Concept of Illness

Pathophysiological Process of Illness

Is the study of biologic and physical manifestations of n illness s they correlate
with the underlying abnormalities and physiologic disturbances

Illness
Is the state in which a person,s physical, emotional, intellectual, social,
developmental and spiritual funtioning is deminished or imapaired; personal state.

Disease
Is the alteration inbody’s function resulting in reduction of capaciies of normal
life span.
‘a person may have an illness as a result of a disease”

Common Causes of Disease

1. Biologic agents
2. Inhereted geneticdefects
3. Developmental defects
4. Physical agents
5. Chemical agents
6. Tissue response to irritation/injury
7. Faulty chemical/ metabolic process
8. Emotional/physical reaction to stress

Stages of Illness
1. Sypmtom experience
A person believes that something is wrong.
Aspects:
Physical – fear, muscleaches, malaise and headache
Cognitive – perception of having “flu”
Emotional – worry on consequences of illness
2. Assumption of sick role
Acceptance of illness
Seek advice, support for decision to give up some activities.
3. Medical Care Contact
Seek advice of health professionals for the following reasons
- Validation of real illness
- Explanation of symptoms
- Reassurance or prediction of outcome
4. Dependent patient role
A person becomes a client on the health professional and seek for help
Accepts/ rejects health professional suggestion
5. Recovery/ rehabilitation
Gives up the sick role and returns to former rules and functions
Classification of Disease
According to etiologic factors
1. heredity – defects on genes of one/both parents
2. congenital – defects during developmental, prenatal and at birth
3. metabolic – disturbances in metabolism
4. deficiency – inadequate absorption of essential dietary factors
5. traumatic – injury
6. allergic – abnormal body response to chemicals
7. neoplastic – abnormal or uncontrolled growth of cells
8. idiopathic – unknown cause; self-origiated
9. degenerative – degenerative changes in tissue or organs
10. iatrogenic – results from treatment of a disease
According to duration or onset
1. acute illness
short duration and severe
signs and symptoms appears abruptly, intense and subsides after a short period
In medicine, an acute disease is a disease with either or both of:
a rapid onset, as in acute infection
a short course (as opposed to a chronic course).
This adjective is part of the definition of several diseases and is, therefore,
incorporated in their name, for instance, severe acute respiratory syndrome, acute
leukemia.
The term acute may often be confused by the general public to mean 'severe'. This
however, is a different characteristic and something can be acute but not severe.
Acute hospitals are those intended for short-term medical and/or surgical
treatment and care. The related medical speciality is called acute medicine.
2. chronic
Persists longer than 6 months
Patient may fluctuate between maximal functioning to serious relapse that may be
life threatening
Characteristics:
Remission – disease is controlled and symptoms are not obvious
Exacerbation – disease becomes
More active and symptoms recurrence becomes more pronounced
3. Subacute
Symptoms are pronounced but more prolonged than an acute disease (e.g.
sunacute endocarditis)
Subacute is defined as between acute and chronic, for example subacute fever
symptoms or subacute endocarditis. An example is subacute sclerosing
panencephalitis, a rare brain disease characterized by diminished intellectual
function and loss of nervous function.
Disease may also be described as:
1. organic – reulsty from changes in normal structure; it is recognizable anatomical
change in organs
2. functional – no anatomical change; results from abnormal response tio a stimuli
3. occupational – associated with occupational hazards
4. familial – genetics; occurs in individual belonging to one family
5. venereal – sexual relation
6. epidemic - attracts a large number of individuals in a community at the same time.
Defining an epidemic can be subjective, depending in part on what is "expected".
An epidemic may be restricted to one locale (an outbreak), more general (an
"epidemic") or even global (pandemic). Because it is based on what is "expected"
or thought normal, a few cases of a very rare disease may be classified as an
"epidemic," while many cases of a common disease (such as the common cold)
would not.
7. endemic – results more or less continuously or recurs in community. (eg. Malaria)
Common diseases that occur at a constant but relatively low rate in the population
are said to be "endemic." An example of an endemic disease is malaria in some
parts of Africa (for example, Liberia) in which a large portion of the population is
expected to get malaria at some point in their lifetime.Another is the bubonic
plague or "Black Death" that swept through Europe in the 1340s, killing millions.
8. pandemic – wide spread.

9. sporadic – disease occuring occasionally. ( dengue –rainy season)

Illness involves 6 basic underlying processess:

1. Cell deviation
2. Break in body defenses ad barriers
3. Changes in fluid and electrolyte balance
 4. Changes in acid and base balance
5. Shock and hemorrhage
6. Degeneration

Cellular Deviation
Serious problems can occur when there is a deviation, change or alteration in the
structure and rowth of cells
Cells may enlarge, increase in number and form in other locations
Cells is the basic structural and functional unit of the body
Cells are covered or lined with a semi-permeable membrane and the process
wherein the fluids pass therough cell membrane is by osmosis.
Cells contains cytoplasm wherein all organelles lies.
Cells contains cytoplasm wherein all organelles lies.
It also contains nucleus, lysosomes, mitochondria, endoplasmic reticulum,
centrioles and golgi complex.
Cells undergo cell division for cell growth.
Any alteration in the cell growth these alteration is then termed as cellular
deviation.
Tissue growth depends on the number of cells actively dividing, cell cycle and the
number of cells lost.
Cell deviation results to cellular disturbance

Cellular disturbance
Occurs when there are more cells dividing, decrease cells in resting phase and
faulty differentiation.
Terminologies
1. agenesis – absence of an organ
In medicine, agenesis refers to the failure of an organ to develop during embryonic
growth and development. Many forms of agenesis are referred to by individual
names, depending on the organ affected:

• Agenesis of the corpus callosum- failure of the Corpus callosum to develop

• Renal agenesis- failure of one or both of the kidneys to develop
• Phocomelia- failure of the arms or legs to develop
• Penile agenesis- failure of penis to develop
• Müllerian agenesis - failure of the uterus and part of the vagina to develop
• Eye agenesis - failure of the eyes to develop.
• Ear agenesis - failure of the ears to develop.
2. aplasia – failure of an organ to grow. From Greek a—not; plésein—to form) is
defective development resulting in the absence of all or part of an organ.
3. dysplasia - (from Greek, roughly: "bad formation") is a term used in pathology to
refer to an abnormality in maturation of cells within a tissue. This generally
consists of an expansion of immature cells, with a corresponding decrease in the
number and location of mature cells. Dysplasia is often indicative of an early
neoplastic process. The term dysplasia is typically used when the cellular
abnormality is restricted to the originating tissue, as in the case of an early, in-situ
neoplasm. For example, epithelial dysplasia of the cervix (cervical intraepithelial
neoplasia - a disorder commonly detected by an abnormal pap smear) consists of
an increased population of immature (basal-like) cells which are restricted to the
mucosal surface, and have not invaded through the basement membrane to the
deeper soft tissues. Myelodysplastic syndromes, or dysplasia of blood-forming
cells, show increased numbers of immature cells in the bone marrow, and a
decrease in mature, functional cells in the blood. Dysplasia is characterised by
four major pathological microscopic changes:
1. Anisocytosis (cells of unequal size)
2. Poikilocytosis (abnormally shaped cells)
 3. Hyperchromatism
4. Presence of mitotic figures (an unusual number of cells which are currently
dividing).

Dysplasia, in which cell maturation and differentiation are delayed, can be contrasted
with metaplasia, in which cells of one mature, differentiated type are replaced by cells of
another mature, differentiated type

4. hyperplasia - (or "hypergenesis") is a general term referring to the proliferation of

cells within an organ or tissue beyond that which is ordinarily seen (e.g.
constantly dividing cells). Hyperplasia may result in the gross enlargement of an
organ, the formation of a benign tumor, or may be visible only upon histological
analysis with a microscope. Hyperplasia is different from hypertrophy in that the
adaptive cell change in hypertrophy is an increase in cell size, whereas
hyperplasia involves an increase in the number of cells. Hyperplasia is considered
to be a physiological (normal) response to a specific stimulus, and the cells of a
hyperplastic growth remain subject to normal regulatory control mechanisms.
This stands in contrast to neoplasia (the process underlying cancer and some
benign tumors), in which genetically abnormal cells proliferate in a non-
physiological manner which is unresponsive to normal stimuli. Hyperplasia may
be due to any number of causes, including increased demand, chronic
inflammatory response, hormonal dysfunctions, or compensation for damage or
disease elsewhere. Hyperplasia may be harmless and occur on a particular tissue.
An example of a normal hyperplastic response would be the growth and
multiplication of milk-secreting glandular cells in the breast as a response to
pregnancy, thus preparing for future breast feeding

5. atrophy - is the partial or complete wasting away of a part of the body. Causes of
atrophy include poor nourishment, poor circulation, loss of hormonal support, loss of
nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the
tissue itself. Hormonal and nerve inputs that maintain an organ or body part are
referred to as trophic [noun] in medical practice. Trophic describes the trophic
condition of tissue. A diminished muscular trophic is designated as atrophy.

Atrophy is a general physiological process of reabsorption and breakdown of tissues,

involving apoptosis on a cellular level. When it occurs as a result of disease or loss of
trophic support due to other disease, it is termed pathological atrophy, although it can
be a part of normal body development and homeostasis as well.

6. hypertrophy - (from Greek ὑπέρ "excess" + τροφή "nourishment") is the increase

in the volume of an organ or tissue due to the enlargement of its component cells. It
should be distinguished from hyperplasia, in which the cells remain approximately
the same size but increase in number. Although hypertrophy and hyperplasia are two
distinct process, they frequently occur together, such as in the case of the hormonally-
induced proliferation and enlargement of the cells of the uterus during pregnancy.

7. metaplasia - (Greek: "change in form") is the reversible replacement of one

differentiated cell type with another mature differentiated cell type. The change from
one type of cell to another is generally caused by some sort of abnormal stimulus. In
simplistic terms, it is as if the original cells are not robust enough to withstand the
new environment, and so they change into another type more suited to the new
environment. If the stimulus that caused metaplasia is removed or ceases, tissues
return to their normal pattern of differentiation. Metaplasia is not synonymous with
dysplasia and is not directly considered carcinogenic. It is also contrasted with
heteroplasia, which is the abnormal growth of cytologic and histologic elements
without a stimulus.
8. neoplasia - Neoplasm is an abnormal mass of tissue as a result of neoplasia. Neoplasia
(new growth in Greek) is the abnormal proliferation of cells. The growth of this clone of
cells exceeds, and is uncoordinated with, that of the normal tissues around it. It usually
causes a lump or tumor. Neoplasms may be benign, pre-malignant or malignant.In
modern medicine, the term tumor is synonymous with a neoplasm that has formed a
lump. In the past, the term tumor was used differently. Some neoplasms do not cause a
lump.

Break in Body Defences and Barriers

Our body is constantly in contact with microbes and most of these are pathogenic
disease producing.

The body has attributes in which to prevent these invasion. We have our
physiological barriers. Physiological barriers prevents the entry of pathogens and protects
the body from infections, invasions and disease.

1. Intact skin – 1st line of defense

2. mucous membranes – secretes asubstances containing chemicals that
inhibit growth of mirobes or they help in the transport of these microbes
into the lymph vessels.

Acid-base imbalance is an abnormality of the human body's normal balance of acids and
bases that causes the plasma pH to deviate out of the normal range (7.35 to 7.45). It can
exist in varying levels of severity, some life-threatening.
Classification
An excess of acid is called acidosis (pH less than 7.35) and an excess in bases is called
alkalosis (pH greater than 7.45). The process that causes the imbalance is classified
based on the etiology of the disturbance (respiratory or metabolic) and the direction
of change in pH (acidosis or alkalosis). This yields the following four basic
processes:

Process pH carbon dioxide compensation

metabolic acidosis down Down respiratory

respiratory acidosis down Up renal

metabolic alkalosis Up Up respiratory

respiratory alkalosis Up Down renal

Causes
There are numerous reasons that each of the four processes can occur (detailed in each
article). Generally speaking, sources of acid gain include:

1. Retention of carbon dioxide

2. Production of nonvolatile acids from the metabolism of proteins and other organic
molecules
3. Loss of bicarbonate in feces or urine
4. Intake of acids or acid precursors

Sources of acid loss include:

1. Use of hydrogen ions in the metabolism of various organic anions

2. Loss of acid in the vomitus or urine

Compensation
The body's acid-base balance is tightly regulated. Several buffering agents exist which
reversibly bind hydrogen ions and impede any change in pH. Extracellular buffers
include bicarbonate and ammonia, while proteins and phosphate act as intracellular
buffers. The bicarbonate buffering system is especially key, as carbon dioxide (CO2) can
be shifted through carbonic acid (H2CO3) to hydrogen ions and bicarbonate (HCO3- ) as
shown below.

Acid-base imbalances that overcome the buffer system can be compensated in the short
term by changing the rate of ventilation. This alters the concentration of carbon dioxide
in the blood, shifting the above reaction according to Le Chatelier's principle, which in
turn alters the pH. For instance, if the blood pH drops too low (acidemia), the body will
compensate by increasing breathing, expelling CO2, and shifting the following reaction to
the right such that less hydrogen ions are free - thus the pH will rise back to normal. For
alkalemia, the opposite occurs.The kidneys are slower to compensate, but renal
physiology has several powerful mechanisms to control pH by the excretion of excess
acid or base. In responses to acidosis, tubular cells reabsorb more bicarbonate from the
tubular fluid, collecting duct cells secrete more hydrogen and generate more bicarbonate,
and ammoniagenesis leads to increased formation of the NH3 buffer. In responses to
alkalosis, the kidney may excrete more bicarbonate by decreasing hydrogen ion secretion
from the tubular epithelial cells, and lowering rates of glutamine metabolism and
ammonia excretion.

Acid-Base Imbalance: Introduction

Acid-Base Imbalance: A disruption to the normal acid-base equilibrium in the body.

There are four main groups of disorder involving an acid-base imbalance: respiratory
acidosis or alkalosis and metabolic acidosis or alkalosis. Obviously the severity of
symptoms is determined by the degree of imbalance. More detailed information about
the symptoms, causes, and treatments of Acid-Base Imbalance is available below.

Symptoms of Acid-Base Imbalance

• Hypercapnia - metabolic alkalosis

• Dilated brain blood vessels - respiratory acidosis
• Increased pressure inside skull - respiratory acidosis
• Headache - metabolic alkalosis
• Confusion - respiratory alkalosis

Cell Injury and Disease

Cellular injury appears to be the common denominator in almost all diseases. Injury is defined as an alteration in
cell structure or functioning resulting from some stress that exceeds the ability of the cell to compensate through
normal physiologic adaptive mechanisms.

Cells typically respond to potentially injurious stress in one of two ways:

• Adaptation - They can alter their structure and/or biochemical processes in order to achieve a new "steady
state" and maintain near-normal physiologic functions (homeostasis). For example, chronic exposure to
sunlight causes melanocytes in the skin to synthesize more melanin to protect cells from potentially
injurious UV radiation.
• Injury - If stressed cells cannot adequately adapt, critical cell functions may be impaired, and the cell is
said to be injured. For example, acute severe exposure of the skin to solar UV radiation may lead to
"sunburn" - an epidermal injury.
o If injured cells recover their normal functions when the stress is removed, the injury is said to be
reversible.
o If the injury is severe enough, however, a “point of no return” is reached and the cell suffers
irreversible injury and dies. Two patterns of cell death are observed: necrosis and apoptosis (see
below).

How a cell responds to stress depends on:

• The severity and duration of exposure to a stressor (dose intensity).

For example, if the coronary blood supply of the heart is interrupted for only 1-2 minutes, the myocardium
may not suffer any long term effects. Prolonged cessation of blood flow, on the other hand, may lead to the
death of functional heart tissue (myocardial infarction).

• The inherent vulnerability of particular types of cells to a given stress. Some cells are more sensitive to
stress than other cells.

For example, hepatocytes and skeletal muscle cells can tolerate several hours of interrupted blood flow
without apparent harm. Neurons and myocardium, by contrast, can only tolerate reduced blood flow for
very short periods without suffering irreversible damage. Generally speaking, the more specialized a cell
is, the more vulnerable it is to injury.

Molecular Targets of Cellular Injury

Cell injury is associated with damage to the structural and functional molecules of the cell. Although any
biologically important molecule in a cell can be the target of injury producing stress, four biochemical systems are
particularly vulnerable: (1) the cell membrane, (2) energy metabolism, (3) protein synthesis, and (4) genes. Because
many of the biochemical systems of the cell are inter-dependent, injury at one site typically causes secondary injury
to other cellular processes.

• Cell Membrane Integrity - Selectively permeable lipid membranes are essential for maintaining the
internal environment of cells. By controlling what molecules enter and leave the cell, the plasma
membrane helps conserve important resources, and keeps the cell in osmotic equilibrium with extracellular
fluid. Energy-dependent protein "pumps" embedded in the plasma membrane establish differences in ion
concentrations and electrical charge between the inside and outside of the cell (resting membrane
 potential). The resting membrane potential is particularly important for nerve and muscle function. The
function of intracellular organelles such as mitochondria, lysosomes, and the endoplasmic reticulum also
depend on the integrity of their lipid membranes.

Cell membranes can be disrupted by degrading phospholipids - the primary molecular component of
biologic membranes. Damage to the plasma membrane increases the cell’s permeability to sodium and
water. This causes the cell to swell, and may even lead to disruption of the cell (lysis). Potassium may leak
out of the cell affecting its ability to maintain resting membrane potential. Injury to the limiting membrane
of mitochondria impairs energy metabolism. Lysosomal injury releases hydrolytic enzymes into the
cytoplasm leading to auto-digestion of cellular proteins. Damage to the endoplasmic reticulum interferes
with protein synthesis and the intracellular transport of biologically important compounds.

o The Role of Calcium - Cells also use energy-dependent membrane "pumps" to keep the
intracellular concentration of calcium ions very low. If cell membranes are injured, calcium ions
can move from the extracellular fluid, and from intracellular storage sites, into the cytoplasm. The
consequence of increased cytosolic calcium is activation of a class of enzymes known as protein
kinases. This leads to the activation of other enzymes such as phospholipases, ATPases,
proteases, and endonucleases which attack and break down critical components of the cell (lipid
membranes, ATP, cytoskeletal proteins, DNA).
• Aerobic Respiration and ATP Production - Cells require a constant energy supply, mainly in the form
of ATP, to drive metabolism and biosynthetic reactions. Depriving the cell of oxygen (hypoxia), or
disturbing mitochondrial function, interferes with the cell’s ability to utilize oxygen to generate adequate
amounts of ATP. This, in turn, impairs the ability of the cell to utilize nutrients to synthesize structural and
functional proteins necessary for maintaining the cell. Depletion of ATP also shifts energy metabolism
towards anaerobic glycolysis. In addition to being less efficient in terms of energy production, glycolysis
is also accompanied by the accumulation of inorganic phosphate and lactic acid which lowers the pH
inside the cell. This "acidosis" interferes with enzyme functioning and can damage nuclear DNA.
o The Role of Oxygen-derived Free Radicals (Reactive Oxygen Species) - While oxygen is vital
for normal energy metabolism, it also plays a special role in cell injury. When mitochondria
generate energy by reducing molecular oxygen to water, small amounts of partially reduced
forms of oxygen (superoxide, hydrogen peroxide, and hydroxyl radicals) are produced in the
process. These "free radicals" are short-lived molecules containing an unpaired electron in an
outer orbital - an electron that is not contributing to normal intramolecular bonding. These are
essentially "free chemical bonds" which are energetically unstable and highly reactive. Free
radicals are generally transient products of oxidation-reduction reactions or result when a
covalent bond is broken and one electron from each pair remains with each atom. Although free
radicals play an important physiologic role in intracellular oxidation-reduction reactions and the
bacteria killing function of white blood cells, they can also interact with biologically important
molecules - removing electrons or hydrogen atoms and disrupting covalent bonds. Fortunately,
cells normally produce only very small amounts of oxygen-derived free radicals, and they also
have molecular scavengers (anti-oxidants) to neutralize them before they can do any harm.

Disease-producing cellular stresses (Pathological Stimuli)

• Hypoxia - Depriving tissues of oxygen is one of the more common mechanisms for cellular
injury. Hypoxia can result from interrupted blood supply (ischemia), inadequate oxygenation of
blood due to pulmonary disease or hypoventilation, inability of the heart to adequately pump
blood (heart failure), or impaired oxygen carrying capacity of the blood (anemia, carbon monoxide
poisoning, etc.). As noted above, hypoxia depletes cellular ATP and generates oxygen-derived
free radicals.
• Chemical injury - A very large number of drugs and environmental chemical agents are capable
of causing cell injury. The list includes inorganic compounds, ions, and organic molecules -
including byproducts of normal metabolism and toxins synthesized by microorganisms.

Two basic mechanisms of chemical injury are recognized: (1) A compound can react directly with
some critical molecular component of the cell interfering with its function. For example, cyanide
inactivates the enzyme cytochrome oxidase in mitochondria required for aerobic respiration. (2) A
compound that is itself harmless to cells can be rendered toxic when it is metabolized and
converted to a toxic substance (such as a free radical). This is the way in which acetaminophen
overdose is toxic to the liver.

• Physical agents - Many forms of physical injury can be harmful to cells and tissues. Common
examples include: (1) Mechanical injury (crush injury, fractures, lacerations, hemorrhage). (2)
 Extremes of heat or cold (burns, heat stroke, heat exhaustion, frostbite, hypothermia). (3) Ionizing
or non-ionizing radiation - (x-rays, radioactive elements, ultraviolet radiation). (4) Electric shock.
(5) Sudden changes in atmospheric pressure (blast injury, decompression injury in divers). (6)
Noise trauma.
• Infection - This very common category of cell injury results from the parasitization of the body by
pathogenic viruses, bacteria, fungi, protozoa, or helminths. Pathogenic organisms produce disease
by either: (1) replicating inside host cells and disrupting the structural integrity of the cell (direct
cytopathic effect - e.g., herpes virus), (2) producing a toxin that is harmful to host cells (e.g.,
clostridia and diphtheria), or by (3) triggering an inflammatory or immune response that
inadvertently injures host cells caught in the “cross fire” between the immune system and invading
microorganism (e.g., rheumatic fever, tuberculosis).
• Immune reactions - Exaggerated immune reactions (anaphylaxis, allergy), or the inappropriate
targeting of the body's own cells by the immune system (autoimmunity) can result in acute or
chronic inflammation and cell injury. Abnormal suppression of the immune system can increase
vulnerability to microbial invasion.
• Nutritional imbalance - Deficiencies or excesses in normal cellular substrates (e.g., calories,
proteins, carbohydrates, minerals, vitamins) can produce problems such as obesity, malnutrition,
scurvy, iron deficiency anemia, etc.
• Genetic derangements - Inherited or acquired mutations in important genes can alter the
synthesis of crucial cellular proteins leading to developmental defects, or abnormal metabolic
functioning. Acquired mutations to somatic cells during life can affect cell differentiation and
replication leading to diseases such as cancer.

Manifestations of Disease at the Cellular Level

• Adaptive Structural Changes

Within limits, most cells can adapt to environmental stresses by modifying their size/shape,
pattern of growth, and/or metabolic activity. In the extreme, adaptive cellular changes are also
markers for injury and disease. Common examples include:

o Atrophy - A decrease in individual cell size due to lower rates of metabolism and
decreased protein synthesis. Atrophic cells have less structural proteins, fewer
mitochondria, and less endoplasmic reticulum. Although atrophic cells have reduced
functions, they are not dead. The reduced metabolic activity of atrophic cells makes them
less vulnerable to injury. When a sufficient number of cells become atrophic, the whole
tissue or organ diminishes in size. Occasionally the numbers of cells in atrophic tissues
may also decrease. This is sometimes referred to as involution.

Causes of atrophy include: (1) Decreased workload (e.g., muscle atrophy in an injured
limb immobilized in a plaster cast). (2) Loss of innervation (e.g., muscle atrophy in
patients with spinal cord or peripheral nerve injuries). (3) Diminished blood supply (e.g.,
chronic stenosis [narrowing] of the renal artery may lead to kidney atrophy). (4)
Inadequate nutrition (e.g., lack of protein in diet leads to muscle atrophy, vitamin B12
deficiency is associated with gastric atrophy). (5) Loss of endocrine stimulation (e.g.,
hypofunction of the pituitary gland can lead to atrophy of thyroid gland, adrenal glands,
ovaries, and testes). Physiologic atrophy of the endometrium, vaginal epithelium, and
breast occur with menopause and the loss of estrogen stimulation. (6) Aging is associated
with cellular atrophy and involution - especially in the heart and brain.
 o Hypertrophy - An increase in tissue mass resulting from an increase in cell size rather
than cell numbers. The increase in cell size is due to accelerated synthesis of proteins and
other structural components of the cell. Hypertrophied tissues and organs do not have
greater numbers of cells, just larger cells. If atrophy is a kind of "cell hibernation"
designed to reduce susceptibility to injury, hypertrophy is equivalent to "calling up the
reserves" to shore up cell defenses.

Hypertrophy may be caused by: (1) Increased functional demand (e.g., increased skeletal
muscle mass in response to exercise; increased heart size in response to the abnormal
workload imposed by chronic hypertension or valvular heart disease). (2) Hormonal
stimulation (e.g., estrogenic stimulation of uterine smooth muscle during pregnancy
contributes to increased uterine size).

Physiologic hypertrophy, as an adaptive mechanism, has its limitations. As hypertrophy

progresses, the increase in cell size eventually is no longer able to compensate for
increased workload. This probably occurs because of the cell's inability to indefinitely
provide oxygen and nutrients as cell size increases. For example, even though
enlargement of the heart is an adaptive mechanism to chronic hypertension, ultimately
the myocardium reaches its adaptive limits and is unable to continue providing adequate
blood output to meet demand. Heart failure then ensues.

o Hyperplasia - Increase in tissue mass due to an increased rate of cell division and
cellular proliferation. A hyperplastic organ is increased in size because it has more cells.

Hyperplasia may be physiologic or pathologic. (1) Physiologic hyperplasia can occur as a

result of normal hormonal stimulation (e.g., female breast enlargement during puberty
and pregnancy; or as a compensatory mechanism for loss of tissue (e.g., hyperplasia of
skin cells during the healing of an abrasion). (2) Pathologic hyperplasia is the result of a
noxious stimulus (e.g., callous formation on the hands of a manual laborer); or excessive
hormonal stimulation (e.g., goiters and hyperthyroidism, prostate enlargement in
response to chronic exposure to androgens).

Hyperplasia and hypertrophy are closely related. The two processes often occur together
in injured tissues. Both are reversible if the stimulus is withdrawn. Pathologic hyperplasia
is probably a step in the development of cancer (neoplasia). Thus hyperplastic changes in
some tissues may be considered premalignant. For example, chronic hyperplasia of the
uterine endometrium (as seen with estrogen replacement therapy) is associated with an
increased risk for endometrial cancer.

o Metaplasia - A reversible change in cell structure from one fully differentiated form to
another in response to a noxious stimulus. Metaplasia represents an attempt by tissue to
replace a susceptible cell type with a more resistant one. For example, the cells lining the
normal trachea and bronchioles are mucous secreting, ciliated columnar epithelium which
is very sensitive to the chemicals in tobacco smoke. In smokers, these cells are eventually
replaced by stratified squamous epithelium which are more resistant to smoke.
Metaplasia is potentially reversible. If the abnormal stimulus is removed, the cells may
revert to their original type. Smokers who quit may regain normal mucous secreting
bronchial epithelium. However, if the stimulus producing metaplasia persists, it may
induce malignant transformation. Thus, like hyperplasia, metaplasia is considered a pre-
malignant change.
o Dysplasia - Disordered cellular morphology, organization, and function. Unlike atrophy,
hypertrophy, and hyperplasia which may be physiologic adaptations as well as
manifestations of disease, dysplasia (and probably metaplasia) is always associated with a
pathologic process. Dysplastic tissues display abnormal variation in overall cell size and
shape as well as nuclear structure. Cell numbers are typically increased in dysplastic
tissue and normal tissue morphology is distorted.

Dysplasia is strongly implicated as a precursor to cancer. Dysplastic cellular changes are

frequently found adjacent to areas of cancer. Dysplasia is distinguished from cancer by
the important fact that dysplastic changes can be reversed if the abnormal stimulus is
removed. Unlike cancer cells, dysplastic cells are not autonomous - they are still capable
of responding to normal physiologic growth and differentiation controls.

• Cell swelling - A common feature of almost all cell injuries. A form of reversible injury
associated with the abnormal influx of sodium and water into the cell.
 • Intracellular accumulations - Another way cells can adapt to injury that disrupts metabolic
pathways is to accumulate and store various substances in the cytoplasm. Intracellular
accumulations may be substrates of biosynthetic processes or normal cellular constituents such as
lipids, proteins, or carbohydrates - or pigments such as melanin and bilirubin. Lipofuschin (a lipid
rich pigment derived from degraded cell membranes) is commonly found in aging or chronically
injured tissues. This substance gives these tissues a characteristic yellow-brown color.

Intracellular accumulations are not usually harmful to the cell in themselves - they are simply
markers indicating cellular dysfunction (e.g., lipid accumulation in hepatocytes with alcoholic
liver disease). In some instances, however, intracellular accumulations can impair cell function
and contribute to a disease process (e.g., iron overload and hemochromatosis, uric acid and gout,
beta amyloid and Alzheimer's disease).

• Calcification - Injury and cell death can cause the release of intracellular phosphate ions and fatty
acids into the extracellular environment. These compounds react with calcium ions forming
insoluble calcium salts which are precipitated in tissues. This type of calcification is particularly
common in atherosclerosis and diseases associated with chronic inflammation. Abnormal
calcifications can also occur in conditions associated with hypercalcemia - excess levels of
calcium in the blood (e.g., hyperparathyroidism).
• Enzyme leakage - Injury to cell membranes can also be associated with the leakage of normal
intracellular enzymes into extracellular fluids. Elevated plasma levels of these enzymes are often
used as indirect laboratory markers for cell injury. A common example is myocardial infarction
which is associated with elevations of serum creatine kinase (CK) and cardiac troponins.
Hepatobiliary disease is frequently accompanied by elevations of the enzymes AST, ALT, and
alkaline phosphatase.
• Cell Death: Necrosis and Apoptosis - The ultimate consequence of irreversible injury is cell
death which usually takes the form of necrosis. The structural changes that accompany necrosis
result from two processes:

1. Enzymatic digestion of the cell by its own hydrolytic lysosomal enzymes (sometimes called
liquefaction necrosis)
2. Denaturation and precipitation of cellular proteins (coagulation necrosis).

Liquefaction necrosis occurs in some bacterial infections (e.g., staphylococcus) and ischemic
injury to brain tissue. Coagulation necrosis is a common manifestation of hypoxic cell injury (e.g.,
myocardial infarction). Tuberculosis infections produce a combination of liquefaction and
coagulation necrosis characterized by a collection of soft, whitish-gray debris resembling clumped
cheese (caseous necrosis). Necrosis is accompanied by inflammation and secondary injury to
surrounding normal tissues.

Necrosis should be distinguished from apoptosis - genetically programmed cell death. In

apoptosis, there is an orderly disassembly of cellular proteins and DNA with minimal disruption to
normal tissue. Apoptosis is a normal physiologic process designed to eliminate unwanted,
functionally abnormal, or senescent (old and worn out) cells. It plays an important role in the
developing embryo, certain hormone-dependent tissues, and in aging. However, in some instances,
apoptosis may be a pathologic process induced by cell injury (e.g., viral infection, radiation injury