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pathphysiology
Sunday
lec 3
23-2-2014
Dr: Eman Alfishat
‫بسم هللا الرحمن الرحيم‬
Hi every one! 
In this lecture we will continue talking about adaptations of cellular growth which are
reversible responses.
The 4 adaptation responses are …Today we will talk about first 3 responses.
1- Hypertrophy
2- Hyperplasia
3- Atrophy
4- Metaplasia
Hypertrophy and hyperplasia are both size increment of the cell as a result of a
stimulus or increase the demand of work load, and this is the most common cause of
hypertrophy . ‫وجه الشبه بينهم‬
 Hypertrophy :
Is the increase of size is to meet to meet the demand of increment of work load.
The increase of demand could be physiologic or pathologic cause of hypertrophy.
*Example of physiologic cause of hypertrophy:
1- is the most important cause of hypertrophy which is exercise which is appear as an
increase of size of muscle cell and muscle mass and size of fiber due to increase of
synthesis of protein .
2-at pregnancy, the increase of stimulation stimulate the growth of uterus due to both
hyperplasia,, and mainly hypertrophy.
** In muscle any increase in stimulation may cause hyperplasia or hypertrophy depend
on the target tissue, if its 1.dividing cell like uterus muscle cell, or
2. non dividing cell which is respond mainly on hypertrophy like myocardial striated
skeletal muscle cell,we know that these cell are capable of some limited capabilities of
dividing but they are responding to any increase of work load by hypertrophy.
 Return to slide 7(mechanism of myochardial hypertrophy) at first sheet For more
understanding.
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We have 3 stimulate mechanism that stimulate hypertrophy :
1- mechanical sensors
2- vasoactive agonist( bind to its receptor )
3-growth factors.( which bind to its receptor and activate the process of
hypertrophy )
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The increase of work load is a stimulus that stimulates mechanical sensors that
act on mechanical stretches on heart chambers that activate signal transductional
pathway to increase the synthesis of transcription factors like (contractile
proteins, growth hormone, growth factor).
The vasoactive agonist like angiotensin 2 also can stimulate the process of
hypertrophy (we will not discuss it in details)... The production of these
vasoactive agents will till this part that now we have increased demand and we
need to increase the size to meet this demand.
We have no problem of increase heart size when its transiently and dealing with
this increase of demand, but at a certain point however the heart increase its size
it will never meet this demand, on the other hand, ischemia will occur because
later on the increase of work load will increase the size without a parallel increase
of blood supply.
# one of the most important factors that will determine the risk of ischemia is:
1- the increase if metabolic demand of that organ which increase the chance of
ischemic heart disease because the blood supply will not meet the demand more
and more.
Ischemia already will be encouraged by the situation of the increase the demand
of hypertrophy, in addition of that
2- the increment of heart size is not accompanied with a parallel increase of
blood supply that also increase the chance of ischemic heart disease.
These compensatory or adaptor mechanisms should stay at a short period of time
,once it prolonged or once it become chronic activation .. A problem will start to
develop...Once neutralize that stimulus occur that’s seemed to be the end of the
problem and the adaptation process and go back to normal.
-On other situations the adaption process will go back to irreversible injury. Mechanical
sensors appear to be the major triggers for physiologic hypertrophy (reversible and go
back to normal), and agonists and growth factors may be more important in pathologic
states (irreversible and go back to cell injury).
**remember that the reversible adaptation responses not mean that everything will be
okay, because we cannot expect the clinically manifestation or consequences of the
reversible injured cell because the cell is not contractile at this moment, it will be
contractile later on but now it’s not,, so we can’t expect how lethal or significant
manifestation will occur through the reversible cell injury.
We say that mechanism can start as a 1- mechanical stretches or can start at 2agonists or... can start at 3- growth factor mechanism ,, moreover mechanical
sensors themseves once they activated they can activate 2 &3 , all of them activate the
signaling transductional pathway ,, the purpose of the presses is to increase of the
syntheses of proteins ,
We have 2 pathways of hypertrophy to increase the synthesis of proteins:
1-G protein coupled receptors (GPCRs): its physiologic stimulus activates this pathway
rather than pathologic, so this pathway is involved in physiologic stimulus.
2-phosphoinositide -3-kinase pathway: more involved in pathologic stimulus.
Hypertrophy involve something called induction of genes like ANF (atrial natriuretic
factor) which produced by atrium and ventricles, they are suppressed unless the
hypertrophy is activated they are re-induced, this molecule is special in neutralizes the
stimulus by decrease the workload by increase the excretion of Na and consequently
water will follow and also decrease the blood volume and that will decrease the
metabolic demand of that organ.
Another thing is the transformation of myosin heavy chain from the Alfa adult
isoform (usually present) to beta form (fetal form) because that provides a slower
contractions and more energetically economic contraction in beta form.
**the differences between the two mechanisms: and 1- induction of fetal genes that
increase the A- mechanical performance and B-decrease the work load” important “.
2- Syntheses of contractile protein: increase the mechanical performance but no
effect on the workload which remain high and the hemodynamic load stay high! The
heart at certain point... Any increase of size it will not be able to deal with the
increment of metabolic demand and lead to deterioration and may develop to heart
failure!
*hyperplasia:
We have talked about it that is:
The increase of size of organ resulting in the increase in the number of these cells (
because they are dividing cell ).
It can be physiologic or pathologic stimulus.
*physiologic:
1-hormonal hyperplasia: hormones are responsible.
2-compensatory: no matter what is the cause of partial hepatectomy but we concern
about the adaptation.
*pathologic: imbalance of hormone without a need.
Example: The endometrial hyperplasias, benign prostatic hyperplasia (BPH) which
appears as androgen are involved instead of estrogen and progesterone.
We should differentiate between the pathologic cause of hyperplasia and between the
cancers.
That cancer is non reversible mutation but pathologic situation can be controlled by
giving the patient the opposite hormone so everything will go back normal.
* *mechanism of hyperplasia:
Due to growth factor- driven proliferation of 1- mature cells and in some cases
2- the stem cells increase the output of new cells .example: the intrahepatic stem cells
in the liver stimulate the growth of the remaining part of the liver after partial
hepatectomy into original size.
So when we talk about compensatory hyperplasia, the partial hepatectomy at the
remaining part of the liver stimulate the production growth factor will go to bind to the
receptors on the liver will stimulate the proliferation of the cells.
** If the patient has hepatitis or this remaining part is infected and these receptors
were compromise... There is another way :>>>
Intra hepatic stem cells activated these cells will allow proliferation of these stem
cells and they will help the growth of the cells back to original size.
In the comparison between hypertrophy and hyperplasia... We consider that:
Hypertrophy is the increment of organ size and the sub-cellular organells such as
Endoplasmic Reticulum (E.R). So the E.R under the effect of certain drugs can undergo
to hypertrophy. Patients take barbiturate( drug act on E.R) if they have hypertrophy in
E.R which lead to increase of the metabolism of barbiturate so he will respond less to
the barbiturate drug because of the up-regulation of certain enzymes such as
cytochrome b54.
*the response of on drug may affect the response of another drug .example: patient
who consuming alcohol while taking barbiturate drug... Alcohol can cause hypertrophy
in E.R that will increase the up-regulation of the enzyme and make him less affected by
drug.
Remember that not any molecule undergoes to metabolism means that its safe, Maybe
it become more toxic than the original one, and may be the reactive oxygen species
were produced and cause an injury for the normal cell.
There are some viral infections that can cause hyperplasia as skin warts (leagent,
mucosal leagent),
 So viral infection causes hyperplasia as skin warts by produce growth factor or by
recruit ‫يحفز‬the infected cell to produce G.F.
*Atrophy : the decrease of size of organ ( cells)and later the maybe the decrease
of the number # of the cells.
* Can be Physiologic and pathologic.
 Physiologic: 1- the decrease of uterus size after giving birth.
 2- At the fetal stage once we developed, certain structures need to loss because
we don’t need it any more like: thyroglossal duct and notochord both are replaced.
Other forms of atrophy...Any decrease of work load appears as a message to cell
to decrease the size and force it to go to atrophy. Remember that the decrease of
size is a reversible adaptation response and a situation forces it to happen and if
we move down to reduction of the # numbers of cell that seems to be irreversible
and cell death.
The reduction of size as a way of survival to reduce energetic requirements
because smaller cells consume less energy, when cell try to shrink to give the cell
more chance to survival.
** Causes of atrophy:
1-decrease work load
2-loss of innervations
3-diminished blood supply
4-inadequate nutrition
5-loss of endocrine stimulation
6- Pressure.
We will consider each cause of hypertrophy in details:
1-decrease workload:
Remember when we talk about persons whom exercises like body builder or to left
weight that stimulate the skeletal muscle cell to increase size as a result in increased
work load, here the situation is vise versa ‫بالعكس‬we will decrease the work load like a
fracture bone immobile in a plastic bag or extended bed rest once the decrease happens
to the size of the cell only and not.. prolonged, if it prolonged then the decrease will
happen on both size and number of cells then it called bone resorbtion or
irreversible osteoporosis of disuse .
2-loss of innervations:
Any muscle in order to function normally need proper innervations unless something
called (denervation atrophy) occurs.
3-diminished blood supply: once it occur due to any cardiovascular disease like
atherosclerosis, the reduction of O2 and nutrient and blood supply will force the cell to
shrink to decrease their energetic requirement and this help it to survive if this not
prolonged enough to proceeded to ischemia and cell death .
The atherosclerosis with the increase of age makes a senile atrophy in elderly people
which are decrease of brain size or heart size to meet the diminished blood supply.
4-Inadiquant nutrition: malnutrition especially protein malnutrition, the body tends to
use muscle as a source of energy because of depleted all other stores, which called
(muscle wasting) or chchexia, this mainly seen in: 1-cancer. 2- Chronic inflammatory
disease because of the heavily production of TNF (tumor necrosis factor) mostly which is
an inflammatory mediator and secreted over a long period of time (chronic disease), this
mediator makes a loss of appetite... So malnutrition... So leads to atrophy.
5-loss of endocrine stimulation: some hormonal cells( hormone sensitive tissue) are
dependent on the endocrine stimulation to survival, hormones mean as a signal for
survival for some cells, so the loss of hormone will force the cell to atrophy ... and die
and …necrosis or apoptosis .
Example: physiologic state... After menopause...The depression of cells will occur as a
result of loss of hormonal signaling as vaginal or endometrial or breast cells..then that
lead the cell to atrophy and if body don’t need it any more it will undergo to apoptosis(
most physiologic states undergo this pathway ) or necrosis.
5-preesure: benign tumor put some compression or pressure on blood supply of normal
tissue surrounding the tumor, and force this normal surrounding tissue to atrophy due
to diminished blood supply.
‫ال تنسونا من صالح دعائكم ^_^ وسامحونا على الزلل‬Done by: Suha Ahmad Saqer S.A.S
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