PATHOLOGY NOTES GENERAL WEEK1
General pathology is the study of the mechanisms of disease (with emphasis on
aetiology and pathogenesis), while systematic pathology is the study of diseases as they
occur within particular organ systems – it involves aetiology, pathogenesis,
epidemiology, macro- and microscopic appearance, specific diagnostic features, natural
history and sequelae.
Academic pathology includes research and teaching, and the discipline of experimental
pathology was derived from this. Clinical pathology is often referred to as laboratory
medicine and includes a number of diagnostic disciplines.
Pathology provides the basis for understanding:
The mechanisms of disease
The classification of diseases The
diagnosis of diseases The basis
of Streatment
Monitoring the progress of disease
Determining prognosis
Understanding complications
SNOMED – standard classification of disease – considers the following aspects: Topography
Morphology
Aetiology
Function
Disease
Procedure
Occupation
• Techniques of Pathology
Gross pathology – macroscopic investigation and observation of disease
Light microscopy – thin section of wax or plastic permeated tissues, snap-frozen tissues
Histochemistry – microscopy of treated tissue sections (to distinguish cell components)
Immunohistochemistry and immunofluorescence – tagged antibodies (monoclonal better) Electron
microscopy
Biochemical techniques – e.g. fluid and electrolyte balance, serum enzymes Cell
cultures – also allowing cytogenetic analysis
Medical microbiology – direct microscopy, culturing and identification
Molecular pathology – in situ hybridisation (specific genes/mRNA), polymerase chain
reaction
CELL INJURY
• The Pathogenesis of Cell Injury
Normal cell structure and function requires:
, Nuclear function for nucleic acid, protein, lipid and carbohydrate synthesis
Enzyme function for assembly and degradation of organelles and cell products
Membrane function for the transport of metabolites/messengers and for the ionic
and fluid homeostasis
Energy production and the formation of high-energy compounds by
aerobic phosphorylation (and/or anaerobic glycolysis)
Injury to the nucleus:
Genetic defects – single gene, multiple gene or whole chromosome abnormalities
Nutritional disturbances – e.g. pernicious anaemia due to B12 deficiency affecting DNA
synthesis in haematopoietic cells
Toxic injury – may inhibit nuclear functions (synthesis, division)
Standard background radiation is approximately 10-3 rads, with minor consequences for
dosages lower than 10 rads. A dose of 100 rads will give mild radiation sickness. A dose
of 1000 rads will give severe radiation sickness, with pancytopenia. Note that UV is
sufficient to create pro-mutagenic damage to DNA and hence has long-term effects.
Ataxia telangiectasia is due to a fundamental failure to repair damaged DNA. Individuals
with this condition have hypersensitivity to DNA damage (e.g. radiation). Fragile X
syndrome is due to an expansion in an unstable codon (6-50 in normal individuals, 250-
4000 in affected individuals) which leads to susceptibility to nuclear damage.
Injury to cell membranes:
Receptor defects – e.g. familial hypercholesterolemia
Complement related injury – e.g. immunological reactions that activate complement,
opening transmembrane channels that alter ionic homeostasis
Free radical injury – atoms/molecules with unpaired e- (usually O2 intermediates): O2
therapy Excess O2
PMNs, macrophages inflammation
PMNs, xanthine oxidase reperfusion injury after ischaemia
Mixed function oxidation, cyclic redox reactions drug-induced/chemical
toxicity Radiotherapy ionising radiation
Initiators, promoters chemical carcinogenesis
O -, H O , ●OH – reactive oxygen intermediates
2 2 2
membrane damage (lipid peroxidation)
Viruses – direct membrane injury (e.g. polio – viral proteins inserted into membrane
forming pores or channels) or indirect membrane injury (e.g. hepatitis B – viral release
from the cell exposes viral proteins at the cell surface leading to immune response)
Another example is the alpha toxin produced by Clostridium perfringens – this disrupts
membrane function.
Lysosomes and cell injury:
Intracellular ‘storage’ diseases – inherited deficiency of lysosomal enzymes leading to failure
to degrade particular substrates that accumulate
Abnormal intracellular release – e.g. gout and silicosis where the ingestion by
phagocytic cells of uric acid/silica leads to rupture of phagosomes
Abnormal extracellular release – e.g. rheumatoid arthritis
Cell injury and energy production:
Hypoxia or ischaemia compromise energy-dependent process like contraction,
, and transmembrane ionic exchange is affected
Reactions of cells to stress and energy:
Adaptation
Abnormalities of growth – atrophy, hypertrophy, hyperplasia, metaplasia
Abnormal storage – accumulation of products in cytoplasm (e.g. lipofuscin)
Reversible cell damage
Irreversible cell injury – typically cell death by necrosis
Note that there is evidence of reversible cell injury:
Cell and organelle swelling – due to failure of energy-dependent ionic exchange
and/or membrane injury, also known as intracellular oedema
Fat accumulation – fatty change in the parenchymal cells of the liver, heart and
kidney due to failure to utilize or convert the NEFA arriving at the cell (e.g.
inadequate synthesis of lipid-acceptor protein in the liver)
• Necrosis and Apoptosis
The type of necrosis is dependent on the nature, intensity and duration of the injurious
agent, and the type of cell involved. Note that initial membrane damage allows Ca+2
leakage with subsequent activation of Ca-dependent phosphatases and lipases.
Coagulative necrosis – cytoplasm of the necrosed cells becomes eosinophilic and
persists for many days (myocardial infarction)
Colliquative necrosis – cells undergo lysis rapidly (brain infarcts)
Caseous necrosis – Mycobacterium tuberculosis interacts with macrophages Gangrenous
necrosis – primary (bacterial toxins) or secondary (ischaemia, infection) Fibrinoid necrosis
– smooth muscle necrosis, fibrin release (malignant hypertension) Fat necrosis –
inflammatory response to liberated fat fibrosis
There are also nuclear changes related to necrosis:
Margination of chromatin – chromatin condensing around the periphery of the nucleus
Pyknosis – small and dense nuclei
Karyolysis – complete lysis of the nuclei
Karyorrhexis – fragmented nuclei (generally seen in apoptosis)
Irreversible cell injury is typically accompanied by:
Release of intracellular enzymes:
Cardiac muscle – creatine kinase (MB isoform), aspartate transaminase, lactate
dehydrogenase
Hepatocytes – alanine transaminase
Striated muscle – creatine kinase (MM isoform)
Exocrine pancreas – amylase
Loss of membrane selectivity – may be helpful in diagnosis through uptake of dyes
Inflammatory response – initiated by products (mediators) of the necrotic cells
Cell death can also occur through apoptosis – it may be physiological deletion of selected cells
(e.g. morphogenesis, cyclic hyperplasia of reproductive processes) or it may occur in response to a
pathological stimuli. Note that there are no gross structural changes involved.
The initiation of apoptosis requires two processes:
Priming – a reversible stage in which the specialist machinery for apoptosis (e.g.
transglutamase, calcium/magnesium endonucleases) are activated
Triggering – the irreversible point which leads to a sustained rise in cytosolic calcium, and
, induction of new mRNA species for c-fos, c-myc and heat-shock proteins
Apoptosis then proceeds:
• Cytosol and nucleus lost half their volume
• Fragmentation of nucleus and cytosol ( activation of transglutamase that forms
an insoluble layer beneath the intact cell membrane)
• Condensation of chromatin (pyknosis)
• Macrophages bind to cell fragments prior to phagocytosis (non-specific mechanism)
Pathological cell death is more often due to necrosis – this process releases intracellular
enzymes (useful diagnostically) and mediators that stimulate inflammation. This is followed by healing by
repair, scarring, contracture and distortion of tissue architecture.
Necrosis Apoptosis
Histology Groups of cells, disrupting tissue Single cells within living tissues
structure
Cytology Cellular swelling, nuclei Pyknotic subdivided nuclei,
initially intact condensed cytoplasm,
rounded
membrane-bound cell fragments
Dye exclusion Dyes enter Dyes initially excluded
Cytoplasm Dilated organelles – Compact and intact
mitochondria show matrix densities, organelles, intact plasma
ruptured plasma and internal membrane
membranes
Nucleus Coarse chromatin patterns Chromatin condensed,
with normal distribution nucleolar disintegration
Circumstances Complement-mediated Programmed cell death,
immune reactions, hypoxia, atrophy, cell-mediated immune
toxins (high killing, toxins
dose) (low dose)
Tissue Effects Acute inflammation, healing by No inflammation, phagocytosis,
repair, scarring with rapid involution without
distortion of tissue affecting tissue structure
TISSUE INJURY
• Introduction to Inflammation
Inflammation is an extravascular process in which the active components of the reaction
(cells and fluid) are derived from the blood vessels supplying the tissue area involved. It
occurs in the connective tissue components, with a characteristic sequence of events
(though the outcome and clinical manifestations vary).
Cause of injury – ischaemic, physical, chemical, infectious, immunological
Time course – rapid and acute, or slow and chronic (depends on the pathogenic mechanism, persistence
of the injurous agent and presence of certain cell types)
Initial reactions – localized, non-specific systemic manifestations (e.g. pyrexia)
Redness (rubor), heat (calor), swelling (tumor), pain (dolor), loss of function (functio laesa)
General pathology is the study of the mechanisms of disease (with emphasis on
aetiology and pathogenesis), while systematic pathology is the study of diseases as they
occur within particular organ systems – it involves aetiology, pathogenesis,
epidemiology, macro- and microscopic appearance, specific diagnostic features, natural
history and sequelae.
Academic pathology includes research and teaching, and the discipline of experimental
pathology was derived from this. Clinical pathology is often referred to as laboratory
medicine and includes a number of diagnostic disciplines.
Pathology provides the basis for understanding:
The mechanisms of disease
The classification of diseases The
diagnosis of diseases The basis
of Streatment
Monitoring the progress of disease
Determining prognosis
Understanding complications
SNOMED – standard classification of disease – considers the following aspects: Topography
Morphology
Aetiology
Function
Disease
Procedure
Occupation
• Techniques of Pathology
Gross pathology – macroscopic investigation and observation of disease
Light microscopy – thin section of wax or plastic permeated tissues, snap-frozen tissues
Histochemistry – microscopy of treated tissue sections (to distinguish cell components)
Immunohistochemistry and immunofluorescence – tagged antibodies (monoclonal better) Electron
microscopy
Biochemical techniques – e.g. fluid and electrolyte balance, serum enzymes Cell
cultures – also allowing cytogenetic analysis
Medical microbiology – direct microscopy, culturing and identification
Molecular pathology – in situ hybridisation (specific genes/mRNA), polymerase chain
reaction
CELL INJURY
• The Pathogenesis of Cell Injury
Normal cell structure and function requires:
, Nuclear function for nucleic acid, protein, lipid and carbohydrate synthesis
Enzyme function for assembly and degradation of organelles and cell products
Membrane function for the transport of metabolites/messengers and for the ionic
and fluid homeostasis
Energy production and the formation of high-energy compounds by
aerobic phosphorylation (and/or anaerobic glycolysis)
Injury to the nucleus:
Genetic defects – single gene, multiple gene or whole chromosome abnormalities
Nutritional disturbances – e.g. pernicious anaemia due to B12 deficiency affecting DNA
synthesis in haematopoietic cells
Toxic injury – may inhibit nuclear functions (synthesis, division)
Standard background radiation is approximately 10-3 rads, with minor consequences for
dosages lower than 10 rads. A dose of 100 rads will give mild radiation sickness. A dose
of 1000 rads will give severe radiation sickness, with pancytopenia. Note that UV is
sufficient to create pro-mutagenic damage to DNA and hence has long-term effects.
Ataxia telangiectasia is due to a fundamental failure to repair damaged DNA. Individuals
with this condition have hypersensitivity to DNA damage (e.g. radiation). Fragile X
syndrome is due to an expansion in an unstable codon (6-50 in normal individuals, 250-
4000 in affected individuals) which leads to susceptibility to nuclear damage.
Injury to cell membranes:
Receptor defects – e.g. familial hypercholesterolemia
Complement related injury – e.g. immunological reactions that activate complement,
opening transmembrane channels that alter ionic homeostasis
Free radical injury – atoms/molecules with unpaired e- (usually O2 intermediates): O2
therapy Excess O2
PMNs, macrophages inflammation
PMNs, xanthine oxidase reperfusion injury after ischaemia
Mixed function oxidation, cyclic redox reactions drug-induced/chemical
toxicity Radiotherapy ionising radiation
Initiators, promoters chemical carcinogenesis
O -, H O , ●OH – reactive oxygen intermediates
2 2 2
membrane damage (lipid peroxidation)
Viruses – direct membrane injury (e.g. polio – viral proteins inserted into membrane
forming pores or channels) or indirect membrane injury (e.g. hepatitis B – viral release
from the cell exposes viral proteins at the cell surface leading to immune response)
Another example is the alpha toxin produced by Clostridium perfringens – this disrupts
membrane function.
Lysosomes and cell injury:
Intracellular ‘storage’ diseases – inherited deficiency of lysosomal enzymes leading to failure
to degrade particular substrates that accumulate
Abnormal intracellular release – e.g. gout and silicosis where the ingestion by
phagocytic cells of uric acid/silica leads to rupture of phagosomes
Abnormal extracellular release – e.g. rheumatoid arthritis
Cell injury and energy production:
Hypoxia or ischaemia compromise energy-dependent process like contraction,
, and transmembrane ionic exchange is affected
Reactions of cells to stress and energy:
Adaptation
Abnormalities of growth – atrophy, hypertrophy, hyperplasia, metaplasia
Abnormal storage – accumulation of products in cytoplasm (e.g. lipofuscin)
Reversible cell damage
Irreversible cell injury – typically cell death by necrosis
Note that there is evidence of reversible cell injury:
Cell and organelle swelling – due to failure of energy-dependent ionic exchange
and/or membrane injury, also known as intracellular oedema
Fat accumulation – fatty change in the parenchymal cells of the liver, heart and
kidney due to failure to utilize or convert the NEFA arriving at the cell (e.g.
inadequate synthesis of lipid-acceptor protein in the liver)
• Necrosis and Apoptosis
The type of necrosis is dependent on the nature, intensity and duration of the injurious
agent, and the type of cell involved. Note that initial membrane damage allows Ca+2
leakage with subsequent activation of Ca-dependent phosphatases and lipases.
Coagulative necrosis – cytoplasm of the necrosed cells becomes eosinophilic and
persists for many days (myocardial infarction)
Colliquative necrosis – cells undergo lysis rapidly (brain infarcts)
Caseous necrosis – Mycobacterium tuberculosis interacts with macrophages Gangrenous
necrosis – primary (bacterial toxins) or secondary (ischaemia, infection) Fibrinoid necrosis
– smooth muscle necrosis, fibrin release (malignant hypertension) Fat necrosis –
inflammatory response to liberated fat fibrosis
There are also nuclear changes related to necrosis:
Margination of chromatin – chromatin condensing around the periphery of the nucleus
Pyknosis – small and dense nuclei
Karyolysis – complete lysis of the nuclei
Karyorrhexis – fragmented nuclei (generally seen in apoptosis)
Irreversible cell injury is typically accompanied by:
Release of intracellular enzymes:
Cardiac muscle – creatine kinase (MB isoform), aspartate transaminase, lactate
dehydrogenase
Hepatocytes – alanine transaminase
Striated muscle – creatine kinase (MM isoform)
Exocrine pancreas – amylase
Loss of membrane selectivity – may be helpful in diagnosis through uptake of dyes
Inflammatory response – initiated by products (mediators) of the necrotic cells
Cell death can also occur through apoptosis – it may be physiological deletion of selected cells
(e.g. morphogenesis, cyclic hyperplasia of reproductive processes) or it may occur in response to a
pathological stimuli. Note that there are no gross structural changes involved.
The initiation of apoptosis requires two processes:
Priming – a reversible stage in which the specialist machinery for apoptosis (e.g.
transglutamase, calcium/magnesium endonucleases) are activated
Triggering – the irreversible point which leads to a sustained rise in cytosolic calcium, and
, induction of new mRNA species for c-fos, c-myc and heat-shock proteins
Apoptosis then proceeds:
• Cytosol and nucleus lost half their volume
• Fragmentation of nucleus and cytosol ( activation of transglutamase that forms
an insoluble layer beneath the intact cell membrane)
• Condensation of chromatin (pyknosis)
• Macrophages bind to cell fragments prior to phagocytosis (non-specific mechanism)
Pathological cell death is more often due to necrosis – this process releases intracellular
enzymes (useful diagnostically) and mediators that stimulate inflammation. This is followed by healing by
repair, scarring, contracture and distortion of tissue architecture.
Necrosis Apoptosis
Histology Groups of cells, disrupting tissue Single cells within living tissues
structure
Cytology Cellular swelling, nuclei Pyknotic subdivided nuclei,
initially intact condensed cytoplasm,
rounded
membrane-bound cell fragments
Dye exclusion Dyes enter Dyes initially excluded
Cytoplasm Dilated organelles – Compact and intact
mitochondria show matrix densities, organelles, intact plasma
ruptured plasma and internal membrane
membranes
Nucleus Coarse chromatin patterns Chromatin condensed,
with normal distribution nucleolar disintegration
Circumstances Complement-mediated Programmed cell death,
immune reactions, hypoxia, atrophy, cell-mediated immune
toxins (high killing, toxins
dose) (low dose)
Tissue Effects Acute inflammation, healing by No inflammation, phagocytosis,
repair, scarring with rapid involution without
distortion of tissue affecting tissue structure
TISSUE INJURY
• Introduction to Inflammation
Inflammation is an extravascular process in which the active components of the reaction
(cells and fluid) are derived from the blood vessels supplying the tissue area involved. It
occurs in the connective tissue components, with a characteristic sequence of events
(though the outcome and clinical manifestations vary).
Cause of injury – ischaemic, physical, chemical, infectious, immunological
Time course – rapid and acute, or slow and chronic (depends on the pathogenic mechanism, persistence
of the injurous agent and presence of certain cell types)
Initial reactions – localized, non-specific systemic manifestations (e.g. pyrexia)
Redness (rubor), heat (calor), swelling (tumor), pain (dolor), loss of function (functio laesa)
