GENERAL ETIOPATHOGENESIS
OF DISEASES
Prof. J. Hanacek, M.D.,CSc.
Etiopathogenesis
• etiology – causes and conditions of diseases
onset
• genesis –
development of disease
Pathomechanisms
• Mechanisms which are involved in
development of diseases
Monofactorial diseases
• One „big“ cause plus appropriate conditions
are necessary, e.g. tuberculosis (other infections)
Multifactorial diseases
• More than one cause and appropriate conditions
are necessary, e.g. atherosclerosis
Homogenous diseases – diseases induced always by the same cause
or complex of causes, e.g. whooping cough,
small pox, poissoning by toadstool
Heterogenous diseases – diseases induced by different kinds of noxae
H
or different complex of noxae, e.g. diabetes
e
mellitus type 1 and 2; hypoxia-hypoxic,
histotoxic, ischemic
Pathogenic factors
Different kinds of energy (inappropriate quantity and/or quality)
which lead to disturbances of homeostasis of iner environement of
human body.
Another name for pathogenetic factors are noxae
Main kinds of pathogenetic noxae
1. physical - mechanical energy, enviromental temperature, electric
current, atmospheric pressure and moisture, lasser beam,
compression and decompresion, vibration, acceleration,
deceleration, microwaves, magnetic field and others
2. chemical – elements and compounds - acids and lyes, plant and
animal toxins, toxic metals, cigarette smoke and other
kinds of smoke, sulphur dioxide, nitrogene oxides, ozon,
pesticides, herbicides...
3. biological – microorganisms (microbes,viruses..), insect and
arthropods, organic dust and pollen
4. psychological, social and ergonomic - psychologic stress,
enormous strain (physical or/and mental)
Physical noxae:
Crush syndrome
Syndrome is characterized by tissue damage induced by their compression
- cells are damaged by pressure and ischemia
- anaerobic metabolism going on  release of myoglobin from cells
precipitation of Mgl in kidney vessels damage of kidney
acute renal failure
After compression is removed:
- recirculation in the damaged tissue can occure after removing the
compression
- washing out the toxic metabolites from the
damaged tissue to the whole organism toxic influence
- accumulation of the blood in the damaged tissue
(blood goes very easy through the leaky capillary wall)
- hypovolemia and hypovolemic shock can occur
Blast syndrome
Syndrome is characterized by tissue damage induced
by strong pressure wave:
Consequences: - bleeding to the tympanic membrane (ear drum)
and/or rupture
- damage of the inner ear
- damage of hollow organs (e.g. stomach, intestines)
- rupture of alveoli and pulmonary capillary
- commotio cerebri
Decompression sickness (caisson disease)
Who is in risk? – underwater construction workers
– deep sea divers
– unpressurised aircraf fly
Mechanisms: – return too quickly from deep level of sea to the
surface causes a form of gas embolism
– CO2 and N which are normally disolved in the blood
come out and forme tiny bubbles gas emboli
Consequences: – nitrogen bubbles may obturate microvessels in
tissue and persist there
– larger bubbles in larger vessels obstruct their
lumenischemia in muscles, joints, tendons 
 pain, necrosis
Ionizing radiation (IR)
IR– any form of radiation capable of removing orbital electrons from
atoms  ions
Sorces of IR: – x-rays, γ rays,  and  particles, neutrons, protons,
sunlight
The most abundant source of exposure to IR is:
– the environment – e.g. cosmic rays, buildings and soil radiation materials
– diagnostic and treatment procedures e.g. CT scans may be responsible for
24% of the total „backround“ radiation to which the population is exposed in
the given year (Sin et al., 2011)
The mechanisms by which IR damages the cells
• Direct damage – influence of vulnerable molecules in the cell
• Indirect damage – radiolysis of water  radicals
Consequences: – damage of DNA, genes, chromosoms

• damage of somatic cells  necrosis, apoptosis, cancer
• damage of gamete  genetic (inherited) diseases
• damage of fetus  spontaneous abortus, increased
perinatal mortality
Prolonged and strong vibration
Main sorces: - vibrating machinery, e.g. track and bus drivers,
construction workers, farmers...
Whole-body vibration (resonance) - begins at 5Hz
Consequences: -  oxygen consumption in tissues
-  pulmonary ventilation
-
development of bone deformities
-
calcification of intervertebral discs
-  incidence of bowel, blood, respiratory and
musculosceletal disorders
Segmental vibration – often the fingers and hands are damaged
People in  risk: - operators of chain saws, pneumatic hammer,
rotary grinders
Cosequences: - Raynaud´s phenomenon
Characteristics: - numbness and white fingers
- some loss of fine movements due to
muscular control disorders
- decreased sensitivity to heat and cold
Noise – it is a sound that has potential for inflicting bodily harm (usually
more than 50dB)
Consequences: – hearing impairment
It can be due to: - acute loud noise
- cumulative effect of various intensities,
frequences and durations of noise
• Acoustic trauma – rupture of eardrum,
– displace of ossicles of the middle ear,
– damage of organ of Corti in the inner ear
• Noise-induced hearing loss
– is gradual due to prolonged exposure to intense
sounds
Mechanism: – vasoconstriction of small vessels in cochlea 
 oxygen dilivery to hair cells  hypoxic
damage
• Neurosis  different kinds of psychosomatic disorders
Acceleration–deceleration: sudden and quick changes in movement
directions of the body in the space
Consequences: - negative influence on CVS
- negative influence on vestibular system
Kinetosis (motion sickness) – your mind perceiving
a movement that doesn't agree with what your sense of
balance is telling you
– manifestation of vestibular system dysfunction
– dysfunction is manifested by „stormy“ reaction of
vegetative nerve system  dysbalance sympathetic
and parasympathetic nerve systems
Main symptoms: - abdominal pain, nausea, dizziness
Main signs: - tachycardia, decrese of BP, vomiting
Damages induced by electricity
Alternate electric current is dangerous for living organisms, only
when its parameters are: - more than 50 V, more than 75 mA
Consequences:
- thermic damage  burns
- depolarisation of the cells  nerv system and heart dysfunctions
- mechanical damage  dysruption of skin and muscles
Mechanisms:
- thermic damage – due to resistance heat creation
- depolarisation – due to depolarisation of the cell membranes by
high voltage current  asystolia, ventricular
fibrilation, muscle cramps
Chemical noxas
1. Exogenous
a/ Inorganic – elements: As, Hg, Pb....
compouds: SO2, NOx, organophosphates...
b/ Organic – organic acids, amonium...
– plant and animal toxins
2. Endogenous – NH3, uric acid, keton bodies...
The effect of chemical noxas on cells depends on:
- dose exposed to
- place of entry to the body
- speed of entry
- duration of exposition
- properties of noxa
- properties of tissue/cells
- capacity of detoxification systems
Main mechanisms involved in injury by chemicals
1. Damage of cell structures
a/ cytoplasmatic – by heavy metals, alcohols, acids...
b/ membranes – by organic solvents, azbest...
2. Disturbancies in synthesis of macromolecules
e.g. ribonukleotides by alfa-amanitin (from toadstool-green)
3. Damage of transport membrane mechanisms
e.g. by bees and snaky venoms
4. Damage of energetic metabolism of the cells
e.g. glycolytic process damaged by fluorids or
oxidative phosphorylation by cyanide
5. Cell division – e.g. by cytostatics
6. DNA – e.g. mutagens
Main consequences of chemical injury
A/ Inactivation or/and denaturation of cell enzymes
B/ Creation of inactive complexes by interaction of noxa with important
cell molecules:
e.g. cyanide +Fe3+ inactive complex  impairment of oxidative
phosphorylation, ihibition of cytochrome oxydase a3  ihibition of
tissue “breathing“
e.g. arsenic +pyruvatedehydrogenase  inactive complex:
- if it is in the heart  there is alternative way for energy
creation  no heart damage
- if it is in nerves  there is not alternative way for energy
production  blockade of energy creation  damage of
the nerve system
C/ Damage of conjugation process
- toxic chemicals can't be conjugated and excrete from the body
D/ Lethal synthesis – due to „mistake“ of detoxication
proces  creation of very toxic product
E/ Binding of chemicals on important molecules
e.g. CO on Hb
Stages of cell injury by chemicals
 cytopathic effect – the functions of the cell is changed/inhibited but it
is able to live and can proliferate
 cytostatic effect – cell is still alive but it lost the ability to proliferate
 cytotoxic effect – cell death
Intoxication by organophoshates
Organophosphates: - chemical compounds used as insecticides
and herbicides (e.g. Fosdrin, Intrathion)
Entry to the body: - skin, conjunctives, mucose membranes of
respiratory and GIT systems
Detoxified in: - liver, kidney
Main effects of organophoshates: – inhibition of ACH-esterases
Consequences: -concentration of ACH in synaptic cleft  stimulation of
postganglionic cholinergic nerve fibres
Manifestations: - muscarinic effect: nausea, vomiting, abdominal
pain, diarhoe, sweating, miosis, overproduction
of mucus in the airway
- nicotinic effect: tremor, muscle twitches, cramps
- stimulation of sympathetic NS: BP, HR
- stimulation of CNS: cramps, coma
Entry of noxae to the organism
Noxae can entry to the organism through:
- skin
- mucous membranes of : respiratory tract
gastrointestinal tract
- CNS (psychogenic predominantly)
Predilection places - places in the organism through which the noxae
can enter the organism more easy then through
other ones
Spreading of noxae in the organism
1. hematogenous way
2. lymphatic way
3. along nerves
4. canalicular way
5. per continuitatem
Types of interaction between causes of disease
and disease itself
Disturbances autoregulation of body functions
- their importance for pathogenesis
• Autoregulation - Autoregulation is a process within many biological
systems, resulting from some internal adaptive
mechanism that works to adjust (or mitigate)
the systems response to stimuli
- processes which are responsible for maintaining
homeostasis
• Mechanisms of autoregulation - they are present and active at different
level of the body structures:
a) autoregulation at the level of subcellular structures
- gen regulation (cell „tels“ to DNA what the cell needs, the DNA to produce)
- enzymatic reactions, cell division, cell death, e.g. by apoptosis
b) supracellular control mechanisms - by releasing different kind of cytokines,
hormons by which the communication cell to cell is performed
– e.g. control number of cells in tissues
c) autoregulation at the level of organs and systems of the body
– neural and endocrine (humoral) mechanisms (feed-back loops)
– result is co-ordinating function of organs and systems
• Homeostatic curve - it shows autoregulative capacity of the body
organs, systems and whole organism
(see scheme)
• Dysregulative pathophysiology - deals with the pathomechanisms
in which the disturbance of autoregulation mechanisms are primary
cause of disease, e.g. endocrine glands dysfunction, malignant
processes
y
HOMEOSTATIC CURVE
A
B
C
x
y = the level of living processes
x = external (internal) damaging factors
• Endogenous amplifying system of cell (EAS)
- the system which amplify the signal coming to the cell
many times (107 - 108)
• Disturbance of EAS
a) activity of EAS is decreased
b) activity of EAS is increased
Decreasing activity of EAS
e.g. enzymatic defect or decreased activity of cell enzymes due to
changed cell environment (acidosis)  cell function
Increased activity of EAS
e.g. increased activity of cell enzymes  cell activity (body
temperature)
Examples:
• Dysregulation of calcium level in a cell
[ Ca++] in cell  activation of cell proteases, lipases  cell proteins
and membrane proteins damage  cell death
• Dysregulation of apoptosis
apoptosis  number of cells
apoptosis  number of cells
● Dysregulation of feed-back mechanisms
Norm: blood glucose levelinsulin production  blood glucose
level insulin production
Pathol: blood glucose levelinsulin production insulin resistance 
another insulin production  development glucose tolerance
• Dysregulative diseases
Examples
- Disturbances of breathing control
(e.g. central sleep apnoea sy., Pikwick sy.)
- Disturbances of blood pressure control
(essential hypertension)
- Diabetes mellitus type 2
- Hypo- or hyperthyreosis, alergy, immunodeficiency,
hyporeactivity, hyperreactivity of airway,...
• Antagonistic regulation of body functions
- repolarization of cell
 depolarisation
- stimulation
 inhibition
- proteases
 antiproteases
- oxidants
 antioxidants
- stress
 antistress
- sympathetic nerve
 parasympathetic nerve
system activity
system activity
Under normal condition there is dynamic balance between
antagonistic functions in the human body  homeostasis
Antagonistic regulation of body functions
Example: it is the existence of two opposing systems (A and neg – A)
activated by a common signal and controling a single target system
Single target system-final reaction
System A
System -A
Common signal
Vasoconstriction-Vasodilation
Skin vessels
Muscle vessels
Catecholamins
Stressor
Apoptosis in the pathogenesis of disease
•
In multicellular organisms, homeostasis is maintained through
a balance between cell proliferation and cell death
• Different cell types vary widely in the mechanisms by which they
maintain themselves over the life of the organism:
• blood cells - constant renewal
• cell of reproductive system
- cyclical expansion and contraction
• neural cells - limited capacity for self - renewal
Control of cell number is determined by balance between
cell proliferation and cell death
Fig. 2
The effect of different rates of cell death on homeostasis
In mature organisms, cell number is controlled as a result of the net effects
of cell proliferation and cell death. Here, the rates of cell proliferation and cell
death are indicated by the size of the arrows. In the absence of compensatory
changes in the rate of cell proliferation, changes in the rate of cell death
can result in either cell accumulation or cell loss
• Regulation of cell death is just as complex as the
regulation of cell proliferation:
-
The cells appear to share the ability to curry out their own death
through activation of an internally encoded "suicide program".
When activated, characteristic form of cell death is initiated.
- This form of cell death is called apoptosis
• Apoptosis can be triggered by a variety of extrinsic and
intrinsic signals
The result is: - elimination of cells:
• produced in excess
• developed improperly
- have sustained genetic damage
• damaged cells
Inducers of Apoptosis
Physiologic activators
1.TNF family
Damage-related Inducers
1.Heat shock
2. Transforming
growth factor 
3. Neurotransmitters
-Glutamate
-Dopamine
-N- methyl-D-aspartate
4. Growth factor withdrawal
5. Loss of matrix attachment
6. Calcium
2. Viral infection
7. Glucocorticoids
3. Bacterial toxins
4. Oncogenes myc, rel, E1A
5. Tumor suppressors p53
6. Cytolytic T cells
7. Oxidants
8. Free radicals
9. Nutrient deprivationantimetabolites
Inducers of Apoptosis
Therapy-associated
1.Chemotherapeutic drugs
- cisplatina, doxorubicin
bleomycin, cytosine
arabinoside, nitrogen
mustard, methotrexate, vincristine
2. Gamma radiation
3. UV radiation
Toxins
1. Ethanol
2. -amyloid
peptide
Diseases Associated with Increased Apoptosis
1. AIDS
2. Neurodegenerative disorders
Alzheimer's disease
Parkinson's disease
Amyotrophic lateral sclerosis
Retinitis pigmentosa
Cerebellar degeneration
3. Myelodysplastic syndromes
Aplastic anemia
4. Ischemic injury
Myocardial infarction
Stroke
Reperfusion injury
5. Toxin-induced liver disease
Alcohol
Neurodegenerative disease
- Due to genetic disorders: mutated gene  repeat CAG nucleotid triplet 
(encodes glutamín)
a)  polyglutamine tract  creation of glutamine residues  toxic
properties of them  polyglutamine disease
b)  alpha – synuclein (amyloid precursor protein – in Alzheimer disease)
Autoregulative pathways in removing of pathologic proteins:
 Proteosome enzymes +ubiquitin  cleaving of irregular protein
 Autophagy-lysosome pathway = a form of programmed cell death
- macroautophagy – involved within nutrient recycling of macromolecules
under condition of starvation
- chaperon-mediated autophagy
If these processes are ineffective  accumulation of toxic protein in cells
• Although diverse signals can induce apoptosis in
a wide variety of cell types, a number of evolutionary
conserved genes regulate a final common cell death
pathway that is conserved from worms to humans
• Apoptotic cell death can be distinguished from
necrotic cell death
● Necrotic cell death = pathologic form of cell death resulting
from acute cellular injury, which is typified by rapid cell
swelling and lysis, accompanied by inflammatory reaction
A hypothetical model for the regulation of
apoptotic cell death
Growth factor
withdrawal
Activation of
death receptors
Protease
activation
Central cell death
signal
P 53
DNA
damage
Cytotoxic
T cells
Endonuclease
activation
Cell surface
alterations
Phagocytosis
BCL 2
Metabolic or cell
cycle perturbations
Cytoskeletal
reorganisation
•
Apoptotic cell death = physiologic form of cell death characterized by
controlled autodigestion of the cell.
No inflammatory reaction is present
-
Cells appears to initiate their own apoptotic death through the
activation of endogenous proteases  cytoskeletal disruption,
cell shrinkage, membrane blebbing
-
The nucleus undergoes condensation as endonucleases are
activated  degradation of nuclear DNA
- Loss of mitochondrial function
- Phagocytosis
- Cells not immediately phagocytosed break down into smaller
membrane – bound fragments called apoptotic bodies
•
Recent evidence suggests that the failure of cells to undergo apoptotic
cell death might be involved in the pathogenesis of a variety of human
diseases
•
Wide number of diseases characterized by cell loss, may
result from accelerated rates of physiologic cell death
•
So, talking about pathogenesis of different kind of diseases we have
to take into account the changed apoptosis for explanation
of some pathological processes
Fig. 6
Inhibitors of Apoptosis
Physiologic Inhibitors
1. Growth factors
2. Extracellular matrix
3. CD40 ligand
4. Neutral amino acids
5. Zinc
6. Estrogen
7. Androgens
1.
2.
3.
4.
5.
6.
Viral genes
Adenovirus E1B
Baculovirus p35
Baculovirus IAP
Cowpox virus crmA
Epstein-Barr virus BHRF1, LMP-1
African swine fever virus LMW5-HL
7. Herpesvirus 34.5
Pharmacological agents
1. Calpain inhibitors
2. Cysteine protease inhibitors
3. Tumor promoters
- PMA Phenobarbital
-  Hexachlorocydohexane
Fig. 5
Diseases Associated with the Inhibition of
apoptosis
1. Cancer
Follicular lymphomas
Carcinomas with p53 mutations
- Hormone-dependent tumors
- Breast cancer
- Prostate cancer
- Ovarian cancer
2. Autoimmune disorders
Systemic lupus erythematosus
Immune-mediated glomerulonephritis
3. Viral infections
Herpesviruses, Poxviruses, Adenoviruses
Regulation of cell volume in health and disease
•
Maintenance of a constant volume in the face of extracellular
and intracelullar osmotic perturbations is critically important
for cells existence and function
• There is a lot of physiological and pathological situations in the body,
which are characterized by changes of osmolality in intra- and/or
extracellular space
● Most cells respond to swelling or shrinking by activating specific
metabolic or membrane – transport processes that return cell
volume to its normal resting state
Remember essential biophysical law: Water will flow from
hypoosmotic space to hyperosmotic one!
Fig. 8
Activation of mechanisms regulating cell volume in
response to volume perturbations
R
e
l
a
t
í
v
e
Extracellular hypotonicity
C
e
l
l
V
o
l
l
u
m
e
Regulatory volume
decrease
Time
Extracellular hypertonicity
Regulatory volume
increase
Time
•
Volume of the cell can be controled by decreasing or increasing
concentration of osmotically active solutes in the cells.
Volume-regulatory accumulation and loss of electrolytes are mediated
by changes in the activity of membrane carriers and channels
(K+; Cl-; Na+K+2Cl-; H+/ Na+; HCO3- /Cl-)
•
Key role in cell-volume homeostasis belongs to organic osmolytes
(polyols - sorbitol, myo-inositol; aminoacids taurine, alanine and proline;
methylamines - betain, glycerylphosphorylcholine).
These are "compatible", "nonperturbing" solutes
Mechanisms involved in cell-volume regulation
 When a shrinkage of a cell is present the cell reacts to the situation
immediately by activation of membrane transport system
(inside of seconds - Fig. 9A - left side). It will lead to accumulation of
anorganic osmolytes (Na+, K+, Cl-) inside the cell, and secondary,
accumulation of water.
•
When extracellular hyperosmolality will last longer (48h and longer)
than anorganic osmolytes in the cell are substituted by organic
one's (Fig. 9B - left side)
•
Swelling of a cell will activate immediately the regulatory volume
decrease mechanisms (Fig. 9 A - right side). If a swelling lasts for
a short time, only, the regulatory volume decrease is done by loss
of KCl, very quickly.
• Cell swelled for a longer time are unable to loss accumulated organic
osmolytes very quickly when exposed to normotonic extracellular space –
this is the reason why they will accumulate water and extreme cell
swelling will occur.
• This is the situation when patient suffering from long-lasting
hyperosmolarity of extracellular fluid (e.g. decompensated diabetes
mellitus - DM) is rehydrated quickly with resulting normoosmolality of
extracellular fluid. Such a situation will lead to cell edema – especially
edema of brain cells
Measurements of cell-volume changes in rat C6 glioma cells
acclimated to brief periods of hypertonicity
HYPERTONICITY
L
-5
I
G
H -3
T
S
C
A
T
T
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R
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NORMOTONICITY
1.4
-1
1.0
1
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V
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E
3
5
(V) 7
0.7
0
400
800
Seconds
1500
Fig. 10 A
Measurements of cell-volume changes in rat C6 glioma
cells acclimated to prolonged periods of hypertonicity
L
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I
G
H-4
T
HYPERTON
NORMOTONICITY
1.4
-3
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T -2
T
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(V) 1
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400
Seconds
800
1.2
R
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1.0
V
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1200
Fig. 10 B
• Disturbances of cell volume regulation is one important patomechanism
involved in development of diabetic complications (peripheral neuropathy,
retinopathy, cataract formation).
• Unproper function of cell volume regulatory
mechanisms are involved in sickle cell crisis (Fig. 11).
Model of Shrinkage- Induced Sickling of Red Cell
in Patients Homozygous for HbS
Essential forms of pathological answers of the
organism to noxae
1. pathological reaction
- essential, the most simple reaction of the organism to
the influence of noxae
- it is usually short and quantitatively and/or qualitatively
different from physiological reaction
Examples:
• pathological reflexes
• allergic reaction (some types, only)
• decreasing of systemic blood pressure for a short time
(syncopa)
2. pathological process - complex of pathological
reactions, adaptive and defensive reactions induced
by influence of noxas
Examples: • malignant neoplasm
• inflammation and fever
• edema
3. pathological state - the result of pathological
process or accident lasted for years or during the
whole life
Examples: • congenital diseases
• deaf and dumb
• leg amputation
Exacerbation of a disease - occurence of repeated
episodes of acute attacs of disease in the course of chronic
disease
Recidivation of a disease - if a disease is interrupted by
full or partial recovery for a certain time and than it flares
up again
Remision of a disease - some symptoms and signs may
disappear in the course of chronic disease or they loss their
intensity for a certain time. This period is called remision
Two types of disease course
• benign course
• malignant course