Pathology Flashcards
Define pathology
The study of structural, biochemical and functional changes in cells, tissues and organs that underlie disease
Define systemic pathology
- Pathology of organ systems
- The study of alterations in specialised organs and tissues that are responsible for disorders that involve these organs
Define anatomic pathology
- Examination of tissues taken during life (biopsy) or after death (necropsy)
- Examines nature and extent of disease process
Define clinical pathology
Examination of blood and other body fluids, as well as cells (cytology) during life
List the 4 aspects of disease
- Aetiology
- Pathogenesis
- Molecular and morphologic changes
- Clinical manifestation
What is meant by aetiology?
- Cause of disease
- Can be internal (e.g. aging, immunologic defects) or external (e.g. external agents or deficiencies)
- Most commonly multifactorial
What is meant by pathogenesis?
- Mechanism of disease development
- Sequence of events in response of cells or tissues to aetiologic agent from initial stimulus to ultimate expression of disease
What is meant by molecular and morphologic changes in disease?
- Biochemical (molecular) and structural (morphologic) alterations induced in cells and organs
Outline the clinical manifestation aspect in disease
- Functional consequences of molecular and morphologic changes
- End results of genetic, biochemical and structural changes in cells and tissues are functional abnormalities
What is the difference between symptoms and signs?
- Symptoms: what the animal is feeling (nausea)
- Signs: what the clinician sees (vomiting)
List the major processes of pathology
- Inflammation
- Healing
- Thrombosis
- Neoplasia
- Metabolic dysfunction
- Necrosis
What are the “pillars of inflammation”
- Heat
- Redness
- Swelling
- Pain
- Loss of function
What is the process and function of inflammation?
- Vascular and interstitial tissue changes that develop in response to tissue injury
- Designed to sequester, dilute and destroy causal agent
What are the processes involved in healing?
- Angiogenesis
- Fibrosis
- Regeneration
What is epithelisation?
Regenerative process that covers defects in injured skin and other epithelial surfaces
What is thrombosis?
Interaction of blood coagulation system and platelets to form (within a vascular lumen) an aggregate of fibrin and platelets (thrombus)
What leads to neoplasia?
- Intrinsic genetic mutations in somatic cells that underlie abnormal mechanisms for control of mitosis, differentiation and cell-to-cell interactions
- Leads to uncontrolled mitosis and expanding mass of uncontrolled cells
What is the effect of neoplasia?
Impinges on adjacent normal tissue
What is the role of metabolic dysfunction in pathology?
- Abnormalities/imbalances of carb, fat and protein metabolism in cell leads to accumulation of glycogen, fat or protein
- Also complexes of abnormally folded and branched proteins, lipoproteins and amyloid
What is necrosis?
Death of cells and tissues in living animals
What is the definition of diagnosis?
Conclusion concerning the nature, cause or name of a disease
List the different types of diagnosis
- Clinical
- Clinical pathologic
- Morphologic (lesion)
- Aetiologic
- Disease
Outline what is meant by a clinical diagnosis
- Based on data obtained from case history, clinical signs and physical examination
- i.e. severe acute contagious blood diarrhoea
Outline what is meant by clinical pathologic diagnosis
- Based on changes observed in chemistry of fluids and haematology, structure and function of cells collected from living patient
- i.e. severe leukocytosis
Outline what is meant by morphologic diagnosis
- Based on predominant lesions in tissue
- Can be macroscopic (gross) or microscopic (histologic)
What is included in a morphologic diagnosis?
- Severity
- Duration
- Distribution
- Location (organ or tissue)
- Nature (degenerative, inflammatory, neoplastic)
Outline what is meant by aetiologic diagnosis
Names the specific cause of the disease
List methods that can be used to reach a diagnosis
- Morphology
- Molecular biology
- Microbiology
- Immunology
- Genetics
- Informatics
What is a biopsy?
Removal and examination of tissue sample from a living animal body for diagnostic purposes
What is a necropsy?
Methodical examination of the dead animal
What is meant by a macroscopic examination?
- Observation by the unaided eye
- Observe deviations in size, colour, texture, location from normal organs/tissues
What is meant by microscopic examination?
- Light microscopy (histopathology, often stained, specialised microscopes e.g. dark field)
- Electron microscopy: trans or scanning
List molecular techniques that can be used in diagnosis
- PCR
- In situ hybridisation (ISH)
- Genomics (DNA sequencing, DNA microarrays)
- Transcriptomics (RNA sequencing)
- Proteomics, metabolomics, immunological approaches
What are molecular techniques used for in diagnosis?
Detection of, or detection of alterations from normal, in nucleic acids and protein
What is putrefaction?
Colour and texture changes, gas production, odours produced by post-mortem bacterial metabolism and dissolution of host tissues (decomposition)
What is rigor mortis?
Contraction of muscles after death
What causes rigor mortis and on what timescale does it occur?
- Depletion of ATP and glycogen
- Starts 1-6 hours after death, persists for 1-2 days
What is algor mortis?
Gradual cooling of the cadaver
Why may gradual heating of the cadaver occur following death?
Bacterial processes
What is livor mortis?
- Hypostatic congestion
- Gravitational pooling of blood on one side of the animal
When and where does post-mortem clotting occur?
- Heart and blood vessels
- Within several hours after death
What is haemoglobin imbibition?
Red staining of tissues
How does haemoglobin imbibition occur?
- Integrity of blood vessel walls lost
- Hb released by lysed RBCs
- Penetrates vessel walls
What is bile imbibition?
Staining of tissues a yellow/green/brown colour
How does bile imbibition occur?
Bile in gall bladder penetrates wall and stains tissues
What is psuedomelanosis?
Blue-green discolouration of tissue by iron sulphide (FeS)
How does pseudomelanosis occur?
Formed by the reaction of hydrogen sulphide (H2S) generated by putrefactive bacteria and iron from haemoglobin released from lysed erythrocytes
How does bloating post mortem occur?
Bacterial gas formation in the lumen of teh GIT
Why does softening occur post mortem?
Softening of tissue results from autolysis of cells and connective tissue, often aided by putrefactive bacteria
When might lens opacity occur post mortem?
- When carcass very cold or frozen
- Reverses when warms up
List common causes of cell injury
- oxygen deprivation
- Physical agents
- Chemical agents and drugs
- Infectious agents
- Immunologic reactions
- Genetic derangements
- Nutritional imbalances
What may lead to oxygen deprivation of a cell?
- Reduced blood flow (ischaemia)
- Inadequate oxygenation of blood (cardiorespiratory failure)
- Decreased oxygen carrying capacity of blood (anaemia, CO poisoning, blood loss)
What physical agents may cause cell injury?
- Mechanical trauma
- Extremes of temperature
- Radiation
- Electric shock
What chemical agents or drugs may cause cell injury?
- Hypertonic concentrations of simple chemicals (glucose, salt)
- Poisons
- Environmental pollutatns (insecticides, herbicides)
- Therapeutic drugs
What infectious agents may cause cell injury?
- Viruses and prions
- Bacteria
- Fungi
- Parasites
What immunologic reactions might lead to cell injury?
- Immune reactions to external agents (microbes) and environmental substances
- Immune reactions to endogenous self-antigens (autoimmune diseases)
What genetic deficiencies may lead to cell injury?
- Deficiency of functional (e.g. enzymes) or structural proteins (errors of metabolism, accumulation of damaged DNA or misfolded proteins)
- Influence the susceptibility of cells to injury by chemical and other environmental insults
Give examples of reversible cell injury
- Depletion of cellular energy stores
- Cellular swelling
- Alterations of intracellular organelles
- Fatty change
What leads to fatty changes in cells?
- Abnormal accumulations of neutral lipids within parenchymal cells
- Often liver
- Excessive production/mobilisation of lipids, defective metabolism and export of lipids (due to toxins or hypoxia for example)
What conditions may lead to excessive production or mobilisation of lipids, leading to fatty change in cells and how?
- Starvation
- Diabetes mellitus
- Depleted carb sotres, breakdown of fat and protein = increased FFAs
What is the difference between necrosis and apoptosis?
- Necrosis is always pathologic, cell membranes damaged, often with inflammation
- Apoptosis: may be pathologic or physiologic, cell membranes in tact, no inflammation, is programmed cell death
Outline the process of necrosis
- Swelling of endoplasmic reticulum and mitochondria
- Denaturation of intracellular proteins and enzymatic digestion of injured cell
- Breakdown of plasma membrane, organelles and nucleus
- Leakage of cellular contents
What enzymes and proteins released from necrotic cells can be detected in the blood?
- Creatine kinase
- Alkalin phosphatase
What molecular and biochemical mechanisms are involved in necrosis?
- Depletion of ATP
- Mitochondrial damage
- Influx of calcium and loss of calcium homeostasis
- Accumulation of oxygen-derived free radicals
- Defects in membrane permeability
- Damage to DNA and proteins
How does ATP depletion in necrosis occur?
Reduced supply of oxygen and nutrients, mitochondrial damage or toxins
How does ATP depletion contribute to necrosis?
- ATP required for virtually all synthetic and degradative processes within the cell
- E..g membrane transport, protein synthesis, lipogenesis
How does mitochondrial damage in necrosis occur?
Hypoxia and toxins are major causes
How does mitochondrial damage contribute to necrosis?
- Leads to reduced ATP
- Release of pro-apoptotic proteins e.g. cytochrome C
How does influx of calcium and loss of calcium homeostasis occur in necrosis?
Ischaemia and toxins are major causes
How does calcium influx and loss of calcium homeostasis contribute to necrosis?
- Increases mitochondrial permeability (reduced ATP, induction of apoptosis)
- Activation of multiple cellular enzymes e.g. phospholipases, proteases, endonucleases, ATPases
How does accumulation of oxygen-derived free radicals (ROS) occur in necrosis?
- Inflammation
- Radiation
- Chemicals
- Reperfusion injury
How does the accumulation of oxygen derived free radicals contribute to necrosis?
Damage to lipids, proteins and DNA
How may defects in membrane permeability occur in necrosis?
- Ischaemia
- Toxins
- Viruses
- Physical/chemical agents
How do membrane defects contribute to necrosis?
Consequences in:
- Mitochondrial membrane (ATP production, apoptosis)
- Plasma membrane (loss of cellular contents and osmotic balance)
- Lysosomal membranes (leakage of enzymes leading to enzymatic digestion of proteins, DNA/RNA, glycogen)
What cytoplasmic morphologic alterations seen on microscopy may occur in necrosis?
- Increases eosinophilia
- Cytoplasmic vacuolation
What nuclear morphologic changes seen on microscopy may occur in necrosis?
- Karyolysis (nuclear fading)
- Pyknosis (nuclear shrinkage)
- Karyorrhexis nuclear fragmentation)
What are the different patterns of tissue necrosis that may be seen?
- Coagulative necrosis
- Liquefactive necrosis
- Gangrenous necrosis
- Caseous necrosis
- Fat necrosis
What is an infarct?
A localised area of coagulative necrosis caused by ischaemia due to vascular obstruction
Outline the key features of coagulative necrosis
- Architecture of tissue preserved
- Firm texture
- Dark colour
How does coagulative necrosis occur?
Injury denatures structural proteins but also enzymes, blocking proteolysis of dead cells so architecture maintained
Outline the key features of lliquefactive necrosis
- Liquid viscous mass
- Enzymatically digested dead tissue, architecture not preserved
- Mainly in microbial infections
- Pus or malacia
Why might liquefactive necrosis occur in microbial infection
Accumulation of leukocytes liberates enzymes
What is malacia?
A type of necrosis of the central nervous system (liquefactive)
Outline the key features of gangrenous necrosis
- Variant of coagulative necrosis
- Usually applies to a limb that has lost its blood supply
What are the types of gangrenous necrosis?
- Dry
- Moist
- Gas
Outline the key features of caseous necrosis
- Conversion of dead cells into friable mass resembling cheese
- Typically more chronic than coagulative necrosis
- E.g. TB, pseudotuberculosis
Outline the key features of fat necrosis
- Focal areas of fat destruction (no specific pattern of necrosis)
- Fat appears white, firm, chalky, resembles flecks of soap
How does fat necrosis occur?
- Typically results from release of pancreatic lipases
- TAG esters metabolised by lipases to fatty acids, react with calcium leading to fat saponification
What fragments do apoptotic cells split into?
- Apoptotic bodies
- Intact plasma membrane
How are apoptotic bodies removed?
Removed by phagocytes, usually macrophages
Give examples of physiologic causes of apoptosis
- Embryogenesis
- Involution of hormone-dependent tissues
- Cell loss in proliferating cell populations
- Elimination of self-reactive lymphocytes
- Leukocytes after inflammatory response
Give examples of pathologic causes of apoptosis
- DNA damage
- Accumulation misfolded proteins
- Certain viral infections
- Atrophy in organs due to disuse/compression
What molecular/biochemical mechanisms are involved in apoptosis?
- Activation of caspases
- DNA and protein breakdown
- Membrane alterations and recognition by phagocytes
Outline the activation of caspases in apoptosis
- Enzymatic cleavage of inactive pro-enzymes to become active
- Are apoptosis specific enzymes that lead to breakdown of cytoskeleton
Give potential causes of DNA and protein breakdown in apoptosis
- Drugs
- Radiation
- Oxidative stress
- Inherited diseases
How does DNA and protein breakdown occur in apoptosis?
- DNA broken down into small pieces by endonucleases activated by caspases
- Protein also broken down by caspases
What is the function of membrane alterations in apoptosis?
- Recognition by phagocytes
- Removal of dead cells by phagocytosis
What microscopic morphologic changes are seen in apoptosis?
- Cell shrinkage
- Chromatin condensation
- Cytoplasmic blebs and apoptotic bodies
- Phagocytosis of apoptotic cells or cell bodies
What are the 2 pathways of apoptosis?
- Intrinsic (mitochondrial)
- Extrinsic (death receptor-initiated)
Outline the intrinsic pathway of apoptosis following injury
- Injury leads to DNA damage
- enzyme p53 activated, increases permeability of mitochondrion membrane (or direct activation of executioner caspases)
- Release of proapoptotic molecules e.g. cytochrome C
- Initator caspases activated
- Executioner caspases activated
- Leads to endonuclease activation and breakdown of cytoskeleton and cytoplasmic bud forms
Outline the mitochrondrial pathway of apoptosis following withdrawal of growth factors or hormones
- Withdrawal leads to activation of proapoptotic molecules e.g. cytochrome C
- Initiator caspases activated, activate executioner caspases
- Endonuclease activation or breakdown of cytoskeleton
- Cytoplasmic bud formation
Outline the extrinsic pathway of apoptosis following receptor-ligand interactions
- Binding of ligand (Fas, TNF) to receptor
- Adapter proteins activated
- Initiator caspases activated, executioner caspases activated
- Endonuclease activation, breakdown of cytoskeleton
- Cytoplasmic bud forms
Outline the pathway of apoptosis initiated by cytotoxic T lymphocytes
- Granzyme B activated
- Activates executioner caspases directly
- Endonuclease activation
- Breakdown of cytoskeleton
