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)

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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)

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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)

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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