Hypoxia

Hypoxia, or lack of sufficient oxygen, is the single most common cause of cellular injury. Hypoxia can result for many reasons, but these can be broadly classified into problems with oxygen entering the blood and problems with transporting oxygen around the body to the cells (see Figure 4-1).

FIGURE 4-1 The different causes of hypoxia.

1 Interruption of oxygen supply to the lungs. 2 Inadequate oxygen entering the blood in the lungs. 3 Inadequate transport of oxygen in the circulation.

Source: Based on Damjanov I. Pathology for the health professions. 3rd edn. St Louis: Saunders; 2006.

Conditions that cause inadequate oxygen delivery to the blood include:

diseases of the respiratory system, such as asthma

blockage of the upper airways in the lungs, whereby air cannot get into the lungs

a lower concentration of oxygen in the atmosphere, which occurs only with increasing altitude.

Hypoxia due to insufficient transport of oxygen through the body can occur because of:

a decrease in haemoglobin (which is the molecule inside red blood cells that carries oxygen around the blood)

decreased production of red blood cells (which means a decreased oxygen-carrying capacity)

diseases of the cardiovascular system (where the pumping ability of the heart is insufficient).

But by far the most common cause of hypoxia in the body is a reduction in blood supply to the cells. This is termed ischaemia, which literally means a restriction in blood flow. This may be observed in many hospital patients and contributes significantly to mortality. For instance, patients with ischaemia of the heart and brain often die because these organs need a constant supply of oxygen.

Ischaemic injury is often caused by the gradual narrowing of arteries (termed arteriosclerosis; see Chapter 23) and complete blockage by blood clots (thrombosis). Progressive hypoxia caused by gradual arterial obstruction is better tolerated than the sudden acute anoxia (total lack of oxygen) caused by a sudden obstruction, as with a blood clot or other plug in the circulation. An acute obstruction in a coronary artery can cause cell death within minutes if the blood supply is not restored.

Chemical agents

Chemical injury to the cell begins with a biochemical interaction between a toxic substance and the cell membrane, which is ultimately damaged, leading to increased permeability. This means that more substances, both harmful and non-harmful, can pass through the cell membrane. There are two general mechanisms:

Many chemical agents cause cellular injury. Highly toxic substances are known as poisons.

Minute amounts of some agents, such as cyanide, can rapidly destroy enough cells to cause the death of the individual in a very short period of time after exposure. Chronic exposure to air pollutants, insecticides and herbicides can also cause cellular injury. Carbon monoxide (in the exhaust of car fumes) and social drugs such as alcohol can significantly alter cellular function and injure cellular structures. Recreational, over-the-counter and prescribed drugs also may cause cellular injury, sometimes leading to death. Accidental or suicidal poisonings by chemical agents cause numerous deaths.

Physical agents

Physical agents that lead to cell injury include blunt trauma to the body resulting in damage to the tissues and penetrating wounds that pass the skin and enter the body, such as surgical incisions. Other forms of physical agents include environmental stressors such as high and low temperatures and sunlight.

Infectious agents

Infectious microorganisms can enter the body and multiply rapidly to cause disease. They may enter the cell, like viruses, or release toxins that are harmful to the cell. Infections in hospital patients are one of the most common clinical presentations and, accordingly, Chapter 14 examines the effects of infection.

Genetic causes

Genetic abnormalities can produce defects in cellular metabolism, alter the structure and function of cells and make cells more susceptible to injury. Genetic abnormalities and environmental influences on genes are discussed in Chapter 37.

Hypoxic injury

Cellular responses to hypoxic injury caused by ischaemia have been demonstrated in studies of the heart muscle. Within 1 minute of blood supply to the heart muscle (myocardium) being interrupted, the heart becomes pale and has difficulty contracting normally. Within 3–5 minutes, the ischaemic portion of the myocardium ceases to contract because of a rapid decrease in the ability of the mitochondria to produce ATP. Lack of ATP leads to increased anaerobic metabolism, which can only generate ATP from glycogen (a stored form of glucose) when there is insufficient oxygen. When glycogen stores are depleted, even anaerobic metabolism ceases and no ATP production occurs.

A reduction in ATP levels causes the cell membrane’s sodium–potassium (Na⁺–K⁺) pump and sodium–calcium exchange to fail, which leads to an intracellular accumulation of sodium and calcium and diffusion of potassium out of the cell. The sodium–potassium pump uses ATP to actively pump sodium out of the cell and potassium into the cell, which is vital to cell homeostasis. Sodium and water then can enter the cell freely causing cellular swelling; as well, early dilation of the endoplasmic reticulum results. Dilation causes the ribosomes to detach from the rough endoplasmic reticulum, reducing protein synthesis. With continued hypoxia, the entire cell becomes markedly swollen, with increased concentrations of sodium, water and chloride, and decreased concentrations of potassium.

It should be noted that these disruptions will be reversed if oxygen is made available and restored. However, if oxygen is not restored, swelling of lysosomes and marked mitochondrial swelling occurs. Continued hypoxic injury with accumulation of calcium subsequently activates multiple enzyme systems, resulting in membrane damage, cytoskeleton disruption, activation of inflammation, DNA degradation and eventual cell death (see Figure 4-2). Structurally, with plasma membrane damage, calcium from outside the cell readily moves into the cell and intracellular calcium stores are released. Intracellular calcium activates enzymes that can further damage cell membrane proteins, ATP and nucleic acids. Irreversible damage is characterised by two events:

FIGURE 4-2 ATP depletion.

Ischaemia causing hypoxia which leads to reduction in ATP production. If the hypoxic insult continues, a series of intracellular changes occur leading to cell death.

Restoration of oxygen, however, can cause additional injury called reperfusion injury (see Figure 4-3). Briefly, this occurs during the process of ATP production in the mitochondria, where oxygen is transformed to water and small amounts of partially reduced oxygen are formed, called free radicals. Reperfusion injury results from the generation of free radicals, which are chemically highly unstable and can cause damage to the cell membrane by undergoing destructive chemical reactions. This process is sometimes referred to as oxidative stress and is discussed in the next section.

FIGURE 4-3 Reperfusion injury.

A Without oxygen, or anoxia, the cells display hypoxic injury and become swollen. B With reoxygenation, reperfusion injury increases because of the formation of reactive oxygen radicals that can cause cell necrosis.

Source: Based on Damjanov I. Pathology for the health professions. 3rd edn. St Louis: Saunders; 2006.

The impact of oxygen and oxygen-derived free radicals

Although we require oxygen to survive, oxygen can actually be particularly harmful to cells — this is extremely surprising! To understand how this occurs, we need to delve into some chemistry. Free radicals are formed during ATP production from partially reduced oxygen molecules called reactive oxygen species. A free radical is an atom that is electrically uncharged yet is unstable; this means that it is prone to stealing or donating a charge from another molecule. When a molecule has its charge stolen, it becomes a free radical. Therefore, it is capable of injurious chemical bonding with proteins, lipids and carbohydrates — key molecules in membranes and nucleic acids (see Chapter 2).

Free radicals are highly reactive and can react with most molecules close by. Normally, this is not an issue, as the body produces only a small amount of free radicals. Furthermore, very efficient scavengers, called antioxidants, clean up these molecules before they can undergo chemical reactions. However, during periods of stress, more reactive oxygen species are produced and free radicals become more difficult to control. They accumulate when cells are injured and initiate many chain reactions, causing damage. The large numbers of reactive oxygen species overwhelm the balance by antioxidants. This inefficiency of antioxidants is even more serious in mitochondria because mitochondria do not have an enzyme to degrade the free radicals.¹ Consequently, excessive production of reactive oxygen species in mitochondria will damage lipids, proteins and mitochondrial DNA (mDNA), leading to irreversible cell death (see Figure 4-4).^{2–5 3 4 5} Mitochondrial oxidative stress has been implicated in heart disease, Alzheimer’s disease and Parkinson’s disease, as well as ageing itself.^{5–8 6 7 8}

FIGURE 4-4 An overview of reactive oxygen species formation and the effects on the cell.

Free radicals cause several damaging effects by (1) lipid peroxidation, which is the destruction of lipids leading to membrane damage and increased permeability; (2) attacking critical proteins that affect ion pumps and transport mechanisms; (3) fragmenting DNA, causing decreased protein synthesis; and (4) damaging mitochondria, causing the liberation of calcium into the cytoplasm. Because of the increased understanding of free radicals, a growing number of diseases and disorders have been linked either directly or indirectly to these oxygen reactive species (see Box 4-1).

Alteration to calcium homeostasis

The concentration of calcium inside the cell is quite low compared with the concentration in the extracellular fluid. Also, it tends to be stored in the mitochondria and endoplasmic reticulum and is released only when needed, so the amount of calcium actually in the cytoplasm is low. The role of calcium is to activate enzymes in the cell and it is intricately involved in muscle contraction. Therefore, like the sodium–potassium pump, calcium too is pumped out of the cell to keep the concentration low. However, if the cell membrane is damaged, such as occurs when the cell is hypoxic, calcium enters the cell and the concentration in the cytoplasm increases. Stored calcium is also released, further increasing the cytoplasmic concentration. Unfortunately, this increased intracellular calcium causes cell injury by:

FIGURE 4-5 The mechanism by which increases in intracellular calcium cause cellular damage.

Calcium enters the cell and is released from the stores in the mitochondria and endoplasmic reticulum. This activates enzymes that cause a decrease in ATP production and damage the cell membrane and nucleus.

Source: Based on Kumar V. Robbins & Cotran pathological basis of disease. 8th edn. Philadelphia: Saunders; 2010.

Atrophy

Atrophy is a decrease or shrinkage in cellular size. If atrophy occurs in a sufficient number of an organ’s cells, the entire organ shrinks and becomes smaller. Atrophy can affect any organ, but it is most common in skeletal muscle, the heart, secondary sex organs and the brain, and is especially related to ageing (see Figure 4-7). Atrophy can be classified as physiological or pathological. Physiological atrophy occurs with early development. For example, the thymus gland, a gland involved in immune system function, undergoes the normal process of physiological atrophy during childhood. The reasons for this are unknown. Pathological atrophy occurs as a result of decreases in workload, pressure, use, blood supply, nutrition and hormonal and nervous system stimulation. Individuals immobilised in bed for a prolonged time exhibit a type of skeletal muscle atrophy called disuse atrophy. This is prevalent in hospitalised patients who cannot be mobilised; for instance, patients with multiple bone fractures or significant obesity. Ageing causes brain cells to become atrophic and endocrine-dependent organs, such as the gonads (testes or ovaries), to shrink as hormonal stimulation decreases. Whether atrophy is caused by normal physiological conditions or by pathological conditions, atrophic cells exhibit the same basic changes.

FIGURE 4-7 Atrophy of the brain.

A Normal brain of a young adult. B Atrophy of the brain of an 82-year-old male with cerebrovascular disease, resulting in reduced blood supply. Note: the meninges (a vascular layer of the brain) have been stripped from the right half of each specimen to reveal the surface of the brain. Viewed from the top of the brain.

Source: Kumar V. Robbins & Cotran pathological basis of disease. 8th edn. Philadelphia: Saunders; 2010.

Cells that have atrophied contain less endoplasmic reticulum and fewer mitochondria than normal cells. These cells also reduce their oxygen consumption and amino acid uptake is reduced. The biochemical changes of atrophy are just beginning to be understood. The mechanisms probably include decreased protein synthesis, increased protein catabolism (breakdown), or both.⁹

Hypertrophy

Hypertrophy is an increase in the size of cells and consequently in the size of the affected organ. The cells of the heart and kidneys are particularly prone to enlargement. The increased cellular size is associated with an increased accumulation of protein in the cellular components (the cell membrane, endoplasmic reticulum and mitochondria) and not with an increase in cellular fluid. Hypertrophy, like atrophy, can be physiological or pathological and is caused by specific hormone stimulation or by increased functional demand. The triggers for hypertrophy include two types of signals: (1) mechanical signals, such as stretch; and (2) chemical signals, such as growth factors, which stimulate growth. For example, in skeletal muscles (the ones you contract to move bones), physiological hypertrophy occurs in response to heavy work. Hypertrophy is the mechanism that occurs in body builders who lift heavy weights repeatedly — the size of their muscles increases. Muscular hypertrophy tends to diminish if the excessive workload diminishes. Another example of normal or physiological hypertrophy is the increased growth of the uterus and mammary glands in response to pregnancy. A pathological example is pathophysiological hypertrophy of the heart, secondary to mechanical problems, such as faulty heart valves (see Figure 4-8).

FIGURE 4-8 Hypertrophy.

A Hypertrophy of heart muscle in the left ventricle (the major chamber of the heart). B Normal left ventricle size. Arrows indicate thickness of the muscle wall and demonstrate the large increase that occurs with hypertrophy. Images show a transverse slice through the heart.

Source: Kumar V et al. Robbins basic pathology. 8th edn. Philadelphia: Saunders; 2007.

Hyperplasia

Hyperplasia is an increase in the number of cells resulting from an increased rate of cellular division. Hyperplasia, as a response to injury, occurs when the injury has been severe and prolonged enough to have caused cell death. Loss of epithelial cells and cells of the liver and kidneys triggers DNA synthesis and mitotic division (discussed in Chapter 5). Increased cell growth is a multistep process involving the production of growth factors, which stimulate the remaining cells to produce new cell components and, ultimately, to divide. Hyperplasia and hypertrophy often occur together and both take place if the cells can produce DNA; however, in non-dividing cells only hypertrophy occurs.

Two types of normal, or physiological, hyperplasia are (1) compensatory and (2) hormonal. Compensatory hyperplasia is an adaptive mechanism that enables certain organs to regenerate. For example, removal of part of the liver leads to hyperplasia of the remaining liver cells (hepatocytes) to compensate for the loss. Even with removal of 70% of the liver, regeneration of the liver occurs over time! Hormonal hyperplasia occurs in response to release of a hormone. The most common example of this is enlargement of the uterus in the female when pregnancy occurs.

Pathological hyperplasia is the abnormal proliferation of normal cells, usually in response to excessive hormonal stimulation or growth factors on target cells. One of the most common examples of pathological hyperplasia in males is enlargement of the prostate, which occurs in a significant proportion of males over the age of 60 years.¹⁰

Metaplasia

Metaplasia is the reversible replacement of one mature cell type by another, sometimes less differentiated, cell type. It is thought to develop from a reprogramming of stem cells (cells that replicate and can turn into one of many different types of cells) in epithelial or connective tissue. These precursor cells mature along a new pathway because of chemical signals in the cells’ environment. This may be precipitated by a persistent irritant to the cells, such as cigarette smoking. Metaplasia occurs when normal epithelial cells lining the upper airways in the lungs (columnar cells) are replaced by stratified squamous epithelial cells (see Figure 4-9). The newly formed cells do not secrete mucus or have cilia (projections that protect the lining of the airway), causing loss of a vital protective mechanism. Metaplasia can be reversed if the inducing stimulus, cigarette smoking in this example, is removed. With prolonged exposure to the inducing stimulus, however, dysplasia and cancerous transformation may occur.

FIGURE 4-9 Metaplasia and dysplasia of cells in the upper airway of the lungs.

These cell changes are reversible if the irritant stimulus is removed.

Dysplasia

Dysplasia refers to abnormal changes in the size, shape and organisation of mature cells (see Figure 4-9). Dysplasia is not considered a true adaptive process but is related to hyperplasia. Dysplastic changes are often encountered in epithelial tissue of the cervix and respiratory tract, where they are strongly associated with cancer development. However, it should be noted that dysplastic cell changes are likely to be adaptive in nature, but have gone off course, meaning that if the inciting stimulus is removed early enough, dysplastic changes are often reversible.

Reversible cell injury

Cellular injury occurs if the cell is unable to maintain homeostasis (see Figure 4-11). However, not all injured cells die — some may recover. The exact mechanisms for why some cells survive and recover and others progress to cell death is not fully understood. This feature has been termed the ‘point of no return’ and is the defining feature of reversible cell injury. If this point is not passed, the cell can recover.

FIGURE 4-11 Stages of cellular response to stress and injurious stimuli.

Source: Kumar V. Robbins & Cotran pathological basis of disease. 8th edn. Philadelphia: Saunders; 2010.

Intracellular accumulations, also known as infiltrations, occur not only when injury is sub-lethal and sustained in injured cells, but also in normal cells. Such accumulations can may or may not be toxic to the cell and consist of substances that are normally present, such as fluids and electrolytes, lipids, glycogen, calcium and proteins. Abnormal accumulations of these substances can occur in the cytoplasm (often in the lysosomes) or in the nucleus if: (1) the normal, endogenous substance is produced in excess or at an increased rate; (2) a substance (normal or abnormal) is not effectively catabolised, usually because of a lack of a vital lysosomal enzyme; or (3) harmful exogenous materials, such as heavy metals or microorganisms, accumulate because of inhalation, ingestion or infection.

Two types of intracellular accumulation are commonly associated with reversible cell injury:

Water swelling. Cellular swelling, the most common degenerative change, is caused by the shift of extracellular water into the cells. In hypoxic injury, movement of fluid and ions into the cell is associated with acute failure of metabolism and loss of ATP production. Normally, the pump that transports sodium ions out of the cell is maintained by the presence of ATP (the sodium–potassium pump). In metabolic failure caused by hypoxia, reduced ATP allows sodium to accumulate in the cell while potassium diffuses outwards. This is not normal, as sodium should be in greater concentrations outside the cell and potassium greater inside the cell. The increased intracellular sodium increases osmotic pressure, drawing more water into the cell. The endoplasmic reticulum becomes distended, ruptures and forms large vacuoles (enclosed compartments) that isolate the water from the cytoplasm. If cellular swelling affects all the cells in an organ, the organ increases in weight and becomes distended (stretched) and pale.

Increased deposition of lipids. Although lipids sometimes accumulate in heart and kidney cells, the most common site of intracellular lipid accumulation, or fatty change, is liver cells. Because hepatic (liver) metabolism and secretion of lipids are crucial to proper body function, imbalances and deficiencies in these processes lead to major pathological changes. Lipid accumulation in liver cells causes fatty liver or fatty change (see Figure 4-12). As lipids fill the cells, vacuolation pushes the nucleus and other organelles aside. Lipid accumulation in liver cells occurs after cellular injury. Grossly, the liver looks yellowish and greasy.

FIGURE 4-12 Fatty liver.

A Normal liver in the upper abdomen (dashed black line). It has a shiny, smooth appearance and is a deep red colour. B Fatty liver due to accumulation of lipid intracellularly. The liver is pale yellow and smooth (the front or anterior part of the liver has been removed).

Source: Klatt EC. Robbins & Cotran atlas of pathology. 2nd edn. Philadelphia: Saunders; 2010.

Irreversible cell injury

If the stimulus is severe and sustained and the ‘point of no return’ is passed, irreversible cell injury ensues and the cell dies. However, there are two types of irreversible cell injury and their mechanisms are quite different (see Figure 4-11):

Apoptosis is programmed cell death that causes self-destruction of the cell.

Necrosis is a common form of cellular death with severe cellular swelling and breakdown of the organelles in response to sustained, severe, noxious stimuli.

The defining feature between these two forms is that apoptosis is usually a normal cellular function that is not associated with any form of cellular insult, whereas necrosis always arises in response to pathophysiological processes.

Apoptosis

Apoptosis (‘dropping off’) is an important, distinct type of cell death that differs from necrosis in several ways (see Figure 4-13). Apoptosis is an active process of cellular self-destruction called programmed cell death. Why would cells be programmed to die after a set amount of time? The answer is very simple: cells need to die otherwise endless proliferation would lead to gigantic bodies. In addition, cells become ‘worn out’ and need to be replaced. Every day the average adult may create 10 billion new cells — and kill off the same number.¹¹ A specific set of enzymes and genes are activated to cause apoptosis. These genes are sometimes called suicide cells because their activation by the nucleus inactivates so-called life-sustaining genes and promotes pathways leading to killer genes.

FIGURE 4-13 Schematic illustration of the changes in cell injury causing necrosis and apoptosis.

A If the cellular injury is reversible, the cell may recover and return to normal. If the injury is irreversible, the cell progresses through to necrosis. B On the other hand, apoptosis is an intentional program to cause cell suicide.

Source: Based on Kumar V. Robbins & Cotran pathological basis of disease. 8th edn. Philadelphia: Saunders; 2010.

Apoptosis affects scattered, single cells; however, there are examples of it occurring in widespread areas. The process of apoptosis consists of nuclear and cytoplasmic shrinkage of a cell. This is followed by fragmentation into membrane-bound fragments and subsequent phagocytosis (literally cell eating — specialised cells (phagocytes) perform this task, and these are discussed in detail in Chapter 12) by neighbouring healthy cells. As a controlled process in normal development, apoptosis determines the size, patterning and function of many tissues.^12,13 Apoptosis occurs throughout the life span — from birth to old age. It can be activated by outside factors — for example, a long-lasting viral infection — or triggered internally by the absence of certain growth factors (these normally stimulate tissues to grow). Accordingly, apoptosis can be classified as physiological or pathological:

Physiological apoptosis is important in the development of body tissue. It is responsible for local deletion of cells during tissue turnover and normal embryonic development. One important example of widespread areas of apoptosis is in the central nervous system during childhood and adolescence. We are born with far more neurons than are required in the adult brain and apoptosis in the early years of life removes the unnecessary neurons.

Pathological apoptosis is the result of intracellular events or adverse external stimuli. For example, deficiencies of specific enzymes can lead to diseases where cells have undergone apoptosis. Liver cells infected with viral hepatitis C, for example, can undergo apoptosis.

Necrosis

Cellular death eventually leads to cellular dissolution or necrosis. Necrosis is the sum of cellular changes after local cell death and the process of cellular self-digestion known as autodigestion, or autolysis (see Figure 4-13). Cells die long before any necrotic changes are noted by light microscopy.¹⁴ The structural signs that indicate irreversible injury and progression to necrosis are dense clumping and progressive disruption of genetic material, and disruption of the cellular and organelle membranes. In later stages of necrosis, most organelles are disrupted and karyolysis (dissolving of the nucleus due to enzymes) is under way. In some cells, the nucleus shrinks and becomes a small, dense mass of genetic material (pyknosis). The pyknotic nucleus eventually dissolves by karyolysis as a result of the action of lysosomal enzymes on DNA. These processes are shown in Figure 4-14.

FIGURE 4-14 Different stages of necrosis — pyknosis and karyolysis.

Different types of necroses tend to occur in different organs or tissues and sometimes can indicate the mechanism or cause of cellular injury. The four major types of necroses are coagulative, liquefactive, caseous and fatty. Another type, gangrenous necrosis, is not a distinctive type of cell death but refers instead to larger areas of tissue death. These necroses are summarised as follows:

Coagulative necrosis. Occurs primarily in the kidneys, heart and adrenal glands and commonly results from hypoxia caused by severe ischaemia. Coagulation is caused by protein denaturation (a process that modifies the molecular structure of protein), which causes the protein albumin to change from a gelatinous, transparent state to a firm, opaque state (see Figure 4-15).

Liquefactive necrosis. Commonly results from ischaemic injury to nerve cells in the brain (see Figure 4-16). Dead brain tissue is readily affected by liquefactive necrosis because brain cells are rich in digestive enzymes and lipids and the brain contains little connective tissue. Cells are digested by their own enzymes, so the tissue becomes soft, liquefies and is walled off from healthy tissue.

Caseous necrosis. Usually results from a lung infection that caused tuberculosis (see Figure 4-17). It is a combination of coagulative and liquefactive necroses. The dead cells disintegrate, but the debris is not completely digested by enzymes. Tissues resemble clumped cheese — hence the name caseous, in that they are soft and granular.

Fat necrosis. Fat necrosis is cellular dissolution caused by powerful enzymes, called lipases, that occur in the pancreas and other abdominal structures (see Figure 4-18). Lipases break down triglycerides, releasing free fatty acids, which then combine with calcium, magnesium and sodium ions, creating soaps (called saponification). The necrotic tissue appears opaque and chalk-white.

Gangrenous necrosis. Refers to the death of tissue and results from severe hypoxic injury. This commonly occurs because of blockages of arteries, particularly those in the lower leg (see Figure 4-19). With hypoxia and subsequent bacterial invasion, the tissues can undergo necrosis. In dry gangrene the skin becomes very dry and shrinks, resulting in wrinkles, and its colour changes to dark brown or black. Wet gangrene develops when the main white blood cells of the body, neutrophils, invade the site, causing liquefactive necrosis. This usually occurs in internal organs, causing the site to become cold, swollen and black. A foul odour is present, and if systemic symptoms become severe, death can ensue.

FIGURE 4-15 Coagulative necrosis.

This picture of a kidney shows a wedge shape of dead cells (yellow).

Source: Kumar V. Robbins & Cotran pathological basis of disease. 8th edn. Philadelphia: Saunders; 2010.

FIGURE 4-16 Liquefactive necrosis.

An area in the brain of necrosis, showing dissolution of the tissue (dashed line). The arrow indicates a blood clot that caused the cell death.

Source: Kumar V. Robbins & Cotran pathological basis of disease. 8th edn. Philadelphia: Saunders; 2010.

FIGURE 4-17 Caseous necrosis.

Tuberculosis of the lung, with a large area of caseous necrosis containing yellow-white and cheesy debris.

Source: Kumar V. Robbins & Cotran pathological basis of disease. 8th edn. Philadelphia: Saunders; 2010.

FIGURE 4-18 Fat necrosis.

The areas of white chalky deposits throughout the tissue represents fat necrosis with soap formation (saponification) at sites of lipid breakdown.

Source: Kumar V. Robbins & Cotran pathological basis of disease. 8th edn. Philadelphia: Saunders; 2010.

FIGURE 4-19 Gangrenous necrosis.

Dry gangrene of the toe from severe ischaemia to the lower leg.

Source: Damjanov I. Pathology for the health professions. 3rd edn. St Louis: Saunders; 2006.

FOCUS ON LEARNING

1. Distinguish between reversible and irreversible cell injury.

2. Explain the mechanisms for the most common forms of intracellular accumulations associated with reversible cell injury.

3. Differentiate between necrosis and apoptosis, and explain the different mechanisms.

4. List four types of necrosis and the tissues that are likely to be affected in each case.

Genetic and environmental factors

Cellular ageing results from wear and tear that causes functional changes and eventual cellular death. Cells may become damaged during replication as a result of factors within the cell, such as DNA and protein mechanisms, or factors outside the cell. Cells may already be programmed at birth or injured during life so as to cause errors in mitosis and in the replication of genetic material, eventually leading to either cellular atrophy or death. Atrophy is common in the testes, ovaries, uterus and breasts of aged individuals, although these organs age differently.

One genetic mechanism of ageing is programmed ageing. Regardless of damaging environmental factors, some investigators think that each normal cell may have a finite life span during which it can replicate. This may be in the form of a genetic program that progressively slows or shuts down physiological mechanisms, including mitosis, and so cells are not replaced.

Extracellular factors (those outside of the cell) that affect the ageing process include the binding of connective tissue, which makes it stiffer; the increase in free radicals’ effects on cells; the structural alterations of tendons, ligaments, bones and joints; and diseases of the blood vessels, particularly athersclerosis (see Chapter 23).

Reactive oxygen species, produced during aerobic metabolism, damage tissues during the ageing process. These oxygen products are extremely reactive and can damage nucleic acids, destroy carbohydrates, damage proteins and fatty acids, and kill cells. Oxidant effects on target cells can also cause DNA damage. That progressive and cumulative damage from oxygen radicals may lead to harmful alterations in cellular function is consistent with those alterations of ageing. Because these oxygen-reactive species not only can permanently damage cells but also may lead to cell death, there is new support for their role in the ageing process. The combination of genetic and environmental factors on ageing is summarised in Figure 4-20.

FIGURE 4-20 Mechanisms involved in ageing.

Genetic and environmental factors combine to produce the characteristic features in cellular structure and function associated with ageing.

Source: Based on Kumar V. Robbins & Cotran pathological basis of disease. 8th edn. Philadelphia: Saunders; 2010.

Cellular, tissue and systemic ageing

The maximal life span of humans is between 80 and 100 years. In Western societies, many individuals attain the maximal life span, which is primarily due to improvements in nutrition, housing, water quality, hygiene, sanitation and, importantly and relevant to you as a student of health science, health care. Although the maximal life span has not changed significantly over time, the average life span, or life expectancy, has increased steadily in Western countries over the last 100 years. It is anticipated that this trend will continue,¹⁶ although this has been disputed due to increasing obesity and diabetes mellitus epidemics.¹⁷ In addition, the death rate in the elderly population — those 65 years of age and older — has declined significantly, largely as a result of decreased incidence and superior management of cardiovascular disease.

Cellular changes characteristic of ageing include atrophy, decreased function and loss of cells, possibly caused by apoptosis. Loss of cellular function from any of these causes initiates the compensatory mechanisms of hypertrophy and hyperplasia of remaining cells, which can lead to metaplasia, dysplasia and cancers. In the aged cell, DNA, RNA, cellular proteins and membranes are most susceptible to injurious stimuli. DNA is particularly vulnerable to such injuries, which can cause breaks, deletions and additions in the DNA code. Lack of DNA repair increases the cell’s susceptibility to mutations that may be lethal or promote the development of cancer (see Chapters 36 and 37).

It is probably safe to say that every physiological process functions less efficiently with increasing age. The most characteristic tissue change with age is a progressive stiffness or rigidity that affects many systems, including the arterial, pulmonary (lungs) and musculoskeletal systems. A consequence of blood vessel and organ stiffness is a progressive increase in the resistance to blood flow, which means that cells and tissues may not receive enough blood supply. Changes in the endocrine and immune systems affect the elderly individual’s ability to combat invasions of foreign substances, like bacteria. In women, the reproductive system loses oocytes, and in men sperm production decreases. The stomach experiences decreases in the rate of emptying and secretion of hormones and acid. Muscular atrophy diminishes mobility by decreasing motor tone and contractility. Sarcopenia, loss of muscle mass and strength, can occur into old age. The skin of the aged individual is affected by atrophy and wrinkling of the epidermis and alterations in the underlying dermis, fat and muscle. We consider each of these changes as we progress through the chapters on individual body systems.

Total body changes include a decrease in height; a reduction in circumference of the neck, thighs and arms; widening of the pelvis; and lengthening of the nose and ears. Several of these changes are the result of tissue atrophy and decreased bone mass. Body composition changes with age. With middle age, there is an increase in body weight (men gain weight until about 50 years of age and women until 70 years) and fat mass, followed by a decrease in stature, weight, fat-free mass (which includes all minerals, proteins and water plus all other constituents except lipids) and body cell mass at older ages. As fat increases, total body water decreases, so older individuals have less body water and are more prone to dehydration. Increased body fat and centralised fat distribution (abdominal) are associated with diabetes mellitus and heart disease. Some of these changes are summarised in Figure 4-21.

FIGURE 4-21 Biological changes associated with ageing.

Insets show the proportion of remaining function in the organs of an elderly person compared with that of a 20-year-old. These data are for illustration only; individuals exhibit highly variable changes over the life span.

Source: Based on Patton KT, Thibodeau GA. Anatomy & physiology. 7th edn. St Louis: Mosby; 2010.

Although some of these alterations are probably inherent in ageing, others represent consequences of the process. Advanced age increases susceptibility to disease, and death occurs after an injury or insult because of diminished cellular, tissue and organic function.