Cell Adaptations and Response to Injury

PTHL 312a: Basic Disease Processes

Cell Adaptations and Responses to Injury

Topic 2:


Introduction

References

Cell Adaptations

Learning Guide

Atrophy Hyperplasia and Hypertrophy General Features Hyperplasia Hypertrophy Metaplasia Developmental Adaptations Aplasia (Agenesis) Hypoplasia

Reversible and Irreversible Cell Responses to Injury

Objectives Definitions Workbook

Web Site Images Study Questions Definitions “Flash Cards” Terms “Flash Cards” Web Reader with Images Reader/Learning Guides PDF

General Cell Responses to Injury Reversible Cell Injury General Features of Reversible Cell Injuries Types of Reversible Cell Injuries Irreversible Cell Injury—Necrosis General Features of Necrosis Recognition of Necrosis Special Types of Necrosis General Etiology of Cell Injury General Pathogenesis of Cell Injury Somatic Death

Accumulations in the Stroma Interstitial Accumulations Stromal Fat Accumulation Hyalinization of Connective Tissue Amyloid Extraskeletal Calcifications Metastatic Calcification Dystrophic Calcification Stone Formation—Lithiasis Pathologic Pigments

©2007 William H. Crawford, Jr., D.D.S., M.S. All rights reserved. Copying for commercial purposes is prohibited.

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Introduction In 1858, Virchow described how cell changes he observed with the light microscope (LM) produce diseases. One hundred and fifty years later pathologists still use the LM to identify cell changes he described and still use many of the names he coined for them. Today, most diseases can be identified and classified by their microscopic features. It is common knowledge that benign tumors are differentiated from malignant ones by their microscopic features. That sick cells can be differentiated for dead ones may be less well known. Virchow showed that cells may adapt to a changing environment or may react unfavorably to loss of blood supply or other injurious stimuli. Stresses and increased demand may produce adaptations like “hyperplasia” and “hypertrophy.” On the other hand, injurious injuries like decreased oxygen supply will, depending on the injury’s intensity and duration, kill cells or just make them sick.

Cell Adaptations A group of changes within cells resulting in decreased or increased size, increased numbers, or change from one cell type to another. These changes are first seen within cells; if enough cells are affected, changes are evident at the tissue and organ levels too (that is, may be seen with the unaided eye). Some populations of cells can adapt to certain kind of stimuli and return to normal after the stimuli are removed. These adaptations include decreasing cell size, increasing cell size, increasing cell numbers, and changing cell type.

Cell adaptations may become visible within tissues or organs. Changes at the cellular level are follow ed by changes at the tissue and organ levels. For example, i f the sizes of cells are decreased, tissues and organs composed of them will decrease in size (volume) as well. Cells may adapt to injury by decreasing their sizes. Cells may change their size in order to adapt to changes in their surrounding environments. If the circumstances warrant, cells often become smaller to accommodate changes in oxygen and nutrient supplies. The most commonly recognized form of decreased cell size is atrophy. Atrophy

Cells often decrease their size in response to an injury—atrophy Atrophy is a very common condition. As defined, “atrophy” is the acquired decrease in cell size leading to decreased tissue and organ size (a- = without; -trophy = nourishment). It is acquired after birth; it is not an inborn genetic defect. Atrophy is the decrease in the size of an organ that has alr eady reached full size or full maturation. In most cases, atrophy is the result of decreased nutrition over a long period of time. Usually the decreased nutrition is related to decreased blood flow to the area (ischemia). Figure 1: Atrophy Normal Development

Atrophy

Atrophy is a condition that affects organs after they are fully developed. It is an acquired decrease in cell size leading to decreased tissue and organ size.

Atrophy may be caused by ischemia, disuse, pressure, exhaustion, or hormone deficiency. As just mentioned pathologic atrophy may be associated with any disease that produces ischemia (ischemic atrophy). It also appears with disuse of a body part. Disuse atrophy of the legs was a common complication of poliomyelitis, a viral disease that attacks the nervous system causing paralysis of the legs. As a consequence of the paralysis, the muscles of the legs wither (atrophy). Leg disuse with immobilization following fractures may lead to muscle atrophy as well. Atrophy can be caused by pressure on the blood vessels surrounding a tissue (pressure atrophy). An expanding tumor is a common source of such pressure.

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Continued over-activity of cell populations may lead to exhaustion and atrophy (exhaustion atrophy). Finally, cessation of hormone supply to cells dependent upon it will lead to atrophy (hormonal atrophy); this situation is a result of underactivity of endocrine glands.

Table 1: Causes of Atrophy •

Ischemia

•

Pressure

•

Disuse

•

Exhaustion

•

Hormones

In atrophy, cells are smaller, the stroma more prominent, and a pigment may be present. There are three changes than assist pathologists in their recognition of atrophy. First, atrophic cells are smaller than normal ones making the tissue appear more cellular. Second, the organ’s framework (stroma) appears to be more prominent than normal. Third, a pigment called “lipofucsin” or “lipochrome” is often seen within cells affected by atrophy. This pigment is now known to be the remnants of cellular organelles being digested by lysosomes (autophagosomes). Sometimes the presence of lipofucsin in at rophic tissue can be prominent enough to give the tissue a decidedly brown appearance with the unaided eye. This appearance is often called “brown atrophy.” Hyperplasia and Hypertrophy

General Features

Hyperplasia and hypertrophy are responses to increased demands on cells. When increased demand is placed on certain cell populat ions, they will respond by i ncreasing their numbers or increasing their size. If a population is composed of cells that often divide they will increase their numbers (hyperplasia). If, on the other hand, a population is composed of cells that cannot divide they will increase their sizes (hypertrophy). Hyperplasia and hypertrophy refer to microscopic appearances. Hyperplasia and hypertrophy produce tissues that are l arger than normal and, therefore, can be seen with the unaided eye. Several oral conditions are characterized by increased size of an oral tissue (gingiva, for example). The term “hypertrophy” is often used to describe their clinical appearance. More often than not, however, microscopic examination of the enlarged tissue will reveal it to be caused by hyperplasia, not hypertrophy. These terms, then, refer to microscopic, not clinical, features. Hyperplasia

Cells may adapt by increasing their numbers When stimulated in certain ways, some cell populations respond by increasing their numbers, a change known as “hyperplasia” (hyper- = increased; -plasia = growth). Hyperplasia is a very common pathologic condition and is the basis for several oral diseases. Hormones and chronic irritation may stimulate hyperplasia. Hormones can stimulate cell proliferation. Benign prostatic hyperplasia of older men is related to elevated androgens. Other cell populations, oral mucosal epithelium for example, may proliferate in the face of chronic trauma. An ill-fitting denture may irritate underlying connective tissue cells causing their hyperplasia resulting in a visible overgrowth of tissue. Hyperplasia depends upon cell division. In order for cells to increase their numbers they must be able to divide—undergo mitosis. Cells with the greatest mitotic ability can be expected to undergo hyperplasia when stimulated by hormones or chronic trauma. Such are covering epithelial cells of the skin or mucous membranes, glandular epithelium, blood cells, and bone marrow cells.

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Hyperplasia is different from neoplasia. While hyperplasia may mimic certain types of tumors (neoplasms) it is a completely different process. The most important difference is that hyperplasia is reversible while neoplasia is not. Once the stimulus is removed, hyperplastic cells will return to normal size and the visible mass will disappear; this is not t he case with benign and malignant tumors. Hypertrophy

Cells may adapt by increasing their size—hypertrophy; it occurs in cells that cannot divide. In cell populations that cannot, or only rarely, divide, hyperplasia is not an option. If these cells are stimulated, they will increase their size instead of increasing their numbers. This size increase is known as “hypertrophy” (hyper- = increase; -trophy = nourishment). The most obvious example of hypertrophy is increased size of skeletal muscles seen in body builders. Their bulging and rippling muscles are caused by the increase in size, not numbers, of skeletal muscle cells. Since hypertrophy is a reversible change, it requires continual stimulation of muscle cells to maintain their state of increased size. Figure 2: Microscopic Features of Hyperplasia and Hypertrophy

Hyperplasia Same sizes, increased numbers

Hypertrophy Increased sizes, same numbers

Metaplasia

Cells may transform themselves—metaplasia Faced with a changed environment, some cell populations undergo transformation in order to cope more effectively with the changes. Fibrous connective tissue, may transform into bone or cartilage. This sort of transformation is known as “metaplasia” (meta- = change; -plasia = growth). When epithelial cells designed for secretion and/or absorption are subjected to chronic trauma, they may become replaced by a lining more able to resist the irritation. Usually the transformation produces stratified squamous epithelium and is, therefore, called “squamous metaplasia.” Like the other cellular adaptations, metaplasia is reversible. Figure 3: Connective Tissue and Epithelial Metaplasia Fibrous C.T.

C.T. Metaplasia Squamous Metaplasia

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Bone or Cartilage



Developmental Adaptations

Aplasia (Agenesis)

Sometimes cells may not develop at all—aplasia. This situation is caused by defective genetic instructions guiding development of cell populations. As a consequence, an organ may not develop at all or become a small “nubbin” (rudiment). The terms “aplasia” (a- = without; -plasia = growth) and “agenesis” (a- = without; genesis = beginning) are used to designate this situation. Aplasia usually affects the paired organs of the body like the kidneys, the adrenal, and salivary glands. Missing teeth, anodontia, is an example of aplasia. In dentistry, congenitally missing teeth is a more common but less serious example of aplasia. Some people do not develop third molars, first bicuspids, or lateral incisors; this condition is called “anodontia” (an- = without; -odontia = teeth). Figure 4: Aplasia (agenesis)

Expected size

Actual size

Aplasia occurs when a cell population does not develop at all. As a consequence, an expected tissue or organ is absent or is rudimentary.

Hypoplasia

Sometimes cells do not reach full-size or full development—hypoplasia. Cell populations may start down the road of full development but not attain it; they are said to be “hypoplastic” or to be undergoing “hypoplasia” (hypo- = under; -plasia = growth). In hypoplasia, tissues and/or organs are smaller than expected. Perhaps the genetic signals necessary for continued development are turned off or perhaps appropriate oxygen or nut rient levels are not available. Whatever the pathogenesis, the cell population never reaches full size. Hypoplastic enamel doesn’t reach expected calcification level. In dentistry, the definition of “hypoplasia” is expanded to include incomplete maturation of a tissue or organ. Hypoplasia commonly occurs in tooth enamel. Normally enamel is 96% calcified giving its characteristic white translucent appearance. If, enamel reaches only, say, 90% calcification, it will lose its translucency and appear chalky-white. Such hypoplastic enamel usually occurs only in spots. In teeth so affected, there are chalky-white spots surrounded by normal-appearing translucent enamel. Figure 5: Hypoplasia Expected size

Actual siz

Hypoplasia is the failure of a tissue or an organ to reach full size or full maturation.

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Reversible and Irreversible Cell Responses to Injury General Cell Responses to Injury

Cells can cope with subtle changes in their environment and with mild injury. If injury is of low intensity or of short duration, afflicted cells may be able to recover. Cells can remove and replace injured parts by fabricating new membranes. If the damage continues or its intensity increases, adaptive changes are swamped, and the cell becomes visibly sick. Cell responses to injury take time to occur. Changes within cells, whether reversible or irreversible, take time to develop. Many hours may elapse before cells exposed to powerful injurious forces and show visible signs (lesions) indicating that they are damaged. Figure 6: Stages in the Development of Reversible Responses to Injury Normal Cell

Injury Intensity/duration

Molecular Lesion

EM Lesion

LM Lesion

Gross Lesion

Reversible Responses

When a normal cell is injured, it und ergoes a reversible series of changes first detected at the molecular level, then at with the EM, then with the LM, and finally with the unaided eye. By the time the degeneration is detected with the LM, the injury is a serious and long-standing one (hours).

Cell responses to injury follow predictable patterns. When a cell is exposed to one or more damaging forces, it starts down a well-worn path. This path depends on the intensity and the duration of the damaging force. If the injury is of low intensity and short duration, the cell may be able to adapt and survive. If, however, the force is of high intensity and long duration, the cell may not adapt but show signs of irreversible damage. Cells may not be able to adapt to serious injury; they undergo “necrosis.” Cell “death” is called “necrosis.” Necrosis i s, of course, irreversible—a dead cell cannot return to life. Some cells are more susceptible to necrosis than others. Cells lining kidney tubules and the intestines are very susceptible to necrosis. Other cells can withstand damage much better. Figure 7: Potential Changes Following Injury of a Cell

Normal Cell

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Adaptive Changes s s e (Adaptations) r t S l o a d o r k W d e a s e I n c r I n j u ri es Reversible Changes (Degenerations)

Irreversible Changes (Necrosis)



Reversible Cell Injury

Changes within cells caused by some injury that allow substances to accumulate within their cytoplasms. Such accumulations indicate that the cells are “sick.” Cells thus affected may recover or die. General Features of Reversible Cell Injuries

Reversible cell changes are caused by mild injuries. Reversible cell changes are responses to injuries of low intensity and/or short duration. They are recognized by subtle changes in cell structure and/or the accumulation of some material in the cytoplasm. These changes take time to develop and are preceded by biochemical and EM changes. By the time cellular responses to injury are detected with the LM, they are far along in their development. Reversible cell injuries more commonly affect active cells. Reversible cell injuries tend to affect actively functioning cells rather than quiescent ones. Absorptive and secretory epithelial cells are more vulnerable than connective tissue cells; put more generally, parenchymal cells are more commonly affected than stromal cells. Table 2: Summary of Features of Reversible Cell Responses to Injury •

Reversible

•

Low intensity injury

•

Short duration injury

•

LM: material in cytoplasm

•

LM changes preceded by molecular and EM changes

•

Parenchymal cells more vulnerable than stromal cells

Types of Reversible Cell Responses to Injury

Water may accumulate in degenerating cells. Cellular Swelling —Water may accumulate in the cytoplasm of cells. Virchow noted t he cytoplasm of some sick cells was swollen and granular; he called this “cloudy swelling.” The granules he saw turned out to be mitochondria and endoplasmic reticula swollen with water that traversed damaged membranes. Modern pathologists, call this condition “cellular swelling.” If water accumulation becomes more severe, granules are replaced by large empty spaces (vacuoles). This accentuated water retention is sometimes called “hydropic degeneration.” Fat droplets may accumulate in degenerating cells. Fatty Change —Fat commonly appears in injured cells. It is recognized (LM) by large vacuoles within the cytoplasm. At first, the vacuoles are small but they soon join together (coalesce) until they compress the nucleus against the cell membrane (signet r ing effect). There have been many competing names gi ven to this condition; most have settled on the term “fatty change.” There are a number of conditions in which fatty change is observed. The most common of these is associated with long-standing alcoholism. In this disease, alcohol interferes with proper fat metabolism leading to its accumulation. Carbohydrates (glycogen) may accumulate in degenerating cells. Glycogen Degeneration —Glycogen is a common substance found in many body cells storing glucose for later use. Sometimes, however, it accumulates in excessive amounts like within kidney tubule cells in diabetes mellitus. The term “glycogen degeneration” is sometimes used t o describe these changes. Although the cytoplasm of parenchymal cells is the most common location for abnormal glycogen, it alternatively may occur in the nucleus. Protein may accumulate in degenerating cells. Hyaline —On occasion a glassy, structureless, substance appears in the cytoplasm of damaged cells. The term “hyaline” is used to describe this appearance. When hyaline accumulates abnormally, the change is called “hyaline degeneration.” In most circumstances the hyaline material is presumed to be some type of protein. It may appear as cytoplasmic droplets (hyaline droplet degeneration) or be scattered through the cytoplasm making the entire cell appear hyalinized.

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Irreversible Cell Damage—Necrosis

A group of changes within cells caused by some injury that causes some irreversible change from which recovery is impossible. Such cell death is recognized by specific changes occurring within nuclei. Sometimes, characteristic tissue patterns suggest the etiology of necrosis. General Features of Necrosis

When an injured cell dies, changes within it can be detected. When a cell is too sick to recover, it dies. The use of the term “cell death” implies, of course, that the cell will not return to normal function; cell death is irreversible. Once death occurs, a series of changes occur in the cell’s cytoplasm and nucleus. The earliest changes are molecular; they are followed by changes detected with the EM and the LM; ultimately, if enough cells die, the changes may be seen with the unaided eye. When cell death is the result of disease in a living patient, the term “necrosis” is used (necrosis = pathologic antemortem cell death). Cells may die without preceding injury. Cells die in two other circumstances as well: physiologically in a living patient, and in a dead patient. When one thinks about it, it is obvious that millions of cells die every day in living persons. Red blood cells live only 120 days, the lining of the intesti nal tract is replaced in about 90 days, and surface skin cells die and are shed at a fantastic rate. Recently, it was recognized that these cells are programmed by their genes to die at certain times or under certain circumstances. The term “apoptosis” is now used to describe such programmed cell death. After death of an organism, all body cells will die. Cellular changes seen in such cells are called “autolysis” (auto- = self; -lysis = dissolve). Table 3: Types of Cell Death Term

Definition

Necrosis

Pathologic antemortem cell death

Autolysis

Postmortem cell death

Apoptosis

Antemortem programmed cell death

Necrosis are changes occurring after a cell dies. Getting back to the term “necrosis,” note that in the figure below, cell death and necrosis are not really synonymous. At some point, a severely injured cell can no longer survive—it dies. After that irreversible event, changes occur within dead cells. Strictly speaking, necrosis is not cell death but the changes that occur after cells die. Cell death is identified by observing necrosis. Cells that died during the life of an individual (antemortem) often are recognized by tell tale LM changes. These changes are those that occur some hours after cell death and may affect the cytoplasm or the nucleus. Figure 8: Stages in the Development of Necrosis Normal Cell

Injury Intensity/duration

Molecular Lesion

EM Lesion

LM Lesion

Gross Lesion

Necrosis Cell Death Necrosis is the changes that occur after a cell has died. These changes can be detected at the molecular, EM, LM, and finally gross levels.

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Recognition of Necrosis

Damage to the cytoplasm may not indicate cell death. Changes seen in the cytoplasm, while abnormal, do not specifically indicate that the cell has died. Often, only irregular faint granules are seen—changes also seen in cells undergoing reversible degenerations. Occasionally however, cytoplasmic contents spew into the cell’s outside world indicating a fatal rupture in the cell membrane. Cytoplasmic rupture of this kind is virtually the only specific cytoplasmic change indicating that a cell has died. Nuclear damage is an important sign of cell death. Cell death is usually followed by changes within the nucleus. The nuclei of dead cells may be small, dark, and shrunken, faint with indistinct features, or fragmented. Small, dark, and shrunken nuclei are said to show “pyknosis” or to be “pyknotic.” Nuclei that are faint and indistinct are said to be undergoing “karyolysis” (karyo- = nucleus; -lysis = dissolve). Fragmented nuclei in dead cells are suffering from “karyorrhexis” (-rrhexis = fragment). Pyknosis, karyolysis, and karyorrhexis are specific nuclear changes that signify a cell has died. Figure 9: Nuclear Changes in Necrosis Pyknosis Karyolysis Normal Nucleus

Karyorrhexis

After a cell has died, its nucleus condenses (pyknosis), dissolves (karyolysis), or fr agments (karyorrhexis). Recognition of these nuclear changes indicate that the cell in which they reside is dead.

Special Types of Necrosis

Certain microscopic patterns of necrosis may point to the cause of cell death. In addition to affecting the cytoplasm or nucleus of dead cells, necrosis may affect groups of cells (tissues) as well. Sometimes the appearance of tissue necrosis is so unique as to suggest a specific etiologic agent. Liquefaction of cells may suggest that bacteria caused their death. Liquefaction Necrosis —Certain bacteria produce dissolving (lytic) factors that break up tissue. Additionally, certain body defense cells contain many enzyme-containing lysosomes targeted to destroy bacteria and other invaders. If in the heat of battle these defensive cells are ki lled, their released enzymes kill surrounding viable tissue. This sort of activity results in “liquefaction necrosis.” Liquefaction necrosis is recognized (LM) by the loss of cell and tissue detail in the affected area and its replacement with a structureless material. Clinically (unaided eye), a yellowish fluid ( not pus) exudes from the area damaged by this intense defensive struggle. Coagulation of cells may suggest that ischemia caused their death. Coagulation Necrosis —While many body cells have enzyme-containing lysosomes, some do not. Cardiac muscle cells and kidney tubule cells are t wo examples of cells that have relati vely few (or no) lysosomes. If some non-bacterial internal body disease kill cells, they will die but not liquefy. Instead, they will die “in their tracks” and not disintegrate for some time; a process known as “coagulation necrosis.” With the LM, affected tissues maintain their overall appearances. Relationships between adjacent cells are maintained, but the cell details are lost. Most often, coagulation necrosis results from sudden stoppage of the arterial blood supply. The tissue dependent on this blood source will die showing signs of coagulation necrosis. Thus, if coagulation necrosis is discovered, it is almost certain that sudden ischemia was its cause.

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Replacement of cells by a “cheesy” material may suggest tuberculosis. Caseous Necrosis —Following infection with the tuberculosis bacterium, the lungs develop lesions called granulomas. The center of these lesions usually consist of dead tissue. When early pathologists saw this necrotic tissue during postmortem examinations, they were struck with its resemblance to cottage cheese and used the name “caseous necrosis” to describe it. The significance of this special type of necrosis is that when it is seen, for example in a biopsy specimen, tuberculosis is the presumptive diagnosis. Destruction of fat cells may be caused by released fat splitting enzymes. Fat Necrosis —Fat necrosis is the death of fat cells (adipocytes). Fat deposits are found in a number of locations, the buttocks, the female breast, and around the pancreas. Trauma t o exposed deposits occasionally can result in death of fat cells—fat necrosis. This condition can also result from release of fat-splitting enzymes (lipases) into nearby fat deposits. Through the action of li pases, fat cells are literally converted into soaps (soap was once made by the action of alkalis on lard). Necrosis of an extremity suggests ischemia and bacterial infection of the part. Gangrenous Necrosis —Gangrenous necrosis is the form of cell death associated with gangrene. It appears when a body part, usually an extremity, loses its blood supply and becomes secondarily infected. In hot humid environments, infected dead (gangrenous) tissues become moist and foul-smell ing—wet gangrene. If gas-producing bacteria (Clostridia) enter the dead extremity, the result is gas gangrene. It is the dry form of gangrene (dry gangrene or mummification) that is a common part of U.S. medical practice. This occurs when blood supply is blocked to an extremity (usually a toe) causing its death and subsequent necrosis. When this event is discovered, antibiotic treatment usually prevents secondary bacterial infection. There is, therefore, no liquefaction and no gas; the extremity just withers away. This event is an all too common complication of diabetes mellitus, a disease associated with blockage of blood flow to the legs. Table 4: Disease Associated with Special Types of Necrosis Special Necrosis Type

Signify These Diseases

Liquefaction

Bacterial Infection

Coagulation

Myocardial Infarction

Fat

Trauma

Gangrenous

Diabetes Mellitus

Caseous

Tuberculosis

Gummatous

Tertiary Syphilis

General Etiology of Cellular Damage

Several “injurious stimuli” can damage cells. There are many adverse stimuli that can damage cells. Because the number is so large, it is customary to devise a manageable list of them. Deficient blood flow (ischemia) can damage cells. Ischemia —Ischemia tops the list: it is responsible for almost 1,000,000 deaths in the United States each year. It is the underlying problem in heart attacks, strokes, and a number of other diseases. “Ischemia” refers to blocked or decreased blood flow to a tissue or an organ. In a heart attack there is blocked blood flow to a portion of the heart wall; in a stroke, blockage prevents blood from reaching parts of the brain. Decreased blood flow to the heart can cause chest pain; decreased flow to the br ain can cause fainting spells, decreased mental acuity, and paralysis. Ischemia causes its damaging effects by depriving cells of oxygen and nutrients. These effects are compounded by the accumulation of waste products because returning blood flow is disrupted as well. Inadequate supplies of oxygen can damage cells. Hypoxia & Anoxia —If cells do not receive adequate supplies of oxygen, they will be injured. The terms “hypoxia” and “anoxia” refer to this situation. In “hypoxia” cells receive decreased amounts of oxygen (hypo- = under). The term “anoxia” is used when cells receive no oxygen at all (an- = without). Hypoxia and

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anoxia are the obvious results of ischemia; it is inadequate oxygen supply that is the major problem with decreased blood flow (ischemia). However, hypoxia and anoxia may occur without ischemia—drowning is an example. Decreased oxygen transport can also occur when there is damage to red blood cells. Respiratory diseases, such as emphysema, may hinder proper oxygen transfer from air spaces to the blood stream.

Table 5: Causes of Reversible & Irreversible Cell Injuries •

Ischemia

•

Anoxia & Hypoxia

•

Physical Agents

•

Chemical Agents

•

Biologic Agents

•

Hypersensitivity Reactions

•

Genetic Disorders

•

Increased Work Load

•

Aging

Radiation, heat, and other physical agents can damage cells. Physical Agents —There are a host of physical agents that can damage cells. Radiant energy like that found in X-rays and sunlight can cause cell damage. Heat can damage cells by direct damage or by increasing the rate of cellular activity so that supply of oxygen becomes inadequate (as in a fever). Electrical energy can damage cells directly or by creating great amounts of heat. Trauma is an all too common cause of cell damage and cell death. Sudden, violent trauma (acute trauma) may injure cells directly while prolonged, less-intense trauma (chronic trauma) may provoke, at least for a while, cellular adaptations to it. Cold is another physical agent that may damage cells either by forming crystals that puncture cells or by slowing metabolic activities to the point that they simply stop. External and internal chemicals can damage cells. Chemical Agents —There are a large number of chemical compounds that may damage cells. There are too many of these to list here. Such chemical compounds may originate from outside or from inside the body. “Exogenous chemical agents” are those that are introduced from the outside world by ingestion, inhalation, or injection. The term “poison” is used if small amounts cause cell damage. The “endogenous chemical agents” are those that arise from cellular metabolism (i.e., waste products). Later, several conditions, including kidney and liver disease, will be described in which endogenous chemicals cause cell injury and cell death. Viruses, bacteria, and other biologic agents can damage cells. Biologic Agents —It is obvious that viruses and bacteria can cause cell damage and cell death. The methods by which these agents cause cell damage properly is the subject of microbiology textbooks. That discussion will be left to the microbiologists except to state that while viral and bacterial infections concern us the most, other biologic agents—fungi, Rickettsia, protozoans, and even worms (helminths)—can produce cell damage too. Immune reactions can damage cells. Immune Reactions —Immunity is usually portrayed as being beneficial. Most of the time that portrayal is accurate; however, there are times when immune reactions make things worse. In recent years, greater understanding of these reactions have become included under “hypersensitivity.” Some hypersensitivity reactions can cause cell injury and cell death. As but one example, a hypersensitivity reaction, the type IV variety, is responsible for the tissue death associated with pulmonary tuberculosis. As another, immune reactions directed at a patient’s own cells produce a group of conditions known as “autoimmune diseases.” Diseases caused by abnormal genes are accompanied by damaged cells. Defective Genes —Some diseases are known to be caused by defective genes. One is a disease i n which glycogen accumulates abnormally in body cells. This uncommon disease is caused by the absence of an

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enzyme that releases glucose from glycogen. Because glucose cannot be released from its storage form, glycogen accumulates in increasing amounts. Patients with this disease are missing the gene that carries the code for glucose-6-phosphatase, the missing enzyme.

Lack of essential nutrients can damage cells. Nutritional Deficiencies —Absences of essential nutrients may cause cell injury and cell death. Lack of vitamin C, for example, interferes with the formation of collagen, a prominent component of connective tissue. Since cells that producing collagen, are dependent on vitamin C, they are not able to produce adequate amounts of collagen and the disease scurvy results. Increased work load upon cells can transform or damage them. Increased Work Load —Sometimes cells are called upon to perform at higher than normal activity levels. Elevation in body temperature is one cause of increased activity already mentioned. It is a common observation that increased physical exercise brings changes in muscle cells. It is, perhaps, less commonly known that increased secretion of hormones can cause target cells to undergo changes. Cells are less adaptable and more easily damaged as they grow older. Aging —Some scientists have noted that cells grown outside the body undergo a finite number of cell divisions before the population dies out. That often repeated experiment has led some to believe that human cells have a finite life expectancy. They go on to extrapolate that human life expectancy may never be able to exceed, say, 150 years. These observations aside, it is true t hat cells in older individuals are less adaptable and more likely to undergo degeneration and death. General Pathogenesis of Cell Damage

There are only a few pathways by which cells are damaged. Given the large number of agents that can initiate cell injury, it might seem that there are an equally large number of pathways by which the injury develops. Actually, t he number of pathways for injury development are limited by the structures and chemical processes with the cell. Put another way, many etiologic agents trigger few destructive sequences. There are three basic paths by which cell injuries manifest themselves: 1) damage to cell membranes, 2) production of hyper-reactive molecules, and 3) interference with cellular respiration. Injurious etiologic agents may trigger one, two, or all three of these pathogenetic pathways. Table 6: Pathogenesis of Cell Injuries Damaged cell membranes Free radical production Altered cell respiration

Injury to cell membranes is a common way cells are injured. Damaged Membranes —As has been mentioned, membranes separating the cell from its outer world (plasma membrane) and composing most internal organelles are susceptible to damage. Once damaged, these membranes may not be able to keep things segregated. As a consequence, 1) destructive m aterials leak from organelles into the sur rounding cytoplasm and 2) unwanted substances cross the damaged memb ranes. There are several ways this occurs. First, the mechanism by which the cell replenishes the components of its membranes may be depressed or stopped. Second, the internal network of supporting tubules that comprises the cell’s cytoskeleton may be damaged. Because the cytoskeleton tubules support the plasma membrane, the loss of this support may lead to plasma membr ane rupture. Third, direct injury to cell the membrane may lead to break down of some of its lipid (fat) molecules. Production of hyperactive molecules is a common way cells are injured. Hyperreactive Molecules —There are certain molecules or compounds so unstable that they attempt to combine with other nearby molecules. Sometimes these molecules are purposefully produced by cells for use in body defenses (i.e. killing or disarming foreign invaders). At other times unwanted hyperreactive molecules, or free radicals as they are now popularly known, may appear in cells. The most important free radicals are superoxide (O 2-), hydrogen peroxide (H2O2), and hydroxyl radicals (OH-). These free radicals can react with cell membrane lipids and in the process destroy membrane integrity. Many investigators now

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believe that these free radicals are the common pathway by which most cell injury is produced. To support this belief, they cite the observations that free radicals appear in radiant energy injury (e.g. X-rays, sunlight, ultraviolet radiation), in metabolism of certain chemical agents (e.g. drugs, poisons), and in some more routine internal cell reactions. The formation of free radicals may underlie many, if not most, cell injuries.

Alterations in cellular respiration may be a way cells are injured. Altered Cell Respiration —Cellular respiration is the name given a series of biochemical reactions that transform glucose into carbon dioxide and w ater generating energy stored in a molecule known as adenosine triphosphate (ATP). Because oxygen is required to drive these reactions, they are often known as the “aerobic pathway,” “aerobic respiration,” or “oxidative phosphorylation.” Aerobic respiration reactions are carried out within mitochondria, im portant cell organelles. In the absence of O2, energy (as ATP) can still be created; however, lactic acid, not CO 2 and H2O, is the end product. During hypoxia or anoxia, the accumulation of lactic acid may lower the pH within cells. As the intracellular environment becomes more acidic, some components, like membranes around lysosomes, may deteriorate causing cell injury or cell death. Figure 10: Summary of Causes, Development, and Results of Cell Injury Ischemia Anoxia Hypoxia Physical Agents Chemical Agents Biologic Agents Hypersensitivity Rxns Genetic Defects Nutritional Disorders Increased Work Load Aging

Etiologic Agents

Membrane Damage Anaerobic Respiration

Reversible Injuries

Free Radicals

Irreversible Injuries

Pathogenetic Pathways

Visible Cell Injuries

Somatic Death

Death of an entire organism is known as somatic death. When an entire organism dies, the event is called “somatic death” (soma- = body). In former days, heart and breathing stoppage were all the criteria necessary to declare someone dead. Now that eyes, kidneys, and other organs are obtained from the recently deceased, more precise legal definitions of death have been devised. Generally, these definitions include cessation for a predetermined length of time of 1) electrical activity in the heart as measured by the electrocardiograph, 2) electrical activity in the brain as measured by the electroencephalograph, and 3) respiratory activity. Television, movies, and highly visible murder trials have made the general public aware of the series of events occurri ng after death that assist in determini ng its time, location, and cause. Cooling of the body is a sign of somatic death—algor mortis. After somatic death, body temperature comes into equilibrium with that of the surrounding environment. Usually, the environmental temperature is lower than that of the body (98.6 oF.). That being the case, the body cools to the surrounding temperature, a process called “algor mortis” (algor = cold). This body cooling occurs at the fairly regular rate of 1 oF. per hour. By measuring the temperature of a corpse, it may be possible to estimate how long it has been dead.

Discoloration of the body is a sign of somatic death—livor mortis A short time after death, reddish splotches usually appear on the underside of the body. This postmortem discoloration is “livor mortis” (livor = color). It is caused by the stoppage of blood flow and the effect of

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gravity pooling blood in the lowest blood vessels. Depending on the position at death, livor mortis may be seen on the back, front, or sides.

Rigidity of the body is a sign of somatic death—rigor mortis About six to ten hours after death (in an unembalmed cadaver), skeletal muscles will become stiff, a condition known as “rigor mortis” (rigor = rigidity). This condition is caused by contraction of muscles through the gradual loss of ATP in the muscle cells (energy is expended to relax, not contract skeletal muscle). It starts with the muscles around the head and neck and descends to other muscle groups. After a day or so, relaxation occurs once again as muscles disintegrate completely. Certain blood clots are a sign of somatic death. With the cessation of blood flow, blood wi ll begin to clot within the vessels. Because blood tends to settle in veins these postmortem blood clots will be found in veins and also in the heart. Microbial putrefaction is a sign of somatic death. Microorganisms are everywhere. They are in the air, in water, on environmental surfaces, and in the body’s intestinal tract. After death, saprophytic (death-loving) organisms gain access to the disintegrating body tissues. They form colonies and digest the tissues by producing enzymes that break it up. This process produces the stench of decaying flesh. Refrigeration or embalming of the recently dead stops the process of putrefaction because microorganisms are inactive at low temperatures and cannot act upon tissue that has been chemically preserved.

Accumulations within the Stroma A group of changes within the stroma of tissues or organs caused by accumulation of some biologic substance. Often the microscopic appearance of these “stromal infiltrations” are specific enough to suggest specific diseases. Sometimes injury damages the stroma more than the parenchyma. Sometimes the effects of injury can be detected within the stroma as well as wi thin the parenchyma. In some cases, substances, usually produced by cells, appear among connective tissue fibers. In other cases they appear within connective tissue cells. Several names for these changes have been proposed; including “interstitial accumulations,” “stromal infiltrations,” and “connective tissue infiltrations.” Interstitial Accumulations

Adipose c.t. may accumulate in the stroma. Stromal Fat Accumulation —The appearance of abnormal amounts of adipose c.t. in atypical locations signifies some disease. Most often, fat accumulation is associated with atrophy of nearby parenchyma—as the parenchyma decreases in volume, the surrounding stroma increases its volume to compensate. If the increased stroma volume is largely adipose c.t., the term “stromal fat accumulation” is an appropriate diagnosis. This change may be seen anywhere; however, pancreas and cardiac stromas are common locations for it. Hyalinization of collagen is a common reaction of the stroma to injury. Hyalinization of C.T. —In certain conditions, collagen fibers composing fibrous c.t. become so abundant that they blend together. The result is a dense avascular (a- = without; -vascular = vessel) tissue that has a uniform, structureless, glassy LM appearance. “Hyalinization of c.t.” is the specific designation for these changes within fibrous connective tissue. Where there are several disease states featuring hyalinized c.t., t he common scar is a more common example. Accumulation of amyloid suggests the presence of some underlying disease. Amyloid —For over 100 years after Virchow discovered it, amyloid was a mystery substance. It was known to appear in the walls of blood vessels and among c.t. fibers in a variety of circumstances. It was also known to respond to special stains in a peculiar way in that it changed the color of the dye applied to it (metachromatic). Virchow called it “amyloid” because he detected carbohydrates with special stains (amyl= starch; -oid = like). Much more is known about amyloid now. This substance is an elongated (fibrous) protein that exists in at least three different states. Each of these forms of amyloid is associated with certain groups of diseases. For example, one form is associated with antibody overproduction, another with chronic

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inflammation, and a third with defective genes. A form of amyloid (beta amyloid) is seen in the brains of those who died of Alzheimer’s disease. Such amyloid accumulation is a subject of intense investigation. Therapies to prevent beta amyloid accumulation are being developed and tested. Extraskeletal Calcifications

Calcified masses may accumulate in the stroma or other extraskeletal sites. Hard, calcified masses sometimes appear in areas that are usually soft. Because the skeleton (and teeth) are the only normally hard calcified (calcium-containing) tissues and because the remainder of the body is uncalcified, the terms “extraskeletal sites” or “soft tissues” have been created to describe non-calcified tissues. Calcified stromal masses may be caused by too much calcium in plasma. Metastatic Calcification —If for some reason the level of calcium (Ca ++) rises in blood plasma (elevated serum calcium level), calcium salts may be deposited within soft tissues. Over-activity of the parathyroid

glands is one cause of this abnormal Ca ++ deposition. Metastatic calcifications appear when the serum levels rise to abnormally high levels forcing calcium salts to be deposited in previously normal tissue. The term “metastatic” is used here because hard calcified tissue in has changed its location (meta- = change; -static = location).

Calcified stromal masses may occur in previously injured tissues. Dystrophic Calcification —The appearance of hard calcified deposits in injured or damaged tissue is known as “dystrophic calcification.” In this form of pathologic calcification, it is tissue injury, not elevated serum Ca++ levels, that attracts calcium salts. The “hardening” the arteries results from calcium salt deposition in damaged arterial walls—dystrophic calcification. The calcification of tuberculosis lung lesions (allowing them to be visible with chest x-rays) is another example of dystrophic calcification.

Large chunks of calcium or cholesterol may occur in a excretory duct—lithasis. Lithiasis (Stones) —Hard masses sometimes block excretory ducts leading away from the liver, kidneys, and salivary glands. These masses are large enough to be detected clinically; they are commonly known as “stones” or more scientifically as condition of “lithiasis” (lith- = stone; -iasis = condition of). Stones block the outflow tracks from important organs. There are two substances from which stones may be created: cholesterol and calcium. Gall bladder stones are usually composed of cholesterol while those of kidney and salivary gland origin are usually composed of calcium. Pathologic Pigments

Colored substances, pigments, may accumulate in the stroma. There are a number of naturally-colored substances that appear in tissues. These are known collectively as “pigments.” Many pigments are products of normal and abnormal hemoglobin metabolism. Bilirubin is a blood pigment that causes jaundice. Bilirubin —Because red blood cells are recycled every three months, a lot of hemoglobin has to be recycled too. As the colored hemoglobin molecule is disassembled, some parts are discarded and others are saved. One of the discarded parts is a yellow-brown colored material called “bilirubin” (bili- = bile; -rubin = red). This substance accumulates in excessive amounts because of, for example, excessive red blood cell destruction. In these circumstances, the pigment may appear in the connective tissue under the skin imparting a yellow color (jaundice) to it. Hemosiderin is blood pigment often found in tissues. Hemosiderin —Another pigment derived from hemoglobin metabolism is “hemosiderin” (hemo- = blood; siderin = iron). This material differs from bilirubin in that it contains iron that is reactive with other chemicals (reactive iron). The presence of chemically reactive iron allows for hemosiderin’s recognition with stains with an affinity for iron. While some hemosiderin may result from normal hemoglobin metabolism, its presence in tissues often signifies some disease state. Prolonged stagnated blood flow with resultant red cell breakdown is one of the most common situations for its occurrence of hemosiderin.

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Melanin is a non-blood pigment normally found in skin. Melanin —There are a number of pigments that do not arise from hemoglobin metabolism. The most important of these is melanin, the pigment responsible for skin color. Melanin is produced from specialized cells known as “melanocytes” that migrate to the skin in embryonic life. Depending on racial and environmental influences there may be more or less of these cells and more or less pigment produced by them. Melanin can be over or under produced in a number of uncommon diseases.

References: Kumar, Abbas, Fausto: Pathologic Basis of Disease. Seventh Edition, Elsevier-Saunders, 2005.

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Learning Guide 1.

After completion of this topic, the student should be able to • write or identify the terms or the definitions presented in the following table • identify or write whether “hyperplasia,” “fatty change,” “atrophy,” “cloudy swelling,” “karyolysis,” “pyknosis,” and “hypertrophy” are “adaptations,” “reversible injuries,” or “necrosis.” • list or identify injurious agents that may cause reversible cell injuries and necrosis. • write or identify the role of membrane damage, free radicals, and anaerobic respiration have in reversible cell injuries and necrosis. • write or identify the differences between “hyperplasia” and “hypertrophy.” • list four reversible cell injuries and indicate the major microscopic features of each. • list and identify three nuclear indications of necrosis. • list and identify four special types of necrosis and the setting in which each occurs. • write or identify the differences between the three major types of stromal infiltrations.” • write or identify the differences between “metastatic” and “dystrophic” calcification.

2.

Associate (by identifying them) the following terms and their definitions. In other words, when confronted with the term or definition of the following, be able to pick the correct term/definition from a list (multiple choice or matching).

Amyloid

A fibrous protein that accumulates abnormally in a variety of diseases

Anoxia

Lack of oxygen.

Aplasia

Failure to develop at all.

Apoptosis

Programmed cell death.

Coagulation Necrosis

Cell death due to sudden ischemia; tissue remains recognizable for many hours.

Dystrophic Calcification

Appearance of calcified deposits in diseased tissues; not associated with hypercalcemia.

Gangrenous Necrosis

Death of cells due to ischemia and superimposed bacterial infection.

Hyalinization of C.T.

Pathologic hyaline transformation of fibrous c.t.

Hypoxia

Decreased amount of oxygen.

Karyolysis

Dissolving of the nucleus in a dead cell.

Karyorrhexis

Fragmentation of the nucleus in a dead cell.

Liquefaction Necrosis

Watery breakup of cells; tissues and cell detail is lost (LM).

Lithiasis

The condition of having stones.

Metaplasia

Conversion of one cell type to another (e.g. fibrous c.t. becoming bone)

Metastatic Calcification

Pathologic appearance of calcified deposits in tissues that were previously normal; usually associated with elevated serum calcium levels (hypercalcemia).

Pigment

A substance that has color in its natural state.

Pyknosis

Shrinkage and condensation of the nucleus in a dead cell.

Somatic Death

Death of the entire body, the entire organism, the entire person.

Squamous Metaplasia

Conversion of a single layered epithelium (e.g. simple columnar) to stratified squamous epithelium.

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3.


Associate (by writing them) the following terms with their definitions or with clinical examples of them. In other words, when confronted with the definition or example of the following, be able to write, and correctly spell, the defined term. In addition, be able to recognize the context in which each exists. In addition be able to pick the correct term/definition from a list (multiple choice or matching).

Anodontia

Failure of teeth to develop

Atrophy

Shrinkage of fully formed organs or tissues caused by shrinkage of individual cells

Hyperplasia

Increased size of a tissue or organ caused by increased number of cells

Hypertrophy

Increased size of a tissue or organ caused by increased size of cells

Hypoplasia

Failure to reach full size or full maturation

Ischemia

Decrease or blockage of blood flow to an organ or tissue.

Necrosis

Cell death; changes that appear (LM) in cells after they die

4.

By placing an “X” in the empty cells, match the printed terms with the definition.

a m u a r T

a i x o n A

a i x o p y H

s t n e g A c i g o l o i B

a i m e h c s I

s u o n e g o x E

s u o n e g o d n E

Definition

n o s i o P

decreased amount of oxygen chemical agents from outside a wound or injury bacteria and viruses decreased blood flow chemical agent damaging cells in very small amounts lack of oxygen chemical agents from inside 5.

By placing the an “X” in the empty cells, match the printed terms with the appropriate listed statement.

n i b u r i l i B

n i n a l e M

n i r e d i s o m e H

Statement

Pigment(s) derived from hemoglobin Pigment(s) NOT derived from hemoglobin

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6.


By placing an “X” in the empty cells, match the three terms with the correct printed explanation.

e g a m a D e n a r b m e M

s l a c i d a R e e r F

n o i t a r i p s e R c i b o r e a n A

Brief Explanation

With hypoxia or anoxia, lactic acid may accumulate lower the cell’s pH. Internal organelles or the cell ’s cytoskeleton may be damaged Hyper-reactive molecules like H202 may accumulate in cells react unfavorable with cytoplasmic fat or internal membranes. 7.

By placing the an “X” in the empty cells, match the printed terms with the appropriate listed feature.

e l b i s r e v E R

e l b i s r e v e r r I

Feature

Fragmented nucleus Low intensity injury High intensity injury Shrunken, dark nucleus Short duration injury Long duration injury Fat droplets in the cytoplasm Dissolving nucleus Water droplets in the cytoplasm Ghost-like cells

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8.


By placing the an “X” in the empty cells, match the printed terms with the appropriate listed condition.

n o i t a t p a d A

y r u j n I l l e C e l b i s r e v e R

y r u j n I l l e C e l b i s r e v e r r I

Condition

Hyperplasia Fatty change Atrophy Cloudy swelling Karyolysis Pyknosis Hypertrophy 9.

By placing the an “X” in the empty cells, match the printed terms with the appropriate listed situation.

a i s a l p r e p y H

y h p o r t r e p y H

Situation

Increased cell size Increased cell numbers Responsible increased size of endocrine glands. Responsible for increased muscle definition in weight-lifting. Occurs in cells incapable of division Occurs in cells capable of division

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10. By placing the an “X” in the empty cells, match the printed terms with the appropriate listed situation.

n o i t a c i f i c l a C c i t a t s a t e M

n o i t a c i f i c l a C c i h p o r t s y D

Situation

Increased plasma Ca +2 Calcification in damaged artery walls Patient with hyperparathyroidism Calcification of a lung lesion in tuberculosis Calcifications in widespread normal tissues Localized calcification in damaged tissues 11. By placing the an “X” in the empty cells, match the printed terms with the appropriate listed statement.

s i s o r c e N n o i t a l u g a o C

s i s o r c e N t a F

s i s o r c e N s u o n e r g n a G

s i s o r c e N s u o e s a C

Situation

Sudden ischemia to heart muscle Trauma to adipose c.t. Center of lesions found in tuberculosis Diabetes mellitus complication 12. placing the an “X” in the empty cells, match the printed terms with the appropriate listed situation

d i o l y m A

e n i l a y H

t a F l a m o r t S

Situation

Associated with parenchymal atrophy Often seen in scars Accumulates in antibody overproduction Dense collagen is a feature First appears in the walls of blood vessels Adipose c.t. a feature

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13. By placing the an “X” in the empty cells, match the printed terms with the appropriate listed situations.

n i n a l e M

a i s a l p r e p y H

y h p o r t r e p y H

a i s a l p a t e M s u o m a u q S

y h p o r t A

a i s a l p o p y H

s i s o r c e N n o i t a l u g a o C

s i s o r c e N s u o n e r g n a G

a i s a l p A

d i o l y m A

e g n a h C y t t a F

Situation

Decreased sizes/functions of organs with age Glycoprotein accumulation in Alzheimer’s brains Unexplained missing teeth Enlarged livers associated with chronic alcoholism Enlargement of the heart in congestive heart failure Spots of decreased calcification in tooth enamel Cell death associated with “heart attacks” Increased thyroid size due to TSH over-secretion Pigmented skin lesion (“mole”) Cell death in feet associated with diabetes mellitus Changes in bronchial epithelium preceding lung cancer

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Cell Adaptations and Response to Injury

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