N1 Lecture 1 Introduction and Cell Injury PDF

Learning Outcomes By the end of this lecture, the students will be able to 1. Describe the basic terminology used in health and disease 2. Define the subdivisions of pathology 3. List the causes of cell injury 4. Discuss the types of cell injury and its outcome 5. Illustrate the morphological change...

Learning Outcomes By the end of this lecture, the students will be able to 1. Describe the basic terminology used in health and disease 2. Define the subdivisions of pathology 3. List the causes of cell injury 4. Discuss the types of cell injury and its outcome 5. Illustrate the morphological changes in reversible cell injury 2 Pathology: Overview The word ‘Pathology’ is derived from two Greek words— Pathos (meaning suffering) and logos (meaning study). “scientific study of changes in the structure and function of the body in disease” Pathology consists of the abnormalities in normal anatomy (including histology) and normal physiology owing to disease. ‘Pathophysiology’ (patho=suffering, physiology=study of normal function). Pathophysiology: study of disordered function(i.e. physiological changes) and breakdown of homeostasis in diseases (i.e. biochemical changes). 3 Pathology: Overview Pathology is the study of the structural, biochemical, and functional changes in cells, tissues, and organs that underlie disease By the use of morphologic, microbiologic, immunologic, and molecular techniques, pathology attempts to explain the whys and wherefores of the signs and symptoms manifested by patients while providing a rational basis for clinical care and therapy. Bridge between the basic sciences and clinical medicine 4 Pathology: Overview What is disease? what is not healthy is disease Health may be defined as a condition when the individual is in complete accord with the surroundings, while disease is loss of ease (or comfort) to the body (i.e. dis+ease) A disease or an illness means a condition marked by pronounced deviation from the normal healthy state. Syndrome (meaning running together) is used for a combination of several clinical features caused by altered physiologic processes. 5 COMMON TERMS IN PATHOLOGY Patient is the person affected by disease. Lesions are the characteristic changes in tissues and cells produced by disease Pathologic changes or morphology consist of examination of diseased tissues. These can be recognised with the naked eye (gross or macroscopic changes) or studied by microscopic examination of tissues. Etiology of disease: Cause Pathogenesis: Mechanism (‘How’ of a disease) Symptoms: Functional implications of the lesion felt by the patient Physical Signs: Functional implications discovered by the clinician 6 COMMON TERMS IN PATHOLOGY Diagnosis: Clinical significance of the morphologic and functional changes together with results of other investigations help to arrive at an answer to what is wrong Prognosis: what is going to happen Treatment: what can be done about it, Prevention: what should be done to avoid complications and spread 7 Disease aspects The four aspects of a disease process that form the core of pathology are 1. Causation (etiology) 2. Biochemical and molecular mechanisms (pathogenesis) 3. Associated structural (morphologic changes) and functional alterations in cells and organs 4. The resulting clinical consequences (clinical manifestations). 8 Disease aspects 9 Subdivisions of pathology 1. General pathology 2. Systemic pathology General pathology is concerned with the common reactions of cells and tissues to injurious stimuli. Such reactions are often not tissue specific: thus, acute inflammation in response to bacterial infections produces a very similar reaction in most tissues. Systemic pathology examines the alterations and underlying mechanisms in diseases of particular organ systems. 10 Subdivisions of Pathology HISTOPATHOLOGY Histopathology, used synonymously with anatomic pathology The study includes structural changes (gross or macroscopic changes), and the changes detected by microscopy, to arrive at the most accurate diagnosis. Modern time anatomic pathology includes sub-specialities such as cardiac pathology, pulmonary pathology, neuropathology, renal pathology, gynaecologic pathology, breast pathology, dermatopathology 11 Subdivisions of Pathology Histopathology or Anatomic pathology includes the following subdivisions 1. Surgical pathology; It deals with the study of tissues removed from the living body by biopsy or surgical resection 2. Experimental pathology: This is defined as production of disease in the experimental animal and study of morphological changes in organs after sacrificing the animal 3. Forensic pathology and autopsy work This includes the study of organs and tissues removed at postmortem for medicolegal work and for determining the underlying sequence and cause of death. 12 Subdivisions of Pathology CYTOPATHOLOGY : study of cells shed off from the lesions (exfoliative cytology) and fine-needle aspiration cytology (FNAC) of superficial and deep-seated lesions for diagnosis 13 Subdivisions of Pathology CLINICAL PATHOLOGY: Analysis of various fluids including blood, urine, semen, CSF and other body Such analysis may be qualitative, semi-quantitative or quantitative. MOLECULAR PATHOLOGY: The detection and diagnosis of abnormalities at the level of DNA of the cell is included in molecular pathology such as in situ hybridisation, PCR etc. These methods are now not only used for research purposes but are also being used as a part of diagnostic pathology reports. 14 Cellular responses to stress and noxious stimuli Cellular responses to stress and stimuli The normal cell is confined to a fairly narrow range of function and structure dictated by its state of metabolism, differentiation, and specialization; by constraints imposed by neighboring cells; and by the availability of metabolic substrates. Homeostasis 16 Cellular responses to stress and stimuli Cells are the basic units of tissues, which form organs and systems in the human body. In 1859, Virchow first published cellular theory of disease, bringing in the concept that diseases occur due to abnormalities at the level of cells. Thus, most forms of diseases begin with cell injury followed by consequent loss of cellular function. 17 Cellular responses to stress and injurious stimuli 18 Cellular responses to stress and stimuli Adaptations Adaptations are reversible functional and structural responses to changes in physiologic states (e.g., pregnancy) and some pathologic stimuli, during which new but altered steady states are achieved, allowing the cell to survive and continue to function If the stress is eliminated, the cell can return to its original state without having suffered any harmful consequences. 19 Cellular responses to stress and stimuli If the limits of adaptive responses are exceeded or if cells are exposed to damaging insults : Cell Injury Cell injury is reversible up to a point If the injurious stimulus is persistent or severe, the cell suffers irreversible injury and ultimately undergoes cell death. Adaptation, reversible injury, and cell death may be stages of progressive impairment following different types of insults. 20 Cellular responses to stress and stimuli 21 Cellular responses to stress and stimuli The relationship among normal, adapted, reversibly injured, and dead myocardial cells 22 Cell injury, cellular adaptations and ageing Cell injury Most forms of diseases begin with cell injury followed by consequent loss of cellular function. Cell injury is defined as the effect of a variety of stresses due to etiologic agents a cell encounters resulting in changes in its internal and external environment The cellular response to stress may vary and depends upon following two variables: i) Host factors i.e. the type of cell and tissue involved. ii) Factors pertaining to injurious agent i.e. extent and type of cell injury. 24 ETIOLOGY OF CELL INJURY 1. Hypoxia and ischaemia 2. Physical agents 3. Chemical agents and drugs 4. Microbial agents 5. Immunologic agents 6. Nutritional derangements 7. Ageing 8. Psychogenic diseases 9. Iatrogenic factors 10. Idiopathic diseases 11. Genetic causes 25 ETIOLOGY OF CELL INJURY HYPOXIA AND ISCHAEMIA Cells essentially require oxygen to generate energy and perform metabolic functions. Deficiency of oxygen or hypoxia results in failure to carry out these activities by the cells. Hypoxia is the most common cause of cell injury. 26 ETIOLOGY OF CELL INJURY PHYSICAL AGENTS i) Mechanical trauma (e.g. road accidents); ii) Thermal trauma (e.g. by heat and cold); iii) Electricity iv) Radiation (e.g. ultraviolet and ionising); and v) Rapid changes in atmospheric pressure. 27 ETIOLOGY OF CELL INJURY CHEMICALS AND DRUGS i) Chemical poisons such as cyanide, arsenic, mercury; ii) Strong acids and alkalis; iii) Environmental pollutants; iv) Insecticides and pesticides; v) Oxygen at high concentrations; vi) Hypertonic glucose and salt; vii) Social agents such as alcohol and narcotic drugs viii) Therapeutic administration of drugs. 28 ETIOLOGY OF CELL INJURY MICROBIAL AGENTS Infections caused by bacteria, rickettsiae, viruses, fungi, protozoa, metazoa, and other parasites. IMMUNOLOGIC AGENTS Immunity is a ‘double-edged sword’—it protects the host against various injurious agents but it may also turn lethal and cause cell injury e.g. i) Hypersensitivity reactions; ii) Anaphylactic reactions; and iii) Autoimmune diseases. 29 ETIOLOGY OF CELL INJURY NUTRITIONAL DERANGEMENTS Nutritional deficiency diseases may be due to overall deficiency of nutrients (e.g. starvation), of protein calorie (e.g. marasmus, kwashiorkor), of minerals (e.g. anaemia), or of trace elements. Nutritional excess is a problem of affluent societies resulting in obesity, atherosclerosis, heart disease and hypertension. 30 ETIOLOGY OF CELL INJURY AGEING Cellular ageing or senescence leads to impaired ability of the cells to undergo replication and repair PSYCHOGENIC DISEASES GENETIC DISEASES 31 ETIOLOGY OF CELL INJURY IATROGENIC CAUSES Diseases as well as deaths attributed to iatrogenic causes (owing to physician). Examples include occurrence of disease or death due to error in judgement by the physician and untoward effects of administered therapy (drugs, radiation). 32 ETIOLOGY OF CELL INJURY IDIOPATHIC DISEASES Idiopathic means “of unknown cause”. For example, most common form of hypertension (90%) is idiopathic (or essential) hypertension. Similarly, exact etiology of many cancers is still incompletely known. 33 Cell injury effects based on duration Sequential development of biochemical and morphologic changes in cell injury. Cells may become rapidly nonfunctional after the onset of injury, although they may still be viable, with potentially reversible damage; a longer duration of injury may lead to irreversible damage and cell death. Note that irreversible biochemical alterations may cause cell death, and typically this precedes ultrastructural, light microscopic, and grossly visible morphologic changes. 34 Cell injury Within limits, the cell can repair the alterations seen in reversible injury and if the injurious stimulus abates, may return to normalcy. Persistent or excessive injury, however, causes cells to pass the rather nebulous “point of no return” into irreversible injury and cell death. Different injurious stimuli induce death mainly by necrosis and/or apoptosis 35 REVERSIBLE CELL INJURY Reversible cell injury is characterized by functional and structural alterations in early stages or mild forms of injury, which are correctable if the damaging stimulus is removed. 36 REVERSIBLE CELL INJURY Two features are consistently seen in reversibly injured cells. 1. Early alterations in reversible injury include Generalized swelling of the cell and its organelles Blebbing of the plasma membrane Detachment of ribosomes from the endoplasmic reticulum (ER) Clumping of nuclear chromatin. 2. Fatty change occurs in organs that are actively involved in lipid metabolism (e.g., liver). 37 REVERSIBLE CELL INJURY: MORPHOLOGY Cellular swelling is the earliest manifestation of almost all forms of injury to cells Pallor, increased turgor, and increased weight of the affected organ. Microscopy: Small clear vacuoles may be seen within the cytoplasm; these represent distended and pinched-off segments of the ER. This pattern of nonlethal injury is sometimes called hydropic change or vacuolar degeneration. The cytoplasm of injured cells appears red (eosinophilc) when stained with hematoxylin and eosin (H&E) due to loss of RNA, which binds the blue hematoxylin dye. The eosinophilia becomes more pronounced with progression toward necrosis. 38 REVERSIBLE CELL INJURY: MORPHOLOGY The ultrastructural changes of reversible cell injury, visible by electron microscopy include the following: 1. Plasma membrane alterations, such as blebbing, blunting, and loss of microvilli 2. Mitochondrial changes, including swelling and the appearance of small amorphous densities 3. Accumulation of “myelin figures” in the cytosol composed of phospholipids derived from damaged cellular membranes 4. Dilation of the ER, with detachment of polysomes 5. Nuclear alterations, with disaggregation of granular and fibrillar elements 39 Cell Death Two principal types of cell death, 1. Necrosis 2. Apoptosis Differ in their mechanisms, morphology, and roles in physiology and disease 40 Morphologic changes in cell injury 41 Morphologic changes in cell injury Morphologic changes in reversible cell injury and necrosis. (A) Normal kidney tubules with viable epithelial cells. (B) Early (reversible) ischemic injury showing surface blebs, increased eosinophilia of cytoplasm, and swelling of occasional cells. (C) Necrosis (irreversible injury) of epithelial cells, with loss of nuclei, fragmentation of cells, and leakage of contents. 42