Cellular Pathology: General & Cellular Pathology PDF

Here is the conversion of the image to markdown format: # NSC 305: General & Cellular Pathology ## INTRODUCTION Cellular pathology, also known as anatomical [or anatomic] pathology, is the branch of pathology that involves the study of body organs and tissues [groups of cells]. It is concerned wit...

Here is the conversion of the image to markdown format: # NSC 305: General & Cellular Pathology ## INTRODUCTION Cellular pathology, also known as anatomical [or anatomic] pathology, is the branch of pathology that involves the study of body organs and tissues [groups of cells]. It is concerned with the study of structural and functional changes in cells, tissues and organs that underlie disease. It is a dynamic and fast-evolving specialty which saves many lives by providing rational clinical care and therapy in the fight against many serious diseases, particularly cancer. Cellular pathology is considered one of the diagnostic branches of medicine, along with radiology and other pathology specialties (e.g. microbiology, haematology, blood transfusion and biochemistry). Its roles include determining the cause of certain diseases and the affect(s) that they are having on the body, assisting with the choice of treatment that will be given, aiding in giving a prognosis and determining what may have caused a person's death. Cellular pathology is vital in those parts of medicine where a specimen of tissue or a sample of tissue cells are taken from the patient and sent to the laboratory. In these situations cellular pathology is the specialty that gives the definitive diagnosis and allows clinicians to give the most appropriate advice and treatment to their patients. There are two main subdivisions within cellular pathology. The first is histopathology, which involves the examination of sampled whole tissues under the microscope. This is often aided by the use of special staining techniques and other associated tests. The second subdivision is cytopathology (cytology), which is the examination of single cells. A common cytology test is the cervical smear. Cellular pathologists are also involved in performing post-mortem examinations (or autopsies), which is the examination of the body of a deceased person. An autopsy is usually performed after a person has died of an illness which could not, for whatever reason, be properly or fully diagnosed before death. This would have to be consented to by the next of kin of the deceased person. If the cause of death is suspicious or unknown (i.e. not known to have been related to illness), the autopsy will be performed by a Coroner's pathologist, a related but separate type of medical specialist. Consent from next of kin is not required for a coronial autopsy. ### Histopathology Histopathology (or histology) involves the examination of sampled whole tissues under the microscope. Three main types of specimen are received by the pathology laboratory. 1. Large specimens include whole organs or parts thereof, which are removed during surgical operations. Examples include a uterus after a hysterectomy, the large bowel after a colectomy or tonsils after a tonsillectomy. 2. Pieces of tissue rather than whole organs are removed as biopsies, which often require smaller surgical procedures that can be performed whilst the patient is still awake but sedated. Biopsies include excision biopsies, in which tissue is removed with a scalpel (e.g. a skin excision for a suspicious mole) or a core biopsy, in which a needle is inserted into a suspicious mass to remove a slither or core of tissue that can be examined under the microscope (e.g. to investigate a breast lump). 3. Fluid and very small pieces of tissue (individual cells rather than groups of cells, e.g. within fluid from around a lung) can be obtained via a fine needle aspiration (FNA). This is performed using a thinner needle than that used in a core biopsy, but with a similar technique. This type of material is usually liquid rather than solid, and is submitted for cytology rather than histology (see Cytopathology). Specimens received by the pathology laboratory require tissue preparation then are treated and analysed using techniques appropriate to the type of tissue and the investigation required. For immediate diagnosis during a surgical procedure a frozen section is performed. ### Biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist involving extraction of sample cells or tissues for examination to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically. When an entire lump or suspicious area is removed, the procedure is called an excisional biopsy. When only a sample of tissue is removed with preservation of the histological architecture, of the tissue's cells, the procedure is called an incisional biopsy or core biopsy. When a sample of tissue or fluid is removed with a needle in such a way that cells are removed without preserving the histological architecture of the tissue cells, the procedure is called a needle aspiration biopsy. Biopsies are most commonly performed for insight into possible cancerous and inflammatory conditions. ### Cancer When cancer is suspected, a variety of biopsy techniques can be applied. An excisional biopsy is an attempt to remove an entire lesion. When the specimen is evaluated. In addition to diagnosis, the amount of uninvolved tissue around the lesion, the surgical margin of the specimen is examined to see if the disease has spread beyond the area biopsied. "Clear margins" or "negative margins" means that no disease was found at the edges of the biopsy specimen. "Positive margins" means that disease was found, and a wider excision may be needed, depending on the diagnosis. When intact removal is not indicated for a variety of reasons, a wedge of tissue may be taken In an incisional biopsy. In some cases, a sample can be collected by devices that "bite" a sample. A variety of sizes of needle can collect tissue in the lumen (core biopsy). Smaller diameter needles collect cells and cell clusters, fine needle aspiration biopsy. Pathologic examination of a biopsy can determine whether a lesion is benign or malignant, and can help differentiate between different types of cancer. In contrast to a biopsy that merely samples a lesion, a larger excisional specimen called a resection may come to a pathologist, typically from a surgeon attempting to eradicate a known lesion from a patient. For example, a pathologist would examine a mastectomy specimen, even if a previous nonexcisional breast biopsy had already established the diagnosis of breast cancer. Examination of the full mastectomy specimen would confirm the exact nature of the cancer and reveal the extent of its spread. ### Pathologists Cellular pathologists (Histopathogists, Cytopathologists) are medical doctors who have specialised in cellular pathology. They have attained their primary medical degree after completing the usual five or six years of medical school. They have thereafter performed at least two year, usually more, of clinical practice involving a mixture of medical jobs Including emergency, surgery, paediatrics and general medicine. They then apply for a training position to study whilst working in the field of cellular pathology, during which time they are called a registrar. In the UK this is a 5 year full-time programme in which the registrar is required to work in a number of different laboratories to get the required experience necessary to work as a consultant (fully qualified) cellular pathologist. Two professional examinations must be sat, one in the 3rd and the other in the 4th or 5th year of training. Training and registration of all pathologists, including cellular pathologists, in the UK is overseen by the Royal College of Pathologists (RCPath). ### Cellular Pathology Pathology, in the broadest terms, is the study of disease. Disease occurs for many reasons. Some diseases represent spontaneous alterations in the ability of a cell to proliferate and function normally, and in other cases, disease results when external stimuli produce changes in the cell's environment that make it impossible for the cell to maintain homeostasis. In such situations, cells must adapt to the new environment. These adaptations include hyperplasia, hypertrophy, atrophy, and metaplasia, and can be physiologic or pathologic, depending upon whether the stimulus is normal or abnormal. A cell can adapt to a certain point, but if the stimulus continues beyond that point, failure of the cell, and hence the organ, can result. If cells cannot adapt to the pathologic stimulus, they can die. This chapter will discuss cellular adaptation, cell injury, cellular accumulations, and cellular aging. In cell biology and pathophysiology, cellular adaptation refers to changes made by a cell in response to adverse environmental changes. The adaptation may be physiologic (al) (normal) or pathologic (al) (abnormal). Five major types of adaptation include atrophy, hypertrophy, hyperplasia, dysplasia, and metaplasia, ### Atrophy Atrophy is a decrease in cell size if enough ceils in an organ atrophy, the entire organ will decrease in size. Thymus atrophy curing early human development (childhood) is an example of physiologic atrophy. Skeletal muscle atrophy is a common pathologic adaptation to skeletal muscle disuse (commonly called "disuse atrophy). Tissue and organs especially susceptible to atrophy include skeletal muscle cardiac muscle, secondary sex organs, and the brain. ### Hypertrophy Hypertrophy is an increase in cell size. if enough celis of an organ hypertrophy so will the whole organ. The heart and kidneys have increased susceptibility to hypertrophy. Hypertrophy involves an increase in intracellular protein rather than cytosol (intracellular fluid). Hypertrophy may be caused by mechanical signals (e.g., stretch) or trophic signals (e.g., growth factors). An example of physiologic hypertrophy is in skeletal muscle with sustained weight bearing exercise. An example of pathologic hypertrophy is in cardiac muscle as a result of hypertension. ### Hyperplasia Hyperplasia is an increase in the number of cells. it is the resuit of increased cell mitosis, or division. The two types of physiologic hyperplasia are compensatory and hormonal. Compensatory hyperplasia permits tissue and organ regeneration. It is common in epithelial cells of the epidermis and intestine, liver hepatocytes, bone marrow celis, and fibroblasts. It occurs to a lesser extent in bone, cartilage, and smooth muscle cells. Hormonal hyperplasia occurs mainly in organs that depend on estrogen. For example, the estrogen dependent uterine cells undergo hyperplasia and hypertrophy following pregnancy. Pathologic hyperplasia is an abnormal increase in cell division. A common pathologic hyperplasia in women occurs in the endometrium and is called endometriosis. ### Metaplasia Metaplasia occurs when a differentiated cell of a certain type is replaced by another cell type, which may be less differentiated. It is a reversible process thought to be caused by stem cell reprogramming. Stem cells are found in epithelia and embryonic mesenchymecf connective tissue. A prominent example of metaplasia involves the changes associated with the respiratory tract in response to inhalation of irritants, such as smog or smoke. The bronchial cells convert from mucus-secreting, ciliated, columnar epithelium to non-cillated, squamous epithelium incapable of secreting mucus. These transformed cells may become dysplasic or cancerous if the stimulus (e.g., cigarette smoking) is not removed. The most common example of metaplasi is Barrett's esophagus, when the non-keratinizing squamous epithelium of the esophagus undergoes metaplasia to become mucinous columnar cells, ultimately protecting the esophagus from acid reflux originating in the stomach. ir stress persists, métaplasia can progress to dysplasia and eventually carcinoma: Barrett's esophagus, for example, can eventually progress to adenocarcinoma if not treated. ### Dysplasia Dysplasia refers generally to abnormal changes in cellular shape, size, and/or organization. Dysplasia is not considered a true adaptation; rather, it is thought to be related to hyperplasia and is sometimes called "atypical hyperplasia." Tissues prone to dysplasia include cervical and respiratory epithelicurs in the vicinity of cancerous cells, and it may be involved in the development of breast cancer. Although dysplasia is reversible, if stress persists, then dysplasia progresses to irreversible carcinoma. ### Hyperplasia Basic description: Increase in the number of cells. Types of hyperplasia * Physiologic hyperplasia: Occurs due to a normal stressor. For example, increase in the size of the breasts during pregnancy, increase in thickness of endometrium during menstrual cycle, and liver growth after partial resection. * Pathologic hyperplasia: Occurs due to an abnormal stressor. For example, growth of adrenal glands due to production of adrenocorticotropic hormone (ACTH) by a pituitary adenoma, and proliferation of endometrium due to prolonged estrogen stimulus. Important point regarding hyperplasia: Only cells that can divide will undergo hyperplasia; therefore, hyperplasia of the myocytes in the heart and neurons in the brain does not occur. ### Hypertrophy Basic description: Increase in the size of the cell. Types of hypertrophy * Physiologic hypertrophy: Occurs due to a normal stressor. For example, enlargement of skeletal muscle with exercise. * Pathologic hypertrophy: Occurs due to an abnormal stressor. For example, increase in the size of the heart due to aortic stenosis. Aortic stenosis is due to a change in the aortic valve, which obstructs the orifice, resulting in the left ventricle working harder to pump blood into the aorta. Morphology of hyperplasia and hypertrophy: Both hyperplasia and hypertrophy result in an increase in organ size; therefore, both cannot always be distinguished grossly, and microscopic examination is required to distinguish the two. ### Definition of Pathology Pathology is the study (logos) of disease (pathos). More specifically, it is devoted to the study of the structural, biochemical, and functional changes in cells, tissues, and organs that underlic disease. Elementary biology exposes to the fact that the cell is the unit of life. Two or more cells form a tissue, two or more tissues form an organ and organs, systems. Disease process will therefore be better understood if events at the cellular level are well-understood, hence the term CELLULAR PATHOLOGY! By the use of molecular, microbiologic, immunologic, and morphologic 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. It thus serves as the bridge between the basic sciences and clinical practice, and is the scientific foundation for all of medicine. Fraditionally, the study of pathology is divided into general pathology and systemic pathology. The former is concerned with the reactions of cells and tissues to abnormal stimuli and to inherited defects, which are the main causes of disease. The latter examines the alterations in spécialized organs and tissues that are responsible for disorders that involve these organs. In general pathology, there are four aspects of a disease disease process that form the core of pathology. These are: its cause (aetiology), the mechanisms of its development (pathogenesis), the biochemical and structural alterations induced in the cells and organs of the body (molecular and morphologic changes), and the functional consequences of these changes (clinical manifestations). For instance, Plasmodium falciparum (etiological agent) following mosquito bite, invade the human red cells multiply and undergo development in them (pathogenesis), leading to eventual haemolysis (molecular/morphological changes) and development of anaemia (clinical manifestations). Pathology is the link between basic sciences and clinical practice. Disease process is better understood with good foundation in pathology. Cellular events precede overt manifestation of disease entity. ### What is cellular pathology? The normal cell is confined to a fairly narrow range of function and structure by its state of metabolism, differentiation, and specialization; by constraints of neighboring cells; and by the availability of metabolic substrates. It is nevertheless able to handle physiologic demands, maintaining a steady state called homeostasis. ### Cell Adaptations These are reversible functional and structural responses to more severe physiologic stresses and some pathologic stimuli, during which new but altered steady states are achieved, allowing the cell to survive and continue to function. The adaptive response may consist of an increase in the size of cells (hypertrophy) and functional activity, an increase in their number (hyperplasia), a decrease in the size and metabolic activity of cells (atrophy), or a change in the phenotype of cells (metaplasia). When the stress is eliminated the cell can recover to its original state without having suffered any harmful consequences. If the limits of adaptive responses are exceeded or if cells are exposed to injurious agents or stress, deprived of essential nutrients, or become compromised by mutations that affect essential cellular constituents, a sequence of events follows that is termed cell injury. Cell injury is reversible up to a certain point, but if the stimulus persists or is severe enough from the beginning, the cell suffers irreversible injury and ultimately cell death. Adaptation, reversible injury, and cell death may be stages of progressive impairment following different types of insults. For instance, in response to increased hemodynamic loads, the heart muscle becomes enlarged, a form of adaptation, and can even undergo injury. If the blood supply to the myocardium is compromised or inadequate, the muscle first suffers reversible injury, manifested by certain cytoplasmic changes. Eventually, the cells suffer irreversible injury and die. Inflammation. The ability to get rid of damaged or necrotic tissues and foreign invaders, such as microbes is essential to the survival of organisms. The host response that accomplishes these goals is called inflammation. It is fundamentally a protective response, designed to rid the organism of both the initial cause of cell injury (e.g., microbes, toxins) and the consequences of such injury (e.g., necrotic cells and tissues). Without inflammation infections would go unchecked, wounds would never heal, and injured tissues might remain permanent festering sores. In the practice of medicine the importance of inflammation is that it can sometimes be inappropriately triggered or poorly controlled, and is thus the cause of tissue injury in many disorders. Inflammation is a complex reaction in tissues that consists mainly of responses of blood vessels and leukocytes. These vascular and cellular reactions of inflammation are triggered by soluble factors that are produced by various cells or derived from plasma proteins and are generated or activated in response to the inflammatory stimulus. Inflam nation may be acute or chronic. inflammation is a protifiue response, designed to This is dependent on 1) the nature of the stimulus and 2) the effectiveness of the initial reaction in eliminating the stimulus or the damaged tissues. Acute inflammation is rapid in onset (typically minutes) and is of short duration, lasting for hours or a few days; its main characteristics are the exudation of fluid and plasma proteins (edensa) and the emigration of leukocytes, predominantly neutrophils (also called polymorphonuclear leukocytes). Wiren acute inflammation is successful in eliminating the offenders the reaction subsides, but if the response fails to clear the invaders it can progress to a chronic phase. Chronic inflammation may follow acute inflammation or be insidious in onset. It is of longer duration and is associated with the presence of lymphocytes and macrophages, the proliferation of blood vessels, fibrosis, and tissue destruction Some historical highlights: Although clinical features of inflammation were described in an Egyptian papyrus dated around 3000 BC, Celsus, a Roman writer of the first century AD, first listed the four cardinal signs of inflammation: rubor (redness), tumor (swelling), calor (heat), and dolor (pain). These signs are typically more prominent in acute inflammation than in chronic inflammation. A fifth clinical sign, loss of function (functio laesa), was added by Rudolf Virchow in the 19th century. Acute inflammation Acute is a rapid host response that serves to deliver leukocytes and plasma proteins, such as antibodies, to sites of infection or tissue injury. Acute inflammation has three major components: (1) alterations in vascular caliber that lead to an increase in blood flow. (2) structural changes in the microvasculature that permit plasma proteins and leukocytes to leave the circulation, and (3) emigration of the leukocytes from the oncrocire alation, their accumulation in the focus of injury, and their activation to climirate the offending agent. Stimulus for Acute Inflammation, Infections (bacterial, viral, fungal, parasitic) and microbial toxins are among the most common and medically important causes of inflammation. Tissue necrosis from any cause, including ischemia (as in a myocardial infarct), trauma, and physical and chemical injury (e.g., thermal injury, as in buras or frostbite; irradiation; exposure to some environmental chemicals). Foreign bodies (splinters, dirt, sutures) typically elicit nflammation because they cause traumatic tissue injury or carry microbes. Immune reactions (also called hypersensitivity reactions) are reactions in which the normally protective immune system damages the individual's own tissues. The injurious immune responses may be directed against self antigens, causing autoimmune diseases, or may be excessive reactions against environmental substances of microbes. All inflammatory reactions share the same basic features, although different stimuli may induce reactions with some distinctive characteristics. A hallmark of acute inflammation is increased vascular permeability leading to the escape of a protein-rich exudate into the extravascular tissue, causing edema. Several mechanisms are responsible for the increased vascular permeability. Reactions of Blood Vessels in Acute Inflammation: In inflammation, blood vessels undergo a series of changes that are designed to maximize the movement of plasma proteins and circulating cells out of the circulation and into the site of infection or injury. The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities is known as exudation. An exudate is an extravascular fluid that has a high protein concentration, contains cellular debris, and has a high specific gravity. Its presence implies an increase in the normal permeability of small blood vessels in an area of injury and, therefore, an inflammatory reaction. In contrast, a transudate is a fluid with low protein content (most of which is albumin), little or no cellular material, and low specific gravity. It is essentially an ultrafiltrate of blood plasma that results from osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability. Edema denotes an excess of fluid in the interstitial tissue or serous cavities; it can be either an exudate or a transudate. Pus, a purulent exudate, is an inflammatory exudate rich in leukocytes (mostly neutrophils), the debris of dead cells and, in many cases, microbes. Reactions of Leukocytes in Inflammation. A critical function of inflammation is to deliver leukocytes to the site of injury and to activate the leukocytes to eliminate the offending agents. The most important leukocytes in typical inflammatory reactions are the ones, capable of phagocytosis, namely neutrophils and macrophages. Outcomes of Acute Inflammation. 1) Complete resolution, 2) Healing by connective tissue replacement (fibrosis) or 3) Progression of the response to chronic inflammation. Chronic Inflammation: Chronic inflammation is inflammation of prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repair coexist, in varying combinations. It may follow acute inflammation, as described earlier, or chronic inflammation may begin insidiously, as a low-grade, smoldering response without any manifestations of an acute reaction. This latter type of chronic inflammation is the cause of tissue damage in some of the most common and disabling human diseases, such as rheumatoid arthritis, atherosclerosis, tuberculosis, and pulmonary fibrosis. It has also been implicated in the progression of cancer and in diseases once thought to be purely degenerative, such as Alzheimer disease. Causes: Persistent infections by microorganisms that is difficult to eradicate, such as mycobacteria, and certain viruses, fungi, and parasites. Immune-mediated inflammatory diseases. Prolonged exposure to potentially toxic agents, either exogenous (e.g. silicosis) or endogenous(e.g. atherosclerosis). Morphologic Features: In contrast to acute inflammation, which is manifested by vascular changes, edema, and predominantly neutrophilic infiltration, chronic inflammation is characterized by: Infiltration with mononuclear cells, which include macrophages, lymphocytes, plasraa celis, eosinophils and mast cells. The predominant cellular components are the macrophages. Tissue destruction, induced by the persistent offending agent or by the inflammatory cells. Attempts at healing by connective tissue replacement of damaged tissue, accomplished by proliferation of small blood vessels (angiogenesis) and, in particular, fibrosis. Granulomatous Inflammation: Granulomatous inflammation is a distinctive pattern of chronic inflammation that is encountered in a limited number of infectious and some noninfectious conditions. A granuloma is a focus of chronic inflammation consisting of a microscopic aggregation of macrophages that are transformed into epithehun-like ceits. surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells. Examples of Diseases with Granulomatous Inflammation Tuberculosis Mycobacterium tuberculosis Caseating granuloma (tubercle): focus of activated macrophages (epithelioid cells), rimmed by fibroblasts, lymphocytes, histiocytes, occasionál Langhans giant celis; central necrosis with amorphous granular debris; acid-fast bacilli Leprosy Mycobacterium leprae Acid-fast bacilli in macrophages; noncaseating granulomas Syphilis Treponema pallidum Gumma: microscopic to grossly visible lesion, enclosing wall of histiocytes; plasma cell infiltrate; central cells necrotic without loss of cellular outline Cat-scratch disease Gram-negative bacillus Rounded or stellate granuloma containing central granular debris and recognizable neutrophils; giant cells uncommon Sarcoidosis Unknown etiology Noncaseating granulomas with abundant activated macrophages Crohn disease (inflammatory bowel disease) Immune reaction against intestinal bacteria, self-antigens Occasional noncaseating granulomas in the wall of the intestine, with dense chronic inflammatory infiltrate 3.2.4 Systemic Effects of Inflammation. The systemic changes associated with acute inflammation are collectively called the acute-phase response, or the systemic inflammatory response syndrome. These changes are reactions to cytokines whose production is stimulated by bacterial products such as lipopolysaccharide (LPS) and by other inflammatory stimuli. The acute-phase response consists of several clinical and pathologic changes: 1) Fever, characterized by an elevation of body temperature, usually by $1^{\circ}$ to $4^{\circ}$C, is one of the most prominent manifestations of the acute-phase response, especially when inflammation is associated with infection. Fever is produced in response to substances called pyrogens that act by stimulating prostaglandin synthesis in the vascular and perivascular cells of the hypothalamus. 2) Acute-phase proteins are plasma proteins, mostly synthesized in the liver, whose plasma concentrations may increase several hundred-fold as part of the response to inflammatory stimuli. 3) Leukocytosis is a common feature of inflammatory reactions especially those induced by bacterial infections. The leukocyte count usually climbs to 15,000 or 20,000 cells /µL, but sometimes it may reach extraordinarily high levels of 40,000 to 100,000 cells/µL. These extreme elevations are referred to as leukemoid reactions, because they are similar to the white cell counts observed in leukemia and have to be distinguished from leukemia. 4) Other man festations of the acute-phase response include increased pulse ang blood pressure; decreased sweating, mainly because of redirection of blood flow fron cutaneous to deep vascu ar beds, to minimize heat loss through the skin; rigors (shivering) chills (search for warmth), anorexia, somnolence, and malaise, probably because of the actions of cytokines on brain cells. 5) High levels of cytokines cause various clinical manifestations such as disseminated ntravascular coagulation, cardiovascular failure, and metabolic disturbance, which are described as septic shock: CONCLUSION. The response of the cell to stress and noxious stimuli, its adaptation to those stimuli and ignition of inflammatory response when cellular adaptation is overwhelmed form the bedrock of disease pathogenesis The understanding of this foundation of pathology is indispensable! This unit teaches that: 1) Disease process commences at the cellular level following the effect of stress and noxious stimuli. 2) Cellular adaptation is necessary to limit progression of the disease. Otherwise, inflammatory process begins. 3) Inflammatory response can be acute or chronic. ### CELL INJURY AND CELL DEATH #### INTRODUCTION As earlier mentioned, cell injury results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to inherently damaging agents or suffer from intrinsic abnormal ties. Injury may progress through a reversible stage and culminate in cell death Reversible cell injury. Icarly stages or unld forms of injury, the functional and morphologic changes are reversible if the damaging stimulus is removed. The hallmarks of reversible injury are reduced oxidative phosphorylation with resultant depletion of energy stores in the form of adenosine triphosphate (ATP), and cellular swelling caused by changes in ion concentrations and water influx. In addition, various intracellular organelles, such as mitochondria and the cytoskeleton, may also show alterations. Cell death. With continuing damage the injury becomes irreversible, at which time the cell cannot recover and it dies. There are two principal types of cell death, necrosis and apoptosis, which differ in their morphology, mechanisms, and roles in physiology and disease. When damage to membranes is severe, lysosomal enzymes enter the cytoplasm and digest the cell, and cellular contents leak out, resulting in necrosis. In situations when the cell's DNA or proteins are damaged beyond repair, the cell kills itself by apoptosis, a form of cell death that is characterized by nuclear dissolution, fragmentation of the cell without complete loss of membrane integrity, and rapid removal of the cellular debris. Whereas necrosis is always a pathologic process, apoptosis serves many normal functions and is not necessarily associated with cell injury. Cell deaths also sometimes the end result of autophagy. Although it is easier to understand these pathways of cell death by discussing them separately, there may be many connections between them. Both apoptosis and necrosis may be seen in response to the same insult, such as ischemin, perhaps at different stages. Apoptosis can progress to necrosis, and cell death during autophagy may show many of the biochemical characteristics of apoptosis. Causes of Cell Injury. The causes of cell injury range from the external gross physical violence of an automobile accident to subtle internal abnormalities, such as a genetic mutation causing lack of a vital enzyme that impairs normal metabolic function. Most injurious stimuli can be grouped into the following broad categories. Oxygen Deprivation. Physical Agents. Chemical Agents and Drugs. Infectious Agents. Immunologic Reactions.. Genetic Derangements.. Nutritional Imbalances. Oxygen Deprivation. Hypoxia is a deficiency of oxygen, which causes cell injury by reducing aerobic oxidative respiration. Hypoxia is an extremely important and common cause of cell injury and cell death. Causes of hypoxia include reduced blood flow (celled ischemia), inadequate oxygenation of the blood due to cardio-respiratory failure, and decreased oxygen-carrying capacity of the blood, as in anemia or carbon monoxidepoisoning (producing a stable carbon monoxy-hemoglobin that blocks oxygen carriage) or after severe blood loss. Depending on the severity of the hypoxic state, cells may adapt, undergo injury, or die. For example, if an artery is narrowed, the tissue supplied by that vessel may initially shrink in size (atrophy), whereas more severe or sudden hypoxia induces injury and cell death. Physical Agents. Physical agents capable of causing cell injury include mechanical trauma, extremes of temperature (burns and deep cold), sudden changes in atmospheric pressure, radiation, and electric shock. Chemical Agents and Drugs. The list of chemicals that may produce cell injury defies compilation. Simple chemicals such as glucose or salt in hypertonic concentrations may cause cell injury directly or by deranging electrolyte balance in cells. Even oxygen at high concentrations is toxic. Trace amounts of poisons, such as arsenic, cyanide, or mercuric salts, may destroy sufficient numbers of cells within minutes or hours to cause death. Other potentially injurious substances are our daily companions: environmental and air pollutants, insecticides, and herbicides; industrial and occupational hazards, such as carbon monoxide and asbestos; recreational drugs such as alcohol; and the everincreasing variety of therapeutic drugs. Infectious Agents. These agents range from the submicroscopic viruses to the large tapeworms. In between are the rickettsine. bacteria, fungi, and higher forms of parasites. Immunologic Reactions. The immune system serves an essential function in defense against infectious pathogens, but immune reactions may also cause cell injury. Injurious reactions to endogenous self-antigens are responsible for several autoimmune diseases. Genetic Derangements. Genetic abnormalities may result in a defect as severe as the congenital malformations associated with Down syndrome, caused by a chromosomal anomaly, or as subtle as the decreased life span of red blood cells caused by a single amino acid substitution in hemoglobin in sickle cell anemia. Genetic defects may cause cell injury because of deficiency of functional proteins, such as enzyme defects in inborn errors of metabolism, or accumulation of damaged DNA or misfolded proteins, both of which trigger cell death when they are beyond repair. Variations in the genetic makeup can also influence the susceptibility of cells to injury by chemicals and other environmental insults. Nutritional Imbalances. Nutritional imbalances continue to be major causes of cell injury. cause an appalling number of deaths, chiefly among underprivileged populations. Deficiencies of specific vitamins are found throughout the world. Nutritional problems can be self-imposed, as in anorexia nervosa (self-induced starvation). Ironically, nutritional excesses have also become important causes of cell injury. Excess of cholesterol predisposes to atherosclerosis; obesity is associated with increased incidence of several important diseases, such as diabetes and cancer. Atherosclerosis is virtually endemic in the United States, and obesity is rampant. In addition to the problems of under nutrition and over nutrition, the composition of the diet makes a significant contribution to a number of diseases. Protein-calorie deficiencies cause an Morphologic Alterations in Cell Injury. All stresses and noxious influences exert their effects first at the molecular or biochemical level. There is a time lag between the stress and the morphologic changes of cell injury or death; the duration of this delay may vary with the sensitivity of the methods used to detect these changes. With histochemical or ultra structural techniques, changes may be seen in minutes to hours after injury; however, it may take considerably longer (hours to days) before changes can be seen by light microscopy or on gross examination. As would be expected, the morphologic manifestations of necrosis take more time to develop than those of reversible damage. For example, in ischemia of the myocardium, celt swelling is a reversible morphologic change that may occur in a matter of minutes, and may progress to irreversibility within an hour or two. Unmistakable light microscopic changes of cell death, however, may not be seen until 4 to 12 hours after total ischemia. Features of Necrosis and Apoptosis | Feature | Necrosis | Apoptosis | | ------- | -------- | -------- | | Cell size | Enlarged (swelling) | Reduced (shrinkage) | | Nucleus | Pyknosis -> karyorrhexis -> karyolysis Fragmentation into nucleosome-size fragments| | | Plasma membrane | Disrupted | Intact; altered structure, especially orientation of lipids | | Cellular contents | Enzymatic digestion; may leak out of cell | Intact; may be released in apoptotic bodies | | Adjacent inflammation | Frequent | No | | Physiologic or pathologic role | Invariably pathologic (culmination of irreversible cell injury) | Often physiologic, means of climinating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage | Reversible injury: Two features of reversible cell injury can be recognized under the light microscope: cellular swelling and fatty change. Cellular swelling appears whenever cells are incapable of maintaining ionic and fluid homeostasis and is the result of failure of energy-dependent ion pumps in the plasma membrane. Fatty change occurs in hypoxic, toxic or metabolic injuries. It is manifested by the appearance of lipid vacuoles in the cytoplasm and seen mainly in cells involved in and dependent on fat metabolism, such as hepatocytes and myocardial cells. NECROSIS: The morphologic appearance of necrosis is the result of denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell (cells placed immediately in fixative are dead but not necrotic) Patterns of tissue necrosis: Coagulative necrosis is a form of necrosis in which the architecture of dead tissues is preserved for a span of at least some days. Liquefactive necrosis, in contrast to coagulative necrosis, is characterized by digestion of the dead cells, resulting in transformation of the tissue into a liquid viscous mass. It is seen in focal bacterial or, occasionally, fungal infections, because microbes stimulate the accumulation. Gangrenous necrosis is not a specific pattern of cell death, but the term is commonly used in clinical practice. It is usually applied to a limb, generally the lower leg, that has lost its blood supply and has undergone necrosis (typically coagulative necrosis) involving multiple tissue planes. Caseous necrosis is encountered most often in foci of tuberculous infection. The term "caseous" (cheeselike) is derived from the friable white appearance of the area of necrosis. On microscopic examination, the necrotic area appears as a collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border; this appearance is characteristic of a focus of inflammation known as a granuloma. Fat necrosis is a term that is well fixed in medical parlance but does not in reality denote a specific pattern of necrosis. Rather, it refers to focal areas of fat destruction, typically resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity. Fibrinoid necrosis is a special form of necrosis usually seen in immune reactions involving blood vessels. This pattern of necrosis typically occurs when complexes of antigens and antibodies are deposited in the walls of arteries. Ultimately, in the living patient most necrotic cells and their contents disappear by phagocytosis of the debris and enzymatic digestion by leukocytes. If necrotic cells and cellular debris are not promptly destroyed and reabsorbed, they tend to attract calciumsalts and other minerals and to become calcified. This phenomenon is called dystrophic calcification. Mechanisms of Cell lujury. The discussion of the cellular pathology of cell injury and necrosis sets the stage for a consideration of the mechanisms and biochemical pathways of cell injury. The mechanisms responsible for cell injury are complex. There are, however, several principles that are relevant to most forms of cell injury. Principles. The cellular response to injurious stimuli depends on the nature of the injury, its duration, and its severity.. The consequences of cell injury depend on the type, state, and adaptability of the injured cell. Cell injury results from different biochemical mechanisms acting on several essential cellular components Any injurious stimulus may simultaneously trigger multiple interconnected mechanisms that damage cells. This is one reason why it is difficut to ascribe cell injury in a particular situation to a single or even dominant biochemical derangement. Accumulation of Oxygen-derived Free Radicals (oxidative stress). Cell injury induced by free radicals, particularly reactive oxygen species, is an important mechanism of cell damage in many pathologic conditions, such as chemical and radiation injury, ischemia-reperfusion injury (induced by restoration of blood flow in ischemic tissue), cellular aging, and microbial killing by phagocytes. Free radicals are chemical species that have a single aupaired electron in an outer orbit. Energy created by this unstable configuration is released through reactions with adjacent molecules, such as inorganic or organic chemicals-proteins, lipids, carbohydrates, nucleic acids-many of which are key components of cell membranes and nuclei. Incomplete reduction of $O_2$ during oxidative phosphorylation; by phagocyte oxidase in leukocytes Clinico-Pathologic Correlations: Selected Examples of Cell Injury and Necrosis. Ischemic and Hypoxic Injury: This is the most common type of cel injury in clinical medicine and has been studied extensively in humans, in experimental animals, and in culture systems. Hypoxia, referring to reduced oxygen availability, may occur in a variety of clinical settings, described earlier. In ischemia, on the other hand, the supply of oxygen and nutrients is decreased most often because of reduced blood flow as a consequence of a mechanical obstruction in the arterial system. It can also be caused by reduced venous drainage. In contrast to hypoxia, during which energy production by anaerobic glycolysis can continue, ischemia compromises the delivery of substrates for glycolysis. Thus, in ischemic tissues, not only is aerobic metabolism compromised but anaerobic energy generation also stops after glycolytic substrates are exhausted, or glycolysis is inhibited by the accumulation of metabolites that would have been removed otherwise by blood flow. For this reason, Ischemia tends to cause more rapid and severe cell and tissue injury than does hypoxia in the absence of ischemia. If ischemia persists, irreversible injury and necrosis ensue. Ischa