ANATOMICAL PATHOLOGY:

CELLULAR ADAPTATION, INJURY & DEATH

For case 301 (PBL):
• No restriction to reading
• No limit to learning
• Everything is ‘nice’ to know

For this resource session:

• Consolidate the learning from Case 301
• ‘Streamline’ the material into an ‘assessment-directed’ summary
• What do we ‘need’ to know?
How to ‘engage’ Robbins:

• First read the chapter like a novel from start to finish

• Visualise a ‘landscape’ of the content
• Construct a framework of headings and sub-headings (‘length and
breadth’)
• (Progressively) Populate with salient information (‘depth’)
• Review, reflect and revise
• Figures, tables and summaries become meaningful
• Look for the patterns and the ‘value’ or application of information …
makes it easier to understand and remember
What is Pathology?

• Study of suffering/disease

• Structural, biochemical and functional changes in cells, tissues and

organs that underlie disease
Core Concepts in Pathology

• Aetiology - Cause/s

• Pathogenesis - Sequence of cellular, biochemical and molecular

events that follow exposure of cells to an injurious agent

• Morphology - Structural alterations in cells or tissues that are

characteristic of a disease or diagnostic of an aetiologic process

• Functional Derangements - Clinical manifestations and

clinicopathological correlations
General Approach to Summarising Pathology

• Definition
• Risk/Predisposing factors
‘Add-ons’
• Aetiology o Classification
• Pathogenesis o Severity Scores
o Staging and grading
• Morphology – Gross and microscopic o Etc.
• Clinical Features
• Investigations
• Treatment
• Prognosis
• Complications
General Approach to Summarising Pathology

• Definition
• Risk/Predisposing factors
Can you spot the integration
• Aetiology with Chemical Pathology,
• Pathogenesis Microbiology, Virology,
Haematology, Pharmacology
• Morphology – Gross and microscopic and Clinical Skills?
• Clinical Features
• Investigations
• Treatment
• Prognosis
• Complications
Cellular Responses to Stress and Noxious Stimuli

• Normal cells are maintained in a steady state (homeostasis)

• Stress and noxious stimuli result in:

o Adaptation

o Injury which may be reversible or irreversible

o Irreversible injury leads to cell death

Adaptations of Cellular Growth and Differentiation

• Reversible changes in size, number, phenotype, metabolic activity or

functions of cells in response to environmental changes

• Hypertrophy

• Hyperplasia

• Atrophy

• Metaplasia
Hypertrophy

• Increase in size

• Mechanism: Due to increased production of cellular proteins

• Physiologic – increased functional demand/workload or stimulation by

hormones and growth factors

• Pathologic – mechanisms to cope with increased burden are

exhausted
Hyperplasia

• Increase in number

• Mechanism: Growth factor-driven proliferation of mature cells and

increased output of new cells from tissue stem cells

• Physiologic – action of hormones and growth factors to increase

functional capacity or compensate after damage

• Pathologic – excessive or inappropriate actions of hormones or

growth factors on target cells
Atrophy

• Reduction in size of organ or tissue due to decrease in cell size and

number

• Mechanism: Decreased protein synthesis (reduced metabolic activity)

and increased protein degradation (ubiquitin-proteasome pathway)

• Physiologic – common during normal development

• Pathologic – several causes

Atrophy

Causes of pathologic atrophy:

• Disuse

• Denervation

• Diminished blood supply

• Inadequate nutrition

• Loss of endocrine stimulation

• Pressure
Metaplasia

• Adaptive change in phenotype whereby one differentiated cell type

(epithelial or mesenchymal) is replaced by another cell type

• Mechanism: Reprogramming of stem cells that are known to exist in

normal tissues, or of undifferentiated mesenchymal cells present in
connective tissue
Causes of Cell Injury

• Oxygen deprivation (hypoxia, ischaemia)

• Physical agents
What is the ‘value’ of this list?
• Chemical agents and drugs

• Infectious agents

• Immunologic reactions

• Genetic derangements

• Nutritional imbalances
Morphologic Alterations in Cell Injury

Reversible Injury:

• Cellular swelling/Hydropic change/Vacuolar degeneration

• Fatty change/Steatosis
Morphologic Alterations in Cell Injury

Irreversible Injury:

• Necrosis

• Apoptosis
Morphologic Alterations in Cell Injury

Necrosis:

• Increased eosinophilia

• Nuclear shrinkage, fragmentation and dissolution

• Breakdown of plasma membrane and organellar membranes

• Abundant myelin figures

• Leakage and enzymatic digestion of cellular contents

Morphologic Alterations in Cell Injury

Patterns of Tissue Necrosis:

• Coagulative

• Liquefactive

• Gangrenous

• Caseous

• Fat

• Fibrinoid
Morphologic Alterations in Cell Injury

Apoptosis:

• Regulated mechanism of cell death to eliminate unwanted and

irreparably damaged cells with the least possible host reaction

• Characterised by caspase-induced enzymatic degradation of proteins

and DNA, and by recognition and removal of dead cells by
phagocytosis

• Initiated by mitochondrial (intrinsic) pathway or death receptor

(extrinsic) pathway
Morphologic Alterations in Cell Injury

Apoptosis:

• Physiologic (e.g. embryogenesis)

• Pathologic (e.g. radiation-induced DNA damage)

Morphologic Alterations in Cell Injury

Apoptosis:

• Cell shrinkage

• Chromatin condensation

• Formation of cytoplasmic blebs and apoptotic bodies

• Phagocytosis of apoptotic cells or cell bodies, usually by

macrophages
Morphologic Alterations in Cell Injury

Necroptosis:

• Hybrid of necrosis and apoptosis

Pyroptosis:

• Occurs in cells infected by microbes

Autophagy:

• Cell cannabilises itself (by fusion with lysosomes) to survive

Mechanisms of Cell Injury

• Cellular response depends on nature, duration and severity of injury

• Consequences depend on type, state and adaptability of the injured

cell

• Results from different biochemical mechanisms acting on several

essential cellular components
Mechanisms of Cell Injury

• ATP depletion

• 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

Key Examples of Cell Injury and Necrosis

• Ischaemic and hypoxic injury

• Ischaemia-reperfusion injury

• Chemical/Toxic injury
Intracellular Accumulations

Four main pathways:

• Inadequate removal of a normal substance due to defective

packaging and transport

• Accumulation of abnormal endogenous substance due to genetic or

acquired defects in its folding, packaging, transport or secretion

• Failure to degrade a metabolite due to inherited enzyme deficiencies

• Deposition and accumulation of abnormal exogenous substance

when cell lacks enzymatic machinery to degrade it or unable to
transport it to another site
Intracellular Accumulations

• Lipids (fatty change, cholesterol deposition)

• Proteins

• Hyaline change

• Glycogen

• Pigments: Exogenous (e.g. carbon) or Endogenous (e.g. lipofuscin,

haemosiderin, melanin, bile)

• Pathologic calcifications: Dystrophic or Metastatic

Intracellular Accumulations

Dystrophic Calcification:

• Calcium deposition at sites of cell injury and necrosis

• May be intracellular and/or extracellular

• Basophilic, amorphous, granular deposits

• Heterotopic bone formation

• Psammoma bodies
Intracellular Accumulations

Metastatic Calcification:

Calcium deposition in normal tissues caused by hypercalcaemia

secondary to:

• Increased secretion of parathyroid hormone with bone resorption

• Resorption of bone tissue due to bone tumours

• Vitamin D-related disorders

• Renal failure causing phosphate retention and hyperparathyroidism

Cellular Aging

• Result of progressive decline in cellular function and viability

• Caused by genetic abnormalities and accumulation of cellular and

molecular damage due to effects of exposure to exogenous
influences

Mechanisms:

• Accumulation of DNA damage

• Replicative senescence

• Defective protein homeostasis

• Nutrient sensing system

What have we learned?
• ‘Core’ knowledge is readily identified within the volume
• Summarising significantly reduces the volume
• However, the ‘need’ to know requires the ‘nice’ to know

Going forward:
• You now have the ‘length, breadth and some depth’
• Supplement the framework with schematics, figures and tables
• Practical sessions/application will require this background theoretical
knowledge