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Module: PX2108 Basic Human Pathology – Fundamental Pathological Processes
What is this module all about?
Pathology is the study (logos) of disease (pathos)
Devoted to understanding the structural and
functional changes in cells, tissues, and organs that
underlie disease
Dr Lim Yaw Chyn (Sr Lecturer / Research Scientist) • Module Coordinator • Email: yawchyn_lim@nuhs.edu.sg
Ms Christina Soh Yu Ting • Administrative officer • Email: patcsyt@nus.edu.sg • Office Tel: 66011219
Contact Christina for all administrative purposes
Administrative Matters
Introduction
Anatomy – study of structure
Physiology – study of function
Pathophysiology:
when physiological functions become
disordered resulting in disease
What is disease?
Disease (dis-ease) occurs when healthy anatomy
(structure) and/or physiology (function) go wrong!
Pathology
• Study is focused on understanding the disease process:
its cause (etiology)
how did it develop (pathogenesis)
structural alterations induced in cells and organs (morphological changes)
functional consequences of the change (clinical significance)
• Bridging discipline involving both the basic science and
clinical practice
direct effect of the injury agent on the cells and
tissues;
consequence of body’s response to the injury;
combination of both (most common)
Structural alterations that affect function (or conversely abnormal function that
alters structures) could be the
Module Structure and Assessment
• Lectures – Topics of General Pathology and selected topics of Systemic Pathology
• Tutorials
• 2 CAs – MCQs
• Final Exam (MCQs and 3 MEQs)
9 Lecturers; 19 Topics
Dr Lim Yaw Chyn
A/Prof Fredrik Petersson
Dr Seet Ju Ee
Dr Brendan Pang
A/Prof Sunil Sethi
Dr Thomas Thamboo
Dr Diana Lim A/Prof Nga Min En
A/Prof Evelyn Koay
Dr Lim Yaw Chyn • Lectures: Cell Injury (L1) Acute and Chronic Inflammation (L4) Healing and Repair (L5) Immunopathology (L6) Anaemia and Haemolysis (L15) Haemostasis and Bleeding Disorders (L19)
Lecturers
A/Prof Fredrik Petersson (Histo-Pathologist) • Email: bengt_fredrik_petersson@nuhs.edu.sg • Lectures: Thrombosis, Embolism and Infarction (L2) Oedema and Shock (L3)
Dr Seet Ju Ee (Histo-Pathologist) • Email: ju_ee_seet@nuhs.edu.sg • Lectures: Infection (L7) Respiratory Diseases(L8)
Hidden slide
Dr Brendan Pang (Histo-Pathologist) • Email: brendan_nk_pang@nuhs.edu.sg • Lectures: Gastrointestinal Diseases (L9) Environmental & Nutritional Pathology (L17) Pathology of Adverse Drug Reactions (L18)
Lecturers
A/Prof Sunil Sethi (Chemical Pathologist) • Email: sunil_sethi@nuhs.edu.sg • Lectures: Diabetes Mellitus(L10) Lipid Disorders (L11)
A/Prof Ng Min En (Histo-Pathologist) • Email: min_en_nga@nuhs.edu.sg • Lecture: Heart Diseases(L12)
Hidden slide
A/Prof Evelyn Koay (Chemical Pathologist) • Email: evelyn_koay@nuhs.edu.sg • Lecture: Jaundice & Liver Failure (L14)
Dr Diana Lim (Histo-Pathologist) • Email: diana_gz_lim@nuhs.edu.sg • Lecture: Tumour Pathology (L16)
Lecturers
Dr Thomas Thamboo (Histo-Pathologist) • Email: thomas_paulraj_thamboo@nuhs.edu.sg • Lecture: Renal Diseases (L13)
Hidden slide
Recommended Texts
The Nature of Disease Pathology for the Health Professions;
2nd Edition, by Thomas H. McConnell
Basic Pathology; 4th Edition,
Sunil R Lakhani , Susan A Dilly,
Caroline J Finlayson
Board Review Series: Pathology;
3rd Edition, Arthur S Schneider and
Phillip A Szanto
Pathology Illustrated; 6th Edition,
Robin Reid and Fiona Roberts
Questions?
Outline of Lecture
What Do Cells Do?
Cell Adaptation to Stress
Cell Injury – Sublethal Injury
Cell Death – Apoptosis and Necrosis
Cell Aging
Cell Adaptation and Injury
What Do Cells Do?
Nucleus
Ribosomes
Golgi
Complex Lysosomes
Plasma
membrane Mitochondria
Plasma membrane
They generate
energy
They talk to, and can be
influenced by, other cells
Signalling pathways
They build things up and they break
things down
Ribosomes/mRNA/
Golgi Complex
…And the Guy in Charge
Nucleus
Plasma membrane
They keep some things Out, and
allow other things In and Out
Conditions Inside A Cell
DNA is software, proteins are hardware
Very crowded
- one protein may interfere with function of next protein
- affects equilibrium processes
Enormous numbers of molecules synthesized and broken
down all the time
Risk of disruption by thermal forces
- importance of quality control mechanisms
From : Garett and Grisham, Biochemistry, 4th ed
What a Successful Cell Needs
• Energy – mitochondria
• Compartmentalization of organelles
- importance of lipid bilayer membranes
• Control mechanisms
– nucleus
signalling pathways
• Quality control systems
- lysosomes
autophagy
• Repair processes
Question : What happens when cells / tissues are stressed?
Answer : 2 types of response are possible :
1) adaptive – to cope with stress
2) damage (cell injury)
- sublethal (reversible)
- lethal (irreversible)
Adaptive responses enable the cells / tissues to
cope with an increased workload.
Some stresses are bad and the cells are damaged,
some are so badly damaged that they die.
Adaptive Responses
Increase in Size – hyperplasiahypertrophy
Decrease in Size – hypoplasiaatrophy / aplasia
Change in Tissue Type – metaplasia
Change to another cell type
Increase in numbers
Increase in size
Decrease in numbers
Decrease in size
Sublethal Cell Damage and Cell Death
Intracellular Accumulations
– water
lipid
pigment
others
Cell Death – apoptosis
necrosis
Can the Changes be Reversed?
Hypertrophy – reversible
Hyperplasia – reversible
Atrophy – probably irreversible
(?possibility of regeneration sometimes)
Metaplasia – reversible
Intracellular Accumulations – sometimes reversible
Cell Death – irreversible
Increase in Size of Organs / Tissues
Uterine Enlargement in Pregnancy
Physiological response
to hormonal changes
Small spindle-shaped
smooth muscle cells Large plump cells
Skeletal Muscle Hypertrophy
When Compensation is Insufficient You Get Symptomatic
Heart – Left and Right Ventricular Hypertrophy
Cross-section of
a normal heart
Response to pressure and/or volume loads
But what if blood supply cannot be increased to
supply increased muscle bulk?
Prostate – Benign Hyperplasia
Clinical Consequences
- urinary retention
- obstructive uropathy
- renal failure
Decrease in Size of Organs / Tissues
– Adaptive
Need to be distinguished from developmental causes
Following
denervation Poliomyelitis
Atrophic Skeletal Muscle
From disuse (recovering
from mid-foot fracture)
Reversible Non reversible
Unilateral Renal
Artery Stenosis with
Renal Atrophy
Marrow Hypoplasia
Drugs and Chemicals,
Ionising radiation,
Immune
Clinical Consequence -
Bone marrow failure : Anemia
Infection
Bleeding
Change in Cell Type – Metaplasia
Replacement of one
differentiated cell type by
another cell type
Commonest –
columnar epithelium
stratified squamous
Often in bronchus in cigarette
smokers
Cell Damage – Sublethal and Lethal
Aetiologies of Injury
Examples of Injurious Stimuli
Physical
Trauma
Cold
Heat
Electrical
Ionizing Radiation
DNA damage
Hypoxia
Lack of oxygen
(e.g. ischemia)
Biological
Infectious agents
Bacteria
Virus
Fungi
Immunological Hypersensitivity
Hyposentitivity
Chemical
Therapeutic (e.g. aspirin)
Non-therapeutic
(e.g. alcohol abuse)
Nutritional
Effects on cells and growth
Genetic
Enzyme deficiency
Abnormalities
(e.g. hemochromatosis)
Aging Lifespan of cells
Environment
(e.g. chronic stress)
Common Mechanisms of Cell Injury
Common sites of Cell Injury:
Cell membranes
Mitochondria
Cytoskeleton
Nuclear DNA
Often multiple components
damaged
Cell Damage – Sublethal and Lethal
Intracellular Accumulations –
Hydropic Change in Renal Tubular Cells
Accumulation of water inside cell when pumps fail.
Hydropic Change in
Hepatocytes
Intracellular Accumulations – Fatty Change
Intracellular Accumulations – Fatty Change in Liver
Large pale liver with
macrovesicular fatty change.
Affected hepatocytes stain red
with Oil Red O.
Pigmentation
Lipofuscin
- wear and tear pigment
Hemosiderin
- breakdown product of hemoglobin
Others :
endogenous - bilirubin
melanin, etc
exogenous - silver
carbon, etc
non-living or dying cells
healthy tissues
Calcium Deposition
Cell Death
Apoptosis :
physiological and programmed
elimination of unwanted cells
pathological when abnormally activated.
Necrosis - always pathological
Initiators :
• Binding of specific ligands – “death pathway”
• Cell damage pathway – mitochondrial
• DNA damage/p53-p73 pathway
• Cell membrane damage pathway
The high-point is the activation of caspases (proteases) that break down the cell into fragments (end point).
• Release of apoptotic bodies carrying “Eat Me” signals
• Rapidly removal by phagocytes
Mechanisms of Apoptosis
Apoptosis in Pathology
Death of native cells in acute inflammation
Death induced by cytotoxic T cells
Some viral diseases e.g. viral hepatitis
Apoptosis – necrosis overlap
e.g. heat, radiation, cytotoxic drugs, and hypoxia
Skin-Drug reaction: Apoptosis of
epidermis in Erythema Multiforme
Necrosis – Nuclear and Cytoplasmic Changes
Nuclear :
1) pyknosis
2) karyorrhexis
3) karyolysis
Cytoplasmic :
eosinophilia
Coagulative necrosis
Liquefactive necrosis
Caseous necrosis
Fat necrosis
Fibrinoid necrosis
Types of Necrosis
Common features :
1) No nuclei
2) Cytoplasmic eosinophilia
Coagulative necrosis Caseous necrosis Liquefactive necrosis
Fibrinoid necrosis fat necrosis
Different morphological changes seen in necrosis
Coagulative Necrosis
Myocardial Infarction
Necrotic cells retain their cell outlines
Cytoplasm is eosinophilic
Loss of nuclei; remaining show nuclear
changes
Increasing incidence of myocardial
infarction and cerebral infarction (stroke)
in Singapore.
Lifestyle changes
diabetes
atherosclerosis
- predispose to arterial obstruction
ischemia of heart and brain
Pathological Lesion – Cerebral infarct
Clinical syndrome – stroke
Infective abscess
Necrotic area is semi-fluid with no
visible cell outlines
Liquefactive Necrosis
Caseous Necrosis
TB infection e.g. pulmonary tuberculosis
Macroscopically: gray-white, soft,
cheese-like material
Microscopically:
• Dead cells persist as solid but
eosinophillic amorphous material
• Cell outline not retained
• No tissue architecture seen
Fat Necrosis
Affects adipose tissue
Follows pancreatitis
Due to release of enzymes that act on fat cells
Released fatty acids complex with calcium to
form white chalky deposits
(saponification; red arrow)
Fibrinoid Necrosis
May follow damage to blood vessels due to
hypertension
Plasma proteins accummulate in the wall
The wall becomes eosinophilic, resembling a
microscopic blood clot or ‘fibrinoid’
Liver - Paracetamol Toxicity
Panadol overdose
acute massive necrosis
Acute liver failure
- loss of detoxification
encephalopathy
- inability to synthesise clotting factors
bleeding tendency
- inability to excrete
jaundice
- release of enzymes
increased AST
ALT
Apoptosis versus Necrosis
Groups of cells affected
Triggered by injury
Cells swell hydropically
Haphazard DNA turnover
Cell (and internal organelles)
rupture; messy and disorganised
Debris triggers inflammation
Single or a few cells involved
Programmed by the cell
Cells shrink cytoskeletally
Orderly fragmentation of nucleus
Fragments (nuclei material and
organelles) released as apoptotic
bodies, rapidly phagocytosed; tidy
and systematic
Minimal inflammatory response
DNA Analysis
A – viable cells
B – apoptotic cells
C – necrotic cells
Cellular Aging
Not understood
Possible mechanisms
- decreased replication
Hayflick limit
telomere shortening
- accumulated damage
genetic and environmental insult
DNA repair defects
- abnormal growth factor signalling
Hayflick Limit
Cells (fibroblasts) have a limited capacity for replication
Fibroblasts from newborn can divide more times than fibroblasts from elderly
Telomerase and Senescence
Aglet
The Aging Brain
After 65 years of age, the brain atrophies;
hemispheres shrink away from skull
Cortical thinning, reduced white matter and
enlargement of the ventricles
Glosis, slight loss of neurons, senile cortical
plaques and diseased cerebral vessels
Changes are not necessarily associated with intellectual impairment
Dementia
An acquired and persistent generalised disturbance of higher
mental functions in the alert person
Progressive deterioration of language and changes in personality
Rare before age 60; 5% prevalent at age 65; 25% at age >80
Corresponded to degeneration and atrophy of temporal and
frontal lobes
Common causes:
Alzheimer’s disease
Cerebrovascular disease
Lewy Body disease
Infection, trauma, nutritive disorders, metabolic
disturbances, demyelination, tumours, and
hydrocephlus can also result in dementia
Recommended