Introduction to Pathophysiology as an integrating medical discipline Pathophysiology – what is it about? Etiology and pathogenesis of disease Definition of health vs. disease Disease vs. illness Problem how to define normality in medicine Pathophysiology (PP) as a medical discipline • medical science dealing with the study of disease – physiology = how the healthy body works – pathophysiology = how the ill body works (or it does not) • PP is “physiology of altered health” • PP explains functional consequences of a disease process • PP studies namely two processes – disease (a)etiology – i.e. what causes the disease to develop – disease pathogenesis – how the disease develops – 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, experience 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) – temporal dynamics of disease (time, aging, chronobiology etc.) – spatial dynamics of disease (e.g. from initially local process to systemic) – complexity (single disease is a rare situation, very often comorbidities) – gender (and possibly ethnic or other) differences • PP has a unique position in medical curriculum 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, 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 • To say that somebody has a disease/is ill can have a profound mental, social, economic and philosophical consequences for the individual, however, distinction is not always easy – see further interindividual variability and normality • 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 od a screening or prevention – an abnormal condition 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, 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 illeness – 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) or Illness is the reason to seek the doctor, disease is what stays afterwards Example of approaches to definition of disease • Neutral (objective) - closer to disease concept – each organ and organ system in our body has its function (that is usually measurable) 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 – 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 phenomenon incl. Its historical context • Perfect body ideal – asthenic vs. obesity – dwarfism, mutilations • Age-related changes can become unacceptable – e.g. post-menopausal complaints – osteoporosis • 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 England 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 and in majority genetics matters to some extent • 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 • 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 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 – 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 etiology pathogenesis Clinical course of the disease • “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 – manifest only in increased load/demand – prodromal – usually unspecific signs of upcoming disease • e.g. fatigue, weakness, anorexia, pain, fever, • acute illness (limited number of days, can be 1 day to 1 month) – severe but self-limiting • chronic illness (longer that 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) – chronic from the very beginning • e.g. due to pathogen making itself inaccessible, or targeting the very means od body defense Chronic disease - intensity • Majority of disease that are subject of health care are chronic – There exceptions of course (traumatology, paediatrics, obstetrics, …) • Chronic disease can stay in the same intensity or not – Exacerbation = aggravation of symptoms, signs and severity of disease – Remission = lessening of severity or disappearance of clinical disease induced by treatment however with the risk of reoccurrence • 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 OF NORMALITY IN MEDICINE Interindividual variability • physiological interindividual variability of phenotypes/traits is a consequence of genetic variability – the more independent factors affect the given trait the more “normal” the population distribution is – if the effect of one factor dominates over the others or there are significant interactions the distribution becomes asymmetrical, discontinuous etc. • genetic variability = v existence of several variants (alleles) with various frequency for a given gene in population – has many sources: – 1) sexual reproduction – 2) independent meiotic segregation • 23 chromosomal pair  223 combinations = 8,388,608 different gamets – 3) recombination (meiotic crossing-over) • >> 8 millions of combinations – 4) mutations de novo • “errors” during DNA replication (proof-reading of DNA polymerase is not 100%) • effect of external mutagens – 5) effects on the population level (evolution) – Hardy/Weinberg law • natural selection = adaptive (reproductive success) • genetic (allelic) drift = random selection of alleles (entirely from chance) • “founder” effect • interindividual variability of a given trait is present in whole population incl. healthy as well as diseases subjects – disease as a “continuous function of the trait” • aetiology of diseases – “monofactorial” incl. monogenic – “multifactorial” incl. polygenic (complex) 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 Diagnosis of disease – problem with “normality” • parameters/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 innpopulation Reference interval (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 pathophysiology is 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 (treatment) – avoid them (prevention) – or at least search for them early (screening) Practical notes • Literature: – Pathophysiology (Damjanov I), Elsevier 2009 – Essentials of Pathophysiology (Porth CM), Lippincot W&W 2007 • Lectures held by senior staff of Dept . of Pathophysiology • handouts of lectures on PP from Dept . of Pathophysiology FoM MU are study literature too! • Available on IS • I am looking fw to see you all next time!!!