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CHAPTER ONE
INTRODUCTION TO PATHOLOGY
Dr. Salim Rasheed Hamoudi
The literal translation of the word pathology is the study (logos) of suffering (pathos). It is a discipline that
bridges clinical practice and basic sciences. Pathology is concerned with the study of diseases in a scientific
way. It comprises a wide foundation of scientific data and investigative procedures that are essential for the
practice of modern medicine.
In the pathology of any given disease there are structural changes of the relevant tissues that are reflected as
functional disturbances, which in turn are perceived as clinical features. The range of the structural changes
is from those affecting sub-cellular organelles (molecular pathology) up to alterations seen by the naked eye
(gross pathology). Pathology is a dynamic science in that its contents are continuously subjected to changes,
revisions and expansions. This is because there are always new findings that shed more light on, add or
modify an already established knowledge of various diseases.
The ultimate goal of pathology is the identification of the cause or causes of a given disease (etiology) that
can eventuate in disease prevention &/or successful therapy.
MORBID ANATOMY (AUTOPSY) (POST-MORTEM EXAMINATION)
This is one of the scientific ways in pathology to study diseases, and consists of external and internal
examination of the body after death. It is through this important investigative technique much information
has been gained to help clarify the nature of many diseases.
Autopsy comprises both gross (naked eye) as well as microscopic examinations of the diseased organs and
tissues. The post-mortem findings enable the pathologist to reach the ultimate pathological diagnosis, to
make a clinico-pathologic correlations, and finally to deduce the cause of death. This technique in pathology
has enlightened us about the natural history (the expected progress) of many diseases as well as the
underlying mechanisms of the relevant clinical features.
Autopsies are useful
1. For the determination of the cause of death
2. The evaluation of the accuracy of clinical diagnosis (and hence management) before death; thus,
postmortems act as a quality control for the medical practice.
3. Education tool for medical students (both undergraduates and postgraduates) to learn pathology. It is an
opportunity to correlate clinical signs with their underlying pathological changes.
4. As a source of research into the causes and mechanisms of different diseases
5. For accurate statistics about disease incidence.
MICROSCOPIC PATHOLOGY
Pathology, and consequently medicine, has been revolutionized by the application of microscopy to the study
of diseased tissues from about the year 1800 AC. Before this, it was postulated that diseases are
spontaneously generated, independent of any external causes or other influences. This attitude seems
unreasonable to us today, but at that time nothing was known of infectious agents (such as bacteria and
viruses, etc.) or cancer causative agents (such as ionizing radiation and carcinogenic chemicals, etc.).
The primitive light microscope of Rudolf Virchow (1821-1902), a German pathologist, enabled him to see
changes in diseased tissues at a cellular level. His observations have had a profound influence on the
understanding of many diseases.
At this point it should be emphasized that the contribution of other branches of pathology is unquestionable
for e.g. the advances in biochemistry are renovating the knowledge of many diseases at a molecular level; we
now have biochemical explanations for many of the cellular and clinical manifestations of disease.
FIELDS OF PATHOLOGY
Pathology is the foundation of medical science and practice. Without pathology, the practice of medicine
would be reduced to legends and traditions.
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Experimental pathology refers to the observation of the effects of manipulations on animal models or cell
cultures regarding researches on human diseases.
Clinical pathology: the approach to the patient’s illness clinically is based on the following sequence of
steps
Patient's history _Examination_Investigations _Diagnosis _Treatment
Clinical pathology is more concerned with analysis of the disease itself that include its cause (etiology), the
mechanisms of its evolution (pathogenesis), its effects on various organs and systems of the body. It should
be noted that clinical medicine and clinical pathology are complementary and can not be separated: clinical
medicine cannot be practiced without an understanding of pathology; pathology is meaningless if it is cut off
clinical conclusions.
Subdivisions of clinical pathology: in practice the major subdivisions of pathology are
Histopathology; concerned with the investigation and diagnosis of disease from examination of tissues
Cytopathology; concerned with the investigation and diagnosis of disease from the examination of isolated
cells
Hematopathology; concerned with the study of disorders affecting the cells and the coagulation system of
blood
Microbiology; concerned with the study of infectious diseases and the organisms responsible for them
Immunopathology; concerned with the study of disturbances affecting the defense mechanisms of the body,
and their contribution to the disease processes.
Chemical pathology; concerned with the study and diagnosis of disease from the chemical changes that
occur in tissues and fluids.
Medical genetics; concerned with the study of abnormal chromosomes and genes and their relevance to
disease processes
Toxicology; concerned with the study of the effects of known or suspected poisons on the body.
Forensic pathology; concerned with the application of pathology to legal purposes (e.g. investigations of
death in suspicious circumstances). Because of the continuous and rapid advances in the above subjects, it is
impossible for one pathologist to cover all these branches. Thus each of these branches requires its own team
of expert specialists; in fact there are currently specialists in the sub-braches of each of the disciplines
mentioned above for e.g. in histopathology there are specialists in liver disease (hepatopathologist), in skin
diseases (dermatopathologist) & in diseases affecting the nervous system (neuropathologist).
TECHNIQUES OF PATHOLOGY
Our knowledge of the nature and causation of diseases has been revealed by the continuing application of
various tools of pathology to their study.
Histopathologic techniques include
1. Gross pathology (macroscopic pathology): this refers to the changes affecting various organs and tissues
in diseases as evident to the naked eye. Much of these changes have been derived from autopsy
(postmortem) examinations, which is still an important investigative method. The gross pathology of
many diseases is so characteristic that an experienced pathologist can give a fairly confident diagnosis of
the disease before further investigations are carried out.
2. Light microscopy: advances in light microscopic examination have resulted in a wealth of new
information about the structure of tissues and cells in health and disease. If solid tissues (e.g. liver,
kidney etc.) are to be examined by light microscopy, the sample must first be thinly sectioned to permit
the transmission of light and to minimize the superimposition of tissue components. These sections are
routinely cut from tissue hardened by permeation with and embedding in wax or. (Fig. 1-1) For some
purposes (e.g. histochemistry, or when very urgent diagnosis is needed) sections have to be cut from
tissue that has been hardened rapidly by freezing (frozen section technique). The sections are stained to
help distinguishing between different components of the tissue (e.g. nuclei, cytoplasm, and other
structures such as collagen). The microscope can
also be used to examine cells derived from fluid
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within cysts or body cavities (exfoliative cytology), scraped from body surfaces e.g. cervical smears
(exfoliative cytology) and from solid lesions through the use of needles (fine needle aspiration cytology).
In fact cytology is currently used widely in cancer diagnosis and screening.
3. Histochemistry: certain cells produce chemical substances the detection of which through
treatment with specific reagents (histochemical stains) is of diagnostic value; e.g. PAS stain (for the
detection of glycogen), PAS with prior treatment of tissue sections with diastase (for the detection of
mucin) Perl’s stain (for the detection of iron).
4. Immunohistochemistry and immunofluorescence
These techniques employ antibodies (with antigen specificity) to visualize substances (for e.g.
cellular proteins or surface receptors) in tissue sections or cytological cell preparations. To visualize the
reaction sites; these antibodies are connected chemically to enzymes (Immunohistochemistry) or
fluorescent dyes (Immunofluorescence) are used. In immunohistochemistry the end product is a deposit of
colored material that can be seen with a conventional light microscope. The list of substances detectable
by these techniques has been greatly enlarged by the development of monoclonal antibodies.
5. Electron microscopy: this has extended the range of pathology to the study of disorders at an organelle
(subcellular) level and the demonstration of viruses in tissue samples from some diseases. The most
common diagnostic use of electron microscopy, however, is the interpretation of renal biopsies i.e. helps
establish the diagnosis of various glomerular diseases.
6. Biochemical techniques: these are applied to the tissues and body fluids and are now one of the principal
factors on the growing understanding of pathological processes. The clinical role of biochemistry is
exemplified by the importance of monitoring fluid and electrolyte changes that occur in many disorders.
Determination of serum enzyme levels are used to assess the integrity and vitality of various tissues; for
example, raised levels of cardiac enzymes in the blood indicate damage to cardiac myocytes and thus very
helpful in establishing the diagnosis of myocardial infarction.
7. Hematological techniques: these are used in the diagnosis and study of blood disorders. They range from
relatively simple blood cells counting, which can be performed electronically, to the more sophisticated
assays of blood coagulation factors.
8. Cell cultures: these are widely used in research and diagnosis. They are an attractive medium for research
because of the ease with which the cellular environment can be modified and the responses to it
monitored. Diagnostically, cell cultures are used to prepare chromosome spreads for cytogenetic analysis.
9. Medical microbiology: this is the study of diseases caused by organisms such as bacteria, fungi, viruses
and parasites. Techniques used include direct microscopy of appropriately stained material (e.g. pus),
cultures to isolate and grow the organism, and methods to identify correctly
the cause of the infection.
In the case of bacterial infections, the most appropriate antibiotic can be selected to treat a given
infection by determining the sensitivity of the bacteria to a variety of therapeutic agents (through the use
of antibiotic discs)
10. Molecular pathology: many important advances are now coming from the science of molecular
pathology for e.g. the disclosure that defects in the chemical structure of molecules are in fact the result
of errors in the genomic DNA, and precisely, in the sequence of the DNA bases that directs amino acid
synthesis. Through the use of in situ hybridization technique, it is possible to make the presence of
specific genes or their messenger RNA visible in tissue sections or cell preparations. Minute quantities
of nucleic acids can be amplified by the use of the polymerase chain reaction (PCR) using
oligonucleotide primers specific for the genes being studied. DNA microarrays can be used to determine
patterns of gene expression (mRNA). This powerful technique can reveal new diagnostic and prognostic
categories, indistinguishable by other methods. Molecular pathology applications include the study, for
example, of abnormal hemoglobin molecules, such as in sickle cell disease and the alterations in the
genome that control cell growth, which is important part in the development of neoplasms.
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DIAGNOSTIC PATHOLOGY
Hospitalized patients are often investigated to diagnose their illness by applying methods to the examination
of tissue biopsies and body fluids (including blood). If there are clinical indications to do so, it may be
possible to obtain a series of samples from which the course of the disease can be monitored.
LEARNING PATHOLOGY
Pathology is best learnt in two stages:
General pathology is concerned with the causations, mechanisms and characteristics of the major categories
of disease (e.g. cell injuries and degenerations, inflammations, healing, neoplasia). The principles of general
pathology must be understood before an attempt is made to study the pathology of various systems of the
body (systemic pathology). This is because the former represents the foundation of knowledge that has to be
acquired before indulging in the pathology of various organs systems the body.
Systemic pathology is the study of various systems that comprise the body such as cardiovascular
pathology, gastrointestinal pathology and so on. It includes the descriptions of specific diseases as they affect
individual organs (e.g. appendicitis, lung cancer, atheroma etc,). Each specific disease can usually be
attributed to the operation of one or more categories featuring in general pathology. Thus, acute appendicitis
is acute inflammation affecting the appendix, whereas carcinoma of the lung is a neoplasia that results from
carcinogens acting upon cells in the lung.
Building knowledge and understanding
There are two difficulties facing the new student of pathology: language and process. Pathology, like most
branches of medicine, has its own special language: this needs to be learnt and understood not just because
they are the language of pathology but they are also a major part of the language of clinical medicine. A
logical and orderly way of thinking about diseases and their characteristics must be cultivated; for each
disease entity the student should be able to list the chief characteristics:
Epidemiology
Etiology
Pathogenesis
Pathological and clinical features
Complications and sequelae
Prognosis
Treatment
Our knowledge about many diseases is still incomplete, but at least the above list will urge the memory and
enable students to organize their knowledge. Pathology is learnt through a variety of media. Even the
bedside, operating theatre and outpatient clinic provide ample opportunities for further experience of
pathology. Hearing a cardiac murmur through a stethoscope should urge the listening student to consider the
pathological features of the abnormal cardiac valve responsible for the murmur, and the effects of this on
other organs such as the heart and lung.
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CHAPTER TWO
CELLULAR ADAPTATIONS & INJURY
Dr. Khitam, Dr Kifah, Dr Sazan, dr Ameer
CELLULAR RESPONSES TO HARMFUL STIMULI
Each cell in the body is designed to carry a specific function or functions, which is dependent on its
machinery and metabolic pathways. These specificities are genetically determined.
Cells are continuously adjusting their structure and function, within a narrow range, to deal with the
continually changing extra-cellular environment. This ability on the part of the cell to maintain a
dynamically stable state is referred to as homeostasis.
Should the cells encounter more severe external changes (physiological or pathological); they can modify the
homeostatic state and achieve a new steady state to counteract the noxious effects of these external stresses.
These changes are referred to as adaptations. The aim behind these adaptations is to avoid cell injury &
death.
The morphological & functional changes induced by the injury may be reversible, i.e. the cells return to a
normal state on the removal of the offending agent, or irreversible i.e. there is no possibility of making a
u-turn to normal. Irreversible changes ultimately eventuate in cell death.
The above mentioned possibilities can be exemplified by the myocardium that is subjected to persistently
increased pressure load (hypertension); this adapts by undergoing hypertrophy i.e. an increase in the size of
individual cells and ultimately the entire heart. This generates the required higher contractile force to
counteract the effect of hypertension (Fig. 2-1). If the hypertension (an injurious external stress) is not
relieved, the muscle cells may undergo injury. The injury may be reversible, if the hypertension is mild;
otherwise irreversible injury (cell death) occurs.
CELLULAR ADAPTATIONS
Adaptations are reversible changes and are divided into physiologic & pathologic adaptations. Physiologic
adaptations usually represent responses of cells to normal stimulations e.g., the hormone-induced
enlargement of the breast and uterus during pregnancy. Pathologic adaptions, on the other hand, can take
several distinct forms (see below).
Examples of adaptations include
Hypertrophy: this refers to an increase in the size of cells that resuls in enlargement of their relevant organ.
Hypertrophy can be physiologic or pathologic and is caused either by increased functional demand or by
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specific hormonal stimulation. Examples of physiologic hypertrophy include that of skeletal muscles in
athletes and mechanical workers & the massive physiologic enlargement of the uterus during pregnancy due
to estrogen-stimulated smooth muscle hypertrophy (and hyperplasia) (Fig. 2-2). Pathologic hypertrophy is
exemplified by cardiomegaly secondary to hypertension (Fig. 2-1). The stimuli of hypertrophy turn on
signals that lead to the induction of a number of genes, which in turn stimulate synthesis of numerous
contractile myofilaments per cell. This leads to improved performance to house the excessive demand
imposed by the external burden. There is, however, a limit for the adaptation beyond which injury occurs; as
for e.g. in the heart, where several degenerative changes occur in the myofilaments that culminate in their
loss. This limitation of cardiac hypertrophy (an adaptation) may be related to the amount of available blood
to the enlarged fibers. The net result of these regressive changes is ventricular dilation and ultimately cardiac
failure. This means that an adaptation can progress to dysfunction if the stress is not relieved.
Hyperplasia refers to an increase in the number of cells. It takes place only if the cells are capable of
replication; it may occur with hypertrophy and often in response to the same stimuli. Hyperplasia can be
physiologic or pathologic.
Physiologic hyperplasia: this is of two types
1. Hormonal hyperplasia, exemplified by the proliferation of the glandular epithelium of the female breast at
puberty and during pregnancy.
The enlargement of the gravid uterus is due to a combination of hypertrophy & hyperplasia.
2. Compensatory hyperplasia, which occurs when a portion of the tissue is removed or diseased. For
example, when a liver is partially resected, mitotic activity in the remaining cells begins that eventually
restore the liver to its normal weight. The stimuli for hyperplasia in this setting are growth factors produced
by remaining hepatocytes & other cells within the organ. After restoration of the liver mass, cell proliferation
is "turned off" by various growth inhibitors.
Pathologic hyperplasia: is mostly caused by excessive hormonal or growth factor stimulation. Examples
include
1. Endometrial hyperplasia: this results from persistent or excessive estrogen stimulation of the
endometrium. This hyperplasia is a common cause of abnormal uterine bleeding. (Fig. 2-3)
2. Skin warts: these are caused by Papillomaviruses, and are composed of masses of hyperplastic epithelium.
(Fig. 2-4) The growth factors responsible may be produced by the virus or by the infected cells.
In all the above situations, the hyperplastic process remains controlled; if hormonal or growth factors
stimulation subsides, the hyperplasia disappears. It is this response to normal regulatory control mechanisms
that distinguishes pathologic hyperplasias from cancer, in which the growth control mechanisms become
ineffective. However, some types of pathologic hyperplasias may become a fertile soil for the development
of carcinoma.
Atrophy: this refers to shrinkage in the size of the cell due to loss of its constituent substances. This
situation is exactly opposite to hypertrophy. When a sufficient number of cells are involved, the entire tissue
or organ diminishes in size i.e. becomes atrophic (Fig. 2-5).
Causes of atrophy include
1. A decreased workload, which is the most common form of atrophy; it follows reduced functional demand.
For example, after immobilization of a limb in a cast as treatment for a bone fracture or after prolonged bed
rest.In these situations the limb's muscle cells atrophy and muscular strength is reduced. When normal
activity resumes, the muscle's size and function return.
2. Denervation of a limb as in poliomyelitis and traumatic spinal cord injury
3. Diminished blood supply e.g. decreased blood supply to a limb or brain due to narrowing of the lumina
of the relevant artery (or arteries) by atherosclerosis.
4. Inadequate nutrition as in starvation and famines
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5. Loss of endocrine stimulation as in postmenopausal endometrial atrophy (due to decrease
in the
levels of estrogen after menopause) and testicular atrophy (due to decrease in the production of LH & FSH
as in hypopituitarism (Fig. 2-6)
6. Aging (senile atrophy).
Although some of these stimuli are physiologic (e.g., the loss of hormone stimulation in menopause) and
others pathologic (e.g., denervation), the fundamental cellular changes in atrophy are identical. They
represent a retreat by the cell to a smaller size at which survival is still possible; a new equilibrium is
achieved between cell size and
diminished blood supply, nutrition, or trophic stimulation. Atrophy
results from decreased protein synthesis together with increased protein degradation in the affected cells. In
many situations, atrophy is also accompanied by increased autophagy ("self-
eating"), with resulting
increases in the number of autophagic vacuoles. The starved
cell eats its own components in an
attempt to find nutrients and survive.
Metaplasia refers to a reversible change in which there is “replacement of normal mature epithelium at a
given site by another mature benign epithelium inappropriate to that site.” In this type of cellular adaptation,
cells sensitive to a particular stress are replaced by other cell types that are more capable of resisting the
adverse environment. Metaplasia is thought to arise by genetic "reprogramming" of stem cells. Epithelial
metaplasia is exemplified by the squamous change that occurs in the respiratory epithelium in habitual
cigarette smokers. The normal ciliated columnar epithelial cells of the trachea and bronchi are focally or
extensively replaced by stratified squamous epithelial cells. Although the metaplastic squamous epithelium
is more resistant to the injurious environemen, it has its adverse effects that include
1. Loss of protective mechanisms, such as mucus secretion and ciliary clearance of particles. 2.
Predisposition to malignancy. In fact, squamous cell carcinoma of the bronchi often coexists with
squamous metaplasia. Squamous metaplasia is also seen in the urinary
bladder harboring Shistosomal
ova. When there persistent regurgitation of the gastric
contents in to the esophagus (chronic
gastro-esophageal reflux disease [GERD]), the
normal stratified squamous epithelium of the lower
esophagus may be replaced by a
metaplastic intestinal-type columnar epithelium. The latter is more
resistant to the highly acidic regurgitating gastric contents (Fig. 2-7).
CELL INJURY AND CELL DEATH
Cell injury results when cells are exposed to
1. Persistent stress so that the affected cells are no longer able to adapt or
2. Inherently damaging agents. (Fig. 2-8)
Reversible cell injury occurs when the injurious agent is mild but persistent or severe but short lived. In this
type of injury the functional and morphologic changes are reversible. With continuing damage, there is
irreversible injury, at which time the cell cannot recover even with the removable of the injurious agent i.e. it
dies.
Causes of Cell Injury include
1. Oxygen deprivation (Hypoxia) insufficient supply of oxygen interferes with aerobic oxidative respiration
and is a common cause of cell injury and death.
Causes of hypoxia include
a. Ischemia i.e. loss of blood supply in a tissue due to interference with arterial flow or reduced venous
drainage. This is the most common cause of hypoxia
b. Inadequate oxygenation of the blood, as in pneumonia or chronic bronchitis
c. Reduction in the oxygen-carrying capacity of the blood, as in anemia or carbon
monoxide (CO)
poisoning.
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2. Chemical agents: various poisons cause damage by affecting either membrane permeability, or the
integrity of the cellular enzymes. Environmental toxins as
pollutants, insecticides, CO, alcohol and
drugs can cause cell injury.
3. Infectious agents including viruses, bacteria, rickettsiae, fungi and parasites.
4. Immunologic reactions; these are primarily defensive in nature but they can also result in cell and
tissue injury. Examples include autoimmune diseases & allergic reactions.
5. Genetic defects including gross congenital malformations (as in Down syndrome) or point mutations
(as in sickle cell anemia). Genetic defects may cause cell injury because of deficiency of enzymes in
inborn errors of metabolism.
6. Nutritional imbalances: nutritional deficiencies are still a major cause of cell injury. Protein-calorie &
vitamins insufficiencies are obvious example. Excesses of nutrition are also important causes of
morbidity and mortality; for example, obesity markedly increases the risk for type 2 diabetes mellitus.
Moreover, diets rich in animal fat are strongly implicated in the development of atherosclerosis as well as
in increased
vulnerability to cancer e.g. that of the colon.
7. Physical agents: trauma, extremes of temperatures, radiation, electric shock, and sudden changes in
atmospheric pressure all are associated with cell injury.
8. Aging: this leads to impairment of replicative and repair abilities of individual cells that result in a
diminished ability to respond to damage and, eventually, the death of
cells and of the individual.
Morphologic features of cell and tissue injury
All harmful influences exert their effects first at the molecular (subcellular) or biochemical level. Function
may be lost long before morphologic changes of cell injury become obvious (Fig. 2-9). For example,
myocardial cells fail to contract after 1 to 2 minutes of ischemia, although they do not die until after 20 to 30
minutes of ischemia. These myocytes do not appear morphologically dead by electron microscopy
until after 3 hours and by light microscopy after 6 to 12 hours. The cellular changes associated with
reversible injury can be repaired once the injurious agent is removed. Changes associated with irreversible
injury (as with persistent or excessively severe injury) are irreversible even with the removal of the injurious
agent, i.e. their occurrence signals the point of no retrun, and the cell inevitably dies.
There are two changes that characterize irreversible injury (cell death)
1. Mitochondrial dysfunction manifested as lack of oxidative phosphorylation leading to ATP depletion
2. Membrane dysfunction including not only the outer cell membrane but also the membranes that surround
intracytoplasmic lysosomes. This results in liberation of the harmful lysosomal enzymes into the cytoplasm,
which in turn leads to dissolution of vital celluar structures.
Morphologic examples of reversible injury
1. Cellular swelling (hydropic change or vacuolar degeneration): this is due to paralysis of energy-dependent
ion pumps of the plasma membrane. This leads to influx of sodium (with water) into the cell and
departure of potassium out. It is the first manifestation of almost all forms of cell injury. Microscopically,
there are clear vacuoles (of water) within the cytoplasm. (Fig. 2-10)
2. Fatty change: this is manifested by the appearance of lipid vacuoles in the cytoplasm. It is principally
encountered in cells participating in fat metabolism
such as hepatocytes; as in alcoholic liver disease,
malnutrition & total parenteral nutrition.
Irreversible cell injury
There are two morphological types of cell death
1. Apoptosis
2. Necrosis
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Apoptosis is an active, energy-dependent, regulated type of cell death. It serves many normal functions and
is not necessarily pathological is the mode of cell death when
a. The cell is deprived of its growth factors or
b. The cell's DNA or proteins are damaged beyond repair
Necrosis is a reflection of the morphological changes that accompany cell death due to the digestion of
cellular contents by the liberated degradative lysosomal enzymes. It is associated with an inflammatory
repose (unlike apoptosis), due to leakage of the cellular contents through the damaged plasma membrane.
The lysosomes of the inflammatory cells also contribute to the digestion of the dying cells. Necrosis is the
major pathway of cell death in many commonly encountered injuries, such as those resulting from ischemia,
exposure to toxins, & various infections.
Morphologic features of necrosis: these consists of cytoplasmic & nuclear changes
Cytoplasmic changes: the necrotic cells show increased cytoplasmic eosinophilia i.e. it appears deep pink
in color than normal cells. This is attributable in part to increased binding of eosin to denatured cytoplasmic
proteins and in part to loss of the basophilia that is normally imparted by the RNA in the cytoplasm
(basophilia is the blue staining from the hematoxylin dye). The cell may have a more homogeneous
appearance than viable cells, mostly because of the loss of glycogen particles. The latter is responsible in
normal cells for the granularity of the cytoplasm.
Nuclear changes (Fig. 2-11): these assume one of three patterns, all due to breakdown of DNA and
chromatin
a. Karyolysis i.e. the basophilia of the chromatin become pale secondary to deoxyribonuclease (DNase)
activity.
b. Pyknosis characterized by nuclear shrinkage and increased basophilia; the DNA condenses into a solid
shrunken mass.
c. Karyorrhexis, the pyknotic nucleus undergoes fragmentation.
Patterns of Tissue Necrosis
There are several morphologically patterns of tissue necrosis, which may provide clues about the underlying
cause.
1. Coagulative necrosis is characterized grossly by firmness of the affected tissue due to denaturation of
structural proteins and microscopically by loss of the cellular fine structural details but preservation of the
basic tissue architecture. (Fig. 2-12) The necrotic cells show homogeneously eosinophilic cytoplasm and are
devoid of nuclei. Ultimately the crotic cells are removed through the degradtative enzymes released from
both the dead cells themselves as well as from the already present inflammatory cells. The latter also
contribute by phagocytosing the cellular debris. Coagulative necrosis is characteristic of ischemic damage in
all solid organs except the brain.
2. Liquefactive necrosis is characterized by complete digestion of the dead cells, resulting in transformation
of the affected tissue into thick liquid mass (hence the name liquefactive). Eventually, the liquefied necrotic
tissue is enclosed within a cystic cavity. This type of necrosis is seenin two situations
a. Focal pyogenic bacterial infections. These bacteria stimulate the the accumulation of
inflammatory cells & the enzymes of leukocytes digest ("liquefy") the tissue. This process is associated acute
suppurative inflammation (abscess); the liquefied material is frequently creamy yellow and is called pus.
(Fig. 12-13)
b. Ischemic destruction of the brain tissue: for unclear reasons, hypoxic death of cells within the central
nervous system often induces liquefactive necrosis (Fig. 2-14).
3. Gangrenous necrosis (gangrene) is not a distinctive pattern of cell death; however, the term is still
commonly used in clinical practice. It is usually applied to a limb, usually a leg that has lost its blood supply
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and has undergone coagulative necrosis involving multiple tissue layers (dry gangrene). When bacterial
infection is superimposed, coagulative necrosis is modified by the liquefactive action of the bacteria and the
attracted leukocytes (wet gangrene). (Fig. 2-15) Intestinal gangrene (the consequences of mesenteric vascular
occlusion) and gangrenous appendix are also commonly used terms; they signify ischemic necrosis of these
structures with superimposed bacterial infection.
4. Caseous necrosis, unlike coagulative necrosis, the tissue architecture is completely lost and cellular
outlines cannot be detected. It is encountered most often in foci of tuberculous infection. The term "caseous"
(cheese-like) is derived from the friable yellow-white appearance of the area of necrosis (Fig. 2-16).
Microscopically, the necrotic focus appears as pinkish, and granular in appearance. Caseous necrosis is often
bordered by a granulomatous inflammation.
5. Fat necrosis is typically seen in acute pancreatitis and results from release of activated pancreatic lipases
into the pancreas and the peritoneal cavity. Pancreatic enzymes that have leaked out of acinar cells liquefy
the membranes of fat cells in and outside the pancrease. Lipases split the liberated triglycerides into fatty
acids that combine with calcium to produce grossly visible chalky white areas (Fig. 2-17). Microscopically,
the foci of necrosis contain vague outlines of necrotic fat cells with bluish calcium deposits. The necrotic
foci are surrounded by an inflammatory reaction. Another example of fat necrosis is seen in female breasts;
at least some of these cases are preceded by a history of trauma (traumatic fat necrosis).
6. Fibrinoid necrosis is typically seen in immune reactions involving blood vessels. Deposits of immune
complexes, together with fibrin that has leaked out of vessels result in a homogeneous bright pink
appearance. This type is exemplified by the necrosis seen in polyarteritis nodosa (Fig. 2-18).
The leakage of intracellular proteins through the damaged cell membrane and ultimately into the blood
provides means of detecting necrosis of specific tissues using blood or serum samples. The measurement of
the levels of these specific enzymes in the serum is used clinically to assess damage to these tissues. Cardiac
muscles contain a unique enzyme creatine kinase (CK) and the contractile protein troponin. The serum levels
of both are elevated after acute myocardial infarction. Hepatocytes contain transaminases & these are
elevated in the serum following an episode of hepatitis (viral or otherwise).
SUBCELLULAR RESPONSES TO INJURY
Some of these alterations occur in acute lethal injury, others in chronic cell injury, and still others are
adaptive responses.
Autophagy refers to lysosomal digestion of the cell's own components. It is a survival mechanism whenever
there is nutrient deprivation; the starved cell lives by eating its own contents. In this process, organelles are
sequestered from the cytoplasm in an autophagic vacuole. The vacuole fuses with lysosomes to form
phagolysosome, & the cellular components are digested by lysosomal enzymes. Lysosomes with undigested
debris may persist within cells. Lipofuscin pigment is indigestible material; it is seen as brownish-yellow
granules within parenchymal cells e.g. of the liver & heart in old age & in atrophy of these organs. Carbon
particles inhaled from the atmosphere and inoculated pigment in tattoos can persist in phagolysosomes of
macrophages for decades. (Fig. 2-19) In hereditary lysosomal storage diseases there are deficiencies of
enzymes that degrade certain macromolecules; the result is an abnormal collection of these in the lysosomes
of cells all over the body.
Induction (hypertrophy) of smooth endoplasmic reticulum (SER): the SER is involved in the
metabolism of various chemicals including some drugs, and cells exposed to these chemicals show
hypertrophy of the SER as an adaptive response that may have important functional consequences for e.g.
induction of hepatic drug-metabolizing activity.
Mitochondrial Alterations: mitochondria may show
1. An increase in their number in cellular hypertrophy.
2. A decrease in number during cellular atrophy (probably via autophagy).
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3. Extremely large and abnormal shapes (megamitochondria), e.g. in hepatocytes in association with
nutritional deficiencies and alcoholic liver disease.
Cytoskeletal Abnormalities:
Cytoskeletone is the cellular scaffold, which is represented by myosin, intermediate filaments and
microtubules
Examples of cytoskeletal abnormalities are seen in
1. Alcoholic liver disease: Mallory bodies are eosinophilic, collections of intermediate filamentsd that
accumulate within the cytoplasm of hepatocytes.
2. Kartagener (immotile cilia) syndrome: due to disorganization of microtubules, which is associated with
sterility due to inhibition of sperm motility? There are also chronic infections of the lung due to defective
motility of cilia of the respiratory epithelium, and thus accumulation of the secreted mucus & impaired
clearance of inhaled bacteria.
MECHANISMS OF CELL INJURY
The outcomes of the interaction between injurious agents & cells depend on
1. The injurious agent: its type, severity, and the duration of its application to the cells.
2. The cells exposed to the injury: its type, adaptability, and their genetic makeup.
The above are exemplified by the following facts
Low doses of toxins or a brief duration of ischemia may lead to reversible cell injury, whereas larger toxin
doses or longer ischemic intervals may result in irreversible injury and cell death.
The same injury has different outcomes depending on the cell type; thus, striated skeletal muscles in the leg
resist complete ischemia for 2 to 3 hours without irreversible injury (as in applying a tornique to stop severe
uncontrable bleeding from a limb trauma), whereas cardiac muscles die after only 20 to 30 minutes of severe
acute ischemia. Individuals who inherit variants of the same gene that encod an enzyme that degrades a
particular toxin show differences in the speed (rate) of toxins degredation. This explains the different
outcomes that may occur when different indivuals are exposed to the same dose of a given toxin.
The most important targets of injurious agnets are
1. Mitochondria (the sites of ATP generation)
2. Cell membranes, which influence the ionic and osmotic homeostasis of the cell
3. Protein synthesis (ribosomes)
4. The cytoskeleton (microtubules, and various filaments)
5. The genetic apparatus of the cell (nuclear DNA)
ATP Depletion
ATP, the energy fuel of cells, is produced mainly by oxidative phosphorylation of ADP within the
mitochondria. In addition, the glycolytic pathway can generate ATP in the absence of oxygen using glucose
derived either from the circulation or from the hydrolysis of intracellular glycogen (anerobic glycolysis).
The major causes of ATP depletion are
1. Reduced supply of oxygen and nutrients
2. Mitochondrial damage
3. The actions of some toxins (e.g., cyanide)
High-energy phosphate in the form of ATP is required for virtually all synthetic and degradative processes
within the cell, including membrane transport, protein synthesis, phospholipid turnover, etc. Depletion of
ATP to less than 5% to 10% of normal levels has widespread effects on many critical cellular systems.
a. The activity of the plasma membrane energy-dependent sodium pump is reduced, resulting in
intracellular accumulation of sodium and efflux of potassium. The net gain of solute is accompanied
by iso-osmotic gain of water, causing cell swelling.
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b. There is a compensatory increase in anaerobic glycolysis in an attempt to maintain the cell's energy
sources. As a consequence, intracellular glycogen stores are rapidly depleted, and lactic acid
accumulates, leading to decreased intracellular pH and decreased activity of many cellular enzymes.
c. Failure of the Ca2+ pump leads to influx of Ca2+, with damaging effects on numerous cellular
components (described below).
d. Structural disruption of the protein synthetic apparatus manifested as detachment of ribosomes from
the rough endoplastic reticulum (RER), with a consequent reduction in protein synthesis.
e. Ultimately, there is irreversible damage to mitochondrial and lysosomal membranes, and the cell
undergoes necrosis.
Mitochondrial Damage
Mitochondria can be damaged by increases of cytosolic Ca2+, reactive oxygen species, and oxygen
deprivation, and so they are sensitive to virtually all types of injurious stimuli, including hypoxia and toxins.
There are two major consequences of
mitochondrial damage:
Failure of oxidative phosphorylation with progressive depletion of ATP, culminating in necrosis of the cell.
Leakage of cytochrome c that is capable of activating apoptotic pathways.
Influx of Calcium
Cytoplasmic free calcium is normally maintained by ATP-dependent calcium pump
(transporter) at concentrations that are10, 000 times lower than the concentration of
extra-cellular
calcium or intracellular mitochondrial and ER calcium. Ischemia and
certain toxins cause an increase in
cytoplasmic calcium concentration, initially because of release of Ca2+ from the intracellular stores, and
later resulting from increased influx across the plasma membrane.
Increased cytosolic Ca2+ leads to
1. Activates a number of enzymes including phospholipases (which cause membrane
damage),
proteases (which break down both membrane and cytoskeletal proteins), endonucleases (which are
responsible for DNA and chromatin fragmentation), and ATPases (worsen ATP depletion).
2. Induction of apoptosis, by direct activation of certain enzymes called caspases.
Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)
These are designated as reactive oxygen species (ROS) & are units with a single unpaired electron
in their outer orbit. When generated in cells they enthusiastically attack nucleic acids, cellular proteins
and lipids. ROS are produced normally in cells
during mitochondrial respiration and energy generation,
but they are degraded and
removed by cellular defense systems. When their production increases or the
defense
systems are ineffective, the result is an excess of these free radicals, leading to a condition
called oxidative stress. Cell injury in many circumstances involves damage
by free radicals; these
include
Reperfusion injury
Chemical and radiation injury
Toxicity from oxygen and other gases
Cellular aging
Inflammatory cells mediated tissue injury
DEFECTS IN MEMBRANE PERMEABILITY
Early loss of selective membrane permeability leading ultimately to overt membrane damage is a consistent
feature of most forms of cell injury (except apoptosis). The plasma membrane can be damaged by ischemia,
microbial toxins, complement components-mediated lysis, etc.
Biochemical mechanisms contribute to membrane damage include:
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1. Decreased phospholipid synthesis due to a fall in ATP levels. This affects all cellular membranes
including mitochondrial, which worsen the loss of ATP.
2. Degradation of membrane phospholipids due to activation of intracellular phospholipases through
increased levels of intracellular Ca2+.
3. Injury to cell membranes by Oxygen free radicals (ROS)
4. Damage to the cytoskeleton through activation of proteases by increased cytoplasmic Ca2+
5. They detergent effect of free fatty acids on membranes. These products result from phospholipid
degradation.
The most important sites of membrane damage during cell injury are
the mitochondrial membrane,
the plasma membrane
membranes of lysosomes.
Damage to DNA & proteins
Cells have mechanisms that repair damage to DNA, but if this damage is too severe to be corrected (e.g.,
after radiation injury or oxidative stress), the cell initiates its suicide program and dies by apoptosis. A
similar reaction is triggered by improperly folded (configured) proteins (see unfolded protein response),
which may be the result of inherited mutations or through free radicals. These mechanisms of cell injury
typically cause apoptosis.
EXAMPLES OF CELL INJURY AND NECROSIS
Ischemic and Hypoxic Injury
Ischemia is the most common cause of cell injury in clinical medicine.
Unlike hypoxia, in which energy generation by anaerobic glycolysis can continue, in ischemia the delivery of
the substrates for glycolysis is also interfered with. Consequently, anaerobic energy generation ceases in
ischemic tissues. Therefore, ischemia injures tissues faster than does hypoxia.
The fundamental biochemical abnormality in hypoxic cells that leads to cell injury is reduced intracellular
generation of ATP, as a consequence of reduced supply of oxygen.
Loss of ATP leads to the failure of many energy-dependent systems of the affected cell; these include
1. Paralysis of ion pumps (leading to cell swelling, and influx of Ca2+)
2. Depletion of glycogen stores with accumulation of lactic acid (anerobic glycolysis)
3. Reduction in protein synthesis
The functional consequences may be severe. For instance, heart muscle ceases to contract within 60 seconds
of coronary occlusion. However, loss of contractility does not mean cell death. If hypoxia continues,
worsening ATP depletion causes further deterioration, for e.g., in renal tubular epithelium, there is loss of
microvilli and the formation of "blebs". (Fig. 2-20) At this time, the entire cell and its organelles
(mitochondria, ER) are markedly swollen, with increased concentrations of water, sodium, and chloride and
a decreased concentration of potassium. If oxygen is restored, all of these disturbances are reversible.
If ischemia persists, irreversible injury and necrosis ensue. Irreversible injury is associated with severe
swelling of mitochondria, extensive damage to plasma membranes, and swelling of lysosomes. Massive
influx of calcium into the cell may occur. The cell's components are progressively degraded, and there is
widespread leakage of cellular enzymes into the extracellular space.
Reperfusion Injury
If cells are reversibly injured, the restoration of blood flow can result in cell recovery.
However, under certain circumstances, the restoration of blood flow to reversibly ischemic tissues results in
worsening the injury. This situation may contribute to tissue damage in myocardial and cerebral infarctions.
The additional damage may be initiated during the blood re-flow by
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1. Increased generation of reactive oxygen species from native parenchymal and endothelial cells, as well as
the infiltrating inflammatory cells.
2. The cellular antioxidant defense mechanisms are already interfered with by ischemia.
3. Ischemic injury is associated with inflammation, which may increase with reperfusion. The products of
activated leukocytes and activation of the complement system may cause additional tissue injury.
Chemical Injury
Chemicals induce cell injury by one of two general mechanisms
1. Direct cytotoxic effect through combination with a vital molecular component or cellular organelle. In
HgCl2 poisoning, mercury binds to various cell membrane proteins, causing inhibition of transport and
increased membrane permeability. Many antineoplastic chemotherapeutic agents also induce cell damage by
direct cytotoxic effects.
2. Formation of free radicals: many chemicals must be first converted to reactive toxic metabolites, which
then act on target cells. Although the metabolites might cause membrane damage and cell injury by direct
binding to protein and lipids, the most important mechanism of cell injury involves the formation of free
radicals. Carbon tetrachloride (CCl4, which was used widely in the dry cleaning industry but is now banned)
and the analgesic paracetamol belong to this category.
APOPTOSIS
This form of cell death is a regulated suicide program in which the relevant cells activate enzymes capable of
degrading the cells' own nuclear DNA and other nuclear and cytoplasmic proteins.
The plasma membrane of the apoptotic cell remains intact, but is altered in such a way that the cell becomes
avid targets for phagocytes. The dead cell is rapidly cleared before its contents have leaked out, and therefore
cell death by this pathway does not elicit an inflammatory reaction in the host.
Thus, apoptosis differs from necrosis; the latter is characterized by loss of membrane integrity, leakage of
cellular contents, and frequently a host reaction.
Causes of Apoptosis
Apoptosis occurs in physiologic situations; it serves to eliminate potentially harmful cells and cells that are
no longer useful to the wellbeing of the body.
It is also a pathologic event when cells are damaged beyond repair, especially when the damage affects the
cell's DNA or proteins; in these situations, the irreparably damaged cell is eliminated.
Apoptosis in Physiologic Situations
Death by apoptosis is a normal phenomenon that serves to eliminate cells that are no longer needed. It is
important in the following physiologic situations:
1. During embryogenesis (organogenesis and involution).
2. Involution of hormone-dependent tissues (hormone deprivation, as endometrial cell breakdown during the
menstrual cycle, and regression of the lactating breast after weaning)
3. In proliferating cells, such as intestinal crypt epithelia (to maintain a constant number).
4. In cells that have served their useful purpose (as neutrophils in an acute inflammation).
Apoptosis in Pathologic Conditions
Apoptosis eliminates cells that are genetically altered or injured beyond repair without eliciting a host
reaction, thus keeping the damage as restricted as possible.
Microscopic features (Fig. 2-21)
Apoptotic cells may appear as round or oval masses with intensely eosinophilic cytoplasm.
Nuclei show chromatin condensation and, ultimately fragmentation (karyorrhexis).
The cells rapidly shrink, and fragment into apoptotic bodies that are composed of membrane-bound vesicles
of cytoplasm and organelles.
These fragments are quickly extruded and phagocytosed without eliciting an inflammatory response.
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The fundamental event in apoptosis is the activation of enzymes caspases that culminate in activation of
nucleases with DNA degredation.
Examples of Apoptosis
1. Growth factor deprivation: hormone-sensitive cells deprived of the relevant hormone, lymphocytes that
are not stimulated by antigens and cytokines, and neurons deprived of nerve growth factor die by apoptosis.
These are attributable to activation of pro-apoptotic members of the Bcl-2 family.
2. DNA Damage: exposure of cells to radiation or cytotoxic anticancer chemotherapeutic agents & extremes
of temperature induces DNA damage, and if this is too severe to be repaired it triggers apoptotic death.
When DNA is damaged, the p53 protein accumulates in cells. It first arrests the cell cycle (at the G1 phase)
to allow time for repair. However, if the damage is too great to be repaired successfully, p53 triggers
apoptosis by stimulating synthesis of pro-apoptotic members of the Bcl-2 family. When p53 is mutated or
absent (as it is in certain cancers), it is incapable of inducing apoptosis, so that cells with damaged DNA are
allowed to survive. This enhances the possibility of mutations or translocations that lead to neoplastic
transformation and subsequently providing the tumor cells with a growth advantage.
3. Accumulation of Misfolded Proteins
During normal protein synthesis, chaperones (escorters) in the ER control the proper folding of newly
synthesized proteins, and misfolded polypeptides are targeted for proteolysis. If, however, unfolded or
misfolded proteins accumulate in the ER because of inherited mutations or stresses, they induce "ER stress"
that triggers a number of cellular responses, collectively called the unfolded protein response. This
response activates signaling pathways that increase the production of chaperones and retard protein
translation, thus reducing the levels of misfolded proteins in the cell. However, if this response is unable to
cope with the accumulation of misfolded proteins, the result is the activation of caspases that lead to
apoptosis. Intracellular accumulation of abnormally folded proteins is now recognized as a feature of a
number of neurodegenerative diseases, including Alzheimer, Huntington, and Parkinson diseases, and
possibly type II diabetes.
4. Apoptosis of Self-Reactive Lymphocytes: lymphocytes capable of recognizing self antigens are normally
produced in all individuals. If these lymphocytes encounter self antigens, the cells die by apoptosis. Failure
of apoptosis of self-reactive lymphocytes is one of the causes of autoimmune diseases.
5. Cytotoxic T Lymphocyte-Mediated Apoptosis: cytotoxic T lymphocytes (CTLs) recognize foreign
antigens presented on the surface of infected host cells and tumor cells. Upon activation, CTL granule
proteases called granzymes enter the target cells. Granzymes are able to activate cellular caspases. In this
way, the CTL kills target cells by directly inducing the effector phase of apoptosis.
6. Cell injury in certain infections, particularly viral infections, in which loss of infected cells is largely due
to apoptotic death that may be induced by the virus (as in HIV infection) or by the host immune response (as
in viral hepatitis)
7. Pathologic atrophy in parenchymal organs after duct obstruction as occurs in the pancreas, parotid gland,
and kidney.
INTRACELLULAR ACCUMULATIONS
Cells may accumulate abnormal amounts of various substances; these may be harmless or associated with
injury. The locations of these substances are either cytoplasmic within organelles (typically lysosomes), or in
the nucleus.
There are three main pathways of abnormal intracellular accumulations (Fig. 2-22):
1. In adequate removal of a substance i.e. the metabolic rate of its removal is inadequate. An example of this
type of process is fatty change in the liver.
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2. Defective transport of a substance: endogenous substance accumulates because of genetic or acquired
defects in its folding, packaging, transport, or secretion. Mutations may lead to accumulation of proteins
(e.g., α1-antitrypsin deficiency).
3. Failure to degrade a metabolite either because of
a. an inherited defect in an enzyme (as in storage diseases) or
b. the cell has neither the enzymatic machinery to degrade an abnormal exogenous substance nor the ability
to transport it to other sites. Accumulations of carbon or silica particles are examples of this type of
alteration.
Fatty Change (Steatosis)
This refers to any abnormal accumulation of triglycerides within parenchymal cells. It is most often seen in
the liver, since this is the major organ involved in fat metabolism, but it may also occur in the heart.
Causes of fatty change include
1. Toxins including alcohol
2. Diabetes mellitus
3. Obesity
4. Protein malnutrition
5. Anoxia
Alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver
(fatty liver) in industrialized nations.
Free fatty acids from adipose tissue or ingested food are normally transported into hepatocytes, where they
are esterified to triglycerides, converted into cholesterol or phospholipids, or oxidized to ketone bodies.
Triglycerides from the hepatocytes require the formation of complexes with apoproteins to form
lipoproteins, which are able to enter the circulation. Excess accumulation of triglycerides may result from
defects at any step from fatty acid entry to lipoprotein exit. Hepatotoxins (e.g., alcohol) alter mitochondrial
and SER functions and thus inhibit fatty acid oxidation; CCl4 and protein malnutrition decrease the
synthesis of apoproteins; anoxia inhibits fatty acid oxidation; and starvation increases fatty acid mobilization
from peripheral stores.
The significance of fatty change depends on the cause and severity of the accumulation. When mild it may
have no effect. More severe fatty change may transiently impair cellular function, but the change is
reversible. In the severe form, fatty change may precede cell death.
Gross features (Fig. 2-23)
Fatty change is most commonly seen in the liver and the heart.
In the liver, mild fatty change may not affect the gross appearance.
With increasing accumulation, the organ enlarges and becomes progressively yellow until, in extreme cases,
it may weigh 5 kg (3 times the normal weight) and appear bright yellow, soft, and greasy.
Microscopic features
Early fatty change is seen by light microscopy as small fat vacuoles in the cytoplasm around the nucleus.
In later stages, the vacuoles coalesce to create cleared spaces that displace the nucleus to the cell periphery.
Cholesterol and Cholesteryl Esters accumulations
Cellular cholesterol metabolism is tightly regulated to ensure normal cell membrane synthesis without
significant intracellular accumulation. However, phagocytic cells may become overloaded with lipid
(triglycerides, cholesterol, and cholesteryl esters) in several different pathologic processes.
1. Macrophages in contact with the lipid debris of necrotic cells or abnormal (e.g., oxidized) forms of
lipoproteins may become stuffed with phagocytosed lipid. These macrophages may be filled with minute,
membrane-bound vacuoles of lipid, imparting a foamy appearance to their cytoplasm (foam cells). In
atherosclerosis, smooth muscle cells and macrophages are filled with lipid vacuoles composed of
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cholesterol and cholesteryl esters; these give atherosclerotic plaques their characteristic yellow color and
contribute to the pathogenesis of the lesion. (Fig. 2-24)
2. In hereditary and acquired hyperlipidemic syndromes, macrophages accumulate intracellular cholesterol;
when present in the subepithelial connective tissue of skin or in tendons, clusters of these foamy
macrophages form masses called xanthomas. (Fig. 2-25)
Protein accumulations
Morphologically visible protein accumulations may occur because excesses of proteins are presented to the
cells or because the cells synthesize proteins in excessive amounts. In renal disorders with heavy protein
leakage across the glomerular filter (nephrotic syndrome), there is a much larger reabsorption of the protein.
Pinocytic vesicles containing this protein fuse with lysosomes, resulting in the histologic appearance of pink,
hyaline cytoplasmic droplets (Fig. 2-26). Another example is the marked accumulation of newly synthesized
immunoglobulins that occurs in the rough endoplasmic reticulum of some plasma cells, forming rounded,
eosinophilic Russell bodies.
Accumulations of intracellular proteins are also seen in certain types of cell injury. For example, the Mallory
body (alcoholic hyaline) is an eosinophilic cytoplasmic inclusion in liver cells that is highly characteristic of
alcoholic liver disease. Such inclusions are composed predominantly of aggregated intermediate filaments
that resist degradation. (Fig. 2-27)) The neurofibrillary tangle found in the brain of Alzheimer disease is an
aggregated protein that and neurofilaments, a reflection of a disrupted neuronal cytoskeleton.
Glycogen accumulations
Excessive intracellular deposits of glycogen are associated with abnormalities in the metabolism of either
glucose or glycogen. In poorly controlled diabetes mellitus, the prime example of abnormal glucose
metabolism, glycogen accumulates in renal tubular epithelium, cardiac myocytes, and β cells of the islets of
Langerhans. Glycogen also accumulates within cells in a group of closely related genetic disorders
collectively referred to as glycogen storage diseases. In these diseases, enzymatic defects in the synthesis or
breakdown of glycogen result in massive accumulations, with secondary injury and cell death.
Pigments
Pigments are colored substances that are exogenous, coming from outside the body, or endogenous,
synthesized within the body itself.
Exogenous pigments; the most common of these is carbon (an example is coal dust), a ubiquitous air
pollutant of urban life. When inhaled, it is phagocytosed by alveolar macrophages and transported through
lymphatic channels to the regional tracheobronchial lymph nodes. Aggregates of the pigment blacken the
draining lymph nodes and pulmonary parenchyma (anthracosis).Heavy accumulations may induce
fibroblastic reaction that can result in a serious lung disease called coal workers' pneumoconiosis (Fig. 2-28).
Endogenous pigments include lipofuscin, melanin, and certain derivatives of hemoglobin. Lipofuscin, or
"wear-and-tear pigment," is an insoluble brownish-yellow granular intracellular material that accumulates in
a variety of tissues (particularly the heart, liver, and brain) as a function of age or atrophy (Fig. 2-29).
Lipofuscin represents complexes of lipid and protein that derive from peroxidation of polyunsaturated lipids
of subcellular membranes. It is not injurious to the cell but is important as a marker of past free-radical
injury. The brown pigment, when present in large amounts, imparts an appearance to the tissue that is called
brown atrophy.
Melanin is an endogenous, brown-black pigment produced in melanocytes following the
tyrosinase-catalyzed oxidation of tyrosine to dihydroxyphenylalanine. It is synthesized exclusively by
melanocytes located in the epidermis and acts as a screen against harmful ultraviolet radiation. Although
melanocytes are the only source of melanin, adjacent basal keratinocytes in the skin can accumulate the
pigment (e.g., in freckles), as can dermal macrophages.
Hemosiderin is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in
tissues when there is a local or systemic excess of iron. Hemosiderin pigment represents large aggregates of
iron, readily visualized by light microscopy; the iron can be identified by the Prussian blue histochemical
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reaction (Fig. 2-30). Local excesses of iron, and consequently of hemosiderin, result from hemorrhage. The
best example is the common bruise. After lysis of the erythrocytes at the site of hemorrhage, the red cell
debris is phagocytosed by macrophages; the hemoglobin content is then catabolized by lysosomes with
accumulation of the heme iron in hemosiderin. The array of colors through which the bruise passes reflects
these transformations. The original red-blue color of hemoglobin is transformed to varying shades of
green-blue by the local formation of biliverdin (green bile) and bilirubin (red bile) from the heme moiety; the
iron ions of hemoglobin accumulate as golden-yellow hemosiderin. Whenever there is systemic overload of
iron, hemosiderin is deposited in many organs and tissues including their macrophages. This condition is
called hemosiderosis. With progressive accumulation, parenchymal cells throughout the body (but
principally the liver, pancreas, heart, and endocrine organs) become "bronzed" with accumulating pigment.
Hemosiderosis occurs in the setting of
1. Increased absorption of dietary iron
2. Impaired utilization of iron
3. Hemolytic anemias, and
4. Transfusions (the transfused red cells constitute an exogenous load of iron).
In most instances of systemic hemosiderosis, the iron pigment does not damage the parenchymal cells or
impair organ function despite an impressive accumulation. However, more extensive accumulations of iron
are seen in hereditary hemochromatosis, with tissue injury including liver fibrosis, heart failure, and
diabetes mellitus. (Fig. 2-31)
Bilirubin
This is a normal major pigment of bile, which is derived from Hb (but unlike hemosiderin contains no iron).
The conversion to bile occurs within hepatocytes. Jaundice results from excess bilirubin pigment that is
distributed throughout all tissues and body fluids. In the liver, particularly when there is obstruction to the
bile flow (e.g. obstruction of the common bile duct by a stone or atresia) bilirubin is seen within bile
canaliculi, kupffer cells and hepatocytes as green-brown globular deposits. This imparts greenish color to the
liver grossly. (Fig. 2-32)
PATHOLOGIC CALCIFICATION
Pathologic calcification is a common process in a wide variety of disease states; it implies the abnormal
deposition of calcium salts. When the deposition occurs in dead or dying tissues, it is called dystrophic
calcification; it occurs in the absence of calcium metabolic derangements (i.e., with normal serum levels of
calcium). In contrast, the deposition of calcium salts in normal tissues is known as metastatic calcification
and almost always reflects some derangement in calcium metabolism (hypercalcemia). It should be noted
that while hypercalcemia is not a prerequisite for dystrophic calcification, it can exacerbate it.
Dystrophic Calcification
Dystrophic calcification is encountered in
- Areas of necrosis (of any type as coagulative, caseous, etc.)
- Advanced atherosclerosis ( as in the aorta and coronaries)
- Aging or damaged heart valves resulting in severely impaired valve motion. Dystrophic calcification of the
aortic valves is an important cause of aortic stenosis in the elderly (Fig. 2-33).
Regardless of the site, calcium salts are grossly seen as fine white granules or clumps, often felt as gritty
deposits. Sometimes a tuberculous lymph node is essentially converted to radio-opaque stone.
Microscopically, calcification appears as intracellular and/or extracellular basophilic (blusih) deposits. In
time, metplastic bone may be formed in the focus of calcification.
Metastatic Calcification
This is seen in cases of hypercalcemia of any cause. The four major causes of hypercalcemia are
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1. Increased secretion of parathyroid hormone, (primary parathyroid tumors or production of parathyroid
hormone-related protein by other malignant tumors)
2. Destruction of bone (effects of accelerated turnover as in Paget disease, immobilization, or tumors due to
increased bone catabolism associated with multiple myeloma, leukemia, or diffuse skeletal metastases
3. vitamin D-related disorders including vitamin D intoxication and sarcoidosis (in which macrophages
activate a vitamin D precursor)
4. Renal failure, in which phosphate retention leads to secondary hyperparathyroidism.
Metastatic calcification can occur widely throughout the body but principally affects the interstitial tissues of
the vessels, kidneys, lungs, and gastric mucosa. The calcium deposits morphologically resemble those
described in dystrophic calcification. Although they do not generally cause clinical dysfunction, extensive
calcifications in the lungs may produce remarkable radiographs and respiratory deficits, and massive
deposits in the kidney (nephrocalcinosis) can cause renal damage.