Cell injury; complete chapter

1 Cell Injury - Pathophysiology
• Explanation of Pathophysiology:
The word ‘Pathology’ is derived from two Greek words—pathos meaning suffering, and logos meaning
study. Pathology is, thus, scientific study of structure and function of the body in disease; or in other
words, pathology consists of the abnormalities that occur in normal anatomy (including histology) and
physiology owing to disease.
Another commonly used term with reference to study of diseases is ‘pathophysiology’ comprised by two
words: pathos = suffering; physiology = study of normal function. Pathophysiology, thus, includes study
of disordered function or breakdown of homeostasis in diseases. Pathologists are the diagnosticians of
disease.
• Health & Disease:
Health may be defined as a condition when the individual is in complete accord with the surroundings,
while disease is loss of ease (or comfort) to the body (i.e. dis-ease).
• Difference between Disease, illness & Syndrome:
A term commonly confused with disease is illness. While disease suggests an entity with a cause, illness is
the reaction of the individual to disease in the form of symptoms (complaints of the patient) and physical
signs (elicited by the clinician). Though disease and illness are not separable, the study of diseases is done
in pathology while the learning and management of illnesses is done in wards and clinics.
In addition to disease and illness, there are syndromes (meaning running together) characterized by
combination of symptoms caused by altered physiologic processes.
• Common Terminologies a Healthcare professional should be aware of:
Patient is the person affected by disease.
Lesions are the characteristic changes in tissues and cells produced by disease in an individual or
experimental animal.
Pathologic changes or morphology consist of examination of diseased tissues.
Pathologic changes can be recognized with the naked eye (gross or macroscopic changes) or studied by
microscopic examination of tissues.
Causal factors responsible for the lesions are included in etiology of disease (i.e. ‘why’ of disease).
Mechanism by which the lesions are produced is termed pathogenesis of disease (i.e. ‘how’ of disease).
Functional implications of the lesion felt by the patient are symptoms and those discovered by the
clinician are the physical signs.
Clinical significance of the morphologic and functional changes together with results of other
investigations help to arrive at an answer to what is wrong (diagnosis), what is going to happen
(prognosis), what can be done about it (treatment), and finally what should be done to avoid
complications and spread (prevention) (i.e. ‘what’ of disease).

History of Pathophysiology:
PRE-Historic ERA (till 1500 AD):
Hippocrates introduced ethical concepts in the practice of medicine and is revered by the medical
profession by taking ‘Hippocratic oath’ at the time of entry into practice of medicine.
Hippocratic teaching was propagated in Rome by Roman physicians, notably by Cornelius Celsus (53 BC-7
AD) and Cladius Galen (130–200 AD). Celsus first described four cardinal signs of inflammation—rubor
(redness), tumor (swelling), calor (heat), and dolor (pain).
Galen postulated humoral theory, later called Galenic theory. This theory suggested that the illness
resulted from imbalance between four humors (or body fluids): blood, lymph, black bile (believed to be
from the spleen), and biliary secretion from the liver.
The hypothesis of disequilibrium of four elements constituting the body (Dhatus) similar to Hippocratic
doctrine finds mention in ancient Indian medicine books compiled about 200 AD—Charaka Samhita, a
finest document by Charaka on medicine listing 500 remedies, and Sushruta Samhita, similar book of
surgical sciences by Sushruta, and includes about 700 plant-derived medicines.
ERA of Gross Pathology (1500 – 1800 AD):
The beginning of the development of human anatomy took place during this period with the art works
and drawings of human muscles and embryos by famous Italian painter Leonardo da Vinci (1452–1519).
Dissection of human body was started by Vesalius (1514–1564) on executed criminals. His pupils, Gabriel
Fallopius, (1523–1562) who described human oviducts (Fallopian tubes) and Fabricius, who discovered
lymphoid tissue around the intestine of birds (bursa of Fabricius) further popularized the practice of
human anatomic dissection for which special postmortem amphitheaters came in to existence in various
parts of ancient Europe.
Richard Bright (1789–1858) who described nonsuppurative nephritis, later termed glomerulonephritis or
Bright’s disease; Thomas Addison (1793–1860) who gave an account of chronic adrenocortical
insufficiency termed Addison’s disease; and Thomas Hodgkin (1798–1866), who observed the complex of
chronic enlargement of lymph nodes, often with enlargement of the liver and spleen, later called
Hodgkin’s disease.
Towards the end of 18th century, Xavier Bichat (1771–1802) in France described that organs were
composed of tissue and divided the study of morbid anatomy into General Pathology and Systemic
Pathology. R.T.H. Laennec (1781–1826), another French physician, dominated the early part of 19th
century by his numerous discoveries. He described several lung diseases (tubercles, caseous lesions,
miliary lesions, pleural effusion, bronchiectasis), chronic sclerotic liver disease (later called Laennec’s
cirrhosis) and invented stethoscope.
ERA of Technological Development in pathology (1800 – 1950):
Sophistication in surgery led to advancement in pathology. The anatomist-surgeons of earlier centuries
got replaced largely with surgeon-pathologists in the 19th century. Pathology started developing as a
diagnostic discipline in later half of the 19th century with the evolution of cellular pathology which was

closely linked to technology advancements in machinery manufacture for cutting thin sections of tissue,
improvement in microscope, and development of chemical industry and dyes for staining.
The discovery of existence of disease-causing microorganisms was made by French chemist Louis Pasteur
(1822–1895), thus demolishing the prevailing theory of spontaneous generation of disease and firmly
established germ theory of disease. Subsequently, G.H.A. Hansen (1841–1912) in Germany identified
Hansen’s bacillus as causative agent for leprosy (Hansen’s disease) in 1873. While the study of infectious
diseases was being made, the concept of immune tolerance and allergy emerged which formed the basis
of immunisation initiated by Edward Jenner.
Paul Ehrlich (1854–1915), German physician, conferred Nobel prize in 1908 for his work in immunology,
described Ehrlich’s test for urobilinogen using Ehrlich’s aldehyde reagent, staining techniques of cells and
bacteria, and laid the foundations of clinical pathology (Fig. 1.5).
Christian Gram (1853–1938), Danish physician, who developed bacteriologic staining by crystal violet.
D.L. Romanowsky (1861–1921), Russian physician, who developed stain for peripheral blood film using
eosin and methylene blue derivatives.
Robert Koch (1843–1910), German bacteriologist who, besides Koch’s postulate and Koch’s phenomena,
developed techniques of fixation and staining for identification of bacteria, discovered tubercle bacilli in
1882 and cholera vibrio organism in 1883.
Sir William Leishman (1865–1926) who described Leishman’s stain for blood films in 1914 and observed
Leishman-Donovan bodies (LD bodies) in leishmaniasis.
Robert Feulgen (1884–1955) who described Feulgen reaction for DNA staining and laid the foundations
of cytochemistry and histochemistry.
Karl Landsteiner (1863–1943) described the existence of major human blood groups in 1900 and was
awarded Nobel prize in 1930 and is considered father of blood transfusion.
Modern Pathology (Post 1950):
21st
century have made it possible to study diseases at molecular level. The major impact of advances in
molecular biology are in the field of diagnosis and treatment of genetic disorders, immunology and in
cancer. Some of the revolutionary discoveries during this time are as under;
• Description of the structure of DNA of the cell by Watson and Crick in 1953.
• Identification of chromosomes and their correct number in humans (46) by Tijo and Levan in 1956.
• Identification of Philadelphia chromosome t (9;22) in chronic myeloid leukemia by Nowell and
Hagerford in 1960 as the first chromosomal abnormality in any cancer.
• In Situ Hybridization introduced in 1969 in which a labelled probe is employed to detect and
localize specific RNA or DNA sequences ‘in situ’ (i.e. in the original place).
• Recombinant DNA technique developed in 1972 using restriction enzymes to cut and paste bits of
DNA.
• In 1983, Kary Mullis introduced polymerase chain reaction (PCR) i.e. “xeroxing” DNA fragments
which revolutionized the diagnostic molecular genetics.

• In 1997, Ian Wilmut and his colleagues at Roslin Institute in Edinburgh, successfully used a
technique of somatic cell nuclear transfer to create the clone of a sheep; the cloned sheep was
named Dolly. This has set in the era of mammalian cloning.
• In April 2003, Human Genome Project (HGP) consisting of a consortium of countries, was
completed which coincided with 50 years of description of DNA double helix by Watson and Crick
in April 1953. The sequencing of human genome reveals that human genome contains
approximately 3 billion of the base pairs, which reside in the 23 pairs of chromosomes within the
nucleus of all human cells. Each chromosome contains an estimated 30,000 genes in the human
genome, which carry the instructions for making proteins. The HGP gave us the ability to read
nature’s complete genetic blueprint for building each human being. All this has opened new ways
in treating and researching an endless list of diseases that are currently incurable.

CELL INJURY AND CELLULAR ADAPTATIONS
Cells are the basic units of tissues, which form organs and systems in the human body. In 1859,
Virchow first published cellular theory of disease, bringing in the concept that diseases occur due
to abnormalities at the level of cells. Since then, study of abnormalities in structure and function
of cells in disease has remained the focus of attention in understanding of diseases. Thus, most
forms of diseases begin with cell injury followed by consequent loss of cellular function. Cell injury
is defined as a variety of stresses a cell encounters as a result of changes in its internal and external
environment.
In general, cells of the body have inbuilt mechanism to deal with changes in environment to an
extent. The cellular response to stress may vary and depends upon the following variables:
a) The type of cell and tissue involved.
b) Extent and type of cell injury.
Various forms of cellular responses to cell injury may be as follows:
Figure 1: Cellular Adaptation under Stress
A. When there is increased functional demand, the cell may adapt to the changes which are
expressed morphologically and then revert back to normal after the stress is removed
(cellular adaptations)
B. When the stress is mild to moderate, the injured cell may recover (reversible cell injury),
while when the injury is persistent cell death may occur (irreversible cell injury).
C. The residual effects of reversible cell injury may persist in the cell as evidence of cell injury
at subcellular level (subcellular changes), or metabolites may accumulate within the cell
(intracellular accumulations).

THE NORMAL CELL
Different types of cells of the body possess features which distinguish one type from another. However,
most mammalian cells have a basic plan of common structure and function, except the red blood cell
which is devoid of nucleus.
The Principle components of a cell are: Cell Membrane, Nucleus, Nucleolus, Endoplasmic Reticulum
(Smooth/Rough), Ribosome (protein factory), Mitochondria (Powerhouse), Vacuole (packaging center of
proteins), Golgi Complex, Cytoplasm, Centrioles, etc.
Figure 2: Principle components of a cell
• Nucleus: The Centre of cell with genetic information
• Nucleosome: Condensed chromosomes and DNA
• Rough Endoplasmic Reticulum & Smooth Endoplasmic Reticulum: Sites for protein
synthesis and packaging
• Ribosomes: Protein Factory (translation site)
• Golgi body & Lysosomes: The packaging unit
• Mitochondria: The powerhouse of the cell (Produces ATP)
• Centrioles: Transporters of cell organelles during cell division

ETIOLOGY OF CELL INJURY
The cells may be broadly injured by two major ways:
A. By genetic causes
B. By acquired causes
Based on underlying agent, the acquired causes of cell injury can be further categorized as under:
1. Hypoxia and ischemia
2. Physical agents
3. Chemical agents and drugs
4. Microbial agents
5. Immunologic agents
6. Nutritional derangements
7. Aging
8. Psychogenic diseases
9. Iatrogenic factors
10. Idiopathic diseases
1. HYPOXIA AND ISCHAEMIA
Cells of different tissues essentially require oxygen to generate energy and perform metabolic functions.
Deficiency of oxygen or hypoxia results in failure to carry out these activities by the cells. Hypoxia is the
most common cause of cell injury. Hypoxia may result from the following:
✓ The most common mechanism of hypoxic cell injury is by reduced supply of blood to cells due to
interruption i.e. ischemia.
✓ However, hypoxia may result from other causes as well e.g. disorders of oxygen-carrying RBCs
(e.g. anemia, carbon monoxide poisoning), heart diseases, lung diseases and increased demand
of tissues.
2. PHYSICAL AGENTS
Physical agents in causation of disease are as under:
✓ mechanical trauma (e.g. road accidents);
✓ thermal trauma (e.g. by heat and cold);
✓ electricity;
✓ radiation (e.g. ultraviolet and ionizing); and
✓ rapid changes in atmospheric pressure.
3. CHEMICALS AND DRUGS
An ever-increasing list of chemical agents and drugs may cause cell injury. Important examples include
the following:
✓ chemical poisons such as cyanide, arsenic, mercury;
✓ strong acids and alkalis;
✓ environmental pollutants;
✓ insecticides and pesticides;
✓ oxygen at high concentrations;
✓ hypertonic glucose and salt;
✓ social agents such as alcohol and narcotic drugs; and therapeutic administration of drugs.

4. MICROBIAL AGENTS
Injuries by microbes include infections caused by bacteria, rickettsia, viruses, fungi, protozoa, metazoan,
and other parasites.
5. IMMUNOLOGIC AGENTS
Immunity is a ‘double edged sword’ it protects the host against various injurious agents but it may also
turn lethal and cause cell injury e.g.
✓ hypersensitivity reactions;
✓ anaphylactic reactions; and
✓ autoimmune diseases.
✓ Immunologic tissue injury
6. NUTRITIONAL DERANGEMENTS
A deficiency or an excess of nutrients may result in nutritional imbalances. Nutritional deficiency diseases
may be due to overall deficiency of
nutrients (e.g. starvation),
protein calorie (e.g. marasmus, kwashiorkor),
minerals (e.g. anemia),
or trace elements.
Nutritional excess is a problem of affluent societies resulting in obesity, atherosclerosis, heart disease and
hypertension.
7. AGING
Cellular aging or senescence leads to impaired ability of the cells to undergo replication and repair, and
ultimately lead to cell death culminating in death of the individual.
8. PSYCHOGENIC DISEASES
There are no specific biochemical or morphologic changes in common acquired mental diseases due to
mental stress, strain, anxiety, overwork and frustration e.g. depression, schizophrenia. However,
problems of drug addiction, alcoholism, and smoking result in various organic diseases such as liver
damage, chronic bronchitis, lung cancer, peptic ulcer, hypertension, ischemic heart disease etc.
9. IATROGENIC CAUSES
Although as per Hippocratic oath, every physician is bound not to do or administer anything that causes
harm to the patient, there are some diseases as well as deaths attributed to iatrogenic causes (owing to
physician). Examples include occurrence of disease or death due to error in judgment by the physician
and untoward effects of administered therapy (drugs, radiation)
10. IDIOPATHIC DISEASES
Idiopathic means “of unknown cause”. Finally, although so much is known about the etiology of diseases,
there still remain many diseases for which exact cause is undetermined. For example, most
common form of hypertension (90%) is idiopathic (or essential) hypertension. Similarly, exact etiology of
many cancers is still incompletely known.

Pathogenesis of Ischemic and Hypoxic injury
Figure 3: Sequence of events in the pathogenesis of reversible and irreversible cell injury caused by hypoxia/ischemia.
Hydroxyl radicle Mechanism of cell injury
Figure 4: Mechanism of cell death by hydroxyl radical, the most reactive oxygen species.

MORPHOLOGY OF CELL INJURY
After having discussed the mechanisms of various forms of cell injury, we now turn to light microscopic
morphologic changes of reversible and irreversible cell injury. Depending upon the severity of cell injury,
degree of damage and residual effects on cells and tissues are variable. In general, morphologic changes
in various forms of cell injury can be classified as:
Morphology of Reversible cell injury:
Following morphologic forms of reversible cell injury are included under this heading:
1. Hydropic change (cloudy swelling, or vacuolar degeneration)
2. Fatty change
3. Hyaline change
4. Mucoid change
Hydropic Change: Hydropic change means accumulation of water within the cytoplasm of the cell. Other
synonyms used are cloudy swelling (for gross appearance of the affected organ) and vacuolar
degeneration (due to cytoplasmic vacuolation). The common causes are bacterial toxins, chemicals,
poisons, burns, high fever, intravenous administration of hypertonic glucose or saline etc. Cloudy swelling
results from impaired regulation of sodium and potassium at the level of cell membrane. This results in
intracellular accumulation of sodium and escape of potassium. This, in turn, leads to rapid flow of water
into the cell to maintain iso-osmotic conditions and hence cellular swelling occurs.
Fatty Change (Steatosis): It is the intracellular accumulation of neutral fat within parenchymal cells. Liver
is the commonest site for accumulation of fat because it plays central role in fat metabolism. Fatty change
in the liver may result from one of the two types of causes:
1. Conditions with excess fat (hyperlipidemia), exceeding the capacity of the liver to metabolize it.
2. Liver cell damage, when fat cannot be metabolized in it.

Hyaline Change: The word ‘hyaline’ means glassy (hyalos = glass). Hyaline change is associated with
heterogeneous pathologic conditions. It may be intracellular or extracellular.
Intracellular hyaline is mainly seen in epithelial cells. A few examples are as follows:
1. Hyaline droplets in the proximal tubular epithelial cells in cases of excessive reabsorption of plasma
proteins.
2. Hyaline degeneration of rectus abdominis muscle called Zenker’s degeneration, occurring in typhoid
fever. The muscle loses its fibrillar staining and becomes glassy and hyaline.
3. Nuclear or cytoplasmic hyaline inclusions seen in some
viral infections.
Extracellular hyaline is seen in connective tissues. A few examples are as under:
1. Hyaline degeneration in leiomyomas of the uterus.
2. Hyaline arteriolosclerosis in renal vessels in hypertension and diabetes mellitus.
3. Hyalinized glomeruli in chronic glomerulonephritis.
Mucoid Changes: Mucus secreted by mucous glands is a combination of proteins complexed with
mucopolysaccharides. Mucin, a glycoprotein, is its chief constituent. Mucin is normally produced by
epithelial cells of mucous membranes and mucous glands, as well as by some connective tissues like in
the umbilical cord.
EPITHELIAL MUCIN: Following are some examples of functional excess of epithelial mucin:
1. Catarrhal inflammation of mucous membrane (e.g. of respiratory tract, alimentary tract, uterus).
2. Obstruction of duct leading to mucocele in the oral cavity and gallbladder.
3. Cystic fibrosis of the pancreas.
4. Mucin-secreting tumors (e.g. of ovary, stomach, large bowel, etc.)
CONNECTIVE TISSUE MUCIN: A few examples of disturbances of connective tissue mucin are as under:
1. Mucoid or myxoid degeneration in some tumors e.g. myxomas, neurofibromas, fibroadenoma, soft
tissue sarcomas, etc.
2. Myxoid change in the synovium in ganglion on the wrist.
SUBCELLULAR ALTERATIONS IN CELL INJURY
These occur at the level of cytoskeleton, lysosomes, endoplasmic reticulum and mitochondria.
1. CYTOSKELETAL CHANGES: Components of cytoskeleton may show the following morphologic
abnormalities:
i) Defective microtubules:
a. Poor sperm motility causing sterility.
b. Immotile cilia syndrome: Immotile cilia of respiratory tract and consequent chronic infection due
to defective clearance of inhaled bacteria.
ii) Defective microfilaments:
a. In myopathies
b. Muscular dystrophies
iii) Accumulation of intermediate filaments:
Various classes of intermediate filaments may accumulate in the cytosol.
For example: Neurofibrillary tangles in Alzheimer’s disease are composed of neurofilaments and paired
helical filaments.

2. LYSOSOMAL CHANGES: Lysosomes contain powerful hydrolytic enzymes. Heterophagy and autophagy
are the two ways by which lysosomes show morphologic changes of phagocytic function.
i) Heterophagy: Phagocytosis (cell eating) and pinocytosis (cell drinking) are the two forms by which
material from outside is taken up by the lysosomes of cells such as polymorphs and macrophages to form
phagolysosomes. This is termed heterophagy. Microbial agents and foreign particulate material are
eliminated by this mechanism.
ii) Autophagy: This is the process by which worn out intracellular organelles and other cytoplasmic
material form autophagic vacuole that fuses with lysosome to form autophago-lysosome.
iii) Indigestible material: Some indigestible exogenous particles such as carbon or endogenous substances
such as lipofuscin may persist in the lysosomes of the cells for a long time as residual bodies.
iv) Storage diseases: A group of lysosomal storage diseases due to hereditary deficiency of
enzymes may result in abnormal collection of metabolites in the lysosomes of cells.
3. SER CHANGES: Hypertrophy of smooth endoplasmic reticulum of liver cells as an adaptive change may
occur in response to prolonged use of barbiturates.
4. MITOCHONDRIAL CHANGES: Mitochondrial injury plays an important role in cell injury. Morphologic
changes of cell injury in mitochondria may be seen in the following conditions:
i) Megamitochondria: Megamitochondria consisting of unusually big mitochondria are seen in alcoholic
liver disease and nutritional deficiency conditions.
ii) Alterations in the number of mitochondria may occur. Their number increases in hypertrophy and
decreases in atrophy.
iii) Oncocytoma in the salivary glands, thyroid and kidneys consists of tumor cells having very large
mitochondria.
iv) Myopathies having defect in mitochondria have abnormal cristae.
Accumulation of Various components inside the cell:
Cholesterol Deposits: As in Atherosclerosis, the foam cell deposits
Protein Deposits: As in proteinuria, antitrypsin deficiency, etc.
Glycogen Deposits: As in diabetes melitus and GCD (glycogen storage disease)
Pigment Deposits: Endogenous Pigments (Melanin, Hemoprotein, Lipofuscin) causing disease like
alkaptonuria, albinism, etc. and Exogenous pigments (Pollutants, Metals (lead, silver), Ink of Tattoo)
causing several toxicities in cell.

CELLULAR ADAPTATIONS
For the sake of survival on exposure to stress, the cells make adjustments with the changes in their
environment (i.e. adapt) to the physiologic needs (physiologic adaptation) and to non-lethal pathologic
injury (pathologic adaptation).
In general, the adaptive responses are reversible on withdrawal of stimulus. However, if the irritant
stimulus persists for long time, the cell may not be able to survive and may either die or progress further
e.g. cell death may occur in sustained atrophy; dysplasia may progress into carcinoma in situ. Thus, the
concept of evolution ‘survival of the fittest’ holds true for adaptation as ‘survival of the adaptable’.
Figure 5: Cellular adaptation forms
Five basic adaptations that a cell undergoes as depicted in figure are as follows:
1. Hyperplasia
2. Hypertrophy
3. Atrophy
4. Metaplasia
5. Dysplasia
1. Hyperplasia: Hyperplasia is an increase in the number of parenchymal cells resulting in
enlargement of the organ or tissue. Quite often, both hyperplasia and hypertrophy occur
together. Hyperplasia occurs due to increased recruitment of cells for any function.
A. Physiological:

a. Hormonal: Influence of hormonal stimulation. Hyperplasia of the female breast
epithelium at puberty or in pregnancy pregnant uterus, normal endometrium after a
normal menstrual cycle.
b. Compensatory: hyperplasia occurring following removal of part of an organ, like
Regeneration of the liver following partial hepatectomy, Regeneration of epidermis
after skin abrasion, nephrectomy on one side, there is hyperplasia of nephrons of the
other kidney.
B. Pathological: Excessive stimulation of hormones or growth factors, as in Endometrial
hyperplasia, wound healing - of granulation tissue due to proliferation of fibroblasts and
endothelial cells. Skin warts from hyperplasia of epidermis due to human papilloma virus.
Pseudo carcinomatous hyperplasia of the skin.
2. Hypertrophy: Hypertrophy is an increase in the size of parenchymal cells resulting in
enlargement of the organ or tissue, without any change in the number of cells. Hypertrophy may
be physiologic or pathologic.
In both cases, it is caused either by increased functional demand or by hormonal stimulation.
Hypertrophy without accompanying hyperplasia affects mainly muscles. In nondividing cells too,
only hypertrophy occurs.
A. Physiologic hypertrophy. Enlarged size of the uterus in pregnancy is an excellent example of
physiologic hypertrophy as well as hyperplasia.
B. Pathologic hypertrophy. Hypertrophy in cardiac muscle may occur in a number of
cardiovascular diseases. Due to increased function of cells of heart.
The relationship between hyperplasia and hypertrophy: Although hypertrophy and hyperplasia are two
distinct processes, frequently both occur together, and they well be triggered by the same mechanism.
3. Atrophy: Reduction of the number and size of parenchymal cells of an organ or its parts which
was once normal is called atrophy (compared from hypoplasia which is the term used for
developmentally small size, and aplasia for extreme failure of development so that only
rudimentary tissue is present).
A. Physiologic Atrophy: Atrophy is a normal process of aging in some tissues, which could be due to
loss of endocrine stimulation or arteriosclerosis. For example:
✓ Atrophy of lymphoid tissue in lymph nodes, appendix and thymus.
✓ Atrophy of gonads after menopause.
✓ Atrophy of brain with aging.
B. Pathological Atrophy: The Causes are as under:
a. Starvation atrophy. In starvation, there is first depletion of carbohydrate and fat stores
followed by protein catabolism. There is general weakness, emaciation and anemia referred
to as cachexia seen in cancer and severely ill patients.

b. Ischemic atrophy. Gradual diminution of blood supply due to atherosclerosis may result in
shrinkage of the affected organ e.g. i) Small atrophic kidney in atherosclerosis of renal artery.
ii) Atrophy of brain in cerebral atherosclerosis.
c. Disuse atrophy: Prolonged diminished functional activity is associated with disuse atrophy of
the organ e.g. Wasting of muscles of limb immobilized in cast or Atrophy of the pancreas in
obstruction of pancreatic duct.
d. Neuropathic atrophy. Interruption in nerve supply leads to wasting of muscles e.g.
Poliomyelitis, Motor neuron disease and Nerve section.
e. Endocrine atrophy. Loss of endocrine regulatory mechanism results in reduced metabolic
activity of tissues and hence atrophy e.g. Hypopituitarism may lead to atrophy of thyroid,
adrenal and gonads. Or Hypothyroidism may cause atrophy of the skin and its adnexal
structures.
f. Pressure atrophy. Prolonged pressure from benign tumors or cyst or aneurysm may cause
compression and atrophy of the tissues e.g. Erosion of spine by tumor in nerve root. Erosion
of sternum by aneurysm of arch of aorta.
g. Idiopathic atrophy. There are some examples of atrophy where no obvious cause is present
e.g. Myopathies, Testicular atrophy.
4. Metaplasia: Metaplasia is a reversible change in which one adult cell type is replaced by another
adult cell type. It is Loss of Differentiation property of cell. Causes: Changes in environment,
Irritation or inflammation or Nutritional. For Example: Squamous cells turn into Columnar cells:
Intestinal metaplasia in healed chronic gastric ulcer and Barrett’s esophagus.
5. Dysplasia: Dysplasia means ‘disordered cellular development’, often accompanied with
metaplasia and hyperplasia; it is therefore also referred to as atypical hyperplasia. Dysplasia
occurs most often in epithelial cells.
Epithelial dysplasia is characterized by cellular proliferation and cytologic changes:
✓ Increased number of layers of epithelial cells
✓ Disorderly arrangement of cells from basal layer to the surface layer
✓ Loss of basal polarity i.e. nuclei lying away from basement membrane
✓ Cellular and nuclear pleomorphism
✓ Increased nucleocytoplasmic ratio
✓ Nuclear hyperchromatism
✓ Increased mitotic activity.
The two most common examples of dysplastic changes are the uterine cervix and respiratory
tract.

CELL DEATH (IRREVERSIBLE CELL INJURY)
Cell death is a state of irreversible injury. It may occur in the living body as a local or focal change
(i.e. autolysis, necrosis and apoptosis) and the changes that follow it (i.e. gangrene and pathologic
calcification), or result in end of the life (somatic death). These pathologic processes involved in
cell death are described below.
NECROSIS: A localized area of death of tissue followed by degradation of tissue by hydrolytic
enzymes liberated from dead cells; it is invariably accompanied by inflammatory reaction. This
series of events of spontaneous death of group of cells or tissue is termed as Necrosis.
Necrosis can be caused by various agents such as hypoxia, chemical and physical agents, microbial
agents, immunological injury, etc. NOTE: Necrosis can only be pathologic, whereas apoptosis can
be physiological or pathological.
Two essential changes characterize irreversible cell injury in necrosis of all types:
1. Denaturation of proteins (Structural & Functional): Structural proteins are denatured and
hence structural integrity of cell is lost and membrane degenerates causing leak of protease
enzymes, leading to more protein digestion in nearby cells also.
NOTE: Necrosis cannot occur in Single cell, it always affects group of cells or tissue because of
leakage, whereas apoptosis can occur in selective cell.
2. Cell digestion by lytic enzymes (Autolysis & Heterolysis): Autolysis is degeneration by self-
released enzymes and heterolysis is degeneration by enzymes of pathogens.
Types of Necrosis: Coagulative, Liquefaction, Caseous, Fat and Fibrinoid
A. Coagulative: This is the most common type of necrosis caused by irreversible focal injury,
mostly from sudden cessation of blood flow (ischemia), and less often from bacterial and
chemical agents. The organs commonly affected are the heart, kidney, and spleen.
B. Liquefaction: also called colliquative necrosis occurs commonly due to ischemic injury and
bacterial or fungal infections. It occurs due to degradation of tissue by the action of powerful
hydrolytic enzymes. The common examples are infarct brain and abscess cavity.
C. Caseous: Caseous necrosis is found in the center of foci of tuberculous infections. It combines
features of both coagulative and liquefactive necrosis. Microscopically it looks like cheese.
D. Fat: Fat necrosis is a special form of cell death occurring at two anatomically different
locations but morphologically similar lesions. These are: following acute pancreatic necrosis,
and traumatic fat necrosis commonly in breasts.
E. Fibrinoid: Fibrinoid necrosis is characterized by deposition of fibrin-like material which has
the staining properties of fibrin. It is encountered in various examples of immunologic tissue
injury (e.g. in immune complex vasculitis, autoimmune diseases, Arthus reaction etc.),
arterioles in hypertension, peptic ulcer etc.

APOPTOSIS: Apoptosis is a form of ‘coordinated and internally programmed cell death’
having significance in a variety of physiologic and pathologic conditions (apoptosis is a Greek
word meaning ‘falling off’ or ‘dropping off’). The term was first introduced in 1972 as distinct
from necrosis by being a form of cell death which is controlled and regulated by the rate of
cell division; when the cell is not needed, pathway of cell death is activated (‘cell suicide’) and
is unaccompanied by any inflammation and collateral tissue damage.
Physiologic Processes:
1. Organized cell destruction in sculpting of tissues during development of embryo.
2. Physiologic involution of cells in hormone-dependent tissues e.g. endometrial shedding,
regression of lactating breast after withdrawal of breast-feeding.
3. Normal cell destruction followed by replacement proliferation such as in intestinal
epithelium.
4. Involution of the thymus in early age.
Pathologic Processes:
1. Cell death in tumors exposed to chemotherapeutic agents.
2. Cell death by cytotoxic T cells in immune mechanisms such as in graft-versus-host disease
and rejection reactions.
3. Progressive depletion of CD4+T cells in the pathogenesis of AIDS.
4. Cell death in viral infections e.g. formation of Councilman bodies in viral hepatitis.
5. Pathologic atrophy of organs and tissues on withdrawal of stimuli e.g. prostatic atrophy
after orchiectomy, atrophy of kidney or salivary gland on obstruction of ureter or ducts,
respectively.
6. Cell death in response to injurious agents involved in causation of necrosis e.g. radiation,
hypoxia and mild thermal injury.
7. In degenerative diseases of CNS e.g. in Alzheimer’s disease, Parkinson’s disease, and chronic
infective dementias.
Mechanism of Apoptosis: 1. Initiation 2. Execution 3. Phagocytosis
1. Initiation: This step generally initiates activation of CASPASE by two mechanisms:
A. Extrinsic Pathway: Regulated by External factor such as T-Lymphocyte, it activates FAS-FADD
pathway and activates CASPASE CASCADE
B. Intrinsic Pathway: Regulated by internal factor, BCL2 and BAX Proteins initiates leakage of
Cytochrome C from mitochondria, which further activates CASPASE CASCADE
2. Execution: Lots of Caspases are activated and they break cell into various parts, in very organized
manner such that no enzyme or any component leaks out. Plasma membrane itself surrounds
various parts that are broken down into pieces. There is formation of Apoptotic Blebs. The plasma
membrane of the apoptotic cell remains intact, but the membrane is altered in such a way that
the cell and its fragments become avid targets for phagocytes.
3. Phagocytosis: Phagosomes identify these blebs and engulf it to digest the dead cell.

SUMMARY OF PROCESSES:
Figure 6: Apoptosis Mechanism
Figure 7: Comparison of Necrosis and Apoptosis
For Animated video on Apoptosis Click Here: https://www.youtube.com/watch?v=-vmtK-bAC5E

FAQ (Frequently asked questions):
Q1. Enlist the etiological factors of Cell injury and explain mechanism of injury caused by radiation.
Q2. Explain mechanism of hypoxic and ischemic cell injury.
Q3. Explain Morphology of cell undergoing Reversible injury
Q4. What are subcellular alterations in cell injury? Write a brief note.
Q5. Explain various modes of Cellular adaptations with suitable examples.
Q6. Explain the molecular concept of Programmed cell death.
Q7. What is Necrosis? and How many types of necrosis are there?
Q8. Write in brief about the difference between Apoptosis and Necrosis.
Self-Evaluation Test
(If you are able to define all the following terms you are crystal clear with this chapter)
Pathology Physiology Pathophysiology Disease
illness Syndrome Etiology Iatrogenic
Idiopathic Adaptation Hypoxia Ischemia
Hydropic Change Steatosis Hyaline change Mucoid Change
Autophagy Hyperplasia Metaplasia Dysplasia
Hypertrophy Atrophy Hypoplasia Necrosis
Apoptosis Phagocytosis Pinocytosis Apoptotic Blebs

Cell injury; complete chapter

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