Introduction​ ​to​ ​pathology

➢ Pathology:​​ ​the​ ​study​ ​(logos)​ ​of​ ​suffering​ ​or​ ​diseases​ ​(pathos).

➢ The​ ​study​ ​of​ ​the​ ​structural,​ ​biochemical,​ ​and​ ​functional​ ​changes​ ​in​ ​cells,​ ​tissues,​ ​and​ ​organs
that​ ​are​ ​caused​ ​by​ ​diseases.

Remember​ ​that​ ​a​ ​group​ ​of​ ​cells​ ​make​ ​up​ ​a​ ​tissue​ ​so​ ​anything​ ​that​ ​affects​ ​a​ ​cell,​ ​will​ ​end​ ​up​ ​affecting
the​ ​tissue​ ​(and​ ​the​ ​whole​ ​organ),​ ​thus​ ​causing​ ​a​ ​disease.

➢ There​ ​are​ ​many​ ​procedures​ ​used​ ​in​ ​Pathology​ ​to​ ​reach​ ​a​ ​diagnosis,​ ​Example:
If​ ​a​ ​patient​ ​has​ ​ ​acute​ ​abdominal​ ​pain,​ ​and​ ​he​ ​is​ ​diagnosed​ ​with​ ​an​ ​inflammation​ ​or​ ​an
intestinal​ ​obstruction,​ ​a​ ​surgical​ ​procedure​ ​is​ ​performed​ ​to​ ​remove​ ​the​ ​part​ ​affected,​ ​then​ ​a
biopsy​ ​from​ ​the​ ​part​ ​of​ ​the​ ​intestine​ ​removed​ ​is​ ​sent​ ​to​ ​the​ ​pathologist,who​ ​diagnoses​ ​the
cause​ ​of​ ​the​ ​disease​ ​(if​ ​it’s​ ​food​ ​particles,​ ​tumor​ ​or​ ​neurological​ ​disease).

​ ​ ​ ​ ​ ​ ​ ​ ​S​o​ ​in​ ​pathology​ ​you​ ​will​ ​define​ ​the​ ​cause​ ​of​ ​the​ ​disease​ ​by​ ​diagnosis

➢ Pathology​ ​is​ ​divided​ ​into​ ​:

❖ General​ ​pathology:​​ ​Reactions​ ​of​ ​cells​ ​and​ ​tissues​ ​to​ ​abnormal​ ​stimuli.​ ​Cell​ ​injury,
inflammation​ ​and​ ​repair,​ ​hemodynamic​ ​disorders,​ ​genetic​ ​disorders,​ ​immune​ ​system
diseases,​ ​infectious​ ​disease​ ​and​ ​environmental​ ​diseases.​ ​(diseases​ ​in​ ​general)
❖ Systemic​ ​pathology:​​ ​Alterations​ ​in​ ​specialized​ ​organs​ ​and​ ​tissues​ ​in​ ​diseased
status​ ​like​ ​the​ ​Respiratory​ ​system.​ ​(diseases​ ​in​ ​a​ ​specific​ ​system​ ​for​ ​example,​ ​we’ll
study​ ​later​ ​that​ ​inflammation​ ​in​ ​the​ ​RS​ ​will​ ​cause​ ​asthma.)

➢ Aspects​ ​of​ ​disease:

❖ Etiology​:​ ​The​ ​underlying​ ​causes​ ​of​ ​a​ ​disease.​ ​The​ ​most​ ​important​ ​Etiologies​ ​of
diseases​ ​are:
1-​ ​Genetic:​ ​Mutations.
2-​​ ​Acquired:​ ​Infections,​ ​Nutritional,​ ​Chemical​ ​.
❖ Pathogenesis​:​ ​A​ ​sequence​ ​of​ ​events​ ​in​ ​response​ ​of​ ​cells​ ​or​ ​tissues​ ​to​ ​the​ ​etiologic
agent,​ ​from​ ​the​ ​initial​ ​stimuli​ ​to​ ​the​ ​ultimate​ ​expression​ ​of​ ​the​ ​disease.​ ​(Mechanism).

❖ For​ ​Example:​ ​If​ ​a​ ​chemical​ ​substance​ ​was​ ​spilt​ ​on​ ​the​ ​skin,​ ​cells​ ​start​ ​to​ ​respond.​ ​Then
leukocytes​ ​will​ ​respond​ ​and​ ​so​ ​on,​ ​responses​ ​will​ ​continue​ ​until​ ​the​ ​final​ ​response.
(healing)
​ ​The​ ​Etiology​​ ​of​ ​this​ ​example:​ ​A​ ​Chemical​ ​Substance
The​ ​Pathogenesis​​ ​of​ ​this​ ​example:​ ​All​ ​of​ ​the​ ​events​ ​after​ ​that.​ ​(progression​ ​of​ ​disease)

To​ ​Put​ ​it​ ​Simply:

❖ Etiology:​ ​Is​ ​why​ ​a​ ​disease​ ​arises.
❖ Pathogenesis:​ ​Is​ ​how​ ​a​ ​disease​ ​develops​​ ​.
 ● Classification​ ​of​ ​pathology​ ​:

❖ Anatomical/​ ​Surgical​ ​pathology​ ​or​ ​histopathology:​​ ​Gross​ ​examination

and​ ​microscopic​ ​examination​ ​to​ ​reach​ ​a​ ​diagnosis.​ ​Depends​ ​on​ ​the​ ​Morphology​.
Ex:​ ​A​ ​colon​ ​is​ ​removed​ ​by​ ​ ​surgery,​ ​and​ ​transferred​ ​to​ ​the​ ​surgical​ ​pathologist​ ​in​ ​order
to​ ​examine​ ​it​ ​under​ ​the​ ​microscope.
Types​ ​of​ ​Anatomical​ ​Pathology​ ​:
- Histopathology:​​ ​ ​ ​is​ ​the​ ​microscopic​ ​examination​ ​of​ ​various​ ​forms​ ​of​ ​human​ ​tissue​.

- Cytopathology(​Cyto​ ​=​ ​cell​)​:​ ​is​ ​a​ ​branch​ ​of​ ​pathology​ ​that​ ​studies​ ​and​ ​diagnoses
diseases​ ​on​ ​the​ ​cellular​ ​level​​ ​under​ ​the​ ​microscope.

For​ ​Example:​ ​Cells​ ​are​ ​taken​ ​from​ ​the​ ​Thyroid​ ​Cyst​ ​by​ ​aspiration​ ​to​ ​be​ ​examined.

- Autopsy:​​ ​thorough​ ​examination​ ​of​ ​a​ ​corpse​ ​by​ ​dissection​​ ​to​ ​determine​ ​the​ ​cause
and​ ​manner​ ​of​ ​death,​​ ​ ​it​ ​is​ ​the​ ​best​ ​way​ ​to​ ​confirm​ ​the​ ​exact​ ​cause​ ​of​ ​death.

​ ​For​ ​Example:​ ​Some​ ​countries​ ​have​ ​to​ ​confirm​ ​the​ ​cause​ ​of​ ​death​ ​by​ ​opening​ ​the​ ​chest,​ ​abdominal
wall,​ ​and​ ​the​ ​head​ ​even​ ​if​ ​the​ ​cause​ ​of​ ​death​ ​is​ ​obvious.​ ​(Like​ ​ischemic​ ​heart​ ​disease​ ​for​ ​very​ ​old
people)

- Subspecialties:​​ ​neuropathology​ ​(brain​ ​&​ ​nerves)​ ​,​ ​dermatopathology​ ​(skin)​ ​,​ ​oral
pathology​ ​(mouth)​ ​&​ ​so​ ​many​ ​……

❖ Clinical​ ​pathology:​​ ​Deals​ ​with​ ​tissues​ ​or​ ​samples​ ​(blood​ ​and​ ​urine),​ ​hematology,
microbiology,​ ​immunology​ ​and​ ​biochemistry.

➢ Diagnosis​ ​in​ ​Anatomical​ ​Pathology

❖ Biopsies:
- Excisional:​ ​Remove​ ​The​ ​Whole​ ​Sample​​ ​to​ ​be​ ​examined​ ​under​ ​the​ ​microscope..
- Incisional:​ ​Remove​ ​Part​ ​of​ ​The​ ​Sample​​ ​to​ ​be​ ​examined​ ​under​ ​the​ ​microscope

​​
❖ Smears​ ​(cytology):​ cyst​ ​=​ ​body​ ​filled​ ​of​ ​fluid.
Exfoliative​ ​and​ ​fine​ ​needle​ ​aspiration.
Ex:​ ​a​ ​patient​ ​has​ ​a​ ​thyroid​ ​cyst,​ ​this​ ​cyst​ ​has​ ​cells,​ ​and​ ​a​ ​sample​ ​must​ ​be​ ​taken​ ​by​ ​a
needle​ ​in​ ​order​ ​to​ ​examine​ ​it​ ​under​ ​the​ ​microscope.
Or​ ​cells​ ​can​ ​be​ ​taken​ ​by​ ​letting​ ​the​ ​patient​ ​cough.
Example​ ​of​ ​biopsies​ ​:

After​ ​the​ ​removal​ ​of​ ​the​ ​colon,​ ​the​ ​specimen​ ​should​ ​have​ ​a​ ​request​ ​form​​ ​that​ ​lists​ ​the​ ​patient's
number,​ ​date​ ​and​ ​time​ ​of​ ​the​ ​surgery,​ ​the​ ​name​ ​of​ ​the​ ​doctor,​ ​ ​and​ ​many​ ​things​ ​should​ ​be​ ​written
on​ ​the​ ​sample​ ​because​ ​it’s​ ​essential​ ​to​ ​make​ ​sure​ ​that​ ​this​ ​sample​ ​belongs​ ​to​ ​its​ ​patient.

​​
When​ ​the​ ​sample​ ​is​ ​transferred​ ​to​ ​the​ ​pathology​ ​section,​ ​it​ ​will​ ​take​ ​a​ ​special​ ​number,​ ​and​ ​will​ ​be
protected​ ​by​ ​formalin​ ​(formaldehyde).

The​ ​sample​ ​maybe​ ​as​ ​big​ ​as​ ​a​ ​colon​ ​or​ ​small.​ ​The​ ​small​ ​samples​ ​are​ ​protected​ ​in​ ​blocks​ ​of​ ​wax,​ ​this
wax​ ​protects​ ​the​ ​sample​ ​up​ ​to​ ​10-15​ ​years,​ ​the​ ​protected​ ​sample​ ​is​ ​called​ ​paraffin​ ​block.

The​ ​paraffin​ ​block​ ​will​ ​be​ ​placed​ ​in​ ​a​ ​device​ ​called​ ​microtome;​ ​the​ ​microtome​ ​will​ ​divide​ ​the​ ​sample
into​ ​small​ ​pieces,​ ​a​ ​small​ ​piece​ ​will​ ​be​ ​taken​ ​with​ ​some​ ​fluid​ ​and​ ​H&E​ ​stain​ ​on​ ​a​ ​slide​ ​for
examination​ ​under​ ​the​ ​microscope.​ ​(the​ ​nucleus​ ​will​ ​be​ ​stained​ ​blue​ ​&​ ​the​ ​cytoplasm​ ​stains​ ​pink.)
​​
Sometimes​ ​you​ ​will​ ​be​ ​lucky​ ​enough​ ​to​ ​see​ ​a​ ​smiley​ ​face​ ​while
examination,​ ​but​ ​as​ ​a​ ​doctor​ ​most​ ​times​ ​you​ ​won’t​ ​be​ ​lucky​ ​and
you​ ​will​ ​face​ ​difficulties.

Remember​ ​whenever​ ​you​ ​treat​ ​a​ ​patient;​ ​treat​ ​him​ ​as​ ​if​ ​he​ ​is​ ​one
of​ ​your​ ​relatives,​ ​you​ ​should​ ​treat​ ​all​ ​patients​ ​the​ ​same​ ​way.

Lecture​ ​2
This​ ​sheet​ ​was​ ​made​ ​using​ ​the​ ​following​ ​sources:

1. Lecture​ ​Record​ ​2,​ ​section​ ​1.

2. Doctor​ ​slides​ ​for​ ​lecture​ ​2.
3. Robbins​ ​Basic​ ​Pathology​ ​10​th​​ ​edition.
4. Pathoma​ ​2017​ ​edition.

The​ ​following​ ​lecture​ ​will​ ​be​ ​divided​ ​into​ ​2​ ​parts;

1. “Cellular​ ​Responses​ ​and​ ​Adaptations​ ​to​ ​Stress”.

2. The​ ​beginning​ ​of​ ​“Overview​ ​of​ ​Cell​ ​Injury​ ​and​ ​Cell​ ​Death”​ ​and​ ​to​ ​be
specific:Reversible​ ​Cellular​ ​Injury.
 Cellular​ ​Responses​ ​and​ ​Adaptations​ ​to​ ​Stress
In​ ​order​ ​to​ ​understand​ ​this,​ ​we​ ​need​ ​to​ ​first​ ​review​ ​2​ ​basic​ ​principles​ ​about​ ​the​ ​cell:

● Point​ ​number​ ​1​ ​is:

Cells​ ​don’t​ ​float​ ​in​ ​space;​ ​they​ ​live​ ​in​ ​an​ ​environment,​ ​which​ ​is​ ​susceptible​ ​to​ ​lots​ ​of​ ​changes​ ​(e.g.,
changes​ ​in​ ​PH,​ ​temperature,​ ​electrolyte​ ​level,​ ​glucose,​ ​etc.)

● Point​ ​number​ ​2​ ​is:

Cells​ ​have​ ​an​ ​intra​cellular​ ​milieu​ ​(​intra​cellular​ ​environment)​ ​which​ ​is​ ​tightly​ ​regulated​ ​in​ ​order​ ​to
maintain​ ​a​ ​fairly​ ​constant​ ​state.​ ​This​ ​state​ ​is​ ​called​ ​homeostasis​.

Keeping​ ​these​ ​two​ ​points​ ​in​ ​mind,a​ ​cell​ ​that​ ​tries​ ​to​ ​maintain​ ​a​ ​constant​ ​internal​ ​environment​ ​with
a​ ​changing​ ​external​ ​environment​ ​has​ ​to​ ​respond​​ ​to​ ​these​ ​changes​ ​in​ ​order​ ​to​ ​keep​ ​the​ ​steady​ ​state
inside!

Here​ ​we​ ​can​ ​start​ ​our​ ​topic​ ​which​ ​is​ ​cellular​ ​responses.

Cellular​ ​Response
Now​ ​we​ ​said​ ​that​ ​a​ ​cell​ ​has​ ​to​ ​respond​ ​to​ ​changes,​ ​but​ ​how​ ​does​ ​it​ ​respond?

There​ ​are​ ​many​ ​ways​ ​in​ ​which​ ​a​ ​cell​ ​can​ ​respond.​ ​Cellular​ ​responses​ ​include:
1. Adaptation​;​ ​hypertrophy,​ ​hyperplasia,​ ​atrophy,​ ​metaplasia.
2. Injury​:​ ​reversible​ ​and​ ​irreversible​ ​(cell​ ​death).
3. Apoptosis​.​ ​a​ ​process​ ​of​ ​programmed​ ​cell​ ​death​ ​that​ ​occurs​ ​in​ ​multicellular​ ​organisms.
4. Intracellular​ ​accumulation​;​ ​calcification.
5. Cellular​ ​aging​.
Today’s​ ​topic​ ​will​ ​be​ ​about​ ​point​ ​1​ ​and​ ​half​ ​of​ ​point2.

Now,​ ​let’s​ ​say​ ​there​ ​was​ ​a​ ​change​ ​in​ ​the​ ​environment,in​ ​what​ ​way​ ​will​ ​the​ ​cell​ ​respond?​ ​This,most
importantly,​ ​will​ ​depend​ ​on:

1. The​ ​nature​ ​,duration​ ​and​ ​severity​ ​of​ ​the​ ​stress(type​ ​of​ ​stimulus).
2. The​ t​ ype​ ​of​ ​the​ ​involved​ ​cell​ ​itself​ ​and​ ​it’s​ ​strength.

Usually,​ ​if​ ​the​ ​stress​ ​was​ ​chronic​ ​(​persisting​ ​for​ ​a​ ​long​ ​time)​ ​and​ ​mild,​ ​the​ ​cell​ ​would​ ​undergo​ ​an
adaptation​.​ ​If​ ​the​ ​stress​ ​was​ ​acute​ ​(​severe​ ​but​ ​of​ ​short​ ​duration)​ ​and​ ​severe,​ ​the​ ​cell​ ​would​ ​undergo
a​ ​cellular​ ​injury​.​ ​The​ ​reason​ ​that​ ​acute​ ​and​ ​severe​ ​stress​ ​doesn’t​ ​lead​ ​to​ ​adaptation​ ​is​ ​because
adaptation​ ​needs​ ​time​ ​to​ ​develop.

As​ ​an​ ​example,​ ​look​ ​into​ ​the​ ​cardiac​ ​myocytes​ ​(​cardiac muscle​ ​cells)​​ ​below​ ​in​ ​figure​ ​1.
 ​​

Figure​ ​1​ ​–​ ​The​ ​relationship​ ​among​ ​normal,​ ​adapted,​ ​reversibly​ ​injured,​ ​and​ ​dead​ ​myocardial​ ​cells.

1. The​ ​image​ ​I​ ​labelled​ ​1​ ​is​ ​the​ ​normal​ ​cardiac​ ​myocyte​ ​with​ ​a​ ​normal​ ​heart​ ​below​ ​it.
2. The​ i​ mage​ ​I​ ​labelled​ ​2​ ​is​ ​a​ ​cardiac​ ​myocyte​ ​that​ ​has​ ​undergone​ ​an​ ​adaptation​ ​(Hypertrophy,​ ​I
will​ ​explain​ ​it​ ​below​ ​don’t​ ​worry)​ ​and​ ​therefore,​ ​a​ ​heart​ ​that​ ​has​ ​undergone​ ​an​ ​adaptation.
The​ ​adaptation​ ​is​ ​called​ ​hypertrophy​ ​which​ ​means​ ​cell’s​ ​size​ ​increases​ ​in​ ​response​ ​to​ ​an
increase​ ​in​ ​stress​ ​(e.g.,​ ​hypertensive​ ​patients​ ​over​ ​long​ ​periods​ ​of​ ​time).​ ​Notice​ ​the​ ​green
line​​ ​I​ ​drew​ ​on​ ​image​ ​1​ ​and​ ​2.​ ​This​ ​line​ ​represents​ ​the​ ​thickness​ ​of​ ​the​ ​left​ ​ventricle​ ​wall.​ ​It’s
much​ ​thicker​ ​in​ ​2​ ​than​ ​1,​ ​indicating​ ​hypertrophy​ ​(a​ ​type​ ​of​ ​adaptation).​ ​This​ ​adaptation​ ​is
made​ ​in​ ​order​ ​to​ ​generate​ ​the​ ​required​ ​higher​ ​contractile​ ​strength.
3. The​ ​image​ ​labelled​ ​3​ ​has​ ​3​ ​parts;​ ​reversibly​ ​injured​ ​myocyte​ ​at​ ​the​ ​top,​ ​an​ ​irreversible​ ​injured
(dead)​ ​myocyte,​ ​and​ ​finally​ ​a​ ​heart​ ​which​ ​contains​ ​a​ ​dead​ ​segment​ ​of​ ​its​ ​wall​ ​(the​ ​white
part).​ ​An​ ​example​ ​of​ ​why​ ​this​ ​may​ ​occur​ ​is​ ​due​ ​to​ ​an​ ​occlusion​ ​(blockage​ ​or​ ​closing)​ ​of​ ​a
coronary​ ​artery​ ​supplying​ ​this​ ​part​ ​of​ ​the​ ​heart,​ ​leading​ ​to​ ​reduced​ ​blood​ ​flow​ ​(ischemia)
followed​ ​by​ ​severe​ ​hypoxia​ ​and​ ​then​ ​eventually​ ​leading​ ​ ​to​ ​irreversible​ ​cell​ ​injury.
Now​ ​the​ ​reason​ ​why​ ​myocytes​ ​in​ ​image​ ​2​ ​has​ ​adapted,avoiding​ ​injury​ ​is​ ​due​ ​to​ ​the​ ​fact​ ​that​ ​the
stress​ ​is​ ​chronic​ ​(​persisting​ ​for​ ​a​ ​long​ ​time​)​ ​and​ ​mild​.​ ​The​ ​reason​ ​why​ ​image​ ​3​ ​got​ ​injured​ ​and
couldn't​ ​adapt​ ​is​ ​because​ ​the​ ​stress​ ​is​ ​acute​ ​and​ ​severe​.

A​ccordingly,​ ​this​ ​illustrates​ ​how​ ​the​ ​stress’s​ ​nature​ ​and​ ​severity​ ​determines​ ​the​ ​cell’s
response.

P.S.​ ​The​ ​intervals​ ​between​ ​responses​ ​aren’t​ ​sharp​ ​intervals​ ​and​ ​hence,​ ​sometimes​ ​the​ ​same
stimulus/stress​ ​if​ ​(1)​ ​with​ ​greater​ ​severity​ ​or​ ​if​ ​(2)​ ​the​ ​cell​ ​is​ ​in​ ​a​ ​weaker​ ​state​,​ ​may​ ​lead​ ​to​ ​a​ ​different
response.

The​ ​following​ ​diagram​ ​(diagram​ ​1)​ ​illustrates​ ​the​ ​stages​ ​in​ ​the​ ​cellular​ ​response​ ​to​ ​stress​ ​and
injurious​ ​stimuli

Diagram​ ​1​ ​-​ ​Stages​ ​in​ ​the​ ​cellular​ ​response​ ​to​ ​stress​ ​and​ ​injurious​ ​stimuli

Summary
As​ ​cells​ ​encounter​ ​changes​ ​in​ ​the​ ​environment,​ ​such​ ​as​ ​physiological​ ​stress​ ​(such​ ​as​ ​increased
workload​ ​on​ ​the​ ​heart)​ ​or​ ​potentially​ ​injurious​ ​conditions​ ​(such​ ​as​ ​nutrient​ ​deprivation),​ ​they​ ​can
undergo​ ​adaptation​,​ ​achieving​ ​a​ ​new​ ​steady​ ​state​ ​and​ ​preserving​ ​viability​ ​and​ ​function.​ ​If​ ​the
adaptive​ ​capability​ ​is​ ​exceeded​ ​or​ ​if​ ​the​ ​external​ ​stress​ ​is​ ​inherently​ ​harmful​ ​or​ ​excessive,​ ​cell​ ​injury
develops​ ​(According​ ​to​ ​the​ ​doctor,​ ​adaptation​ ​will​ ​enable​ ​the​ ​cell​ ​to​ ​withstand​ ​the​ ​stress​ ​for
a​ ​certain​ ​amount​ ​of​ ​time​ ​(because​ ​this​ ​will​ ​come​ ​at​ ​the​ ​cost​ ​of​ ​other​ ​cell​ ​components).​ ​If
the​ ​stress​ ​or​ ​stimulus​ ​remained​ ​for​ ​a​ ​long​ ​period​ ​of​ ​time​ ​and​ ​is​ ​increasing,​ ​the​ ​cell​ ​will​ ​no
longer​ ​adapt​ ​to​ ​cell​ ​injury​ ​(which​ ​is​ ​either​ ​reversible​ ​or​ ​irreversible))​.​ ​Within​ ​certain​ ​limits,
injury​ ​is​ ​reversible​,​ ​and​ ​cells​ ​can​ ​return​ ​to​ ​their​ ​former​ ​state;​ ​however,​ ​if​ ​the​ ​stress​ ​is​ ​severe,
persistent,​ ​or​ ​rapid​ ​in​ ​the​ ​onset,​ ​it​ ​results​ ​in​ ​irreversible​ ​injury​ ​and​ ​the​ ​death​ ​of​ ​the​ ​affected​ ​cells​.
(the​ ​doctor​ ​said​ ​that​ ​if​ ​the​ ​stress​ ​was​ ​severe​ ​and​ ​acute​ ​it​ ​results​ ​in​ ​irreversible​ ​cell​ ​injury).

Adaptations
Definition:​ ​Adaptations​ ​are​ ​reversible​ ​changes​ ​in​ ​the​ ​number,​ ​size,​ ​phenotype,​ ​metabolic​ ​activity,​ ​or
functions​ ​of​ ​cells​ ​in​ ​response​ ​to​ ​changes​ ​in​ ​their​ ​environment.

P.S.​ ​The​ ​changes​ ​are​ ​on​ ​the​ ​cellular​ ​level​ ​by​ ​definition,​ ​however,​ ​this​ ​is
expressed​ ​by​ ​tissues/organs​ ​(e.g.,​ ​previous​ ​example​ ​on​ ​hypertension.
The​ ​cardiac​ ​muscle​ ​cells​ ​are​ ​the​ ​ones​ ​that​ ​enlarged​ ​(Hypertrophied)​ ​but
this​ ​is​ ​expressed​ ​or​ ​seen​ ​as​ ​an​ ​enlarged​ ​left​ ​ventricle​ ​of​ ​the​ ​heart).

Types​ ​of​ ​Adaptation

There​ ​are​ ​4​ ​types​ ​of​ ​adaptation;

1. Hypertrophy.
2. Hyperplasia.
3. Atrophy​ ​.
4. Metaplasia.
I​ ​should​ ​really​ ​stress​ ​the​ ​point​ ​that​ ​all​ ​of​ ​them​ ​are​ ​REVERSIBLE​;​ ​This​ ​means​ ​that​​ ​when​ ​the
stress/stimulus​ ​goes​ ​away,​ ​the​ ​tissues​ ​theoretically​ ​will​ ​return​ ​back​ ​to​ ​it’s​ ​normal​ ​state.​​ ​It​ ​doesn’t
matter​ ​how​ ​long​ ​it​ ​takes​ ​to​ ​return​ ​back​ ​to​ ​normal,could​ ​be​ ​a​ ​day​ ​or​ ​2​ ​years.​ ​What​ ​matters​ ​is​ ​that​ ​it’s
a​ ​reversible​ ​process.​ ​Once​ ​you’ve​ ​lost​ ​this​ ​reversibility,​ ​you​ ​will​ ​no​ ​longer​ ​adapt.

Adaptations​ ​can​ ​be​ ​physiological​ ​or​ ​pathological​ ​depending​ ​on​ ​the​ ​cause;

1. Physiological​ ​adaptations​ ​usually​ ​represent​ ​responses​ ​of​ ​cells​ ​to​ ​normal​ ​stimulation
by​ ​hormones​ ​or​ ​endogenous​ ​chemical​ ​mediators​​ ​(e.g.,​ ​the​ ​hormone​ ​(estrogen)-induced
enlargement​ ​of​ ​the​ ​breast​ ​and​ ​uterus​ ​during​ ​pregnancy),​ ​or​ ​to​ ​the​ ​demands​ ​of​ ​mechanical
stress​​ ​(in​ ​the​ ​case​ ​of​ ​bones​ ​and​ ​muscles).
2. Pathological​ ​adaptations​ ​are​ ​responses​ ​to​ ​stress​ ​that​ ​allow​ ​cells​ ​to​ ​modulate​ ​their
structure​ ​and​ ​function​ ​and​ ​thus​ ​escape​ ​injury,​ ​but​ ​at​ ​the​ ​expense​ ​of​ ​normal​ ​function​ ​.​ ​(For
example​ ​ ​an​ ​increase​ ​in​ ​size​ ​of​ ​a​ ​woman’s​ ​uterus​ ​due​ ​to​ ​pregnancy​ ​is​ ​a​ ​psychological
adaptation,​ ​while​ ​an​ ​increase​ ​in​ ​size​ ​due​ ​to​ ​a​ ​tumor​ ​is​ ​a​ ​pathological​ ​adaptation)

P.S.​ ​Usually​ ​adaptive​ ​processes​ ​are​ ​there​ ​to​ ​protect​ ​the​ ​tissue​ ​(and​ ​enhance​ ​its​ ​function​ ​if​ ​possible),
but​ ​in​ ​most​ ​cases​ ​it’s​ ​to​ ​protect​ ​the​ ​tissue​.​ ​It​ ​won’t​ ​be​ ​able​ ​to​ ​perform​ ​the​ ​function​ ​like​ ​before​ ​being
stressed.

Hypertrophy
Definition​:​ ​Hypertrophy​ ​is​ ​an​ ​increase​ ​in​ ​the​ ​size​ ​of​ ​cells​ ​resulting​ ​in​ ​an​ ​increase​ ​in​ ​the​ ​size​ ​of​ ​the
organ(duh).​

By​ ​definition​ ​it’s​ ​an​ ​increase​ ​in​ ​cell​ ​size,​ ​not​ ​tissue​ ​size​ ​(however​ ​this​ ​will​ ​be​ ​reflected​ ​on​ ​the
tissue/organ​ ​level).

Now,​ ​we​ ​need​ ​to​ ​understand​ ​that​ ​cells​ ​are​ ​of​ ​two​ ​types:

1. Dividing​ ​cells​ ​(e.g.,​ ​skin​ ​or​ ​GI​ ​tract​ ​cells);​ ​which​ ​are​ ​capable​ ​of
undergoing​ ​hypertrophy​ ​with​ ​another​ ​type​ ​of​ ​adaptation​ ​called
hyperplasia​ ​(Increase​ ​in​ ​cell​ ​number,​ ​rather​ ​than​ ​size)​ ​or​ ​hyperplasia
alone.
2. Non-dividing​ ​cells​​ ​(also​ ​known​ ​as​ ​permanent​ ​tissue);​ ​which​ ​can​ ​only
undergo​ ​hypertrophy,​ ​They​ ​simply​ ​can’t​ ​divide​ ​and​ ​hence​ ​can’t
undergo​ ​hyperplasia.

Like​ ​any​ ​other​ ​Adaptation,​ ​hypertrophy​ ​can​ ​be​ ​physiological​ ​or​ ​pathological.

Below​ ​is​ ​an​ ​example​ ​of​ ​hypertrophy;​ ​left​ ​ventricle​ ​hypertrophy.

Figure​ ​3​ ​Heart:​ ​left​ ​ventricle​ ​hypertrophy.

This​ ​is​ ​a​ ​hypertrophied​ ​cardiac​ ​muscle,​ ​which​ ​is​ ​never​ ​physiological.​ ​Usually​ ​associated​ ​with
hypertension​ ​or​ ​a​ ​congenital​ ​anomaly(malformation)​.

*congenital:​ ​a​ ​disease​ ​or​ ​condition​ ​existing​ ​at​ ​or​ ​before​ ​birth(birth​ ​defect).

Hypertrophy​ ​Causes
1. Increased​ ​functional​ ​demand​ ​(workload)​.​ ​For​ ​example,​ ​going​ ​to​ ​the​ ​gym​ ​will​ ​lead​ ​to
skeletal​ ​muscles​ ​enlargement​ ​as​ ​you​ ​increase​ ​the​ ​workload​ ​on​ ​them.​ ​They​ ​want​ ​to​ ​generate
the​ ​higher​ ​required​ ​contractile​ ​force.​ ​Hypertrophy​ ​however,​ ​is​ ​limited.​​ ​The​ ​cells​ ​might
die​ ​(cell​ ​injury)​ ​after​ ​a​ ​while​ ​if​ ​the​ ​hypertrophic​ ​capability​ ​was​ ​exceeded.​ ​(P.S.​ ​this​ ​is
physiological​ ​hypertrophy)
2. Stimulation​ ​by​ ​hormones​ ​or​ ​growth​ ​factors​.​ ​Such​ ​as​ ​in​ ​some​ ​diseases​ ​that​ ​you​ ​will​ ​take
in​ ​systems.

Mechanism​ ​behind​ ​Hypertrophy

Increased​ ​production​ ​of​ ​cellular​ ​structural​ ​proteins​ ​and​ ​organelles.​ ​(Doctor​ ​didn’t​ ​talk​ ​about​ ​it
however.)

Hyperplasia
Definition:​ ​Hyperplasia​ ​is​ ​an​ ​increase​ ​in​ ​the​ ​number​ ​of​ ​cells​ ​in​ ​an​ ​organ​ ​that​ ​stems​ ​from​ ​increased
proliferation,​ ​either​ ​of​ ​differentiated​ ​cells​ ​or,​ ​in​ ​some​ ​instances,​ ​less​ ​differentiated​ ​progenitor​ ​cells.
This​ ​will​ ​lead​ ​to​ ​an​ ​increase​ ​in​ ​tissue​ ​or​ ​organ​ ​mass.

● Occurs​ ​only​ ​in​ ​dividing​ ​cells.

● Could​ ​be​ ​physiological​ ​or​ ​pathological​ ​and​ ​in​ ​both​ ​scenarios,​ ​cellular​ ​proliferation​ ​is
stimulated​ ​by​ ​growth​ ​factors​ ​that​ ​are​ ​produced​ ​by​ ​a​ ​variety​ ​of​ ​cell​ ​types,
The​ ​doctor​ ​said​ ​he​ ​will​ ​not​ ​ask​ ​about​ ​cases​ ​coming​ ​in​ ​between​ ​physiology​ ​and​ ​pathology,​ ​he
would​ ​rather​ ​ask​ ​about​ ​cases​ ​that​ ​are​ ​easily​ ​differentiated​ ​as​ ​either​ ​physiological​ ​or
pathological​ ​(direct​ ​case).
● Hyperplasia​ ​only​ ​occurs​ ​due​ ​to​ ​growth​ ​factors/hormones​​ ​unlike​ ​hypertrophy,​ ​which​ ​can
occur​ ​due​ ​to​ ​increased​ ​workload​ ​or​ ​increased​ ​growth​ ​factors/hormones.

The​ ​two​ ​types​ ​of​ ​physiological​ ​hyperplasia​​ ​are​ ​(1)​ ​hormonal​ ​hyperplasia​,​ ​exemplified​ ​by​ ​the
proliferation​ ​of​ ​the​ ​glandular​ ​epithelium​ ​of​ ​the​ ​female​ ​breast​ ​at​ ​puberty​ ​and​ ​during​ ​pregnancy,​ ​and
(2)​ ​compensatory​ ​hyperplasia​,​ ​in​ ​which​ ​residual​ ​tissue​ ​grows​ ​after​ ​the​ ​removal​ ​or​ ​loss​ ​of​ ​a​ ​part​ ​of
an​ ​organ.​ ​For​ ​example,​ ​when​ ​a​ ​part​ ​of​ ​the​ ​liver​ ​is​ ​resected,​ ​mitotic​ ​activity​ ​in​ ​the​ ​remaining​ ​cells
begins​ ​as​ ​early​ ​as​ ​12​ ​hours​ ​later,​ ​eventually​ ​restoring​ ​the​ ​liver​ ​to​ ​its​ ​normal​ ​size.

Most​ ​forms​ ​of​ ​pathologic​ ​hyperplasia​​ ​are​ ​caused​ ​by​ ​excessive​ ​hormonal​ ​or​ ​growth​ ​factor
stimulation.
Examples​ ​include:

● Hyperplasia​ ​of​ ​the​ ​endometrium​​ ​(excessive​ ​hormone​ ​stimulation)​ ​and​ ​prostate

hyperplasia.
● Wound​ ​healing​​ ​(Effects​ ​of​ ​growth​ ​factors).
● Infection​ ​by​ ​papillomavirus​​ ​(skin​ ​warts).

“Note,​ ​the​ ​next​ ​paragraph​ ​gives​ ​more​ ​details​ ​about​ ​the​ ​pathologic​ ​hyperplasia​ ​and​ ​is​ ​from​ ​Robbins.
If​ ​you​ ​understand​ ​pathologic​ ​hyperplasia,​ ​then​ ​there’s​ ​no​ ​need​ ​for​ ​it.”
--
For​ ​example,​ ​after​ ​a​ ​normal​ ​menstrual​ ​period​ ​,there​ ​is​ ​a​ ​burst​ ​of​ ​uterine​ ​epithelial​ ​proliferation​ ​that
is​ ​normally​ ​tightly​ ​regulated​ ​by​ ​the​ ​stimulatory​ ​effects​ ​of​ ​pituitary​ ​hormones,​ ​ovarian​ ​estrogen​ ​and
the​ ​inhibitory​ ​effects​ ​of​ ​progesterone.​ ​A​ ​disturbance​ ​in​ ​this​ ​balance​ ​leads​ ​to​ ​an​ ​increased​ ​estrogenic
stimulation​ ​causing​ ​endometrial​ ​hyperplasia,​ ​which​ ​is​ ​a​ ​common​ ​cause​ ​of​ ​abnormal​ ​menstrual
bleeding.​ ​Benign​ ​prostatic​ ​hyperplasia​ ​is​ ​another​ ​common​ ​example​ ​of​ ​pathologic
hyperplasia,induced​ ​in​ ​responses​ ​to​ ​hormonal​ ​stimulation​ ​by​ ​androgens.​ ​Stimulation​ ​by​ ​growth
factors​ ​is​ ​also​ ​involved​ ​in​ ​the​ ​hyperplasia​ ​ ​associated​ ​with​ ​certain​ ​viral​ ​infections;​ ​for​ ​example,
papillomaviruses​ ​causes​ ​skin​ ​warts​ ​and​ ​mucosal​ ​lesions​ ​that​ ​are​ ​composed​ ​of​ ​masses​ ​of​ ​hyperplastic
epithelium.
--
VERY​ ​IMPORTANT:​ ​Hyperplasia​ ​can​ ​be​ ​a​ ​fertile​ ​soil​ ​for​ ​the​ ​development​ ​of​ ​malignancies

What​ ​does​ ​this​ ​mean?​ ​ ​Pathologists​ ​found​ ​that​ ​sometimes​ ​if​ ​the​ ​causes​ ​of​ ​pathological​ ​hyperplasia
are​ ​not​ ​treated,​ ​it​ ​might​ ​cause​ ​the​ ​tissue​ ​to​ ​become​ ​malignant​ ​-​the​ ​hyperplasia​ ​itself​ ​does​ ​not
become​ ​malignant​ ​but​ ​rather​ ​may​ ​lead​ ​to​ ​another​ ​type​ ​of​ ​response​ ​and​ ​eventually
malignancy(cancer)​ ​or​ ​dysplasia​.​ ​Hence​ ​we​ ​NEED​ ​to​ ​treat​ ​the​ ​causes​ ​of​ ​pathological
hyperplasia​ ​to​ ​prevent​ ​responses​ ​that​ ​are​ ​not​ ​related​ ​to​ ​hyperplasia(or​ ​adaptations).

*dysplasia:​an​ ​abnormality​ ​in​ ​development​ ​or​ ​an​ ​epithelial​ ​anomaly​ ​of​ ​growth​ ​and​ ​differentiation. 

The​ ​following​ ​images​ ​are​ ​for​ ​hyperplasia

​​

Figure​ ​3​ ​–​ ​Hyperplasia.​ ​3(a)​ ​prostate​ ​hyperplasia​ ​3(b)​ ​endometrial​ ​hyperplasia
 Atrophy​ ​(‫)اﻟﻀﻤﻮر‬
Definition:​ ​Atrophy​ ​is​ ​the​ ​shrinkage​ ​in​ ​the​ ​size​ ​of​ ​cells​ ​by​ ​the​ ​loss​ ​of​ ​cell
substance​ ​.

Why?​ ​due​ ​to​ ​reduction​ ​in​ ​organelles​ ​inside​ ​the​ ​cell​ ​because​ ​of​ ​shortage​ ​of
supply.​ ​When​ ​we​ ​have​ ​a​ ​shortage​ ​of​ ​supply,​ ​the​ ​now​ ​large​ ​organelles​ ​feed​ ​on
smaller​ ​organelles,​ ​using​ ​all​ ​sources​ ​of​ ​energy​ ​in​ ​them.​ ​In​ ​Atrophy​ ​there​ ​is​ ​a
reduction​ ​in​ ​cell​ ​size,​ ​due​ ​to​ ​the​ ​reduction​ ​in​ ​the​ ​number​ ​of​ ​organelles​ ​inside​ ​the
cell,​ ​thus​ ​organ’s​ ​size​ ​decreases.

​ ​Atrophy​ ​by​ ​definition​ ​is​ ​a​ ​cellular​ ​event,​ ​in​ ​which​ ​cells​ ​decrease​ ​in​ ​size​ ​due​ ​to​ ​the​ ​reduction​ ​in
organelle’s​ ​size​ ​and​ ​number,​ ​this​ ​will​ ​end​ ​up​ ​causing​ ​a​ ​decrease​ ​in​ ​organ’s​ ​size.

Atrophy​ ​Causes
Atrophy​ ​ ​could​ ​be​ ​physiological​ ​or​ ​pathological.

Physiological​ ​example:​ ​If​ ​we​ ​leave​ ​a​ ​fetus​ ​to​ ​proliferate​ ​freely,​ ​by​ ​7​ ​months​ ​it​ ​will​ ​become​ ​the​ ​size​ ​of
4​ ​human​ ​beings.​ ​This​ ​is​ ​not​ ​the​ ​case​ ​here.​ ​What​ ​happens​ ​is​ ​that​ ​there​ ​will​ ​be​ ​atrophy​ ​of​ ​some
components​ ​of​ ​fetal​ ​tissue​ ​and​ ​apoptosis​ ​(another​ ​cell​ ​response).​ ​This​ ​should​ ​happen​ ​to​ ​leave
behind​ ​the​ ​best​ ​cells​ ​available.​ ​There​ ​will​ ​be​ ​a​ ​struggle​ ​of​ ​survival​ ​between​ ​fetal​ ​cells.​ ​(1)​ ​The​ ​best
cells​ ​are​ ​the​ ​ones​ ​that​ ​remain​,​ ​(2)​ ​the​ ​less​ ​quality​ ​ones-weak/abnormal​ ​cells-​​ ​are​ ​the​ ​ones​ ​the
body​ ​tries​ ​to​ ​get​ ​rid​ ​of,​ ​they​ ​are​ ​atrophied​ ​in​ ​order​ ​to​ ​give​ ​them​ ​a​ ​chance​ ​or​ ​not.​ ​(3)​ ​The​ ​cells​ ​not
working​ ​100%​ ​will​ ​undergo​ ​apoptosis​.​ ​Why?​ ​In​ ​order​ ​for​ ​the​ ​fetus​ ​to​ ​be​ ​born​ ​in​ ​the​ ​best
condition​ ​((‫))​ ​ﻟﻘﺪ ﺧﻠﻘﻨﺎ اﻹﻧﺴﺎن ﻓﻲ أﺣﺴﻦ ﺗﻘﻮﯾﻢ‬.
Pathological​ ​example:​Fractures.​ ​If​ ​a​ ​person​ ​doesn’t​ ​move​ ​the​ ​fractured​ ​region​ ​for​ ​4-5​ ​months​ ​for
example,​ ​the​ ​muscles​ ​of​ ​the​ ​fractured​ ​region​ ​will​ ​undergo​ ​atrophy,​ ​many​ ​other​ ​examples​ ​exist..

*The​ ​doctor​ ​didn’t​ ​mention​ ​them​ ​but​ ​I​ ​copied​ ​them​ ​from​ ​the​ ​slides.*

Physiologic​ ​Atrophy Pathologic​ ​Atrophy

Embryonic​ ​development Decreased​ ​workload​ ​(Disuse​ ​atrophy)
Involuting​ ​graved​ ​uterus Loss​ ​of​ ​innervation​ ​(Denervation​ ​atrophy)
Diminished​ ​blood​ ​supply
Inadequate​ ​nutrition
Loss​ ​of​ ​endocrine​ ​stimulation
Aging

Atrophy​ ​has​ ​a​ ​very​ ​complicated​ ​pathway.​ ​What​ ​the​ ​doctor​ ​needs​ ​you​ ​to​ ​remember​ ​is​ ​that
because​ ​of​ ​the​ ​shortage​ ​of​ ​blood​ ​supply​ ​(nutrition​ ​to​ ​cell),​ ​cell​ ​size​ ​will​ ​decrease​.​ ​When
organelles​ ​don’t​ ​get​ ​enough​ ​energy​ ​to​ ​work,‫​ ​ﺑﻮﻗﻔﻮا ﻋﻠﻰ ﺟﻨﺐ‬.​ ​When​ ​cells​ ​have​ ​no​ ​nutrition​ ​source​ ​at​ ​all,
it​ ​starts​ ​to​ ​eat​ ​itself​ ​ ​to​ ​get​ ​ATP(eating​ ​organelles).​ ​It​ ​will​ ​eat​ ​them​ ​within​ ​a​ ​reversible​ ​level.​ ​What
does​ ​this​ ​mean?​ ​If​ ​it​ ​eats​ ​organelles​ ​and​ ​the​ ​cell​ ​is​ ​still​ ​capable​ ​to​ ​restore​ ​it’s​ ​original​ ​size​ ​when​ ​you
return​ ​the​ ​blood​ ​supply,​ ​we​ ​are​ ​still​ ​in​ ​atrophy​ ​because​ ​atrophy​ ​is​ ​reversible…​ ​there’s​ ​no​ ​damage
beyond​ ​reversibility.

If​ ​the​ ​cell​ ​however​ ​is​ ​damaged​ ​to​ ​an​ ​irreversible​ ​level​→​ ​this​ ​is​ ​no​ ​longer​ ​atrophy,​ ​this​ ​is​ ​cell​ ​death
(necrosis​ ​or​ ​apoptosis).

Note​ ​that​ ​these​ ​processes​ ​sometimes​ ​intermingle​.​ ​What​ ​does​ ​that​ ​mean?​ ​It​ ​can’t​ ​be​ ​pure​ ​atrophy
or​ ​pure​ ​apoptosis,​ ​because​ ​sometimes​ ​a​ ​cell​ ​can​ ​withstand​ ​stress​ ​more​ ​than​ ​another​ ​cell​ ​or​ ​for
example​ ​an​ ​area​ ​got​ ​more​ ​stressed​ ​than​ ​the​ ​other​ ​region​ ​beside​ ​it,​ ​so​ ​the​ ​same​ ​area​ ​might​ ​undergo
apoptosis​ ​and​ ​the​ ​region​ ​beside​ ​it​ ​might​ ​undergo​ ​atrophy.

The​ ​following​ ​is​ ​copy​ ​pasted​ ​from​ ​the​ ​slides,​ ​the​ ​doctor​ ​didn’t​ ​mention​ ​it.
Mechanisms​ ​behind​ ​Atrophy
1. Decreased​ ​protein​ ​synthesis​ ​and​ ​increased​ ​protein​ ​degradation.
2. Reduced​ ​metabolic​ ​activity,​ ​which​ ​causes​ ​decreased​ ​protein​ ​synthesis​ ​also.
3. Atrophy​ ​is​ ​mainly​ ​induced​ ​by​ ​Ubiquitin-proteasome​ ​pathway:​ ​protein​ ​binds​ ​organelles​ ​→
signals​ ​(kill​ ​me)​ ​→​ ​decrease​ ​#​ ​of​ ​organelles.
4. ​ ​Autophagy​ ​(self-eating)​ ​to​ ​find​ ​sources​ ​of​ ​protein.​ ​(starvation).

Metaplasia
Definition:​ ​Metaplasia​ ​is​ ​a​ ​change​ ​in​ ​which​ ​one​ ​mature​ ​cell​ ​type​ ​(epithelial​ ​or​ ​mesenchymal)​ ​is
replaced​ ​by​ ​another​ ​mature​ ​cell​ ​type​ ​(epithelial​ ​or​ ​mesenchymal).

P.S.​ ​if​ ​the​ ​cell​ ​was​ ​originally​ ​epithelial,​ ​with​ ​metaplasia​ ​it​ ​will​ ​change​ ​into​ ​another​ ​type​ ​of
epithelium​ ​and​ ​if​ ​it​ ​was​ ​mesenchymal​ ​it​ ​will​ ​change​ ​into​ ​another​ ​type​ ​of​ ​mesenchyme.

Metaplasia​ ​enhances​ ​our​ ​cell’s​ ​ ​protection,not​ ​function​.

​ ​*Usually​ ​adaptative​ ​responses​ ​aim​ ​to​ ​protect​ ​the​ ​cell​ ​and​ ​at​ ​the​ ​same​ ​time​ ​enhance​ ​its​ ​function,​ ​but
in​ ​most​ ​cases​ ​metaplasia​ ​protects​ ​the​ ​cell​ ​in​ ​a​ ​way​ ​that​ ​renders​ ​it​ ​with​ ​a​ ​lower​ ​functionality​ ​than
before.

Mechanism​ ​behind​ ​Metaplasia

The​ ​stimulus​ ​(stress​ ​full​ ​event),​ ​reprogrammes​ ​stem​ ​cells​ ​that​ ​are​ ​at​ ​the​ ​basal​ ​layer​ ​of​ ​epithelium​ ​to
a​ ​different​ ​type​ ​of​ ​epithelium.​ ​If​ ​the​ ​stimulus​ ​or​ ​stressful​ ​event​ ​is​ ​removed,​ ​another​ ​reprogramming
occurs​ ​and​ ​cells​ ​return​ ​to​ ​normal.​ ​This​ ​takes​ ​time(could​ ​take​ ​a​ ​couple​ ​of​ ​years​ ​rather​ ​than​ ​days),
and​ ​hence​ ​the​ ​initial​ ​change​ ​is​ ​much​ ​easier​ ​to​ ​occur​ ​than​ ​to​ ​return.​ ​(e.g.,​ ​for​ ​smokers​ ​when​ ​they
stop​ ​smoking,​ ​sometimes​ ​they​ ​might​ ​take​ ​5-10​ ​years​ ​for​ ​Respiratory​ ​tract​ ​to​ ​go​ ​back​ ​to​ ​normal
situation)

Metaplasia​ ​Causes
Why​ ​does​ ​it​ ​occur?​ ​Sometimes​ ​the​ ​stress​ ​placed​ ​on​ ​a​ ​cell​ ​changes.Here​ ​are​ ​ ​two​ ​examples​ ​to
elaborate​ ​this:
 1. The​ ​change​ ​that​ ​occur​ ​in​ ​the​ ​respiratory​ ​epithelium​ ​of​ ​habitual​ ​cigarette
smokers,​ ​in​ ​whom​ ​the​ ​normal​ ​ciliated​ ​columnar​ ​epithelial​ ​cells​ ​of​ ​the​ ​trachea
and​ ​bronchi​ ​often​ ​are​ ​replaced​ ​by​ ​stratified​ ​squamous​ ​epithelial​ ​cells​ ​(See​ ​figures
below).​ ​The​ ​rugged​ ​stratified​ ​squamous​ ​epithelium​ ​may​ ​be​ ​able​ ​to​ ​survive​ ​the
noxious​ ​chemicals​ ​(toxins​ ​and​ ​antigens)​ ​in​ ​cigarette​ ​smoke,​ ​that​ ​the​ ​more
fragile​ ​specialized​ ​epithelium​ ​would​ ​not​ ​tolerate.​ ​Although​ ​the​ ​metaplastic
squamous​ ​epithelium​ ​has​ ​survival​ ​advantages,​ ​important​ ​protective
mechanisms​ ​are​ ​lost,​ ​such​ ​as​ ​mucus​ ​secretion​ ​and​ ​ciliary​ ​clearance​ ​of
particulate​ ​matter.​ ​Epithelial​ ​metaplasia​ ​is​ ​therefore​ ​a​ ​double-edged​ ​sword.
Now​ ​if​ ​we​ ​manage​ ​to​ ​keep​ ​that​ ​metaplastic​ ​epithelium,​ ​that’s​ ​fine,​ ​but
unfortunately​ ​the​ ​same​ ​toxin​ ​will​ ​keep​ ​getting​ ​inside​ ​(a​ ​smoker​ ​won’t​ ​stop
when​ ​he​ ​gets​ ​metaplasia)​ ​he​ ​keeps​ ​his​ ​epithelium​ ​induced​ ​to​ ​antigens​ ​and
toxins​ ​and​ ​this​ ​will​ ​cause​ ​further​ ​damage.​ ​Sometimes,​ ​in​ ​the​ ​same​ ​way​ ​as​ ​with
hyperplasia,​ ​if​ ​we​ ​don’t​ ​treat​ ​the​ ​cause​ ​of​ ​metaplasia,​ ​it​ ​might​ ​progress​ ​to​ ​cancer
and​ ​induce​ ​other​ ​kinds​ ​of​ ​response.​ ​(i.e.​ ​Malignant​ ​transformation​ ​if​ ​the​ ​cause
for​ ​metaplasia​ ​persists).

Note:​ ​some​ ​argue​ ​that​ ​this​ ​is​ ​a​ ​physiological​ ​change​ ​but​ ​others​ ​(our​ ​doctor​ ​included)
believes​ ​that​ ​this​ ​is​ ​a​ ​pathological​ ​response​ ​as​ ​smoking​ ​is​ ​a​ ​pathological​ ​condition
that​ ​leads​ ​to​ ​many​ ​harmful​ ​complications.

​​

2.​ ​The​ ​type​ ​of​ ​epithelium​ ​in​ ​the​ ​esophagus​ ​at​ ​the​ ​junction​ ​with​ ​the​ ​stomach​ ​is​ ​stratified​ ​squamous
epithelium​.​ ​This​ ​type​ ​of​ ​epithelium​ ​is​ ​very​ ​good​ ​at​ ​protecting​ ​the​ ​esophagus​ ​from​ ​food​ ​(​suited​ ​to
handle​ ​friction​ ​of​ ​a​ ​food​ ​bolus​).​ ​The​ ​stomach​ ​on​ ​the​ ​other​ ​hand​ ​has​ ​columnar​ ​epithelium​.​ ​This
epithelium​ ​is​ ​very​ ​good​ ​in​ ​protecting​ ​against​ ​stomach​ ​acid​.​ ​Students​ ​who​ ​come​ ​back​ ​home​ ​and​ ​eat​​ ​a
lot​,cause​ ​the​ ​sphincter​ ​between​ ​the​ ​lower​ ​esophagus​ ​and​ ​stomach​ ​to​ ​slightly​ ​extend​ ​because​ ​the
stomach​ ​is​ ​full.​ ​With​ ​time,​ ​food​ ​reflux​ ​occurs,​ ​stomach’s​ ​contents​ ​will​ ​go​ ​to​ ​the​ ​esophagus,including
HCL​ ​(hydrochloric​ ​acid).​ ​The​ ​squamous​ ​type​ ​of​ ​epithelium​ ​in​ ​the​ ​lower​ ​esophagus​ ​might​ ​not
tolerate​ ​this​ ​acidity,​ ​and​ ​hence​ ​with​ ​time​ ​the​ ​student​ ​might​ ​feel​ ​a​ ​heartburn.​ ​Smoking​ ​leads​ ​to
even​ ​further​ ​relaxation​ ​of​ ​the​ ​sphincter​ ​so​ ​contents​ ​of​ ​the​ ​stomach​ ​will​ ​go​ ​even
higher​.Squamous​ ​epithelium​ ​will​ ​not​ ​tolerate​ ​this​ ​acidity;​ ​it​ ​will​ ​become​ ​metaplastic​.​ ​It​ ​will​ ​change
from​ ​stratified​ ​squamous​ ​to​ ​the​ ​columnar​ ​type​ ​of​ ​epithelium​ ​to​ ​protect​ ​the​ ​esophagus​ ​from​ ​the
acidity​ ​of​ ​the​ ​stomach’s​ ​contents.​ ​The​ ​name​ ​of​ ​the​ ​disease​ ​in​ ​which​ ​epithelium​ ​changes​ ​from
stratified​ ​squamous​ ​epithelium​ ​to​ ​columnar​ ​epithelium​ ​is​ ​called​ ​chronic​ ​gastric​ ​reflux​ ​(from
Robbins).
​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​Is​ ​it​ ​reversible​?​ ​Yes,​​ ​the​ ​stimulus​ ​affects​ ​all​ ​cells,​ ​but​ ​only​ ​the​ ​base​ ​cells​ ​are​ ​reprogrammed​ ​into​ ​the 
another​ ​type​ ​of​ ​cell​ ​and​ ​they​ ​divide​ ​(superficial​ ​cells​ ​don't​ ​change​ ​into​ ​another​ ​type),​ ​when​ ​the​ ​stimulus​ ​is 
removed​ ​the​ ​base​ ​cells​ ​go​ ​back​ ​to​ ​normal.​ ​This​ ​may​ ​take​ ​years​ ​to​ ​happen-​ ​the​ ​first​ ​change​ ​is​ ​easier​ ​than 
going​ ​back,​ ​(smokers​ ​may​ ​take​ ​years​ ​for​ ​their​ ​cells​ ​to​ ​retain​ ​their​ ​normal​ ​type​ ​after​ ​quitting)​. 

Figure​ ​4​ ​-​ ​Columnar​ ​epithelium​ ​in​ ​esophagus

Part​ ​2​ ​of​ ​the​ ​lecture:

Cellular​ ​Injury
If​ ​the​ ​stress​ ​is​ ​more​ ​severe​ ​than​ ​the​ ​cell’s​ ​adaptive​ ​capability​ ​to​ ​adapt,​ ​the​ ​cell​ ​will​ ​go​ ​into​ ​cell​ ​injury
which​ ​could​ ​be​ ​reversible​ ​or​ ​irreversible​ ​depending​ ​on​ ​the​ ​severity​ ​of​ ​stimulus​ ​and​ ​cell’s​ ​response.
Causes​ ​of​ ​cellular​ ​adaptation​ ​are​ ​usually​ ​chronic​ ​and​ ​mild​ ​stresses​ ​but​ ​in​ ​the​ ​case​ ​of​ ​cellular​ ​injury
it’s​ ​severe​ ​and​ ​acute.

Causes​ ​of​ ​cell​ ​injury​ ​(reversible​ ​or​ ​irreversible)

1. Hypoxia​​ ​(low​ ​oxygen​ ​delivery​ ​to​ ​tissue)
2. Physical​ ​agents.
3. Chemical​ ​agents.
4. Infectious​ ​agents.
5. Immunologic​ ​reactions.
6. Genetic​ ​abnormalities​ ​or​ ​derangements.
7. Nutritional​ ​Imbalance.
8. Aging​ ​.

THE​ ​MOST​ ​IMPORTANT​ ​CAUSE​ ​OF​ ​CELL​ ​INJURY​ ​(reversible​ ​or​ ​irreversible)​ ​TO​ ​REMEMBER​ ​IS
HYPOXIA​​ ​which​ ​has​ ​3​ ​causes;

1. Ischemia​​ ​(MOST​ ​COMMON​ ​CAUSE)​ ​–​ ​Ischemia​ ​simply​ ​means​ ​a​ ​reduced​ ​blood​ ​flow.
 2. Inadequate​ ​oxygenation:​ ​cardiorespiratory​ ​failure.
3. Decreased​ ​oxygen​ ​carrying​ ​capacity:​ ​anemia,​ ​carbon​ ​monoxide​ ​poisoning​ ​or​ ​blood​ ​loss.

A​ ​cell​ ​damaged​ ​reversibly​ ​can​ ​return​ ​back​ ​to​ ​its​ ​original​ ​state​ ​if​ ​the​ ​initial​ ​stimulus/stress​ ​is​ ​removed.​ ​That​ ​is
because​ ​the​ ​level​ ​of​ ​damage​ ​inside​ ​the​ ​cell​ ​isn’t​ ​that​ ​severe​ ​to​ ​prevent​ ​the​ ​cell​ ​from​ ​recovering.​ ​Once​ ​the​ ​level
of​ ​damage​ ​becomes​ ​severe​ ​to​ ​the​ ​extent​ ​that​ ​the​ ​cell​ ​can’t​ ​recover​ ​back​ ​it’s​ ​original​ ​state,​ ​even​ ​if​ ​you​ ​remove
the​ ​initial​ ​stimulus,​ ​the​ ​cell​ ​is​ ​irreversibly​ ​injured.

​ ​First​ ​manifestation​​ ​is​ ​the​ ​CELLULAR​ ​SWELLING/CELL​ ​ENLARGEMENT/EDEMA/​ ​HYDROPIC

CHANGE/VACUOLAR​ ​DEGENERATION​​ ​→​ ​all​ ​have​ ​the​ ​same​ ​meaning.Why​ ​does​ ​that​ ​occur?
The​ ​Na+-K+​ ​pump​ ​is​ ​disrupted,​ ​resulting​ ​in​ ​sodium​ ​building​ ​up​ ​in​ ​the​ ​cell.​ ​Wherever​ ​we​ ​see​ ​sodium​ ​we​ ​see
water.
Accordingly,​ ​water​ ​builds​ ​up​ ​in​ ​the​ ​cell​ ​leading​ ​to​ ​cellular​ ​swelling.

“Important​ ​note​ ​to​ ​keep​ ​in​ ​mind:

Some​ ​cells,​ ​such​ ​as​ ​hepatocytes​ ​might​ ​have​ ​fat​ ​accumulated,
which​ ​also​ ​increases​ ​cell​ ​size.”

Second​ ​change​​ ​that​ ​follows​ ​the​ ​first​ ​change​ ​is​ ​plasma​ ​membrane​ ​changes​.​ ​There​ ​will​ ​be​ ​lots​ ​of

​​
changes​ ​to​ ​the​ ​plasma​ ​membrane​ ​including​ blebs,​ ​blunting​ ​or​ ​loss​ ​of​ ​villi​ ​ ​and​ ​loosening​ ​of
intercellular​ ​attachments​.

​ ​Whatever​ ​these​ ​changes​ ​are,​ ​it’s​ ​important​ ​to​ ​know​ ​that​ ​they​ ​don’t​ ​reach​ ​to​ ​the​ ​level​ ​of​ ​plasma
membrane​ ​rupture!​ ​Plasma​ ​membrane​ ​rupture​ ​indicates​ ​irreversible​ ​cell​ ​injury​ ​and​ ​the​ ​cell​ ​won’t​ ​be
able​ ​to​ ​recover​ ​back​ ​to​ ​its​ ​normal​ ​state​ ​even​ ​if​ ​you​ ​remove​ ​the​ ​stimulus/stress​ ​causing​ ​the​ ​injury.
Other​ ​manifestations​​ ​also​ ​include​ ​mitochondrial​ ​change​ ​and​ ​dilation​ ​of​ ​ER​ ​(endoplasmic
reticulum).

P.S.​ ​mitochondrial​ ​change​ ​and​ ​dilation​ ​of​ ​ER​ ​occur​ ​with​ ​both​ ​reversible​ ​and​ ​irreversible​ ​cell​ ​injury
but​ ​are​ ​more​ ​severe​ ​in​ ​irreversible​ ​injury.

The​ ​most​ ​important​ ​thing​ ​to​ ​remember​ ​(according​ ​to​ ​what​ ​the​ ​doctor​ ​said)​ ​is:​ ​Nuclear​ ​alterations​;
nuclear​ ​chromatin​ ​clumping​ ​(so​ ​that​ ​the​ ​instant​ ​the​ ​stimulus​ ​ceases,​ ​the​ ​cell​ ​is​ ​able​ ​to​ ​recover).
Take​ ​a​ ​look​ ​at​ ​this​ ​image:

Figure​ ​A​ ​shows​ ​normal​ ​cells.​ ​The​ ​red​ ​arrows​ ​(hazy​ ​things)​ ​indicates​ ​microvilli​.​ ​You​ ​can​ ​also​ ​see​ ​that
the​ ​cells​ ​are​ ​adherent​ ​with​ ​no​ ​spaces​ ​in​ ​between​ ​them,​ ​and​ ​also​ ​the​ ​nuclear​ ​material​ ​isn’t​ ​clumped
(not​ ​dark).

Figure​ ​B​ ​however​ ​shows​ ​reversibly​ ​injured​ ​cells.​ ​Microvilli​ ​are​ ​lost​,​ ​cells​ ​are​ ​no​ ​longer​ ​adherent
(​loosening​ ​of​ ​intercellular​ ​attachments​ ​has​ ​created​ ​spaces​ ​in​ ​between​ ​the​ ​cells​).​ ​Also​ ​notice
the​ ​red​ ​circle​​ ​showing​ ​how​ ​dark​ ​the​ ​nucleus​ ​is​ ​when​ ​compared​ ​to​ ​nuclei​ ​in​ ​figure​ ​A.​ ​Nuclear
clumping​​ ​along​ ​with​ ​other​ ​changes​ ​are​ ​responsible​ ​for​ ​the​ ​darker​ ​nucleus​ ​in​ ​figure​ ​B.
Figure​ ​C​ ​shows​ ​irreversible​ ​cell​ ​injury​ ​(not​ ​our​ ​current​ ​topic).

THE​ ​END.

​ ​Thanks​ ​everybody​ ​for​ ​your​ ​time​ ​reading​ ​this​ ​sheet.​ ​Forgive​ ​me​ ​if​ ​I​ ​made​ ​a​ ​mistake,
whether​ ​scientific​ ​or​ ​spelling.​ ​I​ ​tried​ ​my​ ​absolute​ ​best​ ​to​ ​make​ ​this​ ​sheet​ ​as
scientifically​ ​accurate​ ​as​ ​possible,​ ​but​ ​that’s​ ​not​ ​always​ ​possible.
If​ ​you​ ​don’t​ ​understand​ ​anything​ ​make​ ​sure​ ​to​ ​message​ ​me​ ​and​ ​I​ ​will​ ​happily​ ​reply
Insha’Allah.