1 Pathophysiology Jimin Shao ( ) Welcome to 2 1 Introduction 3 What is Pathophysiology? Pathophysiology is a science to study the etiology and pathogenesis of human diseases more concerning the mechanisms of functional and metabolic alterations in diseases. Target: Human diseases For: Etiology, pathogenesis, and mechanisms Focus on: Functional and metabolic alterations Basis for: diagnosis, treatment, prevention of diseases 4 How Pathophysiology is Arranged? (1) Cellular and molecular pathophysiology: Cell proliferation, differentiation, death and diseases Signal transduction and diseases Genetic and epigenetic changes in diseases Introduction and Conspectus of Disease: what pathophysiology is. What disease is. The basic laws and mechanisms those underlie all disease. 5 Fundamental pathological processes: Common and whole set alterations in metabolism, function and structure, which may occur in different diseases. Organic & systemic pathophysiology : Specific responses and mechanisms of the critical systems and organs in diseased body. DIC How Pathophysiology is Arranged? (2) 6 Gene aberrant in structure and function Abnormal epigenetic regulation Cell proliferation, differantiation, apoptosis and the Related Disorders Signal transduction and the Related Disorders Cellular and molecular pathophysiology Genetic and epigenetic alterations in cancer 8 Autoimmune disease, Tumor, virus infection, etc Proliferation Apoptosis Cell proliferation, differentiation, death and the related diseases Insufficient Apoptosis in Diseases 9 Apoptosis and Diseases Diseases Mechanism Apoptosis Heart failure Ischemia, inflammation, etc. AIDSHIV infection of T 4 cell AD, PDIschemia, inflammation, etc CancerP53, Bcl-2 Autoimune diseasesAutoreactive T cells or B cells AtherosclerosisEndothelial cell, muscle cell 10 Signal transduction and diseases 11 Fundamental pathological processes Water and Electrolytes Imbalance Acid-Base Balance and Imbalance Stress and the Related Disorders Fever Hypoxia Free Radical Injury DIC Coagulation-Anticoagulation Disorders and DIC Ischemia-Reperfusion Injury Shock and MODS Tumor 12 An elevation of body temperature is fever? 35 40 Physiologic elevation of body temperature Fever 13 A pathologic elevation of body temperature is fever? Heatstroke Hyperthyroidism Central nervous system damage Hyperthermia 14 Pyrogenic activators: microorganisms, non-microbial pyretic substances EP-producing cells: Monocytes/macrophages, endothelial cells, etc Endogenous pyrogens (EP)/ pyrogenic cytokines: IL-1,6, TNF, IFN,MIP-1,etc Hypothalamus thermoregulatory center Central mediators of fever (Positive PGE2,CRH,cAMP,Na+/Ca2+,NO; Negative: AVP, -MSH, Lipocortin-1) Elevated thermoregulatory set point OVLT, BBB, Vagus nerve Heat conservation; heat production FEVER Pathogenesis of fever 15 Tumor 16 Organic & systemic pathophysiology Heart Failure Respiratory Failure Hepatic Encephalopathy Renal Failure Endocrine disorders Metabolic Syndrome Brain disfunction Liver disease neuropsychiatric syndrome Hepatic Encephalopathy Flapping tremor (asterixis) (hepatic coma) Clinical presentation: Pathogenesis: Multifarious toxins Dysfunction of CNS (No obvious morphological change) Several hypotheses Ammonia intoxication Ammonia intoxication False neurotransmitter False neurotransmitter Amino acid imbalance Amino acid imbalance GABA (-amino butyric acid ) - GABA (-amino butyric acid ) & HE Integrative mechanism 20 Biochemistry Genetics Cell Biology Molecular Biology Anatomy Histology and Embryology Physiology Neuroscience Immunology Microbiology and Parasitology Pathology Pathophysiology Pharmacology Relationship with other disciplines (1) Basic Medical Sciences Clinical Medical Sciences Public Health 21 Relationship with Physiology Pathologic physiology Clinical Physiology Physiology under diseased situation Relationship with other disciplines (2) Relationship with Pathology Pathology emphasizes the structural changes and the mechanisms. Pathophysiology deals with functional and metabolic alterations and the mechanisms. 22 Why Is Pathophysiology Important? A bridge between basic medical sciences and clinical medicine. Why and how diseases develop and various clinical manifestations appear. Underlying of general rules and mechanisms. Bases for diagnosis and rational therapeutics. 23 Major Points in Learning Pathophysiology The general concepts The etiology and pathogenesis The alterations of metabolism and function The principles for prevention and therapies 24 How to Learn Pathophysiology Grasp the major points Review related knowledge learned previously, such as physiology, biochemistry, molecular biology, immunology, pathology, clinical disciplines, and etc. Pay attention to clinical practices Update your knowledge frequently 25 26 27 28The American Association for the Advancement of Science 29 30 33 The Methodologies Used in Pathophysiology Molecular biology, genomics, proteomics, other omics Cell, tissue, and organ levels Integrated medicine/Systems biology Animal experiments Clinical research Epidemiological analysis Comprehensive, multi-disciplines Translational research 34 - Flag Bait Column particle m/z 0 % y1y1 y2y2 y3y3 y4y4 y5y5 y7y7 y9y9 y8y8 y6y6 y10y10 RSALEIEGSN 35 36 37 38 Mitochondria hRRM2 merge hRRM1p53R2 RR subunits CY MIT CY MIT CY MIT Non-stimulation St96h St96h+Rel 2h hRRM1 -tubulin hRRM2 p53R2 39 40 Phase I Triapine and Gemcitabine CT scan Comparison pre- and post- Treatment Tumor Sampling Phase II GTI 2040/Capecitabine in Breast Cancer Protocol Microdissection of Tumor from Normal Tissue Biopsy 41 42 (Molecular biology) (Genomics) (Genomics) (Transcriptomics) (Proteomics) (Proteomics) (Metabonomics) (Interactomics) (Interactomics) (Phenomics) (Computational Biology) 43 2 Conspectus of Disease 44 Concept of Health Traditional definition: The state of the organism when it functions optimally without any evidence of disease. The definition of health from WHO: Without any evidence of disease, and a state of complete well-being physically, socially and psychologically. 45 Concept of Disease An abnormal life process or a pathologic process which is induced by disorders of homeostasis under the action of certain causes and conditions, with a characteristic set of signs and symptoms. Homeostasis: The body maintains a steady state of the internal environment in the face of continual environmental variation, which is required for optimum functioning. 46 Symptom: Subjective feeling of discomfort that can be reported by the affected individual. Sign: Objectively identifiable aberration of the disease. Syndrome: A collection of different signs and symptoms that occur together in specific disease. 47 Sub-health A situation, in which the person does not show specific symptoms and signs of disease, but lives a low-quality of life both physically and mentally. e.g. chronic fatigue syndrome (CFS) with possible latent alterations, or functional alterations 48 Etiology of Disease Etiology studies the contributing factors that cause diseases, including: (1)Etiological factors / Causes of diseases (2)Conditions for / Precipitating factors of disease (3)Predisposing factors of disease 49 Etiological factors/Direct causes of diseases: An etiological factor causes a disease and determines its characteristics. Extrinsic Causes Intrinsic Causes 1.Etiological Factors 50 (1) Extrinsic Factors Biological agents: microorganisms, parasites, and products Chemical agents: non-specific and specific Physical agents: mechanical injuries, extremes of temperature, electricity, and radiation Nutritional imbalance: excesses or deficiencies 51 (2) Intrinsic Factors Genetic factors: gene mutation, chromosome aberration. Epigenetic factors: DNA methylation, histone code, etc Congenital factors: abnormal embryonic development. Immunological factors: the immune response is deficient, inappropriately strong, or misdirected. Psychological factors: Anxiety, strong or persistent psychological stress; hypertension, peptic ulcer, coronary heart disease, and depression. 52 2.Conditions for disease Precipitating factors enhance the effects of causative factors and promote the onset and development of diseases, through influence upon the role of etiological factors or body condition: Natural condition: exposed to cold environment ---develop a cold Physical condition: hypertension --- vulnerable to myocardial infarction Social condition: such as poor labor and hygiene conditions 53 3.Predisposing factors A predisposing factor refers to the factor that influences the susceptibility or resistance to certain disease: Genetic constitution (Genetic predisposition) Physiological diathesis Psychological characteristics 54 Pathogenesis Pathogenesis studies the general rules and common mechanisms underlying the development of diseases, including how the primary pathological agents cause disease and how the disease develops. (1) Basic mechanisms of disease (2) General rules of disease development (3) Outcome of disease 55 1.Basic mechanisms of disease Mechanism of disease: to explain alteration during disease, including how and why the symptoms and signs of the disease may occur and develop, how the body attempts to overcome the disease. Although various specific mechanisms may underlie different disorders, they all generally involve the following four levels of deregulations: Neural regulations Hormonal regulations Organic regulations Cellular and Molecular regulations 56 2. General rules for the onset and development of diseases (1) Disruption of homeostasis (2) Process of damage and anti-damage (3) Reversal role of cause and result (4) Correlation between systemic and local alterations 57 (1) Regulation and disruption of homeostasis Homeostasis: to keep the internal environment of an organism to remain balanced and stable. e.g. maintenance of body temperature homeostasis. Disruption of homeostasis by harmful agents may cause diseases. e.g. fever 58 (2) Damages and anti-damage responses Damages induce anti-damage responses, and the interactions go through the whole process of diseases and determines the development and outcome of diseases. e.g. Microbeanti-infection (Physic barrier, Monocyte, Inflammation, Immunoreaction) Overdo of anti-damages cause new injuries, becoming a damaging factor. e.g. Burning injury (damage)-- constriction of small blood vessels: maintaining proper blood pressure (anti-damage). However, sustained vasoconstriction--hypoxia, cellular necrosis, and dysfunction. 59 60 A cause of a disease leads to a result, which can be a new cause for another result in the development of the disease, even forming vicious cycle. e.g. hemorrhagic shock. (3) Reversal rule of cause and result Primarycauses Response s Furtheralterations Secondaryalterations(causes) 61 (4) Systemic and local regulations Local alterations and the systemic states can affect each other and disease development. e.g. a severe furuncle will not only cause local inflammation, but also lead to systemic reactions of fever and elevated leukocytes. On the other hand, a furuncle may be caused by diabetes and could only be cured by proper control of diabetes. 62 Phases of A Disease Latency Prodrome Clinic symptoms Recovery Disease 3.Outcome of Disease 63 Outcome of a disease Recovery Death Complete recovery Incomplete recovery Prognosis: Probable course and outcome of a disease. 64 (1) Complete recovery The alterations of the function, metabolism, and structure of the body during the disease are perfectly restored, and the symptoms and signs of the disease are disappeared entirely. the etiological factors disappear the pathologically altered metabolism, structure and function are perfectly restored the symptoms and signs of the disease disappear entirely homeostasis is recovered 65 (2) Incomplete recovery the main symptoms and signs are absent but some pathological changes are still present in the body. Transition to chronicity Sequela is generally brought about by the compensatory response to maintain a relatively normal activity. For example, the permanent damage to the heart valve after rheumatic fever. 66 (3) Death The body as a whole stop working forever. Brain dearth is the marker for the diagnosis. Brain death is a state of prolonged irreversible cessation of all brain activity with the complete absence of conscious and voluntary movements, responses to stimuli, brain stem reflexes, and spontaneous respirations. 67 Brain Death (WHO criteria) Cessation of spontaneous respiration Irreversible coma Absence of cephalic reflexes Dilated or fixed pupils Absence of any electrical activity of the brain Absence of brain blood flow 68 Significance for diagnosis of brain death In favor of recording the time of death Define the time to terminate for the rescue In favor of organ transplantation 69 Brain death ( )Vegetative state 70 3 Case study A 34-year-old man was well until 3 days prior to admission, when he noted the onset of fever, weakness, fatigue, headache, sore throat, and a cough productive of white sputum. One day prior to admission he awakened with burning chest discomfort that was made worse by coughing and by deep breathing. He developed shortness of breath and was seen at a university infirmary, where he appeared acutely ill with a fever. A chest radiograph demonstrated bilateral infiltrates consistent with pneumonia. An arterial blood gas analysis, done while the patient was breathing room air, was notable for significant hypoxemia (PaO2, 48mmHg; normal, mmHg). The patients shortness of breath increased markedly, and he was transferred to the hospital, where he was found to be cyanotic and febrile to 39.8 and to have a respiratory rate of 44/min with labored respirations. Examination of the sputum revealed a grossly bloody background, numerous neutrophils, and sheets of gram-positive cocci in clusters. 71 Questions 1.What disease did the patient suffer from: bacterial infection or viral disease? 2. What pathogenic mechanism accounts for this patients fever? 3. What alterations of metabolism and function may occur in a patient suffering from fever? 72 Learning Objectives 73 Exercises 74 1. Pathophysiology 2. Disease 3. Bio-psycho-social medical model 4. Etiology 5. Pathogenesis 6. genetic predisposition 7. Prognosis 8. brain death 9. Vegetative state