BASIC PRINCIPLES OF CELL INJURY AND ADAPTATION
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Introduction to Homeostasis
The concept of internal harmony was proposed by Claude Bernard in the 19th century, Walter Cannon coined the term homeostasis to describe the state of internal (Physiologic and psychological) balance or organization of function.
Homeostasis may be defined as “The maintenance of the internal conditions of body at equilibrium, despite changes in the external environment”. For example, the core temperature of human body remains at about 37°C despite fluctuations in the surrounding temperature. Similarly, the blood glucose level remains normal despite carbohydrate rich diet. Stable internal conditions are important for the efficient functioning of enzymes.
Adaptation
Adaptation refers to process by which a system seeks to restore or maintain homeostasis. Adaptive mechanism may also be referred to as compensatory mechanisms, homeostatic mechanisms, control and regulatory mechanism. Although adaptation may be physiological, psychological, behavioural, in system's terminology adaptive mechanisms are examples of feedback to the system and may be represented by either negative or positive feedback loops.
a. Negative Feedback Loops:
Nearly, all physiologic adaptive responses are negative feedback loops. These processes act to restore homeostasis by inducing changes in the opposite direction of a force perturbing the system. For example, if injury with hemorrhage causes a decrease in blood pressure, sensors in blood vessels activate neural responses that causes increase in cardiac pumping and constriction of blood vessels.
Once the message is received by the hypothalamus, a series of reactions follow. The first of which is by the hypothalamus, which secretes thyroid releasing hormone (TRH). This hormone’s target is the anterior lobe of the pituitary gland. When the TRH reaches its target, it releases Thyroid Stimulating Hormone (TSH) which enters the blood stream and stimulates thyroid gland to produce thyroxin. The role of thyroxin is to increase cellular metabolism in order to generate heat.
When the body temperature increases, messages are sent in the same way as if the body is cold to the hypothalamus. This causes an increase in the amount of sweating, this is releasing heat via water, and the water on the skin evaporates, cooling the body down. Vasodilatation is also apparent. In this instance, blood is diverted to the skin in order to loose heat. The erector pilli muscles relax, allowing the skin hairs to be lowered, and the bodies’ metabolic rate is reduced.
Blood glucose is another contributing factor to homeostasis. The blood glucose concentration in the blood is vital to the functioning of cells within the body and is controlled by a number of internal structures and external influence (food and drink). If too much glucose is present within the blood, then specific receptors located within the pancreas detect this. These receptors then send messages to the cerebellum, feelings of satiety (feeling full) are induced, and therefore the individual’s intake of food is decreased.
On the other hand, if there is not enough glucose in the bloodstream, then the very same receptors, which are located in the pancreas, detect the change. Once again, a message is sent to the cerebellum, which brings around feelings of hunger, therefore increases the consumption of food and drink. Messages are also sent to cells in the islets of Langerhans to start the production of glucagon. This glucagon is released by the islets of Langerhans into the capillary circulation.
Homeostasis is also heavily involved with the control of the respiratory rate. In the norm, individuals are not conscious of their respiration. This is because the act of respiration is involuntary. Respiration is under involuntary control through an area of the brain termed as the medulla. Within the medulla is an area known as the breathing centre. The breathing centre is composed into sections, allowing each to tackle an alternate aspect to respiration. Both the dorsal and the lateral areas assist with inspiration and provide stimulation for respiration. In addition, the ventral area increases both the depth and rate of respiration.
The medulla is chief in maintaining a constant rate of respiration and depth. However, both external and internal stimuli can alter the rate of respiration, making it higher or lower than the norm. The main influence to this is the level of carbon dioxide in the blood stream. If the concentration of carbon dioxide in the blood stream increases, then chemoreceptors located within both aortic and carotid bodies become aroused.
b. Positive Feedback Loops:
The response to disruptive forces is in the same direction as the force; thus tending to increase the instability of the system. Positive feedback loops are almost always maladaptive or harmful and are often termed vicious cycles, downward spirals, or decompensation states.
These states can lead to death if not interrupted by treatment. In advanced shock, for example, the increased rate and pumping force of the heart eventually increase the demand of the heart muscle for oxygenated blood. The gap between oxygen supply and demand widens, and cardiac failure results. Positive feedback systems generally control infrequent conditions such as ovulation, childbirth and blood clotting.
Uterine contractions during childbirth:
When contractions start, oxytocin is released which stimulates more contractions and more oxytocin is released, hence contractions increase in intensity and frequency. Production and release of oxytocin stops after the baby is delivered.
Secretion of breast milk:
The stimulation of a baby sucking its mother's breast leads to secretion of oxytocin into the mother's blood, which leads to milk being available to the baby via the breast. The mother's production and release of oxytocin ceases when the baby stops feeding.
Example for Negative and Positive feedback mechanism
Cell Injury
Cell injury is the common denominator in almost all diseases. It is defined as 'an alteration in cell structure or biochemical functioning, resulting from some stress that exceeds the ability of the cell to compensate through normal physiologic adaptive mechanisms'. 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 abnormalities. Different injurious stimuli affect many metabolic pathways and cellular organelles. Injury may progress through a reversible stage and culminate in cell death.
Reversible cell injury:
In early stages or mild forms of injury the functional and morphologic changes are reversible if the damaging stimulus is removed. At this stage, although there may be significant structural and functional abnormalities, the injury has typically not progress to severe membrane damage and nuclear dissolution.
Irreversible cell injury (Cell death):
Because of cell death with continuing damage, the injury becomes irreversible, at which time the cell cannot recover and it dies. There are two types of cell death, necrosis and apoptosis which differ in their morphology, mechanisms, and roles in disease and physiology. When damage to membranes is severe, enzymes leak out of lysosomes, enter the cytoplasm, and digest the cell, resulting in necrosis. Cellular contents also leak out through the damaged plasma membrane and elicit a host reaction (inflammation).
Necrosis:
Necrosis is one of the basic patterns of irreversible cell injury and death. Necrosis has long been considered the "unregulated" pattern of cell injury and death, representing a messy end to a damaged cell that consequently causes a potent inflammatory response.
Apoptosis:
This is a pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die by activating enzymes capable of degrading the cell's own nuclear DNA, nuclear and cytoplasmic proteins. Fragments of the apoptotic cells then break off; giving the appearance that is responsible for the name (apoptosis, “falling off”). The plasma membrane of the apoptotic cell remains intact, but the membrane is altered in such a way that the cell and its fragments become avid targets for phagocytes.
Difference between Necrosis and Apoptosis
Etiology of Cell Injury
Cell injury is a sequence of events that occur if the limits of adaptive capability are exceeded, or no adaptive response is possible. This can be due to physical, chemical, infectious, biological, immunological factors and nutritional cellular abnormalities.
Acquired cause:
Acquired causes of cell injury are further
categorized as:
(a) Oxygen deprivation (Hypoxia)
(b) Physical agents
(c) Chemical agents and drugs
(d) Microbial agents
(e) Immunologic agents
(f) Nutritional derangement
(g) Psychological factors
(h) Idiopathic agents
(a) 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 (ischemia), inadequate oxygenation of the blood due to cardiorespiratory failure, and decreased oxygen-carrying capacity of the blood, as in anemia or carbon monoxide poisoning (producing a stable carbon Mon oxyhemoglobin that blocks oxygen carriage) or after severe blood loss. Depending on the severity of the hypoxic state, cells may adapt, undergo injury, or die.
(b) Physical agents for cell injury:
Mechanical trauma (e.g., Road accident), Thermal trauma (e.g., Heat and cold), Electricity, Radiation (e.g., U.V. radiation), Rapid changes in atmosphere pressure.
(c) Chemicals and Drugs:
The list of chemicals that may produce cell injury defines 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 damage sufficient number 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 ever-increasing variety of therapeutic drugs.
(d) Microbial agents:
Injuries by microbes include infection caused by bacteria, rickettsia, viruses, fungi, protozoa and other parasites.
(e) Immunological Agents:
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. Immune reactions to many external agents, such as viruses and environmental substances, are also important causes of cell and tissue injury. Example: Hypersensitivity reactions, anaphylactic reactions, autoimmune diseases.
(f) Nutritional derangement:
A deficiency or an excess of nutrients may result in nutritional imbalances. Nutritional deficiency diseases may be due to overall deficiency of nutrients (starvation), protein calorie (Marasmus, Kwashiorkor), and minerals (Anemia) or of trace elements. Nutritional excess is a problem of society which results from obesity, in atherosclerosis, heart diseases and hypertension.
(g) Psychological factors:
There are number of specific biochemical or morphological changes in common acquired mental diseases due to mental stress, strain, anxiety, overwork and frustration. Problems of drug addiction, alcoholism and smoking results in various diseases such as liver damage, chronic bronchitis, lung cancer, peptic ulcer, hypertension, ischemic heart diseases etc.
(h) Idiopathic factor:
The causative factor of cell injury is unknown.
Pathogenesis of Cell Injury
Cell damage can be reversible or irreversible. Depending on the extent of injury, the cellular response may be adaptive, and homeostasis is maintained. Cell death occurs when the severity of the injury (Stress) exceeds the cell’s ability to repair itself. Cell death is relative to both the length of exposure to a harmful stimulus and the severity of the damage caused. Cell death may occur by severe cell swelling or cell rupture, denaturation and coagulation of cytoplasmic proteins and breakdown of cell organelles (necrosis) or internally controlled cell death, chromatin condensation and fragmentation (apoptosis). Now, we have discussed the causes of cell injury and necrosis and their morphologic and functional correlates, we next consider in more detail the molecular basis of cell injury, and then illustrate the important principles with a few selected examples of common types of injuries. The biochemical mechanisms linking any given injury with the resulting cellular and tissue manifestations are complex, interconnected, and tightly interwoven with many intracellular metabolic pathways. It is therefore often difficult to pinpoint specific molecular alterations caused by a particular insult.
Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components. The most important targets of injurious stimuli are:
- Mitochondria, the sites of ATP generation.
- Cell membranes, on which the ionic and osmotic homeostasis of the cell and its organelles depends.
- Protein synthesis.
- The cytoskeleton; and
- The genetic apparatus of the cell.
Mechanism of Hypoxia Induced Cell Injury
As the name implies, this occurs if extreme stress persists and the cell is unable to adapt to overcome the stress. Reversible cell injury results in cellular and morphological changes that can still be reversed if the stress is eventually removed. There are three mechanisms by which reversible cell injury may occur.
- Depleted resources of ATP in the cell owing to decreased levels of Oxidative Phosphorylation.
- Hydropic cellular swelling, a phenomenon caused by changes in ion concentrations and water influx.
- Organelles within the cell show minute alterations.
a) ATP depletion:
ATP depletion and decreased ATP synthesis are frequently associated with both hypoxic and chemical (toxic) injury. High-energy phosphate in the form of ATP is required for many synthetic and degradative processes within the cell. These include membrane transport, protein synthesis, lipogenesis, and the deacylationreacylation reactions necessary for phospholipid turnover. Depletion of ATP to 5% to 10% of normal levels has widespread effects on many critical cellular systems. The activity of the plasma membrane energy dependent sodium pump is reduced. Failure of this active transport system, due to diminished ATP concentration and enhanced ATPase activity, causes sodium to accumulate intracellularly and potassium to diffuse out of the cell. The net gain of solute is accompanied by isosmotic gain of water, causing cell swelling, and dilation of the endoplasmic reticulum and cellular energy metabolism is altered. If the supply of oxygen to cells is reduced, as in ischemia, oxidative phosphorylation ceases and cells rely on glycolysis for energy production. This switch to anaerobic metabolism is controlled by energy pathway metabolites acting on glycolytic enzymes.
Glycolysis results in the accumulation of lactic acid and inorganic phosphates from the hydrolysis of phosphate esters. This reduces the intracellular pH, resulting in decreased activity of many cellular enzymes.
b) Damage to Mitochondria:
Mitochondria are the cell’s suppliers of life sustaining energy in the form of ATP, but they are also critical players in cell injury and death. Mitochondria can be damaged by increase of cytosolic Ca2+, reactive oxygen species, and oxygen deprivation, and so they are sensitive to virtually all types of injurious stimuli, including hypoxia and toxins.
There are two major consequences of mitochondrial damage:
- Mitochondrial damage often results in the formation of a high-conductance channel in the mitochondrial membrane, called the mitochondrial permeability transition pores. The opening of this channel leads to the loss of mitochondrial membrane potential and pH changes, resulting in failure of oxidative phosphorylation and progressive depletion of ATP, culminating in necrosis of the cell.
- The mitochondria also contain several proteins that are capable of activating apoptotic pathways, including cytochrome C (the major protein involved in electron transport). Increased permeability of the mitochondrial membrane may result in leakage of these proteins into the cytosol and death by apoptosis. Thus, cytochrome C plays a key dual role in cell survival and death. In its normal location inside mitochondria, it is essential for energy generation and the life of the cell, but when mitochondria are damaged so severely that cytochrome C leaks out, it signals cells to die.
c) Influx of Calcium:
Failure of the Ca2+ pump leads to influx of Ca2+, with damaging effects on numerous cellular components. With prolonged or worsening depletion of ATP, structural disruption of the protein synthetic apparatus occurs, manifested as detachment of ribosomes from the rough endoplasmic reticulum and dissociation of polysomes into monosomes, with a consequent reduction in protein synthesis. Ultimately, there is irreversible damage to mitochondrial and lysosomal membranes, and the cell undergoes necrosis.
1. Defects in membrane permeability:
Early loss of selective membrane permeability leading ultimately to overt membrane damage is a consistent feature of most forms of cell injury. The plasma membrane can be damaged by ischemia, various microbial toxins, lytic complement components, and a variety of physical and chemical agents. Several biochemical mechanisms may contribute to membrane damage.
2. Decreased phospholipid synthesis:
The production of phospholipids in cells may be reduced whenever there is a fall in ATP levels, leading to decreased energy dependent enzymatic activities. The reduced phospholipid synthesis may affect all cellular membranes including the mitochondria themselves, thus exacerbating the loss of ATP.
3. Increased phospholipid break-down: Severe cell injury is associated with increased degradation of membrane phospholipids, probably due to activation of endogenous phospholipases by increased levels of cytosolic Ca2+.
4. ROS:
Oxygen-free radicals cause injury to cell membranes by lipid peroxidation, discussed earlier.
5. Cytoskeletal abnormalities:
Cytoskeletal filaments serve as anchors connecting the plasma membrane to the cell interior. Activation of proteases by increased cytosolic Ca2+ may cause damage to elements of the cytoskeleton.
6. Lipid breakdown products:
These include unesterified free fatty acids, acyl carnitine, and Lys phospholipids, catabolic products that are known to accumulate in injured cells as a result of phospholipid degradation. They have a deterrent effect on membranes. They also either insert into the lipid bilayer of the membrane or exchange with membrane phospholipids, potentially causing changes in permeability and electrophysiologic alterations.
7. Mitochondrial membrane damage:
As discussed above, damage to mitochondrial membranes results in decreased production of ATP, culminating in necrosis, and release of proteins that trigger apoptotic death.
8. Plasma membrane damage:
Plasma membrane damage leads to loss of osmotic balance and influx of fluids and ions, as well as loss of cellular contents. The cells may also leak metabolites that are vital for the reconstitution of ATP, thus further depleting energy stores.
9. Injury to lysosomal membranes:
Injury to lysosomal membranes results in leakage of their enzymes into the cytoplasm and activation of the acid hydrolases in the acidic intracellular pH of the injured (e.g., ischemic) cell. Lysosomes contain RN Aases, DNases, Proteases, Glucosidases, and other enzymes. Activation of these enzymes leads to enzymatic digestion of cell components, and the cells die by necrosis.
10. Damage to DNA and proteins:
Cells have mechanisms that repair damage to DNA, but if this damage is too severe to be corrected (e.g., after radiation injury or oxidative stress), the cell initiates its suicide program and dies by apoptosis. A similar reaction is triggered by improperly folded proteins, which may be the result of inherited mutations or external triggers such as free radicals. Since these mechanisms of cell injury typically cause apoptosis.
11. Reduced protein synthesis:
As a result of continued hypoxia, membranes of endoplasmic reticulum and Golgi apparatus swell up. Ribosomes are detached from granular endoplasmic reticulum and polysomes are degraded to monosomes, thus dispersing ribosomes in the cytoplasm and inactivating their function. Similarly reduced protein synthesis occurs in Golgi apparatus. Up to this point, withdrawal of acute stress that resulted in reversible cell injury can restore the cell to normal state.
1. Mitochondrial damage:
As a result of continued decrease in oxygenated blood supply, irreversible cell damage occurs and on reperfusion with injured cell, excess intracellular calcium collects in the mitochondria disabling its function. Morphologically, mitochondrial changes are vacuoles in the mitochondria and deposition of amorphous calcium salts in the mitochondrial matrix.
1. Mitochondrial damage:
As a result of continued decrease in oxygenated blood supply, irreversible cell damage occurs and on reperfusion with injured cell, excess intracellular calcium collects in the mitochondria disabling its function. Morphologically, mitochondrial changes are vacuoles in the mitochondria and deposition of amorphous calcium salts in the mitochondrial matrix.
2. Membrane damage:
Damage to plasma membrane loses its normal function is the most important event in irreversible cell injury. Due to damage of the plasma membrane, cytosolic influx of calcium in the cell increases. Calcium activates endogenous phospholipase. Activated phospholipase degrade membrane phospholipids progressively which are the main constituents of lipid bilayer membrane. Besides these, activation of lytic enzymes ATPase which causes further depletion of ATP leads to decrease in the synthesis of new phospholipid for replacement.
3. Cytoskeletal damage:
Activated intracellular protease or by physical effect of
cell swelling, damages of cytoskeleton
may lead to irreversible cell membrane
injury.
4. Nuclear damage:
The nucleoproteins are damaged by the activated lysosomal enzymes such as proteases and endonucleases. Irreversible damage to the nucleus can be in three forms.
- Pyknosis: Condensation and clumping of nucleus which becomes dark basophilic.
- Karyorrhexis: Nuclear fragmentation into small bits dispersed in the cytoplasm.
- Karo lysis: Dissolution of the nucleus.
5. Lysosomal damage, cell death and phagocytosis:
The lysosomal membranes are damaged and result in escape of lysosomal hydrolytic enzymes. These enzymes are activated due to lack of oxygen in the cell and acidic ph. These hydrolytic enzymes include, Hydrolase, protease, glycosidase phosphatase, lipase, amylase, RN Aase and DN Aase which on activation bring about enzymatic digestion of cellular components and hence cell death. The dead cell is eventually replaced by masses of phospholipids called myelin figures which are either phagocytosed by macrophages or there may be formation of calcium soaps. Liberated enzymes just mentioned leak across the abnormally permeable cell membrane into the serum, the estimation of which may be used as clinical parameters of cell death. In myocardial infarction, estimation of SGPT, LDH, CKMB and cardiac troponins useful guides for death of heart muscle.
Mechanism of Irreversible Cell Injury
Hypoxia is caused by inadequate oxygenation to the cell because of the lack of blood supply to a tissue due to thrombosis. Hemorrhage can cause hypoxia by interrupting the blood supply or blood is not getting oxygenated properly, as it occurs in cardiorespiratory failure, and the oxygen carrying capacity of blood is diminished in carbon monoxide poisoning hypoxia will occur.
The first point of attack of hypoxia is on the cell's aerobic respiration, in other words, oxidative phosphorylation. Lack of ATP generation leads to an inability of the cell to maintain its ion-transport systems and the cell begins to swell. If the hypoxia continues, extensive damage to the cell membrane and cell death will ensue.
Free Radical Induced Injury
Most agents acting this way cause cell damage by affecting directly cell membranes and trigger a lethal sequence of events. Free radicals are chemical species that have a single unpaired electron in outer orbit, it initiates autocatalytic reaction which mainly occur in reperfusion of the ischemic cell. Activated oxygen radicals are now known to be the common mechanism to cell in injury in many conditions, i.e., aging, chemical and radiation injury, bacterial infections, inflammation, tumor necrosis etc. Free radicals like superoxide radicals, hydroxyl ions and peroxide ions are very destructive to cells which cause lipid peroxidation, oxidation of protein, DNA damage, and cytoskeleton damage etc. They are initiated within cells by enzymatic reactions and non-enzymatic systems. The system has a series of protective mechanisms to protect the cells from these free radicals like antioxidant enzymes such as catalase, glutathione peroxidase and superoxide dismutase. Vitamin E and selenium also help for protection from free radical induced cellular damage.
The deficiency of all these protective mechanisms may lead to free radical reactive cellular damage, especially in muscle.
Different causes for initiation of free radical:
- Ionizing Radiation: Exposure of Ionizing Radiation causes the generation of a variety of free radical species. This occurs following radiation-induced splitting of molecules which often generates free radical products.
- Enzymatic metabolism of chemicals or drugs. For e.g., carbon tetrachloride can generate [CCl3] * which cause autooxidation of the polyenoic fatty acid present within membrane phospholipids.
- Cellular Respiration: Regulated transfer of free radicals is the basis of the Electron Transport Chain that powers Cellular Respiration. Although the free radicals generated during electron transport are tightly controlled, a small amount can escape and cause damage. Escape of free radicals is substantially enhanced when mitochondria are injured which occurs frequently following metabolic cell injury.
- Chemical Cell Injury: Metabolism of several exogenous chemicals can result in the generation of free radicals. Some metals which accept or donate electron (e–). For e.g., Cu and Fe (Fenton reaction). Nitric oxide (NO) can act as a free radical and converted into highly reactive per oxynitrate anion (ONOO–) as well as NO2* and NO– 3. Normally, NO can be produced by endothelial, neurons, macrophages etc.
The redox reactions occur during normal metabolism. For e.g., in respiration, molecular oxygen is reduced to water by accepting 4 electrons. During this process, small amount of toxic intermediates are formed. Free radical reaction can be studied as follows:
1. Lipid Peroxidation:
Polyunsaturated fatty acid of membrane is attacked repeatedly by free radicals to form highly destructive polyunsaturated fatty acid (PUFA) radicals like lipid hydroperoxyl radicals and lipid hypo peroxides. This is termed as lipid peroxidation. These lipids are widely speeded to other part of membrane that is lipid peroxidation takes place at adjoining part of membrane causing damage to entire cell membrane.
2. Oxidation of protein:
Free radical causes cleavage by oxidation of protein macromolecules of cell causing cross linkage in the amino acid sequences of protein and fragmentation of polypeptides.
3. Effect on DNA damage:
Free radical breaks DNA fragments to single strand, so there will be formation of DNA which is defective. Replication of this DNA is not possible and thereby cell death may occur.
4. Cytoskeleton Damage:
Free radicals interfere with mitochondrial aerobic phosphorylation and decreases synthesis of ATP leading to cytoskeleton damage. There are certain antioxidants present endogenously to fight against these oxidative free radicals like Vitamin-E, sulfhydryl containing substances like cystine, SOD, catalase, GTH & serum proteins.
Morphology of Cell Injury– Adaptive Changes
Cell adaptation within limits:
Most cells have the ability to adapt to changes in their environment by altering their morphology, pattern of growth and metabolic activity. These adaptive responses may be part of the normal physiology of a cell or tissue, or they may represent an attempt to limit the harmful effects of a pathological stress. Several basic patterns of macroscopic change have been described and are detailed below. It should be pointed out that physiologic signals such as hormonal stimuli can also cause tissues to change with similar patterns. Consequently, the adaptive mechanisms described below can be considered basic patterns of macroscopic change which can be induced by both pathological injury and in certain cases physiologic stimuli. Common examples include atrophy, hypertrophy, hyperplasia, metaplasia and dysplasia.
a. Hypertrophy:
Hypertrophy refers to an increase in the physical size of cells. When hypertrophy occurs simultaneously in a population of adjacent cells this can lead to increased tissue or organ size. In certain clinical settings, the word "Hypertrophy" is loosely used in reference to any increase in tissue or organ size even if the increase is due to cellular Hyperplasia. Such conflation of hypertrophy and hyperplasia is difficult to avoid since in most cases hyperplasia and hypertrophy occur concurrently. The few cases in which an increased organ size occurs purely due to cellular hypertrophy (and includes no component of hyperplasia) is in expansion of skeletal muscle and the myocardium whose cells cannot divide. In general, hypertrophy is due to increased functional demand on a tissue or due to specific hormonal stimulation.
b. Hyperplasia:
Hyperplasia refers to an increase in the number of cells within a tissue due to mitosis. It is important to note that hyperplastic cells still maintain strict regulatory control of their cell cycle. Consequently, when the stimuli which induce hyperplasia are removed, cells will terminate their divisions. In contrast, cell division in the absence of stimuli is considered as neoplasia. Hyperplasia can be induced by specific hormonal stimuli, increased functional demand on the tissue or by injury to the tissue. Due to tissue injury, surviving cells often enter mitosis to replace those lost due to cell death. Use the search function for specific examples.
c. Atrophy:
Atrophy refers to a decrease in the physical size of cells. When atrophy occurs simultaneously in a population of adjacent cells this can lead to decreased tissue or organ size. In certain clinical settings, the word "Atrophy" is loosely used in reference to any decrease in tissue or organ size even if the decrease is due to reduction in cell number. Such usage is difficult to avoid since in most cases reduction in cell size and number frequently occur together. Atrophy can occur due to reduced functional demand or reduced nervous or hormonal stimulation of the tissue. Long-term declines in blood supply can also lead to atrophic regression of perfused tissues.
d. Metaplasia:
Metaplasia refers to a reversible histological replacement of one differentiated cell type with another. Although by definition metaplasia is a reversible adaptation, it frequently precedes and may represent the initial steps of malignant transformation. Metaplasia is frequently induced by chronic cellular injury and represents an adaptation in which a tissue replaces a sensitive cell type with one better able to resist the injury.
e. Dysplasia:
The cells look abnormal under a microscope but are not cancer cells. Hyperplasia and dysplasia may or may not become cancer. Dysplasia refers to an abnormal and potentially reversible process where there is disordered growth and maturation of cells and the tissues and organs. The number of adult and mature cells decreases while the number of immature cells increases. The microscopic changes which occur in reversible cell injury are cellular swelling (organelle changes) and fatty changes.
Cellular Swelling
The plasma membrane forms a barrier against excessive amounts of Na+ within the extracellular fluid from entering the cell. However, the plasma membrane is slightly “leaky” to Na+ , allowing minimal amounts of Na+ to gradually move into the cell. To compensate this, there is a perpetually active Na+ /Kapasi pump, which move Na+ out of the cell constantly, in exchange for K+ into the cell. The normal functioning of these pumps is hampered due to depletion of ATP which leads to accumulation of Na+ intracellularly creating osmotic pressure which causes cellular swelling.
Fatty Change (Steatosis):
This steatosis is caused in hypoxic, toxic and metabolic injuries and is related to a dysfunction in the cell’s regulation of synthesis and elimination of triglycerides. Excess lipids accumulate within the cells, usually parenchymal cells that form numerous vacuoles that displace the cytoplasm. If these vesicles are large enough to displace and distort the nucleus, it is referred to as macro vesicular steatosis.
Intracellular Accumulations
Under some circumstances, cells may accumulate abnormal amounts of various substances, which may be harmless or associated with varying degrees of injury. The substance may be located in the cytoplasm, within organelles (typically lysosomes), or in the nucleus, and it may be synthesized by the affected cells or may be produced elsewhere. There are three main pathways of abnormal intracellular accumulations:
- A normal substance is produced at a normal or an increased rate, but the metabolic rate is inadequate to remove it. An example of this type of process is fatty change in the liver.
- A normal or an abnormal endogenous substance accumulates because of genetic or acquired defects in its folding, packaging, transport, or secretion. Mutations that cause defective folding and transport may lead to accumulation of proteins (e.g., α1-antitrypsin deficiency).
- An inherited defect in an enzyme may result in failure to degrade a metabolite. The resulting disorders are called storage diseases.
An abnormal exogenous substance is deposited and accumulates, because the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. Accumulations of carbon or silica particles are examples of this type of alteration.
Fatty change refers to any abnormal accumulation of triglycerides within parenchymal cells. It is most often seen in the liver, since this is the major organ involved in fat metabolism, but it may also occur in heart, skeletal muscle, kidney and other organs. Steatosis (fatty changes) may be caused by toxins, protein malnutrition,
diabetes mellitus, obesity and anoxia. Alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver (fatty liver) in industrialized nations. Free fatty acids from adipose tissue or ingested food are normally transported into hepatocytes, where they are esterified to triglycerides, converted into cholesterol or phospholipids, or oxidized to ketone bodies. Some fatty acids are synthesized from acetate within the hepatocytes as well.
Excess accumulation of triglycerides may result from defects at any step from fatty acid entry to lipoprotein exit, thus accounting for the occurrence of fatty liver after diverse hepatic insults. Hepatotoxins (e.g., alcohol) alter mitochondrial and smooth endoplasmic reticulum function and thus inhibit fatty acid oxidation; CCl4 and protein malnutrition decrease the synthesis of apoproteins; anoxia inhibits fatty acid oxidation; and starvation increases fatty acid mobilization from peripheral stores. The significance of fatty acid change depends on the cause and severity of the accumulation. When mild, it may have no effect on cellular function. More severe fatty acid change may transiently impair cellular function, but unless some vital intracellular process is irreversibly impaired, fatty acid change is reversible. In the severe form, fatty acid change may precede cell death, and may be an early lesion in a serious liver disease called non-alcoholic steatohepatitis.
Calcification
It occurs when calcium builds up in body tissue, blood vessels or organs. This buildup can harden and disrupt body’s normal processes. Calcium is transported through the bloodstream and found in every cell. As a result, calcification can occur in almost any part of the body. About 99 % of body’s calcium is in teeth and bones. The other 1 % is in the blood, muscles, fluid outside the cells, and other body tissues.
Types of Calcifications: Calcifications can form in many places throughout body, including:
- Small and large arteries
- Heart valves
- Brain, where it is known as cranial calcification
- Joints and tendons, such as knee joints and rotator cuff tendons
- Soft tissues like breasts, muscles, and fat
- Kidney, bladder and gallbladder
Some calcium buildup is harmless. These deposits are believed to be the body’s response to inflammation, injury, or certain biological processes. However, some calcifications can disrupt organ function and affect blood vessels.
Causes of Calcification:
Many factors have been found to play a role in calcification. These include infections, calcium metabolism disorders that cause hyperkaliemia, genetic or autoimmune disorders affecting skeletal system and connective tissues, persistent inflammation.
Alkalosis
Alkalosis is excessive blood alkalinity caused by an overabundance of bicarbonate in the blood or a loss of acid from the blood (metabolic alkalosis), or by a low level of carbon dioxide in the blood that results from rapid or deep breathing (respiratory alkalosis).
Metabolic Alkalosis:
Metabolic alkalosis is a primary increase in serum bicarbonate (HCO3 –) concentration.
This occurs as a consequence of a loss of H+ from the body or a gain in HCO3. Metabolic alkalosis is a pH imbalance in which the body has accumulated too much of an alkaline substance, such as bicarbonate, and does not have enough acid to effectively neutralize the effects of alkali.
Respiratory Alkalosis:
Respiratory alkalosis is a condition where the amount of carbon dioxide found in the blood drops to below normal range. This condition produces a shift in the body’s pH balance and causes the body’s system to become more alkaline). This condition results in rapid, deep breathing called hyperventilation.
Acidosis
Acidosis is caused by an overproduction of acid in the blood or an excessive loss of bicarbonate from the blood (metabolic acidosis) or by a build-up of carbon dioxide in the blood that results from poor lung function or depressed breathing (respiratory acidosis).
Metabolic Acidosis:
Metabolic acidosis is a pH imbalance in which the body has accumulated too much acid and does not have enough bicarbonate to effectively neutralize the effects of the acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low (less than 7.35) due to increased production of hydrogen ions by the body or the inability of the body to form bicarbonate (HCO3 –) in the kidney.
Respiratory Acidosis:
Respiratory acidosis is a condition which occurs when the lungs are unable to remove all the carbon dioxide processed in body. The acid-base balance of body is hampered by this, causing the blood to become acidic.
Electrolytes
There are many chemicals in blood stream that regulate important functions of bodies. These chemicals are called electrolytes. When dissolved in water, electrolytes separate into positively and negatively charged ions. Human body's nerve reactions and muscle functions are dependent upon the proper exchange of these electrolyte ions outside and inside cells. Examples of electrolytes are calcium, magnesium, potassium and sodium. Electrolyte imbalance can cause a variety of symptoms.
Normal Adult values:
- Calcium: 4.5-5.5 mEq/L
- Chloride: 97-107 mEq/L
- Potassium: 3.5-5.3 mEq/L
- Magnesium: 1.5-2.5 mEq/L
- Sodium: 136-145 mEq/L
Electrolyte Imbalance:
The level of electrolyte in the body is abnormal called as electrolyte imbalance. An excess or deficiency of certain electrolytes may lead to abnormality in various functions of the body. The most serious electrolyte disturbance involves abnormalities in the levels of Sodium, Potassium or Calcium. Other electrolyte imbalance is less common. There are many causes of electrolyte imbalance, including rapid water loss through diarrhea, vomiting, perspiration, injury, blood loss, fluid loss from burns, eating disorders, alcoholism, cancer, diabetes and certain medication.
Malabsorption:
The body may be unable to absorb these electrolytes due to a variety of stomach disorders, medications, or may be how food is taken in Hormonal or endocrine disorders and Kidney disease. A complication of chemotherapy is tumorlysis syndrome. This occurs when body breaks down tumor cells rapidly after chemotherapy, causing a low blood calcium level, high blood potassium levels, and other electrolyte abnormalities. Certain medications may cause an electrolyte imbalance such as: Chemotherapy drugs (Cisplatin) Diuretics (furosemide [Lasix] or Bumetanide) Antibiotics (Amphotericin B) Corticosteroids (Hydrocortisone).
Symptoms of Electrolyte Imbalance:
An electrolyte imbalance may create a number of symptoms. The symptoms of electrolyte imbalance are based on which of the electrolyte levels are affected.
- Blood test results indicate an altered potassium, magnesium, sodium, or calcium levels, may experience muscle spasm, weakness, twitching, or convulsions.
- Blood test results showing low sodium levels may lead to irregular heartbeat, confusion, blood pressure changes, nervous system or bone disorder.
- Blood test results showing high levels of calcium may lead to weakness or twitching of the muscles, numbness, fatigue, and irregular heartbeat and blood pressure changes.
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