recruit other cells into the area
- macrophages process lipids that accumulate in atheromatous plaques
how does inflammation feature in the tissue injury associated with neurodegenerative disorders of the CNS?
- chronic inflammation is involved in MS
- perivascular cuffing by plasma cells and T lymphocytes is seen in zones of white matter, where macrophages break down myelin
what factors does cell survival depend on?
- constant supply of energy
- intact plasma membrane
- biologically safe and effective function of cellular activities
- genomic integrity
- controlled cell division
- internal homeostatic mechanisms
at what rate do cells replicate in the human body?
c. 10000 new cells per second
what are types of mechanisms of cellular injury?
- energy failure
- failure of membrane functional integrity
- membrane damage
- blockage of metabolic pathways
- mechanical disruption
- DNA damage or loss
what can energy failure in a cell be caused by?
- oxygen and glucose lack
- mitochondrial failure
what can failure of membrane functional integrity be caused by?
- damage to ion pumps
- complement or perforin
- bacterial toxins
what can membrane damage be caused by?
- free radicals
what can blockage of metabolic pathways be caused by?
- interruption of protein synthesis
- respiratory poisons
- hormone/growth factor lack
what can mechanical disruption be caused by?
- trauma
- osmotic pressure
what can DNA damage or loss be caused by?
- ionising radiation
- chemotherapy
- free radicals
what are some major types of cellular injury?
- trauma
- thermal injury (hot or cold)
- poisons
- drugs
- infectious organisms
- ischaemia and reperfusion
- plasma membrane failure
- DNA damage
- loss of growth factors
- ionising radiation
how do most physical agents cause passive cell destruction?
- gross membrane disruption
- catastrophic functional impairment
how do trauma and thermal injury kill cells?
- disrupting cells
- denaturing proteins
- cause local vascular thrombosis with tissue ischaemia and infarction
how does freezing damage cells?
- mechanically; membranes are perforated by ice crystals
how do chemicals cause cell injury?
- act as toxins to specific metabolic pathways
- local damage
- local and systemic damage
how do caustic agents cause rapid local cell death?
- extreme alkalinity or acidity
- corrosive effect on tissue by digesting proteins
how does trauma cause cellular injury?
- mechanical disruption of tissue
how does carbon monoxide cause cellular injury?
- prevents oxygen transport
how does contact with strong acid cause cellular injury?
- coagulates tissue proteins
how does paracetamol overdose cause cellular injury?
- metabolites bind to liver cell proteins and lipoproteins
how do bacterial infections cause cellular injury?
- toxins and enzymes
how does ionising radiation cause cellular injury?
- damage to DNA
what happens in the blockage of cellular respiration? what do cyanide ions do?
- prevention of oxygen utilisation leads to death of many cells
- cyanide ions bind to cytochrome oxidase and interrupting oxygen utilisation
- cells with higher metabolism are most vulnerable
what is an example of the effects of glucose deprivation on cells?
- cerebral neurones are highly dependent on glucose
- in diabetes mellitus, there’s inadequate use of glucose due to lack of insulin
why does blockage of protein synthesis damage cells?
- constant requirement to replace enzymes and structural proteins
what is an example of the effects of blocking protein synthesis on cells?
- ricin is a potent toxin from the castor oil plant
- acts on the ribosomal level
- antibiotics, e.g. streptomycin, chloramphenicol and tetracycline interfere with protein synthesis
what are examples of loss of growth factor/hormonal influence affecting cells? how can this affect organs?
- growth factor deficit, receptor loss/blockade, tyrosine kinase inhibitors
- affected cells undergo apoptosis
- hormone withdrawl
- organ may shrink (atrophy)
what is an example of a tyrosine kinase inhibitor drug?
imatinab
what are the effects of impaired blood flow (ischaemia)?
- causes inadequate oxygen delivery
- mitochondrial production of ATP ceases
- anaerobic glycolysis leads to acidosis due to accumulation of lactate
- acidosis promotes calcium influx
why does anaerobic glycolysis lead to acidosis?
accumulation of lactate
what cells are most vulnerable to effects of ischaemia?
those with high metabolic activity e.g. cortical neurones and cardiac myocytes
what is reperfusion injury? why does it occur?
when blood flow is restored after ischaemia, the oxygen leads to a burst of mitochondrial activity and excessive release of ROS (free radicals)
what are free radicals?
atoms or groups of atoms with an unpaired electron
- avidly form chemical bonds
what are properties of free radicals?
- highly reactive
- chemically unstable
- present only at low concentrations
- participate in or initiate chain reactions
how can free radicals be generated?
- deposition of energy
- interaction between oxygen and a free electron in relation to oxidation-reduction reactions
how are free radicals generated by deposition of energy?
electron is replaced, resulting in free radicals
what are the body’s mechanisms for protection against free radical damage?
- free radical may be scavenged by endogenous or exogenous antioxidants
- superoxide radicals may be inactivated by copper-containing enzyme superoxide dismutase, generating hydrogen peroxide, which is converted to water by catalase
what are clinicopathological events involving free radicals?
- toxicity of some poisons (e.g. carbon tetrachloride)
- oxygen toxicity
- tissue damage in inflammation
- intracellular killing of bacteria
what are mechanisms of cell membrane damage?
- complement-mediated cytolysis
- perforin-mediated cytolysis
- specific blockage of ion channels
- failure of membrane ion pumps
- free radical attack
what is verapamil?
- calcium channel blocker
- used in treatment of hypertension and ischaemic heart disease
what can depletion of ATP affect?
- membrane ion pumps that are dependent on ATP
how can chemical agents deplete ATP?
- interfering with mitochondrial oxphos
- by consuming ATP in their metabolism
what are the actions of ouabain?
- naturally occurring toxin
- Na/K ATPase is inhibited
what does failure of membrane ion pumps lead to?
- cell swelling (oncosis or hydropic change)
how can membrane proteins/layers be altered?
- reactions with phospholipid or protein moieties
- phospholipids may be altered through peroxidation by ROS and phospholipases
- membrane proteins altered by cross-linking induced by free radicals
what happens when membrane damage leads to lysosome permeability?
release of contents precipitates further cell damage/death
what is the process of neoplastic transformation that results in tumours?
- non-lethal DNA damage is inherited by daughter cells
- a clone of transformed cells with abnormal growth characteristics is formed
what are the types of DNA damage?
- strand breaks
- base alterations
- cross-linking
what are the effects of different numbers of strand breaks?
- one: repair can be accomplished accurately
- double: no template
- multiple double-strand breaks: rejoin incorrectly, leading to chromosome translocation or inversion
what is a mutation?
DNA strand no longer transcribes correctly
what causes DNA strand cross-linking?
- ROS cause linkage between the complementary strands
- leads to an inability to separate strands and make new copy
- DNA replication is blocked
what do alkylating agents and platinum-based drugs do to DNA strands?
- alkylating agents cause cross-linkage
- platinum based drugs cause strand breaks
what is reproductive death? when do cells die?
- where double strand breaks lead to misrepairing or failure to repair
- combination of genetic instability and lethal mutations leads to cell death after 2-3 mitotic cycles
- smaller proportion of cells die immediately by apoptosis/necrosis
how do ATM mutations affect cells? what is an example?
- loss of function mutations of the ATM gene impair excision repair of double-strand breaks
- explains the enhanced radiation sensitivity of patients with ataxia telangiectasia
what is xeroderma pigmentosum? what is it caused by?
- extreme skin sensitivity to sunlight, causing tumors
- mutated ERCC6 gene
what are two common patterns of sublethal cellular alteration?
- hydropic change
- fatty change
what happens in hydropic change? what is it caused by?
- cytoplasm becomes pale and swollen due to accumulation of fluid
- disturbances of metabolism e.g. hypoxia or chemical poisoning
are changes in hydropic change reversible?
yes, but they may cause irreversible damage if causal injury is persistent
what is fatty change? what is it caused by?
- vacuolation of cells
- due to the accumulation of lipid droplets due to a disturbance to ribosomal function and uncoupling of lipid from protein metabolism
what is commonly affected by fatty change?
- liver
- due to hypoxia, alcohol, diabetes, etc
is fatty change reversible?
moderate degrees are, but severe fatty change may not be
what is autophagy? what happens in it?
- cellular response to stress, e.g. deficiency of nutrients or growth factor-mediated effects, or organelle damage
- cell components are isolated into intracellular vacuoles and processed through to lysosomes
- means of staving off cell death
what can autophagy lead to?
- may progress to cell death if stimulus is more severe
- cell metabolic pathways may switch to apoptosis
what are the two distinct mechanisms by which cells die?
- necrosis
- apoptosis
what is a key outcome difference between apoptosis and necrosis?
in apoptosis the cell membrane remains intact and there is no inflammatory reaction
what happens to mitochondria during necrosis?
- anaerobic conditions lead to acidosis, leading to calcium inflow
- calcium uptake by mitochondria exceeds their storage capacity and leads to disruption of the inner membrane
- ATP production ceases and contents leak into cytosol
- exacerbated by reperfusion, leading to ROS production
what are the distinct morphological types of necrosis?
- coagulative
- colliquative
- caseous
- gangrene
- fibrinoid
- fat necrosis
what is the commonest type of necrosis?
coagulative necrosis
why do cells retain their outline in coagulative necrosis?
- after devitalisation, they retain their outline as their proteins coagulate and metabolic activity ceases
what is the gross appearance in coagulative necrosis?
- depends on cause of cell death and vascular alteration
- tissue texture is normal/firm initially
- becomes soft later due to macrophage digestion
what is the microscopic appearance in coagulative necrosis?
- first few hours: no discernable abnormality
- progressive loss of nuclear staining until it ceases to be haemotoxyphilic
- loss of cytoplasmic detail
- collagenous stroma is more resistant to dissolution
tissue retains a faint outline of its structure until the damaged area is removed by phagocytosis
where does colliquative necrosis occur? why?
- brain
- lack of substantial supporting stroma - necrotic neural tissue may totally liquefy
what happens in colliquative necrosis?
- glial reaction around the periphery
- site of necrosis is eventually marked by a cyst
what is caseous necrosis? when is it commonly seen?
- pattern of necrosis where the dead tissue is structureless
- TB
what is the histological appearance of caseous necrosis?
amorphous eosinophilic area stippled by haematoxyphilic nuclear debris
what is gangrene?
necrosis with putrefaction of the tissues, sometimes due to action of certain bacteria, e.g. clostridia
what bacteria is associated with gangrene?
clostridia
why do gangrenous tissues appear black?
deposition of iron sulphide from degraded haemoglobin
why is intestinal necrosis liable to proceed to gangrene?
clostridia are very common in the bowel
what is the difference between wet and dry gangrene?
- dry gangrene is due to blockage of blood supply to local tissues
- wet gangrene is due to infection
what is the cause of gas gangrene?
infection by clostridium perfringens
what is the cause of synergistic gangrene?
infection by combinations of organisms, e.g. bacteroides and borrelia vincentii
what is fibrinoid necrosis?
- arterioles are under such pressure that there’s necrosis of the smooth muscle wall
- seepage of plasma into the media, with deposition of fibrin
what is the histological appearance of fibrinoid necrosis?
with H&E staining, the vessel wall is a homogenous bright red
what are causes of fat necrosis?
- direct trauma to adipose tissue and extracellular liberation of fat
- enzymatic lysis of fat due to release of lipases
what happens after trauma to adipose tissue?
- release of intracellular fat elicits an inflammatory response
- polymorphs and macrophages phagocytose fat
- development of fibrosis
- may produce a palpable mass
what happens to fat released in acute pancreatitis?
- release of pancreatic lipase leads to fat cells having stored fat split into fatty acids
- fatty acids combine with calcium to precipitate out as white soaps
- may lead to hypocalcaemia
how are cells classified according to their potential for renewal?
- labile cells
- stable cell population
- permanent cells
what are labile cells? give examples
- good capacity to regenerate
- e.g. surface epithelial cells
- lost from surface, replaced by deeper layers
what are stable cell populations? give examples
- divide at a very slow rate
- retain capacity to divide when needed
- e.g. renal tubular cells and hepatocytes
what are permanent cells? give examples
- cells with no effective regeneration
- e.g. nerve cells and striated muscle cells
what happens in stem cell differentiation?
- mitotic division
- one of the daughter cells progresses along a differentiation pathway according to needs and functional state of the tissue
- other daughter cell retains stem cell characteristics
where are stem cells located in the epidermis?
- basal layer immediately adjacent to the basement membrane
- hair follicles
- sebaceous glands
where are stem cells located in the intestinal mucosa?
- near the bottom of the crypts
