Cell Adaptations and Response to Injury

PTHL 312a: Basic Disease Processes Cell Adaptations and Responses to Injury

©2007 William H. Crawford, Jr., D.D.S., M.S. All rights reserved. Copying for commercial purposes is prohibited. 15

Topic 2:

Cell Adaptations and Responses to Injury

IntroductionCell Adaptations

AtrophyHyperplasia and Hypertrophy

General FeaturesHyperplasiaHypertrophy

MetaplasiaDevelopmental Adaptations

Aplasia (Agenesis)Hypoplasia

Reversible and Irreversible Cell Responses to Injury

General Cell Responses to InjuryReversible Cell Injury

General Features of Reversible Cell InjuriesTypes of Reversible Cell Injuries

Irreversible Cell Injury—NecrosisGeneral Features of NecrosisRecognition of NecrosisSpecial Types of Necrosis

General Etiology of Cell InjuryGeneral Pathogenesis of Cell InjurySomatic Death

Accumulations in the StromaInterstitial Accumulations

Stromal Fat AccumulationHyalinization of Connective TissueAmyloid

Extraskeletal CalcificationsMetastatic CalcificationDystrophic CalcificationStone Formation—Lithiasis

Pathologic Pigments

ReferencesLearning Guide

ObjectivesDefinitionsWorkbook

Web SiteImagesStudy QuestionsDefinitions “Flash Cards”Terms “Flash Cards”Web Reader with ImagesReader/Learning Guides PDF


IntroductionIn 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 AdaptationsA 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 followed by changes at the tissue and organ levels. For example, if 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.

AtrophyCells often decrease their size in response to an injury—atrophyAtrophy 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 already 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).

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.

Figure 1: Atrophy

NormalDevelopment

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.

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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.

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 atrophic 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 HypertrophyGeneral FeaturesHyperplasia and hypertrophy are responses to increased demands on cells.When increased demand is placed on certain cell populations, they will respond by increasing 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 larger 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.HyperplasiaCells may adapt by increasing their numbersWhen 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.

Table 1: Causes of Atrophy

• Ischemia• Pressure• Disuse• Exhaustion• Hormones

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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 the case with benign and malignant tumors.HypertrophyCells 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

MetaplasiaCells may transform themselves—metaplasiaFaced 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.

Hyperplasia

Hypertrophy

Same sizes,

Increased sizes,

increased numbers

same numbers

Figure 3: Connective Tissue and Epithelial Metaplasia

SquamousMetaplasia

Fibrous C.T. Bone or CartilageMetaplasia

C.T.

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Developmental AdaptationsAplasia (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)

HypoplasiaSometimes 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 nutrient 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.

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

Expected size

Actual size

Figure 5: Hypoplasia

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

Expected size Actual siz

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Reversible and Irreversible Cell Responses to Injury

General Cell Responses to InjuryCells 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.

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 is, 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 6: Stages in the Development of Reversible Responses to Injury

When a normal cell is injured, it undergoes 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-stand-ing one (hours).

NormalCell

InjuryIntensity/duration

Reversible Responses

MolecularLesion

EMLesion

LMLesion

GrossLesion

Figure 7: Potential Changes Following Injury of a Cell

NormalCell

ReversibleChanges

(Degenerations)

Adaptive Changes

(Adaptations)

Irreversible Changes(Necrosis)

Stress

Increased Workload

Injuries

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Reversible Cell InjuryChanges 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.

Types of Reversible Cell Responses to InjuryWater may accumulate in degenerating cells.Cellular Swelling—Water may accumulate in the cytoplasm of cells. Virchow noted the 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 ring effect). There have been many competing names given 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 to 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.

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

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Irreversible Cell Damage—NecrosisA 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 NecrosisWhen 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 intestinal 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).

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.

Table 3: Types of Cell Death

Term Definition

Necrosis Pathologic antemortem cell death

Autolysis Postmortem cell deathApoptosis Antemortem programmed cell

death

Figure 8: Stages in the Development of Necrosis

NormalCell

InjuryIntensity/duration

Necrosis

MolecularLesion

EMLesion

LMLesion

GrossLesion

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.

Cell Death

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Recognition of NecrosisDamage 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.

Special Types of NecrosisCertain 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 killed, 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 two examples of cells that have relatively 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.

Figure 9: Nuclear Changes in Necrosis

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

is dead.

Normal Nucleus

Pyknosis

Karyolysis

Karyorrhexis

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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 to 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 lipases, 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-smelling—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.

General Etiology of Cellular DamageSeveral “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 brain 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

Table 4: Disease Associated with Special Types of Necrosis

Special Necrosis Type Signify These DiseasesLiquefaction Bacterial InfectionCoagulation Myocardial InfarctionFat TraumaGangrenous Diabetes MellitusCaseous TuberculosisGummatous Tertiary Syphilis

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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.

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 in which glycogen accumulates abnormally in body cells. This uncommon disease is caused by the absence of an

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

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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 that cells in older individuals are less adaptable and more likely to undergo degeneration and death.

General Pathogenesis of Cell DamageThere 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, the 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.

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 materials leak from organelles into the surrounding cytoplasm and 2) unwanted substances cross the damaged membranes. 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 membrane 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 (O2

-), 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

Table 6: Pathogenesis of Cell Injuries

Damaged cell membranesFree radical productionAltered cell respiration

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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 water 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, important cell organelles. In the absence of O2, energy (as ATP) can still be created; however, lactic acid, not CO2 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.

Somatic DeathDeath 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 occurring after death that assist in determining 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 (98.6oF.). 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 1oF. 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 mortisA 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

Figure 10: Summary of Causes, Development, and Results of Cell Injury

IschemiaAnoxia

HypoxiaPhysical AgentsChemical AgentsBiologic Agents

Hypersensitivity RxnsGenetic Defects

Nutritional DisordersIncreased Work Load

Aging

Membrane DamageAnaerobic Respiration

Free Radicals

Reversible InjuriesIrreversible Injuries

Etiologic Agents Pathogenetic Pathways Visible Cell Injuries

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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 mortisAbout 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 will 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 StromaA 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 within 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 AccumulationsAdipose 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., the 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

28


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 CalcificationsCalcified 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 PigmentsColored 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 dis-eases

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 pre-viously normal; usually associated with elevated serum calcium lev-els (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).

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

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

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

Trau

ma

Anox

ia

Hyp

oxia

Biol

ogic

Age

nts

Isch

emia

Exog

enou

s

Endo

geno

us

Pois

on

Definition

decreased amount of oxygenchemical agents from outsidea wound or injurybacteria and virusesdecreased blood flowchemical agent damaging cells in very small amountslack of oxygenchemical agents from inside

Bilir

ubin

Mel

anin

Hem

osid

erin

Statement

Pigment(s) derived from hemoglobinPigment(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.

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

Mem

bran

e D

amag

e

Free

Rad

ical

s

Anae

robi

c Re

spir

atio

nBrief Explanation

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

REve

rsib

le

Irre

vers

ible

Feature

Fragmented nucleusLow intensity injuryHigh intensity injuryShrunken, dark nucleusShort duration injuryLong duration injuryFat droplets in the cytoplasmDissolving nucleusWater droplets in the cytoplasmGhost-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.

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

Adap

tatio

n

Reve

rsib

le C

ell I

njur

y

Irre

vers

ible

Cel

l Inj

ury

Condition

HyperplasiaFatty changeAtrophyCloudy swellingKaryolysisPyknosisHypertrophy

Hyp

erpl

asia

Hyp

ertro

phy

Situation

Increased cell sizeIncreased cell numbersResponsible increased size of endocrine glands.Responsible for increased muscle defini-tion in weight-lifting.Occurs in cells incapable of divisionOccurs 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.

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

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

Met

asta

tic C

alci

ficat

ion

Dys

troph

ic C

alci

ficat

ion

Situation

Increased plasma Ca+2

Calcification in damaged artery wallsPatient with hyperparathyroidismCalcification of a lung lesion in tuberculosisCalcifications in widespread normal tissuesLocalized calcification in damaged tissues

Coa

gula

tion

Nec

rosi

s

Fat N

ecro

sis

Gan

gren

ous N

ecro

sis

Cas

eous

Nec

rosi

s

Situation

Sudden ischemia to heart muscleTrauma to adipose c.t.Center of lesions found in tuberculosisDiabetes mellitus complication

Amyl

oid

Hya

line

Stro

mal

Fat

Situation

Associated with parenchymal atrophyOften seen in scarsAccumulates in antibody overproductionDense collagen is a featureFirst appears in the walls of blood vesselsAdipose 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. M

elan

in

Hyp

erpl

asia

Hyp

ertro

phy

Squa

mou

s Met

apla

sia

Atro

phy

Hyp

opla

sia

Coa

gula

tion

Nec

rosi

s

Gan

gren

ous N

ecro

sis

Apla

sia

Amyl

oid

Fatty

Cha

nge

Situation

Decreased sizes/functions of organs with ageGlycoprotein accumulation in Alzheimer’s brainsUnexplained missing teethEnlarged livers associated with chronic alcoholismEnlargement of the heart in congestive heart failureSpots of decreased calcification in tooth enamelCell death associated with “heart attacks”Increased thyroid size due to TSH over-secretionPigmented skin lesion (“mole”)Cell death in feet associated with diabetes mellitusChanges in bronchial epithelium preceding lung cancer

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Cell Adaptations and Response to Injury

Documents

basic disease

decreased

reach full

cell size

kidney tubule

calcified

reversible

injurygeneral