Introduction to Pathophysiology
as an integrating medical discipline
Pathophysiology – what is it about?
Definition of health vs. disease/illness
Etiology and pathogenesis of disease
Problem how to define normality in medicine
Pathophysiology (PP) as a medical discipline
• medical science dealing with the study of disease, in particular how the disease
develops and progresses (i.e. aetiology and pathogenesis) and also how the cells,
tissues, organ systems and whole body react in time (i.e. adaptation and
compensation)
– physiology = how the prototypical/textbook healthy body works
– pathophysiology = how the real ill body works (or it does not)
• PP is “physiology of altered health”
• PP explains functional consequences of a disease process
• PP has to consider interindividual variability in disease susceptibility, onset, rate of progression, response to
therapy, …
• PP studies namely two processes
– disease (a)etiology – i.e. what causes the disease to develop
– disease pathogenesis – how the disease develops
– has to considetr also disease pathology – describes what anatomic changes disease produces
• PP bridges basic medical sciences with clinical medicine
• PP knowledge on etiopathogenesis of disease is based on:
– basic research and experimental approach
• molecular biology, genetics, immunology, …
• models (in vitro, animals, humans)
• human samples (DNA, proteins, fluids, tissues)
– clinical observation, evidence and trials
• observational studies – no intervention, just observation of natural history
• interventional studies – intervention in controlled settings (drugs, surgery, behavioral therapy, …)
How does pathophysiology differs from previous disciplines?
• Physiology and other previous subjects mainly focuses/assumes
– a prototypical human being (e.g. 70kg healthy man of unknown age)
– and isolated processes (healthy or pathological)
• PP on the contrary tries to bring the knowledge close to clinics and general population by accounting for:
– variability (intra- and inter-individual)
• e.g. chronobiology
– temporal dynamics of disease (time, aging, exposures etc.)
– spatial dynamics of disease (e.g. from initially local process to systemic)
• e.g. coronary AS to congestive heart failure
– complexity (single disease is a rare situation, very often comorbidities)
– gender (and possibly ethnic or other) differences
• PP has a unique position in a medical curriculum enabling to
– synthetize all preclinical knowledge
• morphology, biochemistry, physiology, immunology etc.
– document its clinical relevance
– extent particular information to general (generalisation) and vice versa
• many diseases share the same etiopatogenetic mechanisms – analogy
– we do not need to repeat them again and again
– thereby we can use the time effectively
Pathophysiology (PP) as a medical discipline
• What we are going to study?
– General PP
• deals with general pathologic processes and mechanisms that are involved in pathogenesis of more
than one disease
• in fact, majority of diseases are a mixture of just a few pathologic processes
– hypoxia/ischemia, abnormal cell proliferation (too much or too little), inflammation, various metabolic
abnormalities inducing toxic or hypo-nutritive environment, effect of external factors (such as temperature,
mechanical forces, radiation, …) etc.
• there are also powerful defensive mechanisms in body operating together with disease mechanisms
– innate and adaptive immunity, atrophy/hypertrophy, cellular and tissue remodelling, hypo-/hyperfunction, altered
homeostasis etc.
– Special (organ, systems) PP
• explanation of pathomechanisms involved in functional disturbances of the organs and systems of the
organism
– Pathophysiology help us to understand the logic of life during development of
pathological processes
HEALTH vs. DISEASE
Distinction between health and disease
• In order to study diseases we have to be able to distinguish between health and disease
– the pragmatic reason – who should be given a health care
• on the other hand many physiological conditions are a subject of health care system
– childhood paediatric care, pregnancy, preventive measures, aesthetic reasons (dentistry, surgery, dermatology), …
– the philosophical/ethical reason
• to say that somebody has a disease/is ill can have a profound mental, social, economic and consequences for the
individual, however, distinction is not always easy
• Disease is perceived both subjectively
– “I am not feeling well”, anxiety, fear, failure, …
• and objectively by medical specialists
– to some extent independently from the subject
• WHO definition of health
– Health is a state of complete physical, mental and social well-being and not merely the absence of
disease or infirmity
• preamble to the Constitution of the World Health Organization as adopted by the International Health Conference, New
York, 19-22 June, 1946
• signed on July 22, 1946 by the representatives of 61 member states (Official Records of the World Health Organization,
no. 2, p. 100) and entered into force on 7 April 1948
• this definition has not been amended since 1948
Disease vs. Illness
• It is not “just” a discussion of semantics – it’s about clarity
– these two words are often used interchangeably, but this is incorrect
• Disease is an objectively detectable state, very often a subject of a screening or prevention
– an abnormal condition/process affecting cell, tissue, organ or organism (quite often in this order)
• could be due to infection, degeneration of tissue, injury/trauma, toxic exposure, development of cancer, etc.
– disease does not need to be accompanied by subjective symptoms (asymptomatic, latent)
• Illness best refers to the feelings that might come with having a disease, it borders the patient,
creates reason for treatment
– pain, fatigue, weakness, discomfort, distress
– illness is profoundly affected by many factors such as education, cultural and socio-economical
circumstances, experience, mentality, age etc.
• Disease and illness are mutually interconnected – possible scenarios:
– disease leads to illness = following asymptomatic phase (of variable length) symptoms appear
– disease without illness = e.g. mild hypertension, hypercholesterolemia or compensated illness
– illness without disease = e.g. surgery, trauma, „psychosomatic“ diseases
• “Disease is something an organ has; illness is something a man has” (Eric J. Cassell, 1978)
• Illness is the reason to seek the doctor, disease is what stays afterwards
Example of approaches to definition of disease
• Neutral (objective) - closer to PF and clinical disease concept
– each organ and organ system in our body has its function (that is usually measurable – e.g.
cardiac output, GFR, pO2/CO2, …) and when the function is impaired than there is a disease
• health equals to the ability of organism (and its parts/organs and systems) to perform all the functions
under the typical circumstances with at least typical efficiency (closely related terms are adaptation and
homeostasis)
– it is necessary to define normality (reference population/reference interval – statistical approach) 
• disease is a state that is a subject of healthcare
• does not take into account the subjective feelings of a subjects, although later nearly every disease can
cause discomfort, disability, pain, suffering and be thus perceived subjectively
– on the contrary there are plethora of situations when the same feelings are not considered pathological (such as dentition,
menstruation, pregnancy etc.)
• more close to the current medicine paradigm
• Normative (subjective) – closer to illness concept
– if the person is not limited by his/her condition and can achieve the desired goals than he/she is
healthy
• blindness, dwarfism or autism is not a disease if the person suffering from it does not feel limited in any way
Disease and health are however natural and cultural
phenomena incl. their historical context
• Historical stigma – very often rare conditions
– albinism, dwarfism, …
• Perfect body ideal
– asthenic vs. obesity
– mutilations/body decorations
• Age-related changes can become unacceptable
– e.g. post-menopausal complaints
– osteoporosis
– skin, hair, dental age-related changes
• On the contrary, some conditions are
no longer diseases
– e.g. homosexuality
• And new ones are emerging
– ADHD, dyslexia, … Alison Lapper (8 months) by Marc Quinn (2000). This sculpture caused
controversy in UK when it was chosen as one of two pieces to occupy the
vacant fourth plinth in Trafalgar Square, London.
ETIOLOGY and PATHOGENESIS OF DISEASE
Disease etiology
• endogenous = internal factors
– congenital
• genetic (monogenic as well as polygenic)
• malformations due to prenatal exposure to viruses of toxins
• fetal programing
– acquired
• metabolic
• immune
• circulatory
• neoplastic
• exogenous = external factors
– physical
• mechanical, thermal, irradiation, electricity, …
– chemical
• xenobiotics incl. drugs
• toxins and poisons
• environmental contaminant
• smoke
• excess or deficit of nutrients
– biological
• infections (bacterial, viral, fungal, parasites, …)
• toxins
• prions
– psychological and social
• mental trauma
• stress
majority of
diseases are
multifactorial
in origin
• Monofactorial
– one single cause potent enough to cause disease
– diagnosis often based on qualitative parameters
• e.g. X-ray visible fracture, wound, malformations, …
– easy to distinguish between health and disease
– environment and lifestyle play generally minor role
– examples
• trauma
• highly virulent infection
• poisoning
• monogenic disease
• chromosomal abnormalities (i.e. aneuploidy)
– trisomy - autosomal (Down)
– trisomy of monosomy – gonosomal (i.e. Turner, Klinefelter)
• Multifactorial (= complex)
– products of concomitant exposure to internal and
external factors with typically equal role of both, so called
“diseases of civilization”
– diagnosis often based on quantitative parameters
(disease is a continuum of health)
• e.g. normal BP/hypertension, normal glycaemia/diabetes
– often difficult to distinguish between health and disease
– examples
• obesity
• diabetes
• atherosclerosis
• allergy
• cancer
Factors
Large effect Small effects
Non-genetic severe trauma, intoxications, highly virulent infections, highly
penetrant population environmental exposures
(e.g. nuclear catastrophe)
common environmental exposures, physical activity, dietary
factors, stress, drugs, aging, …
Genetic monogenic diseases due to rare alleles gender, common alleles
Diseases according to the number of ethiological
factors and genetic contribution
početpredisponujícíchgenů
celkový počet etiologických faktorů
10
10
monofaktoriální
(úrazy, vysoce
virulentní
infekce)
monogenní
(cystická fibróza, familární
hypercholesterolemie, ...)
“single” gen
oligogenní
(T1DM, celiakie, AMD,
Crohnova chroba, ...)
“major”/”modifier” geny
komplexní
(hypertenze, obezita,
T2DM, nádory, ...)
n genů v interakci
fenokopie
(obezita),
degenerativní
onemocnění, ...
předmět
genetické
epidemiologie
početpredisponujícíchgenů
celkový počet etiologických faktorů
10
10
monofaktoriální
(úrazy, vysoce
virulentní
infekce)
monogenní
(cystická fibróza, familární
hypercholesterolemie, ...)
binární fenotyp s obvykle časnou manifestací
oligogenní
(T1DM, celiakie, AMD,
Crohnova chroba, ...)
binární fenotyp s
obvykle pozdější
manifestací
komplexní
(hypertenze, obezita,
T2DM, nádory ...)
spojitý IM fenotyp (QTL)
s typicky pozdní manifestací
fenokopie
(obezita),
degenerativní
onemocnění, ...
neparametrické
linkage
studie
početpredisponujícíchgenů
celkový počet etiologických faktorů
10
10
monofaktoriální
(úrazy, vysoce
virulentní
infekce)
monogenní
(cystická fibróza, familární
hypercholesterolemie, ...)
oligogenní
(T1DM, celiakie, AMD,
Crohnova chroba, ...)
komplexní
(hypertenze, obezita,
T2DM, nádory, ...)
fenokopie
(obezita),
degenerativní
onemocnění, ...
asociační
studie
parametrické
linkage
studie
What indicates that disease is, at least partly,
genetically conditioned ??
• binary phenotype (yes/no)
– familiar aggregation
• prevalence of affected probands in families >>> prevalence
in general population
– true for monogennic as well as complex diseases
– segregation analysis
• finding the mode of inheritance of given phenotype in
families (i.e. recessive or dominant)
• only for monogennic (“major” genes)
• continuous phenotype (how much)
– intra-family correlation coefficient
• proportion of overall variability in phenotype caused by
variability between families
– heritability
• percentage of variability in phenotype due to variability in
genotype (twin studies MZT, DZT)
Complex diseases
examples of complex diseases: essential hypertension (BP, …), diabetes
(glycaemia, insuliniaemia, C-peptide, …), dyslipidaemia (TCH, LDL, HDL, …),
obesity (BMI, WHR, …), allergy (provocation tests, circulating cells, cytokines, …),
atherosclerosis (coronarography, …), Alzheimer disease and other types of
dementia (scales, grading systems, …), others
Complex diseases • diseases developing due to the ethiopathogenic “complex“ of
genetic, epigenetic and environmental factors
– phenotype does not follow Mendel rules (i.e. dominant or recessive mode of
inheritance)
• “predisposing genes/alleles” increase probability to become affected,
however, do not determine unequivocally disease development
– effect of non-genetic factors is a necessary modifier
• diet, physical activity, smoking, ….
– genes interact between themselves
• typical features of complex diseases
– incomplete penetrance of pathological phenotype
• some subjects who inherited predisposing alleles never become ill if not exposed to
environmental factors
– existence of „phenocopies“
• pathological phenotype can develop in subjects not predisposed, entirely due to the
exposure to non-genetic factors (e.g. massive overeating leading to obesity despite
the genetics)
– genetic heterogeneity (locus and allelic)
• manifestation (clinical) is not entirely specific but the same syndrome can develop as
a consequence of various loci (= locus heterogeneity) in which there could be several
variants (= allelic heterogeneity)
– e.g. many loci contributing to the regulation of blood pressure = essential hypertension likely
not a homogenous PF entity
– polygenic inheritance
• predisposition to disease is significantly increased only in the presence of a set of
several risk alleles (polymorphisms), hence their high population frequency
– in isolated occurrence the effect is mild, therefore no genetic selection
– other modes of transmission
• mitochondrial, imprinting (<1% of all alleles in genome), epigenetics
Disease pathogenesis
• Response of the body to the action of etiological factor(s)
– adaptation = no change in functional abilities = no disease
– dysadaptation = impairment of function = disease
• Pathogenesis of disease
– sequence of molecular, cellular, tissue and organ events taking the place from the
initial contact/exposure to etiological factor(s) until the expression of disease
– organ-centered
• limited to a single organ (system)
– however, usually only at the beginning of the disease
• later , majority of diseases becomes systemic, i.e. having systemic signs
– for example tumors, liver steatosis and fibrosis, …
– systemic
• some disease are widespread/systemic from the very beginning
SYSTEMICORGAN-SPECIFIC
Common misconceptions
• Atherosclerosis might be cited as a etiology of
coronary artery disease (CAD)
• However, progression of the process from
initial clinically unapparent lesion (fatty streak)
to manifest occlusive vessel disease is a
continuum of pathogenesis
• The very cause(s) of atherosclerosis are
generally unknown and subjects of research
with many identified etiologic contributors (risk
factors)
– external – diet, exercise, smoking,
– internal – genetic susceptibility, metabolic,
inflammation, …
• CAD is therefore late clinical manifestation of
atherosclerosis
Clinical manifestation of diseases
• diagnosis of diseases is based on the recognition and proper
interpretation of diseases manifestation
– symptom = feature recognized subjectively by the patient
– sign = objectively noticeable
• physical examination
• diagnostic method (laboratory, X-ray, ultrasound, …)
• typical cluster of signs and symptoms present usually together
creates a syndrome
– however, many conditions can present by the same syndrome, therefore
one must test multiple working hypotheses as to what led to this particular
state = differential diagnosis
Pathophysiology vs. clinical medicine
pathophysiology is inductive
clinical medicine is deductive
Natural history of disease
• refers to the progression of a
disease process in an individual
over time in the absence of
treatment
• this is how the PP is usually taught
• classifies the modes of prevention
Clinical course of the disease
• susceptibility (“disease background”)
– individual constitution (incl. genetic susceptibility and lifelong fitness) matters, i.e. the same etiological
factor will not have the same effect in various people
– risk factors
• variable exposure due to environment (incl. geographical location, altitude, climate etc.), individual lifestyle, history and
social habits etc.
• pre- or subclinical stage
– latent/asymptomatic/silent – manifest only in increased load/demand
– prodromal – usually unspecific signs of upcoming disease
• e.g. fatigue, weakness, nausea, anorexia, pain, fever, dizziness
• acute illness (limited number of days, can be 1 day to 1 month)
– severe but self-limiting
• chronic illness (longer than typical pro given disease)
– long term, continuous process
– follows the acute stage
• disease was not eliminated completely due to various reasons (e.g. immune deficiency, persistent injury)
– chronic from the very beginning
• e.g. due to pathogen making itself inaccessible, or targeting the very means od body defense, auto-aggressive
Chronic disease - intensity
• Exacerbation = aggravation of symptoms, signs and severity of disease
• Remission = lessening of severity or disappearance of a clinical disease induced by
treatment
– however with the risk of reoccurrence = relaps
– e.g. cancer – with current methods we cannot be sure we eliminated all cancer cells
• Residual disease = detectable with lab test but not by symptoms and clinical signs
– e.g. leukemia – PCR detection of genetic changes typical of leukemic clone but otherwise
patients appears healthy
• Carrier status = patient harbors the microorganism but may have few or no
symptoms, clinical or laboratory signs
• Complication = possible adverse extensions of a disease in spite of
the treatment
Vicious cycle
• A situation in which the apparent solution
of one problem in a chain of circumstances
creates a new problem and increases the
difficulty of solving the original problem
• Many examples in PP
Problem with normality in medicine
Inter-individual variability makes definition of normality
(and therefore distinction between health and disease) problematic
repeated measurements
of temperature
18.2°C
18.5°C
19.1°C
18.7°C
variability of height
in population
180 cm
175 cm
165 cm
157 cm
diversity in biological
populations
inter-population or ethnical
differences
= BIODIVERZITY
temporal changes/
fluctuations
time
Interindividual variability
• physiological interindividual variability of phenotypes/traits is
a consequence of genetic variability and variable exposure
to external factors
– higher the number of independent factors affecting the given trait
the more likely “normal” the population distribution is
– if the effect of one factor dominates over the others or there are
significant interactions the distribution becomes asymmetrical
• interindividual variability of a given trait is present in the whole
population incl. healthy as well as diseases subjects!
– both all healthy and all ill people are not the same
– disease as a “continuous function of the trait”
• etiology of diseases (see earlier)
– “monofactorial” incl. monogenic
• even here the subjects affected by the same disease are not the same
– allelic heterogeneity – e.g. familiar hypercholesterolemia
– mosaicism vs. classical Down syndrome
– complex (“multifactorial” incl. polygenic diseases)
• classical example of interindividual variability and „disease as a continuation of the continuous trait“ model
Genetic variability
• one particular gene/locus is typically present in several variants/alleles
in population which can be variably frequent
– genetic variability is a result of several processes
• 1) sexual reproduction
– inbreeding as risk factor for monogenic diseases
• 2) independent meiotic segregation
– 23 chromosome pairs  223 combinations = 8,388,608 different gametes
• 3) meiotic recombination (crossing-over)
– there is a >> combinations than 8 millions
• 4) de novo mutations
– replication errors
» proof-reading ability of DNA polymerase and mismatch DNA repair are not 100%
error free)
– exposure to mutagens (more typical for somatic cells, but germinal cells exposed as well)
• 5) genetic drift
• 6) natural selection
– cave eugenics!
• the terminology genetic mutation vs. polymorphism is based on population
allele frequency
– genetic polymorphism = existence of several (at least 2) alleles for given gene, in
which less one common has a frequency at least 1%
– mutation = population frequency <1%
• types
– genomic
• alteration of the number of chromosomes or of the whole sets (aneuploidy, polyploidy)
– chromosomal aberrations
• structural anomaly of individual chromosomes (duplication, deletion, insertion, inversion,
translocation)
– genetic (mutations or polymorphisms)
• shorter changes (1 – thousand base pairs)
• SNPs – single nucleotide polymorphisms
Meiotic recombination (crossing-over)
Statistical approach to defining
normality / health
(1) simple lie
(2) treacherous lie
(3) statistics
Diagnosis of disease – problem with “normality”
• parametrs/traits used as diagnostic parameters
might be
– qualitative
• alternatives yes/no
– e.g. cleft palate, congenital valve disease etc.
– quantitative
• measurable
• continuous distribution in population
• typically influenced by many factors
• problem to distinguish what is normal and what is not
• alternative vs. continuous model of disease
• practical approach = reference intervals
– mean  2 SD (for normally distributed parameters)
– 95% of values in a given population
Normal distribution is rare in biology/medicine
Reference interval („normal range“) - implications of
eliminating extreme results from reference intervals
Distribution vs. selection (mortality)
Reference range (or upper or lower cut-offs) can be
further modified by mortality/morbidity data
PP as part of the evidence-based medicine paradigm
Summary - why is pathophysiology important for
medical students and physicians
• It helps them to find answers to important questions related to
disease processes:
– What is the cause/causes of the disease, and why the disease is developing
– What are the mechanisms responsible for disease onset, progression, and
recovery
– What are the mechanisms responsible for development of symptoms and
signs of disease
• If doctors are able to understand the causes and mechanisms of the
disease, then they are able to find the way how to influence them
rationally