HUMAN PATHOLOGY

WILSON A.L
 INTRODUCTION

• Pathology study of disease.

• Study (logos) of suffering (pathos).
• Study of suffering of individuals caused by disease.
• Shows how organs and tissues of healthy body change in relation to those of sick
person.
 CONT

• Pathology divided into;

– General pathology
• Focuses on basic cellular and tissue responses to
pathologic stimuli.
• Explores and explains development of basic pathologic
mechanisms without detailing specific changes
occurring in different organs.
 CONT

– Systemic pathology
• Responses of specialized organs.
• Pathologic mechanisms are related to various organs.
• Each system normal structure, function, and signs and symptoms that arise
from pathologic changes.
 In hospitals

• Pathology two main divisions:

– Clinical pathology
• Concerned with biochemical and microbiologic
procedures performed on;-
– Blood,
– Tissue fluids,
– Sputum,
– Urine,
– Amniotic fluid
– Cerebrospinal fluid.
• Laboratory divided;-
– Chemistry,
– Microbiology, immunology, special chemistry .
 CONT

– Anatomical pathology
• Concerned with structural abnormalities of cells and tissues that can be
detected by gross and microscopic examination of tissues.
• Laboratory sub-divisions such as;-
– Surgical pathology,
– Cytology,
– Hematopathology,
– Autopsy pathology.
 The core aspects of diseases in pathology

• Diseases-abnormal variation in structure or function of any

part of the body.
• 4 components of disease/core aspects of disease.
– Etiology,
– Pathogenesis,
– Morphologic changes and
– Functional derangements and clinical significance.
 Etiology

• Means the cause of the disease.

– If known- primary etiology.
– Unknown- idiopathic.
• Knowledge or discovery of primary cause remains the
backbone on which;-
– Diagnosis can be made,
– Disease understood,
– Treatment developed.
• Two major classes of etiologic factors:
– Genetic
– Acquired -infectious, nutritional, chemical, physical, etc.
 Pathogenesis

• Mechanism through which cause operates to produce pathological and clinical

manifestations.
• Pathogenetic mechanisms could take place in;-
– Latent or
– Incubation period.
• Pathogenesis leads to morphologic changes.
 Morphologic changes

• Refer to structural alterations in cells or tissues that occur

following the pathogenetic mechanisms.
• Can be seen with;-
– Naked eye- gross morphologic changes
– Microscope-microscopic changes.
• Both may only be seen in that disease, i.e. specific to that
disease hence can be used by the pathologist to identify (i.e. to
diagnose) disease.
• Morphologic changes lead to functional alteration & clinical
signs & symptoms of the disease.
Functional derangements and clinical significance

• Morphologic changes in the organ influence normal function.

• Hence determine clinical features-
– Symptoms and signs
– Course,
– Prognosis of the disease.
In summary, pathology studies:-
 Importance of studying human pathology

• Provides an understanding of the disease process encountered, its causes, and

clinical effects.
• Builds bridge between clinical practice and basic science, and involves:
– Study of the causes (aetiology) of disease
– Study of the underlying processes (pathogenesis) that results in the signs
and symptoms that the patient presents with.
– Basis for planning the management of the human responses to pathology.
 CONT

• Understanding core aspects of disease i.e.pathology;-

– Help understand how clinical features of different diseases
occur
– How treatments work.
– Use morphologic changes seen in diseases to diagnose
different diseases.
• Most of diagnostic techniques are based on morphologic
changes.
 Other specialized types of pathology

• Forensic pathology,
– Determines causes of death;
• Transfusion medicine,
– Ensures safety of collection, storage and transfusion of blood components;
• Experimental pathology,
– Basic scientific research into cellular processes.
 Sub-specialties in the discipline of pathology

• Cellular Pathology
– Histopathology ;study of tissues,
– Cytopathology study of affected cells.
• Both are important imaging disciplines.
• Pathologist interpret an image acquired through microscopy,
from which they deduce relevant diagnosis and possible causes
of the disease in question.
• Able to recommend treatment and also predict the likely
outcome.
 CONT

• Haematology
– Laboratory study of diseases of the blood.
– Most haematologists find that they need to work in both
clinical settings and in the laboratory.
 CONT

• Microbiology
– Study of infectious diseases such as cholera, tuberculosis, HIV/AIDS, and their
various causes.
• Includes
– Bacteriology, virology,
– Mycology -study of infections caused by fungi,
– Protozoology, study of infections caused by protozoa.
 CONT

• Chemical pathology
– Chemical biochemistry-study of body chemistry.
– Done through assays, measures of levels of substances
such as lipids, enzymes and electrolytes in blood or urine.
 CONT

• Immunology
– Study of defence mechanisms protecting the body against a
whole range of microbial and chemical pathogens.
– Study of autoimmunity when body’s defence mechanisms
break down.
 CONT

• Genetics
– Study of inheritance of various characteristics and of
various diseases, or predisposition to diseases.
– Clinically based or laboratory based.
• Clinical based haematologists deal directly with
patients,
• Lab based use various techniques to diagnose genetic
characteristics and predispositions.
 CONT

• Morbid Anatomy
– Refers to post-mortem dissection.
– Forensic pathology, which is concerned with medico-legal post-mortem, is a
related branch.
 Common terms used in Human Pathology

• Pathologist
– Anyone who studies the disease process
– Associated with those who have a day-to-day involvement
in providing services that help in diagnosing disease, or
those carrying out research in pathology.
• Diagnosis
– Determination and/or labelling of a disease or condition by
a scientific evaluation of signs, symptoms, history and
laboratory test results.
– Different types of diagnoses;
• Clinical,
• Differential,
• Laboratory, nursing and physical.
 CONT

• Disease
– Pathological condition that impairs the functions of a part,
organ, or system of an organism.
– Caused by external factors, such as infections, toxins,
nutritional deficiencies and environmental stress,
– May be caused by internal dysfunctions, such as
autoimmune diseases and genetic defects.
– Characterized by identifiable group of signs or symptoms.
 CONT

• Cell
– Basic structural and functional unit of all known living
organisms.
– Smallest unit of life that is classified as a living thing, and
contains chemicals and water wrapped in a membrane, the
cell membrane.
– Each cell contains, all the genetic information necessary to
build a human being, with each of the 46 chromosomes in
the cell containing the Deoxyribonucleic Acid (DNA) for
thousands of individual genes, which are the units of
heredity.
 CONT

• Pathogenesis
– Step by step development of a disease from its initial appearance through its
critical development.
– Consists of a chain of cellular events and reactions and other pathologic
mechanisms occurring in the development of disease.
– Evident in the changes in the structure and /or function of a cell, tissue or organ,
and are caused by a microbial, chemical or physical agent.
 CONT

• Etiology
– Derived from Greek word ‘aitiologia’, which means "giving a reason for".
– Study of causation, or origination, where it deals with the causes or origin of
disease, and studies the factors which produce or predispose toward a certain
disease or disorder.
 Review Questions

• What is human pathology?

• Why should nurses study human pathology?
• Define the following terminologies; disease, diagnosis, cell and aetiology.
• State the various sub – specialities of Pathology
• Who is a pathologist?
 Diagnostic techniques used in pathology

• Histopathology
• Cytopathology
• Hematopathology
• Immunohistochemistry
• Microbiological examination
• Biochemical examination
• Cytogenetics
• Molecular techniques
• Autopsy
 Histo-pathological techniques

• Studies tissues under microscope.

• Pathologist looks for abnormal structures in the tissue.
• Tissues for histopathological examination are obtained by
biopsy- tissue sample from a living person to identify the
disease.
– Biopsy can be;-
• Incisional
• Excisional.
 CONT

• Once the tissue is removed from the patient, immediately fixed by putting it into
adequate amount of 10% Formaldehyde (10% formalin) before sending it to the
pathologist.
• Purpose of fixation is:
– Prevent autolysis, bacterial decomposition and putrefaction
– Coagulate tissue to prevent loss of easily diffusible substances
– Fortify tissue against deleterious effects of various stages in preparation of
sections and tissue processing.
– Leave the tissues in a condition which facilitates differential staining with dyes
and other reagents.
 Immuno-histochemistry

• Hematoxylin/Eosin stain is usually abbreviated as H&E stain.

• The H&E stain is routinely used.
• Gives the nucleus a blue color & the cytoplasm & the extracellular matrix a pinkish
color.
• Pathologist will look for abnormal structures in the tissue.
• Based on this abnormal morphology he/she will make the diagnosis.
• Histopathology is usually the gold standard for pathologic diagnosis.
 Cyto-pathologic techniques

• Cytopathology-study of cells from various body sites to

determine cause or nature of disease.
• Applications:
– Screening for early detection of asymptomatic cancer eg
examination of scrapings from cervix for early detection
and prevention of cervical cancer.
– Diagnosis of symptomatic cancer
 CONT

• May be used alone or in conjunction with other modalities to;-

– Diagnose tumors revealed by physical or radiological examinations.
– Diagnosis of cysts, inflammatory conditions and infections of various organs.
– Surveillance of patients treated for cancer;-some types of cancers, cytology is the
most feasible method of surveillance to detect recurrence. Eg periodic urine
cytology to monitor the recurrence of cancer of the urinary tract.
 Advantages of cytologic examination

• Cheap,
• Takes less time
• Needs no anesthesia to take specimens.
• Therefore, it is appropriate for developing countries with limited resources like
Kenya.
• In addition, it is complementary to histo-pathological examination.
 Cyto-pathologic methods

• Fine-needle aspiration cytology (FNAC)

– Cells are obtained by aspirating diseased organ using a very
thin needle under negative pressure.
– Virtually any organ or tissue can be sampled by fine-needle
aspiration.
– Aspirated cells are stained & studied under microscope.
– Superficial organs (e.g. thyroid, breast, lymph nodes, skin
and soft tissues) can be easily aspirated.
– Deep organs,-lung, mediastinum, liver, pancreas, kidney,
adrenal gland, and retro-peritoneum are aspirated with
guidance by fluoroscopy, ultrasound or CT scan.
– FNAC is cheap, fast, & accurate in diagnosing many
diseases.
 CONT

• Ex-foliative cytology
– Refers to examination of cells that are shed spontaneously
into body fluids or secretions, examples include;-
• Sputum,
• Cerebrospinal fluid,
• Urine,
• Effusions in body cavities-pleura, pericardium,
peritoneum,
• Nipple discharge
• Vaginal discharge.
 CONT

• Abrasive cytology
– Refers to methods by which cells are dislodged by various tools from body
surfaces -skin, mucous membranes, and serous membranes.
• E.g. preparation of cervical smears with a spatula or a small brush to detect
cancer of the uterine cervix at early stages.
• Such cervical smears, also called Pap smears, can significantly reduce the
mortality from cervical cancer.
 CONT

• Hematological examination
– Abnormalities of the cells of the blood and their precursors in the bone marrow
are investigated to diagnose the different kinds of anemia & leukemia.
 CONT

• Immunohistochemistry
– Method used to detect a specific antigen in the tissue in order to identify the type
of disease.

• Microbiological examination
– Method, by which body fluids, excised tissue, etc. are examined by micro-
scopical, cultural and serological techniques to identify micro-organisms
responsible for many diseases.
 CONT

• Biochemical examination
– Method by which metabolic disturbances of disease are investigated by assay of
various normal and abnormal compounds in the blood, urine, etc.
• Clinical genetics (cytogenetics),
– Method in which inherited chromosomal abnormalities in the germ cells or
acquired chromosomal abnormalities in somatic cells are investigated using the
techniques of molecular biology.
 CONT

• Molecular techniques
– Such as fluorescent in situ hybridization, Southern blot,
etc... can be used to detect genetic diseases.
• Autopsy
– Examination of dead body to identify cause of death.
– Can be for;-
– Forensic
– Clinical purposes.
 CONT

• The relative importance of each of the above disciplines to our understanding of

disease varies for different types of diseases.
– For example,
• In diabetes mellitus, biochemical investigation provides the best means of
diagnosis and is of greatest value in the control of the disease.
• Whereas in the diagnosis of tumors, FNAC & histopathology contribute much.
• However, for most diseases, diagnosis is based on a combination of
pathological investigations.
 The causes of disease

• Environmental factors,
• Genetic factors
• Combination of the two.
 Environmental factors

• Classified into:
– Physical agents
– Chemicals
– Nutritional deficiencies & excesses
– Infections & infestations
– Immunological factors
– Psychogenic factors
 CONT

• Physical agents
– Include;-
• Trauma,
• Radiation,
• Extremes of temperature,
• Electric power.
– These agents apply excess physical energy, in any form, to
the body.
 CONT

• Chemicals
– Chemical agents such as drugs,.
• Effects vary:
– Some act in a general manner, for example cyanide is toxic to all cells.
– Others act locally at the site of application, for example strong acids and
caustics.
– Another group exhibit a pre-dilection for certain organs, for example – the
effect of paracetamol and alcohol on liver.
– Many toxic chemicals are metabolized in liver and excreted in kidney, as a
result, these organs are susceptible to chemical injury.
 CONT

• Nutritional deficiencies and excesses

– Arise as a result of;-
• Poor supply,
• Interference with absorption,
• Inefficient transport within the body,
• Defective utilization.
– Deficiency either of major classes of food, usually;-
• Protein and energy,
• Vitamins
• Elements essential for specific metabolic processes, e.g.
iron for haemoglobin production.
•
 CONT

• Often, deficiencies are multiple and complex.

• Dietary excess plays an important role in diseases in Western countries.
• Obesity has become increasingly common, with its attendant dangers of;-
– Type 2 diabetes,
– High blood pressure
– Heart disease.
 CONT

• Infections and infestations

– Viruses, bacteria, fungi, protozoa, and metazoa all cause
diseases.
– Cause ;-
• Cell destruction directly as in virus infections-example
poliomyelitis or protozoal infections-malaria.
• Toxins elaborated by the infecting agent as in diphtheria
and tetanus.
– Like chemicals, they may have a general effect or they may
show a predilection for certain tissues.
 CONT

• Immunological factors
– Essential for protection against micro-organisms and parasites.
– Abnormalities of the immune system include:
• Hypersensitivity reaction;-exaggerated immune response to an antigen. Eg.
bronchial asthma occur due to response to pollen.
• Immunodeficiency;-deficiency of a component of immune system leads to
increased susceptibility to different diseases, eg. AIDS.
• Autoimmunity;-abnormal (exaggerated) immune reaction against self antigens
of the host-hypersensitivity reaction against the self antigens. Eg Type 1 DM -
autoimmune destruction of beta cells of islets of Langerhans of pancreas.
 CONT

• Psychogenic factors
– Mental stresses imposed by conditions of life, particularly in technologically
advanced communities, are probably contributory factors in some groups of
diseases.
 Genetic Factors

• Hereditary factors that are inherited genetically from parents.

 Course of disease

• Exposure
• Biological Onset
• Clinical Onset
• Permanent damage
• Death
• Latency period
 Natural history of the disease

• Course of a disease in absence of any intervention

• Stages include:
– Exposure to various risk factors (causative agents)
– Latency, period between exposure and biological onset of
disease
– Biological onset of disease;
• Marks initiation of disease process, however, without
any sign or symptom.
• May remain asymptomatic or subclinical (i.e. without
any clinical manifestations), or may lead to overt
clinical disease.
 CONT

• Incubation (induction) period ;-refers to variable period of time without any obvious
signs or symptoms from time of exposure.
• Clinical onset of the disease;- when signs and symptoms of disease become apparent.
Expression of disease may be variable in severity or in terms of range of
manifestations.
• Onset of permanent damage, and
• Death
• Natural recovery, i.e. recovery without any intervention, can occur at any stage in the
progression of the disease.
 Outcome and consequences of disease

• Following clinical onset, disease may follow any of the following trends:
– Resolution can occur leaving no sequelae,
– The disease can settle down, but sequelae are left, or
– It may result in death.
 Clinical & biologic death

• Clinical death
– Reversible transmission between life and biologic death.
– Defined as period of;-
• Respiratory,
• Circulatory
• Brain arrest
– During which initiation of resuscitation can lead to
recovery.
– Begins with either last agonal inhalation or last cardiac
contraction.
 Signs indicating clinical death

• Patient is without pulse or blood pressure

• Completely unresponsive to painful stimulus.
• Pupils are widely dilated
• Some reflex reactions to external stimulation are preserved.
– Example, during intubations, respiration may be restored in response to
stimulation of receptors of superior laryngeal nerve, nucleus of which is located in
medulla oblongata near the respiratory center.
• Recovery can occur with resuscitation.
 Biological Death

• Sure sign of death

• Sets in after clinical death,-irreversible state of cellular destruction.
• Manifests with irreversible cessation of;-
– Circulatory and respiratory functions, or
– All functions of the entire brain, including brain stem.
• However, one should notice that there are internationally accepted criteria to
diagnose biological death.
UMMA UNIVERSITY SCHOOL OF NURSING
AND MIDWIFERY-PATHOLOGY-LECT 2
CELLULAR ADAPTATION, CELL INJURY and
DEATH

WILSON A.L
CELLULAR ADAPTATION,
CELL INJURY and DEATH
Normal cell is in a steady state-
“Homeostasis”
Change in Homeostasis due to stimuli -

Injury
Injury - Reversible / Irreversible

Adaptation / cell death

Cellular responses to stress and noxious stimuli

 Cells constantly adjust their structure and function to accommodate changing

demands and extracellular stresses.
 They maintain their intracellular environment within a fairly narrow range of
physiologic factors -homeostasis.
 As cells encounter physiologic stresses or pathologic stimuli, they adapt to a
new steady state and preserve their capability and function.
 The main adaptive responses are:
◦ Hypertrophy
◦ Hyperplasia
◦ Atrophy
◦ Metaplasia.
CONT

 If adaptive capability is exceeded or if external stress is

inherently harmful, cell injury develops.
 Cell death is one of the most crucial events in the evolution of
disease in any tissue or organ.
 It a normal and essential process in embryogenesis, the
development of organs, and the maintenance of homeostasis.
 CONT

 Example of heart tissues.

◦ Heart has different responses to different types of stress.
 Myocardium subjected to persistent increased load, as in hypertension or
with a stenotic valve,
 Adapts by undergoing hypertrophy (an increase in the size of the
individual cells and ultimately the entire heart), to generate the required
higher contractile force.
CONT

 If increased demand is not relieved, or if the myocardium is

subjected to reduced blood flow (ischemia) from an occluded
coronary artery,
 The muscle cells may undergo injury.
◦ The myocardium may be reversibly injured if the stress is
mild or the arterial occlusion is incomplete or sufficiently
brief, or
◦ It may undergo irreversible injury (infarction) after
complete or prolonged occlusion.
CONT

 Stresses and injury affect;-

◦ Morphology
◦ Functional status of cells and tissues.
 Reversibly injured myocytes are not dead and may resemble
normal myocytes morphologically but non-contractile, and
therefore, even mild injury can have a lethal clinical impact.
 CONT

 Whether or not stress induces;-

◦ Adaptation
◦ Reversible or
◦ Irreversible injury
 Depends on the nature and severity of the stress and other variables,
including;
 Cellular metabolism,
 Blood supply,
 Nutritional status.
CELLULAR ADAPTATION TO STRESS

Adaptations
• Reversible changes in the number, size, phenotype, metabolic
activity or functions of cells in response to changes in their
environment
Physiologic adaptations
• Responses of cells to normal stimulation by hormones
or endogenous chemical mediators. For example, the
hormone-induced enlargement of the breast and uterus
during pregnancy.

Pathologic adaptations
Responses to stress that allow cells to modulate their
structure and function and thus escape injury
Such as: hypertrophy, hyperplasia, atrophy, and
metaplasia
Hypertrophy
Is an increase in the size of cells & consequently an increase
in the size of an organ.
Enlargement is due to an increased synthesis of structural
proteins & organelles
Occurs when cells are incapable of dividing
• Increased workload on a muscle may lead to hypertrophy
• Avid weightlifter can develop a muscled physique only by
hypertrophy of individual skeletal muscle cells induced by
an increased workload.
• Examples of pathologic cellular hypertrophy include the
cardiac enlargement that occurs with hypertension or aortic
valve disease.
Types:
Physiologic
Pathologic
Causes:
Increased functional demand
Hormonal stimulation
Physiologic Hypertrophy of the Uterus During Pregnancy

Gravid Uterus Normal Uterus

Small spindle-shaped uterine Large, plump hypertrophied
smooth muscle cells from a smooth muscle cells from a
normal uterus gravid uterus
Heart hypertrophy in
hypertension
Hyperplasia
Is an increase in the number of cells in an organ or tissue
Adaptive response in cells capable of replication
Critical response of connective tissue cells in wound healing
Types:
a) Physiologic hyperplasia
1) Hormonal
ex. Proliferation of glandular epithelium of the female
breast at puberty & during pregnancy
2) Compensatory – hyperplasia that occurs when a portion of
a tissue is removed or diseased
e.g. partial resection of a liver > mitotic activity 12
hours later
b) Pathologic hyperplasia
Caused by excessive hormonal or growth factor
stimulation
• Example pathological hyperplacia, after a normal
menstrual period there is a sudden increase of uterine
epithelial proliferation that is normally tightly regulated
by stimulation through pituitary hormones and ovarian
estrogen and by inhibition through progesterone.
• However, if the balance between estrogen and
progesterone is disturbed, endometrial hyperplasia
ensues,
• Common cause of abnormal menstrual bleeding.
CONT

 Hyperplasia is also a response of connective tissue cells in

wound healing,
 Proliferating fibroblasts and blood vessels aid in repair during
the process and growth factors are produced by white blood
cells (leukocytes) responding to the injury and by cells in the
extracellular matrix.
 Another example of hyperplasia is when normal body cells are
infected with viral infections.
 Example is the human papilloma virus (HPV).
◦ Papilloma viruses cause skin warts and mucosal lesions
composed of masses of hyperplastic epithelium.
◦ This is an example of hyperplasia due to stimulation by
growth factors in certain viral infections.
◦ Here the growth factors may be produced by the virus or by
infected cells.
CONT

 Hyperplastic process remains controlled;

 If hormonal or growth factor stimulation decreases,
hyperplasia disappears
 It is this sensitivity to normal regulatory control mechanisms
that distinguishes benign pathologic hyperplasias from cancer,
in which the growth control mechanisms become dysregulated
or ineffective.
 Pathologic hyperplasia constitutes a fertile soil in which
cancerous proliferation may eventually arise.
 Thus, patients with hyperplasia of the endometrium are at
increased risk of developing endometrial cancer,
 Certain papillomavirus infections predispose to cervical
cancers.
CONT

 Hypertrophy and hyperplasia can occur together, and

obviously both result in an enlarged (hypertrophic) organ.
 Massive physiologic enlargement of the uterus during
pregnancy occurs as a consequence of estrogen-stimulated
smooth muscle hypertrophy and smooth muscle hyperplasia.
 In contrast, striated muscle cells in both skeletal muscle and
the heart can undergo only hypertrophy in response to
increased demand because in the adult they have limited
capacity to divide.
 Therefore hyperplasia may occur with hypertrophy and often
in response to the same stimuli.
HYPERPLASIA OF THE PROSTATE GLAND
Atrophy
Shrinkage in the size of the cell by the loss of cell substance
Results from decreased protein synthesis and increased protein
degradation in cells
Accelerated proteolysis seen in a variety of catabolic
conditions, including cancer cachexia.
Accompanied by increased autophagy, ("self-eating"), the
process in which the starved cell eats its own components in an
attempt to find nutrients and survive.
Causes:
Decreased workload
Loss of innervation
Diminished blood supply
Inadequate nutrition
Loss of endocrine stimulation
Aging (senile atrophy)
Disuse or excessive pressure for example,
immobilization of a limb to permit healing
of a fracture
CONT

 Although atrophic cells may have diminished function, they

are not dead, and whether physiologic or pathologic, the
fundamental cellular changes 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 of the brain in an Normal brain of a 25-year-old
82-year-old man man
ATROPHY IN OSTEOPOROSIS
Metaplasia
Reversible change in which one adult cell type ( epithelial or
mesenchymal) is replaced by another adult cell type.
Cellular adaptation whereby cells sensitive to a
particular stress are replaced by other cell types better
able to withstand the adverse environment
Epithelial metaplasia
Examples
Squamos change that occurs in the respiratory epithelium
in habitual cigarette smokers ( normal columnar
epithelial cells of trachea & bronchi are replaced -
stratified squamos epithelial cells
Vitamin A deficiency
Chronic gastric reflux, the normal stratified squamos
epithelium of the lower esophagus may undergo
metaplasia to gastric columnar epithelium
CONT

 Metaplasia is thought to arise by genetic "reprogramming" of

stem cells rather than trans-differentiation of already
differentiated cells.
 Metaplastic squamous epithelium has survival advantages,
important protective mechanisms are lost, such as mucus
secretion and ciliary clearance of particulate matter.
 Epithelial metaplasia is therefore a double-edged sword.
 Influences that induce metaplastic transformation, if persistent,
may predispose to malignant transformation of the epithelium.
 Cigarette smoking initially causes squamous metaplasia, and
cancers arise later in some of these altered foci.
A.Schematic diagram of columnar to squamos epithelial
B. Metaplastic transformation of esophageal epithelium
Mesenchymal metaplasia Ex. Bone formed in soft
tissue particularly in foci of injury
METAPLASIA-ESOPHAGUS
METAPLASIA-LUNGS
 Cell injury

 There are occasions when things go wrong during cell growth

and differentiation.
 Body tissues are composed of;-
◦ Parenchymal cells-specialized to perform the functions of
that particular tissue,
◦ Interstitial connective tissue elements-act as supporting
framework for the tissue.
 Human disease results from biochemical agents or from the
structural damage caused by various injurious agents on
tissues.
 Injury may result either in;
◦ Cell degeneration (reversible changes)
◦ Cell death (irreversible changes).
 CELLULAR INJURY
Cell Injury- pertains to the sequence of events when cells have no
adaptive response or the limits of adaptive capability are
exceeded

Types of Cell Injury

1. Reversible Injury- injury that persists within certain limits, cells
return to a stable baseline

2. Irreversible Injury- when the stimulus causing the injury persists

and is severe enough from the beginning that the affected
cells die
a. necrosis
b. apoptosis
 MECHANISMS OF CELL INJURY

➢ ATP depletion: failure of energy-dependent functions

reversible Injury necrosis
➢Mitochondrial damage: ATP depletion failure of energy-
dependent cellular functions ultimately necrosis;
under some conditions, leakage of proteins that causes apoptosis
➢Influx of calcium: activation of enzymes that damage cellular

components and may also trigger apoptosis

➢Accumulation of reactive oxygen species: covalent modifications of

cellular proteins, lipids, nucleic acids

➢Increased permeability of cellular membranes: may affect plasma

membrane, lysosomal membranes, mitochondrial membranes;

typically culminates in necrosis
➢Accumulations of damaged DNA and misfolded proteins triggers

apoptosis
• Cell injury can either be:
• Direct injury
– A harmful agent may interfere directly with tissue
structure or biochemical function.
– For instance, in burns, the heat causes direct
destruction of cell membranes and other tissue
components and coagulation of intracellular proteins.
• Indirect Injury
– Examples include accumulation of toxic agents in kidney
and liver failure, or a change in extracellular pH, electrolyte
concentrations or core body temperature.
– Result in structural and functional abnormalities in brain and
in liver as is in liver failure (hepatic encephalopathy).
• Cell injury results
• Cells are stressed so severely-no longer able to adapt
• Cells are exposed to inherently damaging agents or suffer from
intrinsic abnormalities.
• Different injurious stimuli affect many metabolic pathways and
cellular organelles.
• Injury may progress through a reversible stage and culminate in
cell death.
 Causes of cell injury

 Range from gross physical trauma of a motor vehicle accident

to the single gene defect which results in a defective enzyme
underlying a specific metabolic disease.
 Injurious stimuli can be grouped into the following categories:
1. Hypoxia/Oxygen Deprivation

Causes:
• Hypoxia/oxygen deficiency,-interferes with aerobic oxidative
respiration-important and common cause of cell injury and death.
• Ischemia-loss of blood supply in a tissue due to impeded
arterial flow or reduced venous drainage. Common cause of
hypoxia,
• Oxygen deficiency -result from inadequate oxygenation of the
blood, as in pneumonia, or reduction in oxygen-carrying
capacity of the blood-blood loss anemia or carbon monoxide
(CO) poisoning. (CO forms a stable complex with hemoglobin
that prevents oxygen binding.)
 Thrombosis.

• Formation of clot intimal lining of blood vessel or heart.

• May decrease blood flow (ischemia) or totally occlude vessel
(infarction).
• Disruption of endothelial lining of blood vessels causes
platelets to aggregate and clotting to begin.
• Stasis of blood and increased viscosity contribute to process.
• Common in deep veins of legs. May result in emboli to lungs.
• Mural thrombosis may occur in heart, with resulting arterial
emboli.
 Embolism.

• Embolus. Traveling mass in the blood.

• Embolism. Obstruction caused by embolus.
• Usually derived from thrombi (Thrombotic embolization).
• Also pieces of fat, valves or foreign particles.
• Arise in venous circulation, lodge in pulmonary bed.
• Arise in left side of heart, travel through aorta to arterial beds
 Infarction-Ischemic necrosis

Localized area of tissue death due to occlusion of arterial supply.

Classifications
– Pale infarct. Tissue deprived of arterial circulation due to
ischemia
– Hemorrhagic infarct. Red appearance due to hemorrhage into
area
– Septic infarct. Bacterial infection leads to abscess and
inflammation.
 Chemical Agents

 Chemical substances can injure cells.

 Even innocent substances such as glucose or salt, if
sufficiently concentrated, can create imbalance in the osmotic
environment, resulting in cell injury or death.
 Oxygen at sufficiently high partial pressures is also toxic.
 Agents commonly known as poisons cause severe damage at
the cellular level by altering ;
◦ Membrane permeability,
◦ Osmotic homeostasis,
◦ Integrity of an enzyme or cofactor,
 Exposure to these poisons can result in the death of the whole
organism.
 CONT

 Other potentially toxic agents are encountered daily in our environment.

◦ Air pollutants,
◦ Insecticides,
◦ Carbon-monoxide (CO),
◦ Asbestos,
◦ Social "stimuli" such as ethanol.
 Even therapeutic drugs can cause cell or tissue injury in a susceptible patient
or if used excessively or inappropriately.
 Infectious Agents

 These infectious agents include; viruses, tapeworms, rickettsiae, bacteria,

fungi, and protozoans.
 Immunologic Reactions
◦ Although the immune system defends the body against pathogenic
microbes, immune reactions can also result in cell and tissue injury.
◦ Examples include autoimmune reactions against one's own tissues and
allergic reactions against environmental substances in genetically
susceptible individuals.
 Genetic Defects

 Result in pathologic changes as conspicuous as the congenital

malformations associated with Down’s syndrome or as subtle as the
single amino acid substitution in hemoglobin S giving rise to sickle
cell anemia.
 Genetic defects may cause cell injury because of deficiency of
functional proteins, such as enzymes in inborn errors of metabolism, or
accumulation of damaged DNA or misfolded proteins, both of which
trigger cell death when they are beyond repair.
 Variations in the genetic makeup can also influence the susceptibility
of cells to injury by chemicals and other environmental insults.
 Nutritional Imbalances

 Even in the current era of growing global affluence, nutritional

deficiencies remain a major cause of cell injury.
 Protein-calorie insufficiency among underprivileged populations is
only the most obvious example;
 Specific vitamin deficiencies are common even in developed countries
with high standards of living.
 Ironically, excesses of nutrition are also important causes of illness and
death; for example, obesity increases the risk for type 2 diabetes
mellitus.
 Moreover, diets rich in animal fat are strongly associated with
atherosclerosis as well as in increased vulnerability to many disorders,
including cancer.
 Physical Agents

 Trauma,
 Extreme temperatures,
 Radiation,
 Electric shock, and sudden changes in atmospheric pressure all have wide-
ranging effects on cells.
 Aging
◦ Cellular aging leads to alterations in replication and repair abilities of
individual cells and tissues.
 All of these changes result in a reduced ability to respond to damage and,
eventually, the death of cells and of the organism.
 CONT

 In early stages or mild forms of injury the functional and

morphologic changes are reversible if the damaging stimulus
is removed.
 At this stage, although there may be significant structural and
functional abnormalities, the injury has typically not
progressed to severe membrane damage and nuclear
dissolution.
 MORPHOLOGY OF CELL AND TISSUE INJURY

All stresses & noxious influences exert their effects first at the
molecular or biochemical level
Cellular function is lost far before cell death occurs
Morphologic changes of cell injury (or death) lag far behind both
 Ultrastructural Changes of Reversible Cell injury

 Alteration in plasma membrane reflecting disturbance in ion and volume

regulation induced by loss of ATP
• Mitochondrial changes
• Endoplasmic reticulum changes
• Nuclear alterations
Plasma membrane alterations
•Cellular swelling

•Formation of cytoplasmic
blebs

•Blunting and distortion of

microvilli

•Deterioration and loosening

of intercellular attachments
Mithochondrial Changes
Early it appears condensed as a
result of loss of matrix protein
following loss of ATP

Followed by swelling due to ionic

shifts

Amorphous densities which

correlate with the onset of
irreversibility

Finally, rupture of membrane

followed by progressing increased
calcification
Endoplasmic Reticulum Changes
•Dilation

•Detachment of
ribosomes and
dissociation of
polysomes with
decreased protein
synthesis

•Progressive
fragmentation and
formation of
intracellular
aggregates of myelin
figures
 Nuclear Alterations

• Disaggregation of
granular and
fibrillar elements
Two Patterns of Morphologic Change Correlating to
Reversible Injury that can be recognized under the light
Microscope:
Cellular swelling
Fatty change
Cellular Swelling
Result of failure of energy-dependent ion pumps in plasma
membrane leading to an inability to maintain ionic & fluid
homeostasis
First manifestation of almost all forms of injury to cells
microscopically small, clear vacoules may be seen within
the cytoplasm sometimes called hydropic change or vacoular
degeneration
Swelling of cells is reversible
Hydropic degeneration: kidney
Cloudy swelling & hydropic change reflect failure of membrane
ion pumps, due to lack of ATP, allowing cells to accumulate
fluid
Fatty Change
Occurs in hypoxic injury & various forms of toxic( alcohol &
halogenated hydrocarbons like chloroform ) or metabolic injury
like diabetes mellitus & obesity manifested by the appearance of
lipid vacoules in the cytoplasm principally encountered in cells
participating in and involved in fat metabolism e.g. hepatocytes
& myocardial cells
Reversible
Morphologic Alterations in Reversible Cell Injury

Cell swelling
Fatty change
Plasma membrane blebbing and loss of microvilli
Mitochondrial swelling
Dilation of the ER
Eosinophilia (due to decreased cytoplasmic RNA)
NECROSIS
Refers to a series of changes that accompany cell
death, largely resulting from the degradative action of
enzymes on lethally injured cells
• Occurs when damage to membranes is severe, enzymes leak out
of lysosomes, enter the cytoplasm, and digest the cell.
• Cellular contents also leak out through the damaged plasma
membrane and cause an inflammatory reaction.
• Necrosis is the main pathway of cell death in many injuries, such
as those resulting from ;
– Ischemia,
– Exposure to toxins,
– Various infections,
– Trauma.
 The enzymes responsible for digestion of the cell are derived
either from the:
Lysosomes of the dying cells themselves or from
Lysosomes of leukocytes that are recruited as
part of the inflammatory reaction to the dead cells
Morphologic alterations in Necrosis
✔Increased eosinophilia (pink staining from eosin dye)

✔Myelin figures ( whorled phospholipid masses)

✔Nuclear changes assume one of three patterns all due to

breakdown of DNA & chromatin:

Karyolysis
Pyknosis characterized by nuclear shrinkage and increased
basophila
Karyorrhexis – fragmentation and dissolution
✔Breakdown of plasma membrane and organellar Membranes

✔Leakage and enzymatic digestion of cellular contents

 Patterns of Tissue Necrosis

Coagulative Necrosis
➢A form of tissue necrosis in which the component cells are dead
but the basic tissue architecture is preserved for at
least several days
➢ It is characteristics of infarcts ( areas of ischemic

necrosis) in all solid organs except the brain

A wedge-shaped
kidney Infarct (yellow)
with preservation of
the outlines
Liquefactive Necrosis
Seen in focal bacterial or occasionally fungal infections
because microbes stimulate the accumulation of Inflammatory
cells and the enzymes of leukocytes digest ( “liquefy”) the
tissue
This necrosis is characteristic of hypoxic death of cells within
the CNS
➢Associated with suppurative inflammation (accumulation of

pus)
➢The areas undergoing necrosis are transformed into a

Semi-solid consistency or state (liquid viscuous mass)

Example: abcess
Liquefactive necrosis. An infarct in the brain, showing
dissolution of tissue
Caseous Necrosis
Encountered most often in foci of tuberculous infection
Characterized by a cheesy yellow-white appearance of the area
of necrosis
It is often enclosed within a distinctive inflammatory border

A tuberculous lung with a

large area of caseous necrosis
containing yellow-white and
cheesy debris
Fat Necrosis
➢ Refers to focal areas of fat destruction, typically resulting

from release of activated pancreatic lipases into the

substance of the pancreas and the peritoneal cavity
➢Occurs in acute pancreatitis

Fat necrosis in aqcute pancreatitis. The areas of white chalky deposits

represent foci of fat necrosis with calcium soapformation (saponification)
at sites of lipid breakdown in the mesentery
Fibrinoid necrosis
➢A special form of necrosis usually seen in immune

reactions involving blood vessels

➢This pattern of necrosis is prominent when complexes of

antigens and antibodies are deposited in the walls of

Arteries
➢Deposits of these immune complexes together with fibrin

that has leaked out of vessels result in a bright pink and

amorphous appearance called 'fibrinoid”

Fibrinoid necrosis in an artery

in a patient with Polyarteritis
Nodosa. The wall of the artery
shows a circumferential bright
pink area of necrosis with
protein deposition and
inflammation
Gangrenous Necrosis
➢ This is not a distinctive pattern of cell death

➢It is usually applied to a limb, generally the lower leg, that

has lost its blood supply involving multiple tissue layers

➢Types:

✔Wet gangrene

✗Occurs in naturally moist areas like mouth, bowels lungs

✗Characterized by numerous bacteria

✔Dry gangrene

✗begins at the distal part of the limb due to ischemia and

often occurs in the toes and feet of elderly
patients due to arteriosclerosis
✗This is mainly due to arterial occlusion

✗There is limited putrefaction and bacteria fail to

survive
 Subcellular responses to injury

Autophagy
Refers to lysosomal digestion of the cell's own components
It is thought to be a survival mechanism in times of nutrient
deprivation
Organelles are enclosed in vacoules that fuse with lysosomes
Heterophagy
Cell usually a macrophage ingests substances from the outside for
intracellular destruction
 Hypertrophy of Smooth Endoplasmic Reticulum
Cells exposed to toxins that are metabolized in the SER show
hypertrophy, a compensatory mechanism to maximize
removal of the toxins
Mitochondrial Alterations
* alterations in size, number, shape & function
Ex. Mitochondria assume extremely large & abnormal
shapes (megamitochondria) in hepatocytes in various
nutritional deficiencies & alcoholic liver disease
Cellular hypertrophy > # of mitochondria in cells
Atrophy < # of mitochondria

Cytoskeletal Abnormalities
some drugs & toxins interfere with the assembly & functions
of Cytoskeleton filaments or result in abnormal
accumulations of filaments
General Principles Relevant To Most Forms Of Cell Injury
The cellular response to injurious stimuli depends on the ;-
Type of injury,
Duration,
Severity
• Consequences of an injurious stimulus depend on the;-
• Type ,
Status ,
Adaptability ,
Genetic makeup of the injured cell
Cell injury results from functional & biochemical abnormalities in
one or more of several essential cellular components
The most important target of injurious stimuli are:
Cell membrane integrity, critical to cellular ionic and osmotic
homeostasis
Mitochondrial, the site of adenosine triphosphate (ATP)
generation
Protein synthesis
Integrity of the genetic apparatus
Cytoskeleton
Accumulation of Oxygen-Derived Free radicals (Oxidative
Stress)

Free radicals are chemical species with single unpaired electron

in an outer orbital. In such a state the radicals are extremely
unstable & readily react with inorganic or organic chemicals.

Free radicals may be generated within cells by

•Reduction-oxidation (redox) reactions
•Nitric oxide (NO)
•Absorption of radiant energy (e.g. ultraviolet light, x-rays)
•Enzymatic metabolism of exogenous chemicals (e.g. carbon
tetrachloride)
•Inflammation, because free radicals are produced by leukocytes
that enter tissues
Mechanisms that remove Free radicals
●Action of superoxide dismutases (SODS)

●Glutathione (GSH) peroxidase

●Catalase present in perixisomes

●Endogenous or exogenous antioxidants (e.g. vitamins E, A

and C, and beta-Carotene may either block the formation of

free radicals or scavenge them once they have formed
●Iron and Copper can catalyze the formation of Reactive

Oxygen Species (ROS)

APOPTOSIS (“FALLING OFF”)
Is a pathway of cell death that is induced by a tightly regulated suicide
program in which cells destined to die activate enzymes capable of
degrading the cells own nuclear DNA and nuclear and cytoplasmic
proteins
➢It differs from necrosis in the following characteristics

1) Plasma membrane of the apoptotic cell remains intact

2) Has no leakage of cellular contents
3) Does not elicit an inflammatory reaction in the host
➢Sometimes coexist with necrosis

➢Apoptosis induced by some pathologic stimuli may progress to necrosis

Causes of Apoptosis

Apoptosis in Physiologic Situations

Death by apoptosis is a normal phenomenon that serves to eliminate
cells that are no longer needed and to maintain a steady number of
various cell populations in tissues
Programmed destruction of cells during embryogenesis, Including
implantation, organogenesis, developmental involution, and
metamorphosis

Involution of hormone- dependent tissues upon hormone deprivation

such as endometrial cell breakdown during the menstrual cycle and
regeression of the lactating breast after

Weaning
Cell loss in proliferating cell populations, such as intestinal
Crypt epithelia
Death of cells that have served their useful purpose, such as
neutrophils in an acute inflammatory response and Lymphocytes
at the end of an immune response

Elimination of potentially harmful self-reactive lymphocytes

Either before or after they have completed their maturation

Cell death induced by cytotoxic T lymphocytes, a defense

mechanism against viruses and tumors that serves to kill
eliminate virus-infected and neoplastic cells
Apoptosis in Pathologic Situations
Apoptosis eliminates cells that are genetically altered or
Injured beyond repair without eliciting a severe host reaction,
thus keeping the damage as contained as possible
DNA damage
Radiation, cytotoxic anticancer drugs, extremes of
temperature and even hypoxia can damage DNA either
directly or via production of free radicals

Accumulation of misfolded proteins

✔These may arise because of mutations in the genes

encoding these proteins or because of extrinsic factors

such as free radicals
✔Excessive accumulation of these proteins in the ER leads

to a condition called ER stress

 Cell injury in certain infections particularly viral infections

Pathologic atrophy in parenchymal organs after duct

obstruction such as in pancreas, parotid gland and kidney

Morphologic Alterations in Apoptosis

●Nuclear chromatin condensation

●Formation of apoptotic bodies ( fragments of nuclei and

cytoplasm)

The fundamental event in apoptosis is the activation of enzyme

called caspases
Two Major Pathways in the Initiation of Apopotosis

Mitochondrial ( intrinsic) pathway;-Triggered by loss of survival

signals, DNA damage and accumulation of misfolded proteins
(ER stress)

Death receptor (extrinsic) pathway;-Responsible for the

elimination of self-reactive lymphocytes and damage by cytotoxic
T lymphocytes
Review questions

 Define the term human pathology.

 Explain the processes involved in mitosis and meiosis.
 Distinguish the terms hypertrophy, hyperplasia, atrophy and metaplasia.
 Write down the three ways in which cell growth can be controlled.
 Describe four ways by which cells can adapt to stress.
 INTRACELLULAR ACCUMULATIONS

THREE MAIN PATHWAYS OF ABNORMAL INTRACELLULAR

ACCUMULATIONS
• Normal substance is produced at abnormal or an increased rate, but
metabolic rate is inadequate to remove it. Example. Fatty change in
the liver
• Normal or abnormal endogenous substance accumulates because
of genetic or acquired defects in its folding, packaging, transport or
secretion. Example. Accumulation of proteins in anti-trypsin
deficiency
• Abnormal exogenous substance is deposited and Accumulates
because the cell has neither the enzymatic Machinery to degrade
the substance nor the ability to transport It to other sites. Example.
Accumulation of carbon or silica particles
Fatty Change (Steatosis)

Refers to any abnormal accumulation of triglycerides within

✔

parenchymal cells

Most often seen in the liver but may also occur in the heart,
✔

Skeletal muscle, kidney and other organs

May be caused by toxins, protein malnutrition, diabetes

✔

mellitus, obesity and anoxia

Alcohol abuse and diabetes associated with obesity are

✔

the most common causes of fatty liver

Fatty Liver
Cholesterol and Cholesteryl Esters

✔ Result of defective catabolism and excessive intake

Present in lipid vacoules of smooth muscle cells and

✔

macrophages in atherosclerosis (hardening of the aorta)

Give atherosclerotic plaques their characteristic yellow color

✔

and contibute to the pathogenesis of the lesion

✔ Xanthomas are hypercholesterolemic tumurous masses

found in the connective tissue of the skin or tendons
Proteins
✔ Less common than lipid accumulations

✔Occur because excess are presented to the cells or

because the cells synthesize excessive amounts

✔Examples:

1) Nephrotic syndrome there is heavy protein leakage

across the glomerular filter due to a much larger
reabsorption of albumin
2) accumulation of newly synthesized imunoglobulins
in RER of some plasma cells forming rounded,
eosinophilic Russell bodies
3) Mallory body or “ alcoholic hyalin” is an eosinophilic
cytoplasmic inclusion in liver cells highly characteristic
of alcoholic liver disease
4) Neurofibrillary tangle found in the brain in Alzheimer
disease
Protein reabsorption droplets in the renal tubular
epithelium
Glycogen
✔Accumulations of these are associated with abnormalities

in the metabolism of either glucose or glycogen

✔Ex.

1) In poorly controlled diabetes mellitus, glycogen

accumulates in renal tubular epithelium, cardiac
myocytes, and β cells of Islets of langerhans
2) Glycogen storage diseases or glycogeneses are
Genetic disorders where glycogen accumulates in
macrophages of patients with defects in lysosomal
enzymes
Pigments
➢ colored substances that are either exogenous or

endogenous

●Exogenous – coming from outside the body

1) Carbon ( ex. Coal dust)
➔Most common air pollutant

➔Aggregates of the pigment blacken the

draining lymph nodes and pulmonary

parenchyma (Anthracosis)
➔Heavy accumulations may induce emphysema

or a fibroblastic reaction that can result in a

serious lung disease called coal workers
pneumoconiosis
● Endogenous – synthesized within the body itself
1) Lipofuscin or “wear-and -tear pigment or lipochrome
✔an insoluble brownish-yellow granular intracellular

material that accumulates in the heart, liver, & brain as

a function of age or atrophy
✔represents complexes of lipid & protein that derive

from the free radical-catalyzed peroxidation of

polyunsaturated lipids
✔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
The pale golden brown finely granular pigment seen here in nearly
all hepatocytes is lipochrome (lipofuscin).
 2) Melanin
✔An endogenous, brown-black pigment synthesized

exclusively by melanocytes when the enzyme tyrosinase

catalyzes tyrosine to (DOPA) dihydroxyphenylalanine
located in the epidermis
✔Acts as a screen against harmful ultraviolet radiation

✔Basal keratinocytes in the skin can accumulate the

pigment (e.g. in freckles)

Melanin pigment in
melanoma
3) Hemosiderin
✔ 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

✔Iron is normally stored within cells in association with the

protein apoferritin, forming ferritin micelles
✔Iron can be identified by the Prussian blue reaction
 Local excess of iron & consequently of hemosiderin result
✔

from hemorrhage
Ex. Bruise

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 of hemoglobin accumulate as golden- yellow

hemosiderin
 Hemosiderosis
✔a condition where hemosiderin is deposited in many

organs and tissues whenever there is systemic overload

of iron
✔It occurs in the following settings

1)Increased absorption of dietary iron

2)Impaired utilization of iron
3)Hemolytic anemias
4)Transfusions
Hereditary Hemochromatosis
✔A condition where there is extensive accumulations of iron

with tissue injury like liver fibrosis, heart failure and

diabetes mellitus
✔Characterized principally by

1) the deposition of hemosiderin in the following organs (in

decreasing order of severity):liver, pancreas,
myocardium, pituitary, adrenal, thyroid, joints & skin
2) cirrhosis and 3) pancreatic fibrosis
 PATHOLOGIC CALCIFICATION
➢implies the abnormal deposition of calcium salts, together

with small amounts of iron, magnesium, and other minerals

TYPES
A. Dystrophic calcification
✔deposition of calcium in dead or dying tissues

✔occurs in the absence of calcium metabolic

derangements ( with normal serum levels of calcium)

✔Local deposits of calcium may occur in

1) Necrotic tissue which is not absorbed

●old infarcts

●tuberculous foci

●old collection of pus

●dead parasites

●acute pancreatic necrosis

2) Tissue undergoing slow degeneration
●Hyaline areas in benign tumors

●Fibroids

●In arteries due to atheromatous degeneration or old age

●Old thrombi

●Diseased or abnormal heart valves

Pathogenesis
➢Initiation ( or nucleation)

➢Propagation

Both may be intracellular or extracellular with calcium

phosphate as the end product
B. Metastatic Calcification
✔ deposition of calcium salts in normal tissues

✔almost always reflects some derangement in calcium

metabolism ( hypercalcemia)

Four major causes of hypercalcemia

1) Increased secretion of parathyroid hormone, due to either
parathyroid tumors or production of parathyroid hormone-
Related protein by other malignant tumors
2) Destruction of bone due to the effects of accelerated
turnover (e.g. Paget disease),immobilization, or tumors
(increased bone catabolism associated with multiple
myeloma, leukemia or diffuse skeletal metastases)
3) Vitamin D-related disorders like vitamin D intoxication and
sarcoidosis ( in which macrophages activate a vitamin D
precursor
4) Renal failure, in which phosphate retention leads to
secondary hyperparathyroidism
CELLULAR AGING
➢ results from combination of accumulating cellular damage

(e.g., by free radicals), reduced capacity to divide (replicative

senescence), and reduced ability to repair damaged DNA

Cellular senescence
➢Aging of a person is intimately related to cellular aging

Mechanisms known or suspected to be responsible for cellular

aging
●DNA damage

✔defective DNA repair mechanisms

DNA repair may be activated by calorie restriction (known

to prolong aging in model organisms)
●Replicative senescence
✔Reduced capacity of cells to divide because of decreasing

amounts of telomerase and progressive shortening of

chromosomal ends (telomeres)
Telomeres
➔are short repeated sequences of DNA present at the

linear ends of chromosomes

➔Importance

* for ensuring the complete replication of chromosome

ends
* and for protecting the ends from fusion & degradation

●Progressive accumulation of metabolic damage

✔Repeated environmental exposure to radiation

✔Progressive reduction of antioxidant defense mechanism

Like Vit. E & glutathione peroxidase

●Possible roles of growth factors
 Telomerase in Ageing:

Germ
cells

Somatic
cells
WERNER SYNDROME
➢A rare disease characterized by premature aging
 UMMA UNIVERSITY-SCHOOL OF NURSING
AND MIDWIFERY-PATHOLOGY LECTURE 3-
CLINICAL CHARACTERISTICS OF DISEASED
STATE OF ORGANS
WILSON A.L
 CLINICAL CHARACTERISTICS OF DISEASED STATE
OF ORGANS

• Host response to injury known -inflammation,

 Inflammation

• Responses to injury
• Inflammation is a protective reaction which aims to get rid of the original
source of cell injury as well as the dead cells and tissues.
• It does so by;-
• diluting, destroying, or neutralizing harmful substances including microbes
and toxins.
• It then begins the events that eventually heal and repair the injury sites.
• In the absence of inflammation, infections would be unimpeded and wounds
would not heal.
• Inflammation is one of the protective responses to infections that
immunologists refer to as innate immunity.
 CONT

• Inflammatory reaction and repair process can cause significant

harm.
• Components of inflammatory reaction that destroy and
eliminate microbes and dead tissues are capable of destroying
normal tissues if the reaction is ;
– Severe,
– Prolonged
– Inappropriate and directed against self-antigens in
autoimmune diseases.
• Cells and molecules of host defense normally circulate in the
blood, and the goal of the inflammatory reaction is to bring
them to the site of infection or tissue damage.
 CONT

• Several types of cells and molecules play important roles in inflammation.

• These include:
– Blood leukocytes and plasma proteins
– Cells of the vascular walls
– Cells and extracellular matrix (ECM) of the surrounding connective tissue.
 Classical signs of acute inflammation

• Inflammation can be acute or chronic and it manifests in various ways.

• External cardinal signs result from vascular changes and cell recruitment;
– Heat,
– Redness,
– Swelling.
• As consequences of mediator amplification and leukocyte-mediated damage
– Pain
– Loss of function.
 CONT

• As the injurious agent is eliminated and anti-inflammatory mechanisms become

active, the process subsides and the host returns to a normal state of health.
• If the injurious agent cannot be quickly eliminated, the result may be chronic
inflammation.
 Acute inflammation

• Rapid in onset and of short duration, lasting from a few

minutes to as long as a few days, characterized by fluid and
plasma protein exudation and a predominantly neutrophilic
leukocyte accumulation.
• It is a response to injury, microbes or foreign substances, and
is designed to deliver leukocytes and plasma proteins to sites
of injury.
• Once there, leukocytes clear the invaders and begin the
process of digesting and getting rid of necrotic tissues.
• All acute inflammatory reactions follow a fairly stereotypical
sequence in which blood vessels and leukocytes are the main
participants,
• Steps of the inflammatory response can be remembered as the
five Rs.
 The 5 Rs of Inflammatory response include

• Recognition of the injurious agent

• Recruitment of leukocytes
• Removal of the agent
• Regulation (control) of the response
• Resolution (repair).
 CONT

• Acute inflammation either culminates in;

– Elimination of the noxious stimulus,
– Decline of the reaction
– Repair of the damaged tissue,
– Persistent injury resulting in chronic inflammation.
 Components of Acute inflammation

• Acute inflammation has two major components:

• Vascular changes:
– Changes in blood vessel quality resulting in increased blood flow (as in
vasodilatation) and structural alterations that allow plasma proteins to leave
the circulation (also known as increased vascular permeability).
• Cellular events:
– Cellular recruitment and activation where leukocytes emigrate from the
microcirculation and accumulation to the focus of injury.
– The principal leukocytes in acute inflammation are neutrophils.
 Vascular Changes: Changes in Vascular Caliber and Flow

• Changes in blood vessels begin soon after infection or injury but may develop at
variable rates, depending on the nature and severity of the original inflammatory
stimulus.
• After temporary brief vasoconstriction that lasts only for seconds, arteriolar
vasodilation occurs, resulting in locally increased blood flow and engorgement of the
down-stream capillary beds.
• Vasodilation is the cause of the redness (erythema) and warmth characteristically
seen in acute inflammation.
 CONT

• As the smaller vessels become more permeable, protein-rich

fluid moves into the extravascular tissues.
• This causes a concentration of the red blood cells, thus
increasing blood viscosity and slowing down blood
circulation.
• These changes are reflected microscopically by numerous
dilated small vessels packed with erythrocytes and slowly
flowing blood, a process called stasis.
• As stasis develops, leukocytes begin to accumulate along the
endothelial surface-margination.
• This is the first step in the journey of the leukocytes through
the vascular wall into the interstitial tissue.
 Responses of Lymphatic Vessels

• Small amount of interstitial fluid formed normally is removed by lymphatic drainage.

• In inflammation, lymph flow is increased and helps drain edema fluid from the
extravascular space.
• Because the junctions of lymphatics are loose, lymphatic fluid eventually equilibrates
with extravascular fluid.
• In addition to fluid, leukocytes and cell debris may also find their way into lymph.
 CONT

• In severe inflammatory reactions, especially to microbes, the lymphatics may

transport the offending agent.
• The lymphatics may become secondarily inflamed (lymphangitis), as may the
draining lymph nodes (lymphadenitis).
• Inflamed lymph nodes are often enlarged, because of hyperplasia of the
lymphoid follicles and increased numbers of lymphocytes and phagocytic cells
lining the sinuses of the lymph nodes.
• This constellation of pathologic changes is termed reactive, or inflammatory,
lymphadenitis.
 Causes of Acute Inflammation

• Acute inflammatory reactions may be triggered by a variety of

stimuli.
– Infections
– Trauma, physical and chemical agents, thermal injury, such
as, burns or frostbite, irradiation and some environmental
chemicals
– Tissue necrosis
– Foreign bodies
– Immune reactions (also called hypersensitivity reactions)
against environmental substances or against self tissues.
 CONT

• Each of these stimuli may induce reactions with some

distinctive characteristics, but all inflammatory reactions have
the same basic features.
• The major local manifestations of acute inflammation include:
– Vascular dilation and increased blood flow (causing
erythema and warmth)
– Extravasation and deposition of plasma fluid and proteins
(edema)
– Leukocyte (mainly neutrophil) emigration and
accumulation in the site of injury.
 Cellular Events: Leukocyte Recruitment and Activation

• As mentioned above, an important function of the inflammatory response is to

deliver leukocytes to the site of injury and to activate them.
• Leukocytes;
– Ingest offending agents,
– Kill bacteria and other microbes,
– Eliminate necrotic tissue and foreign substances.
 CONT

• Leukocytes, once activated, they may induce tissue damage

and prolong inflammation, since the leukocyte products that
destroy microbes can also injure normal host tissues.
• Therefore, key to the normal function of leukocytes in host
defense is to ensure that they are recruited and activated only
when needed (that is, in response to foreign invaders and dead
tissues).
 Leukocyte Recruitment

• The sequence of events in the recruitment of leukocytes from the vascular lumen to
the extravascular space consists of:
– Margination; adhesion to endothelium, and rolling along the vessel wall
– Firm adhesion to the endothelium
– Transmigration between endothelial cells
– Migration in interstitial tissues toward a chemotactic stimulus
 CONT

• Rolling, adhesion, and transmigration are mediated by the binding of complementary

adhesion molecules on leukocytes and endothelial surfaces.
• Chemical mediators (chemo-attractants and certain cytokines), affect these processes
by modulating the surface expression or avidity (hunger) of the adhesion molecules
and by stimulating directional movement of the leukocytes.
 Margination and Rolling

• Leukocyte accumulation at the periphery of vessels is called

margination.
• Subsequently, leukocytes tumble on the endothelial surface,
transiently sticking along the way, a process called rolling.
• The leukocytes
– First roll,
– Become activated
– Adhere to endothelium,
– Transmigrate across the endothelium,
– Pierce the basement membrane,
– Migrate toward chemo-attractants emanating from the
source of injury.
 CONT

• As blood flows from capillaries into post-capillary venules,

circulating cells are swept by laminar flow against the vessel
wall.
• Smaller red cells tend to move faster than the larger white
cells.
• As a result, leukocytes are pushed out of the central axial
column and thus have a better opportunity to interact with
lining endothelial cells, especially as stasis sets in.
 Adhesion and Transmigration

• The next step in the reaction of leukocytes is firm adhesion to endothelial

surfaces.
• After being arrested on the endothelial surface, leukocytes migrate through the
vessel wall primarily by squeezing between cells at intercellular junctions.
• This movement of leukocytes, called diapedesis, occurs mainly in the venules
of the systemic vasculature however, it has also been noted in capillaries in the
pulmonary circulation.
• Migration of leukocytes is driven by chemokines produced in extravascular
tissues, which stimulate movement of the leukocytes toward their chemical
gradient.
 Chemotaxis

• After extravasating from the blood, leukocytes migrate toward sites of

infection or injury along a chemical gradient by a process called chemotaxis.
• Both exogenous and endogenous substances can be chemotactic for
leukocytes.
• Example of which are;
– Bacterial products
– Cytokines
– Components of the complement system
– Products of the lipoxygenase pathway of arachidonic acid (AA) metabolism
 CONT

• These mediators, are produced in response to infections and

tissue damage and during immunologic reactions.
• Leukocyte infiltration in all these situations results from the
actions of various combinations of mediators.
• The type of emigrating leukocyte varies with the age of the
inflammatory response and with the type of stimulus.
• In most forms of acute inflammation, neutrophils predominate
in the inflammatory infiltrate during the first 6 to 24 hours and
are replaced by monocytes in 24 to 48 hours.
• This is because neutrophils are more numerous in the blood,
they respond more rapidly to chemokines, and they may attach
more firmly to the adhesion molecules that are rapidly induced
on endothelial cells.
• In addition, after entering tissues, neutrophils are short- lived,
they die by apoptosis and disappear within 24 to 48 hours
whereas monocytes survive longer.
 CONT

• There are exceptions to this pattern of cellular exudation.

• In certain infections for example, those caused by
Pseudomonas aeruginosa, the cellular infiltrate is dominated
by continuously recruited neutrophils for several days.
• Viral infections lymphocytes may be the first cells to arrive
whereas in some
• Hypersensitivity reactions eosinophilic granulocytes may be
the main cell type.
 Leukocyte Activation

• Once leukocytes have been recruited to the site of infection or tissue

necrosis, they must be activated to perform their functions.
• Stimuli for activation include microbes, products of necrotic cells, and
several mediators.
• Leukocytes express on their surface different kinds of receptors that
sense the presence of microbes.
• Engagement of these receptors by microbial products or by various
mediators of inflammation induces a number of responses in
leukocytes that are part of their normal defensive functions and are
grouped under the generic term leukocyte activation.
 CONT

• Leukocyte activation results in many enhanced functions.

• These include;
– Phagocytosis of particles, an early step in the elimination of
harmful substances
– Production of substances that destroy phagocytosed
microbes and remove dead tissues. These leukocyte
products include lysosomal enzymes and reactive oxygen
and nitrogen species.
– Certain mediators amplify the inflammatory reaction. They
include arachidonic acid metabolites and cytokines.
 Phagocytosis

• Defined as the process of engulfing and digesting of particles by the cell or a

phagocyte such as a macrophage to form a phagosome or a food vacuole.
• The process involves clearing of injurious agents.
• It consists of three separate but interrelated steps;
– Recognition and attachment of the invading particle to the ingesting
neutrophil
– Engulfment, with subsequent formation of a phagocytic vacuole
– Killing and degradation of the ingested material by inflammatory cells
 CONT

• Leukocytes bind and ingest most microorganisms and dead

cells via specific surface receptors, which recognize either
components of the microbes and dead cells, or host proteins,
called opsonins that coat microbes and target them for
phagocytosis.
• These opsonins either are present in the blood ready to coat
microbes or are produced in response to the microbes.
• Leukocytes express receptors for opsonins that facilitate rapid
phagocytosis of the coated microbes.
• Different classes of cell surface receptors of leukocytes
recognize different stimuli.
• The receptors initiate responses that mediate the functions of
the leukocytes.
 CONT

• All the three factors of recognition, binding and crosslinking of receptors

allow progression to engulfment, which binds the opsonized particles and
triggers engulfment.
• In addition, the binding of certain leukocytes to certain receptors induces
cellular activation that enhances degradation of ingested microbes.
• In engulfment, cytoplasmic extensions or pseudopods are extended around the
object, eventually forming a phagocytic vacuole or phagosome.
• The membrane of the vacuole then fuses with the membrane of a lysosomal
granule, resulting in discharge of the granule's contents into the
phagolysosome, leading to the final stage of phagocytosis namely bacterial
killing.
 Bacterial killing

• The culmination of the phagocytosis of microbes is killing and

degradation of the ingested bacteria or particles.
• The key steps in this reaction are the production of
microbicidal substances within lysosomes and fusion of the
lysosomes with phagosomes, thus selectively exposing the
ingested particles to the destructive mechanisms of the
leukocytes.
• The most important microbicidal substances are reactive
oxygen species (ROS) and lysosomal enzymes.
• Phagocytosis stimulates an oxidative burst characterized by a
sudden increase in oxygen consumption, glycogen catabolism
(glycogenolysis), increased glucose oxidation, and production
of ROS.
 CONT

• The generation of the oxygen metabolites is due to rapid

activation of a leukocyte NADPH oxidase, called the
phagocyte oxidase, which oxidizes NADPH (reduced
nicotinamide adenine dinucleotide phosphate) and, in the
process, converts oxygen to superoxide ion.
• Superoxide is then converted by spontaneous dismutation into
hydrogen peroxide.
• The dead microorganisms are then degraded by the action of
lysosomal acid hydrolases.
• The most important lysosomal enzyme involved in bacterial
killing is elastase.
 Leukocyte-Induced Tissue Injury

• Leukocytes are important causes of injury to normal cells and tissues under several
circumstances:
– As part of a normal defense reaction against infectious microbes, when
"spectator" tissues are injured.
– In some infections that are difficult to eradicate, such as tuberculosis and in
certain viral diseases, the host response contributes more to the pathology than
does the microbe itself.
 CONT

– As a normal attempt to clear damaged and dead tissues for example, after a
myocardial infarction. Inflammation may prolong and exacerbate the injurious
consequences of the infarction, especially upon reperfusion.
– When the inflammatory response is inappropriately directed against host tissues,
as in certain autoimmune diseases, or when the host reacts excessively against
non-toxic environmental substances, such as allergic diseases that induce asthma.
 Take Note

• It is important to know that in all these situations,

• The mechanisms by which leukocytes damage normal tissues are the same as the
mechanisms involved in antimicrobial defense, because once the leukocytes are
activated, their effector mechanisms do not distinguish between the microorganism
(offenders) and the host.
 CONT

• During activation and phagocytosis, leukocytes may release

toxic products not only within the phagolysosome but also into
the extracellular space.
• The most important of these substances are lysosomal
enzymes, present in the granules, and reactive oxygen and
nitrogen species.
• If unchecked or inappropriately directed against host tissues,
leukocytes themselves become offenders.
• Leukocyte - dependent tissue injury underlies many acute and
chronic human diseases.
• The contents of lysosomal granules are secreted by leukocytes
into the extracellular milieu by several mechanisms.
 CONT

• If the phagocytic vacuole remains transiently open to the

outside before complete closure of the phagolysosome
(regurgitation during feeding).
• If cells encounter materials that cannot be easily ingested, such
as immune complexes deposited on immovable flat surfaces
(for example, glomerular basement membrane), the attempt to
phagocytose these substances (frustrated phagocytosis)
triggers strong leukocyte activation, and lysosomal enzymes
are released into the surrounding tissue or lumen.
 Defects in Leukocyte Function

• Leukocytes play a central role in host defense, defects in leukocyte function, both
acquired and inherited, lead to increased susceptibility to infections, which may be
recurrent and life-threatening.
• Most common causes of defective inflammation are bone marrow suppression caused
by tumors and chemotherapy or radiation (resulting in decreased leukocyte numbers),
and metabolic diseases such as diabetes mellitus (causing abnormal leukocyte
functions).
 Outcomes of Acute Inflammation

• The results of acute inflammation are dependent on;

– The nature and intensity of the injury,
– The site and tissue affected,
– The ability of the host to mount a response,
• Acute inflammation generally has four possible outcomes:
• Resolution –
– When the injury is limited or short-lived,
– when there has been no or minimal tissue damage,
– when the tissue is capable of replacing any irreversibly
injured cells.
 CONT

• Chronic inflammation
– This may follow acute inflammation if the offending agent is not removed.
– In some instances, signs of chronic inflammation may be present at the onset of
injury (for example, in viral infections or immune responses to self-antigens).
 CONT

• Scarring or fibrosis –
– Results after substantial tissue destruction or when
inflammation occurs in tissues that do not regenerate.
– In addition, extensive fibrinous exudates (due to increased
vascular permeability) may not be completely absorbed and
are organized by in-growth of connective tissue, with
resultant fibrosis.
• Abscesses
– These may form in the setting of extensive neutrophilic
infiltrates or in certain bacterial or fungal infections (these
organisms are then said to be pyogenic, or ‘pus forming’.
– Because of the underlying tissue destruction the usual
outcome of abscess formation is also scarring.
 Activity

• Reflect and write down the three steps of Phagocytosis.

• List and briefly describe the four possible outcomes of acute inflammation.
 Chronic inflammation

• Chronic inflammation is inflammation of prolonged duration (weeks

to months to even years) in which active inflammation, tissue injury,
and healing proceed simultaneously.
• An increase of lymphocytes and macrophages cause vascular
proliferation and fibrosis.
• As indicated earlier, acute inflammation may progress to chronic
inflammation.
• This transition occurs when the acute response cannot be resolved,
either because of the persistence of the injurious agent or because of
interference with the normal process of healing.
 CONT

• For example, a peptic ulcer of the duodenum initially shows acute inflammation
followed by the beginning stages of resolution.
• However, recurrent bouts of duodenal epithelial injury interrupt this process and
result in a lesion characterized by both acute and chronic inflammation.
• Alternatively, some forms of injury (for instance, viral infections) provoke a response
that involves chronic inflammation from the onset.
 CONT

• Chronic inflammation arises in the following settings:

• Persistent infections –
– By microbes that are difficult to eradicate.
– These include mycobacteria, Treponema pallidum
(causative organism for syphilis), and certain viruses and
fungi, all of which tend to establish persistent infections
and elicit a T lymphocyte-mediated immune response
called delayed-type hypersensitivity.
 CONT

• Immune-mediated inflammatory diseases (hypersensitivity diseases) –

– These are caused by excessive and inappropriate activation of the immune system.
– They are increasingly recognized as being significant health problems. Under
certain conditions, immune reactions develop against the individual's own tissues,
leading to autoimmune diseases.
 CONT

• Prolonged exposure to potentially toxic agents

– They include non-degradable exogenousmaterials such as inhaled particulate
silica, which can induce a chronic inflammatory response in the lungs (silicosis),
and endogenous agents such as chronically elevated plasma lipid components,
which may contribute to atherosclerosis.
 Chronic Inflammatory Cells and Mediators

• A fundamental feature of chronic inflammation is its persistence.

• It results from complex interactions between the cells that are recruited to the site of
inflammation and are activated at this site.
• Understanding the pathogenesis of chronic inflammatory reactions requires an
appreciation of these cells and their biologic responses and functions.
 Macrophages

• Dominant cells of chronic inflammation, are tissue cells

derived from circulating blood monocytes after their
emigration from the bloodstream.
• Normally diffusely scattered in most connective tissues, and
are also found in organs such as the;
– Liver (Kupffer cells),
– Spleen and lymph nodes (sinus histiocytes),
– CNS (microglial cells),
– Lungs (alveolar macrophages).
• Together these cells comprise mononuclear phagocyte system,
/reticulo-endothelial system.
• In all tissues, macrophages act as filters for particulate matter,
microbes, and senescent cells, as well as acting as guards to
alert the specific components of the adaptive immune system
to injurious stimuli.
 The roles of activated macrophages in chronic inflammation

• Macrophages are activated by non-immunologic stimuli such as bacterial endotoxin

or by cytokines from immune-activated T cells, particularly interferon-γ (IFN-γ).
• The products made by activated macrophages that repair and also cause tissue injury
and fibrosis include;
– Arachidonic acid (AA),
– Platelet-derived growth factor (PDGF),
– Fibroblast growth factor (FGF)
– Transforming growth factor β (TGF-β).
 CONT

• Half-life of circulating monocytes is about 1 day.

• Under the influence of adhesion molecules and chemotactic
factors, they begin to migrate to a site of injury within 24 to 48
hours after the onset of acute inflammation.
• When monocytes reach the extravascular tissue, they undergo
transformation into larger macrophages, which have longer
half-lives and a greater capacity for phagocytosis than do
blood monocytes.
– Macrophages may also become activated, resulting in
– Increased cell size,
– Increased content of lysosomal enzymes,
– More active metabolism,
– Greater ability to kill ingested organisms.
 CONT

• By light microscopy, activated macrophages appear large, flat, and pink.

• This appearance may be similar to that of squamous epithelial cells, and cells with
such an appearance are therefore sometimes called epithelioid cells.
• Activation signals include bacterial endotoxin and other microbial products,
cytokines secreted by sensitized T lymphocytes (in particular the cytokine IFN-γ),
various mediators produced during acute inflammation and ECM proteins such as
fibronectin.
 CONT

• After activation, macrophages secrete a wide variety of biologically active products

that, if unchecked, can result in the tissue injury and fibrosis that are characteristic of
chronic inflammation.
• These products include acid and neutral proteases. Recall that the latter were also
implicated as mediators of tissue damage in acute inflammation.
• Other enzymes, such as plasminogen activator, greatly amplify the generation of pro-
inflammatory substances.
 CONT

• After the initiating stimulus is eliminated and the inflammatory reaction

decreases, macrophages eventually die or wander off into lymphatics.
• In chronic inflammatory sites, however, macrophage accumulation persists,
and macrophages can proliferate.
• Steady release of lymphocyte-derived chemokines and other cytokines is an
important mechanism by which macrophages are recruited to or immobilized
in inflammatory sites.
• IFN-γ can also induce macrophages to fuse into large, multinucleated cells
called giant cells.
 CONT

• Prolonged host response to persistent stimulus caused by

microbes that resist elimination, immune responses against self
and environmental antigens, and some toxic substances such
as silica, underlies many medically important diseases
characterized by coexisting inflammation, tissue injury,
attempted repair by scarring, and immune response.
• Cellular infiltrate consists of macrophages, lymphocytes and
plasma cells.
• Fibrosis is often prominent, mediated by cytokines produced
by macrophages and lymphocytes (notably T lymphocytes).
• The bidirectional interactions between these cells tend to
amplify and prolong the inflammatory reaction.
 Granulomatous Inflammation

• This is a distinctive pattern of chronic inflammation

characterized by aggregates of activated macrophages that
assume an epitheloid appearance.
• Granulomas form after macrophages have initially digested
pathogenic organisms.
• They are encountered in certain specific pathologic states such
as tuberculosis, leprosy, brucellosis and Crohn’s disease.
• Recognition of the granulomatous pattern is therefore
important because of the limited number of conditions (some
life-threatening) that cause it.
 CONT

• Granulomas can form in the setting of persistent T - cell responses to certain

microbes (such as Mycobacterium tuberculosis, Treponema pallidum, or
fungi), where T-cell-derived cytokines are responsible for chronic macrophage
activation.
• Tuberculosis is the prototype of a granulomatous disease caused by infection
and should always be excluded as the cause when granulomas are identified.
• Granulomas may also develop in response to relatively static foreign bodies
such as sutures or splinters, forming so-called foreign body granulomas.
 CONT

• The formation of a granuloma effectively forms a wall around the offending agent
and is therefore a useful defense mechanism.
• Despite that, granuloma formation does not always get rid of the causal agent, which
is often resistant to killing or degradation.
• Eventually granulomatous inflammation with subsequent fibrosis may even be the
major cause of organ dysfunction in some diseases, such as tuberculosis.
 Systemic effects of inflammation

• Collectively called the acute-phase reaction, or the systemic inflammatory response

syndrome.
• The cytokines TNF, IL-1, and IL-6 are the most important mediators of the acute-
phase reaction.
• These cytokines are produced by leukocytes (and other cell types) in response to
infection or in immune reactions and are released systemically.
 Acute-phase reaction (Systemic Inflammatory
Response Syndrome - SIRS)
• Fever,
– Characterized by an elevation of body temperature, usually
by 1° to 4°C, is one of the most prominent manifestations
of the acute-phase response, especially when inflammation
is caused by infection.
– Fever is produced in response to substances called
pyrogens that act by stimulating prostaglandin (PG)
synthesis in the vascular and perivascular cells of the
hypothalamus.
– Bacterial products stimulate leukocytes to release cytokines
(called endogenous pyrogens) that increase the levels of
cyclooxygenases that convert arachidonic acid (AA) into
prostaglandins.
– In the hypothalamus the prostaglandins stimulate the
production of neurotransmitters, which function to reset the
temperature set point at a higher level.
 CONT

• Elevated plasma levels of acute-phase proteins –

– These are plasma proteins, mostly synthesized in the liver,
whose concentrations may increase 100-fold as part of the
response to inflammatory stimuli.
– Three of the best-known of these proteins are;
– C-reactive protein (CRP),
– Fibrinogen,
– Serum amyloid A (SAA) protein.
– Synthesis of these molecules by hepatocytes is up-regulated
by cytokines.
– Many acute-phase proteins, such as CRP and SAA, bind to
microbial cell walls, and they may act as opsonins and fix
complement, thus promoting the elimination of the
microbes.
 CONT

• Fibrinogen binds to erythrocytes and causes them to form stacks (rouleaux)

that sediment more rapidly at unit gravity than do individual erythrocytes.
• This is the basis for measuring the erythrocyte sedimentation rate (ESR) as a
simple test for the systemic inflammatory response, caused by a variety of
stimuli.
• Elevated serum levels of CRP are now used as a marker for increased risk of
myocardial infarction or stroke in patients with atherosclerotic vascular
disease.
• Inflammation is involved in the development of atherosclerosis, and increased
CRP is a marker of inflammation.
 CONT
• Leukocytosis
– Common feature of inflammatory reactions, especially
those induced by bacterial infection.
– Leukocyte count usually climbs to 15,000 or 20,000
cells/μL, but sometimes it may reach extraordinarily high
levels, as high as 40,000 to 100,000 cells/μL.
– These extreme elevations are referred to as leukemoid
reactions because they are similar to the white cell counts
obtained in leukemia.
– The leukocytosis occurs initially because of accelerated
release of cells from the bone marrow post mitotic reserve
pool and is therefore associated with a rise in the number of
more immature neutrophils in the blood.
– Prolonged infection also stimulates production of colony-
stimulating factors (CSFs), leading to increased bone
marrow output of leukocytes, which compensates for the
loss of these cells in the inflammatory reaction.
 CONT

• Most bacterial infections induce an increase in the blood

neutrophil count, called neutrophilia.
• Viral infections, such as infectious mononucleosis, mumps,
and German measles, are associated with increased numbers of
lymphocytes (lymphocytosis).
• Bronchial asthma, hay fever, and parasite infestations all
involve an increase in the absolute number of eosinophils,
creating an eosinophilia.
• Certain infections (typhoid fever and infections caused by
some viruses, rickettsiae, and certain protozoa) are
paradoxically associated with a decreased number of
circulating white cells (leukopenia), likely because of
cytokine-induced sequestration of lymphocytes in lymph
nodes.
 CONT
• Other manifestations of acute-phase response include;
– Increased heart rate and blood pressure,
– Decreased sweating (mainly because of redirection of
blood flow from cutaneous to deep vascular beds to
minimize heat loss through the skin),
– Shivering,
– Chills (perception of being cold as the hypothalamus resets
the body temperature),
– Anorexia,
– Somnolence, and malaise (probably because of the actions
of cytokines on brain cells).
– Chronic inflammation is associated with a wasting
syndrome called cachexia, which is mainly the result of
Tumour Necrosis Factor (TNF) - mediated appetite
suppression and mobilization of fat stores.
 CONT

• In severe bacterial infections (sepsis),

• The large amounts of organisms in the blood or extravascular tissue stimulate the
production of enormous quantities of several cytokines, notably TNF, as well as IL-
12 and IL-1.
• As a result, circulating levels of these cytokines increase, and the nature of the host
response changes.
• High levels of TNF cause;
– Disseminated intravascular coagulation (DIC),
– Hypoglycemia,
– Hypotensive shock.
• This clinical triad is described as septic shock.
 Mediators of inflammatory response

• Many mediators are known, and this knowledge has been used to design a large
number of anti-inflammatory drugs.
• In this session, we will emphasize general properties of the mediators of
inflammation and highlight only some of these important molecules.
• Mediators may be produced locally by cells at the site of inflammation, or they may
be circulating in the plasma as inactive precursors that are activated at the site of
inflammation
 Cell-Derived Mediators

• Tissue macrophages, mast cells, and endothelial cells at the site of inflammation, as
well as leukocytes that are recruited to the site from the blood, are all capable of
producing different mediators of inflammation.

• CHECK OUT FOR TABLE

 CONT

• Reactive Oxygen Species (ROS)

• Produced at low levels can increase chemokine, cytokine, and adhesion
molecule expression, therefore increase the cascade of inflammatory
mediators.
• At higher levels, they are responsible for tissue injury by
– Endothelial damage,
– Protease activation and antiprotease inactivation,
– Direct injury to some cell types
• Fortunately, various antioxidant protective mechanisms (such as, catalase,
superoxide dismutase, and glutathione) are present in tissues and blood to
minimize the toxicity of the oxygen metabolites.
 CONT

• Nitric Oxide (NO)

• Plays many roles in inflammation including:
– Relaxation of vascular smooth muscle (vasodilation),
– Antagonism of all stages of platelet activation (adhesion, aggregation, and
degranulation),
– Reduction of leukocyte recruitment at inflammatory sites
– Action as a microbicidal (cytotoxic) agent (with or without superoxide radicals) in
activated macrophages.
 Lysosomal enzymes

• The lysosomal granules of neutrophils and monocytes contain many molecules that
can mediate acute inflammation.
• These may be released after cell death, by leakage during the formation of the
phagocytic vacuole, or during futile attempts to phagocytose large, indigestible
surfaces.
• Their main role is in microbial killing and tissue injury.
• The most important of these lysosomal molecules are enzymes, Acid proteases and
neutral proteases.
 CONT

• The potentially damaging effects of lysosomal enzymes are checked by anti-

proteases present in the serum and tissue fluids.
• These include α1-antitrypsin, the major inhibitor of neutrophil elastase, and α2-
macroglobulin.
• Deficiencies of these inhibitors may result in sustained activation of leukocyte
proteases, resulting in tissue destruction at sites of leukocyte accumulation.
• For instance, α1-antitrypsin deficiency in the lung can cause severe panacinar
emphysema.
 Neuropeptides

• Like the vasoactive amines, neuropeptides can initiate inflammatory responses.

• They are small proteins, such as substance P, that transmit pain signals, regulate
vessel tone, and modulate vascular permeability.
• Nerve fibers that secrete neuropeptides are especially prominent in the lung and
gastrointestinal tract.
 Plasma Protein - Derived Mediators
• Classified under circulating proteins of three interrelated
systems:
– Complement
– Kinin and
– Coagulation systems
• The complement system
– Plasma proteins which are important role in host defense
(immunity) and inflammation.
– On activation, different complement proteins coat
(opsonize) particles, such as microbes, for phagocytosis
and destruction, and contribute to the inflammatory
response by increasing vascular permeability and leukocyte
chemotaxis.
– Complement activation ultimately generates a pore-like
membrane attack complex (MAC) that punches holes in the
membranes of invading microbes.
 Take Note 3.5

• Complement components (numbered C1 to C9) are present in plasma in inactive

forms, and many of them are activated by proteolysis, thus setting up an enzymatic
cascade.
 CONT

• The effects of the complement system include;

• Vascular effects.
– C3a and C5a increase vascular permeability and cause vasodilation by
inducing mast cells to release histamine. -also called anaphylatoxins
because their actions mimic those of mast cells, which are the main cellular
effectors of the severe allergic reaction called anaphylaxis.
• Leukocyte activation, adhesion, and chemotaxis.
– C5a activates leukocytes, increasing their adhesion to endothelium, and is a
potent chemotactic agent for neutrophils, monocytes, eosinophils, and
basophils.
 CONT

• Phagocytosis.
– When fixed to a microbial surface,
– C3b and its inactive proteolytic product iC3b act as
opsonins, augmenting phagocytosis by neutrophils and
macrophages, which express receptors for these
complement products.
• Activation of complement is tightly controlled by cell -
associated and circulating regulatory proteins.
• Presence of these inhibitors in host cell membranes protects
normal cells from inappropriate damage during protective
reactions against microbes.
• Inappropriate or excessive complement activation (for
example, in antibody-mediated diseases) can overwhelm the
regulatory systems, and therefore complement activation is
responsible for serious tissue injury in a variety of
immunologic disorders.
 CONT

• Kinin system activation

– Leads ultimately to the formation of bradykinin from a
proteolytic cleavage of precursors.
– Like histamine, bradykinin causes increased vascular
permeability,
– Arteriolar dilation, and bronchial smooth muscle
contraction.
– It also causes pain when injected into the skin.
– The actions of bradykinin are short-lived because it is
rapidly degraded by kininases present in plasma and
tissues.
 CONT

• In the clotting system,

– Factor XIIa-driven proteolytic cascade leads to activation of thrombin, which then
cleaves circulating soluble fibrinogen to generate an insoluble fibrin clot.
– Factor Xa, an intermediate in the clotting cascade, causes increased vascular
permeability and leukocyte emigration.
– Thrombin participates in inflammation by binding to protease-activated receptors
that are expressed on platelets, endothelial cells, and many other cell types.
 CONT

• Binding of thrombin to these receptors on endothelial cells leads to their activation

and enhanced leukocyte adhesion.
• In addition, thrombin generates fibrinopeptides (during fibrinogen cleavage) that
increase vascular permeability and are chemotactic for leukocytes.
 CONT

• Fibrinolytic system:
– This mechanism exists to limit clotting by cleaving fibrin,
thereby solubilizing the fibrin clot.
– Without fibrinolysis and other regulatory mechanisms,
initiation of the coagulation cascade, even by trivial injury,
would culminate in continuous and irrevocable clotting of
the entire vasculature.
– It is evident from the preceding discussion that many
molecules are involved in different aspects of the
inflammatory reaction, and these molecules often interact
with, amplify, and antagonize one another.
– From this collection of chemical mediators, it is possible to
identify the major contributors to various components of
acute inflammation.
 Wound Healing and Repulsion/ Fracture Healing

• Occur through regeneration and repair.

• Organism to posses the ability to repair damage caused by toxic insults and
inflammation.
• The inflammatory response to microbes and injured tissues not only serves to
eliminate these dangers but also sets into motion the process of repair.
• Repair
– Defined as the restoration of tissue structure and function after an injury.
 CONT

• Some tissues can replace damaged cells and return to a normal

state through regeneration.
• If complete restitution is not possible, or there is severe
damage, healing occurs by laying down of connective
(fibrous) tissue, a process resulting in scar formation.
• Fibrous scar provides structural stability to enable function.
• Both regeneration and scar formation contribute to the ultimate
repair.
• Fibrosis describes the extensive deposition of collagen in the
lungs, liver, kidney, and other organs as a consequence of
chronic inflammation, or in the myocardium after major
ischemic necrosis or cardiac infarction.
• If fibrosis develops in a tissue space occupied by an
inflammatory exudate it is called organization.
 Cutaneous Wound Healing

• Repair involves proliferation of various cells, and close

interactions between cells and the extracellular matrix (ECM).
• Therefore, an understanding of the process of repair requires
some knowledge of the control of cell proliferation and the
functions of the ECM.
• The repair process involves both epithelial regeneration and
the formation of connective tissue scar.
• It illustrates the general principles that apply to wound healing
in all tissues.
• Specialized cell types first clear the injurious agent and then
gradually build the defect.
• Regeneration of the epithelium of the wound surface takes
place mostly by cell migration from the edges of the wound.
 CONT

• These events are made possible by interplay of growth factors

and ECM, physical conditions, including the forces generated
by changes in cell shape, also contribute.
• Cutaneous (Skin) wound healing has three main phases:
– Inflammation,
– Formation of granulation tissue
– ECM deposition and remodeling
• Larger wounds also contract during the healing process.
• Events in wound healing overlap to a great extent and cannot
be completely separated from each other.
• Based on the nature of the wound, the healing of cutaneous
wounds can occur by first or second intention.
 Healing by First Intention

• One of the simplest examples of wound repair is the healing of a clean, uninfected
surgical incision approximated by surgical sutures.
CONT
 CONT

• Primary union, or healing by first intention.

• Incision causes only focal disruption of epithelial basement
membrane continuity and death of a relatively few epithelial
and connective tissue cells.
• As a result, epithelial regeneration predominates over fibrosis.
• A small scar is formed, but there is minimal wound
contraction.
• The narrow incisional space first fills with fibrin-clotted
blood, which is rapidly invaded by granulation tissue and
covered by new epithelium.
 CONT

• First 24 hours –
– Neutrophils migrate toward the fibrin clot.
– Basal cells at the cut edge of the epidermis begin increased mitotic activity.
• Within 24 to 48 hours,
– Epithelial cells from both edges have begun to migrate and proliferate along the
dermis, depositing basement membrane components as they progress.
– The cells meet in the midline beneath the surface scab, yielding a thin but
continuous epithelial layer.
 CONT

• By Third Day –
– Neutrophils are largely replaced by macrophages, and
granulation tissue gradually invades the incision space.
– Collagen fibers become apparent at the incision but do not
yet bridge the incision.
– Epithelial cell proliferation yields a thickened epidermal
covering layer.
• By Fifth Day –
– Granulation tissue fills the incisional space.
– Collagen fibrils increase and begin to bridge the incision.
– The epidermis recovers its normal thickness as
differentiation of surface cells yields a mature epidermal
structure with surface keratinization.
 CONT

• During the second week

– There is continued accumulation of collagen and fibroblast proliferation.
– The leukocyte infiltrate, edema, and increased vascularity are substantially
diminished.
– The long process of "blanching" begins, accomplished by increasing collagen
deposition within the incisional scar and the regression of vascular channels.
 Healing by Second Intention

• When cell or tissue loss is more extensive, (for example in full thickness
burns, large wounds, abscess formation, and ulceration), the repair process is
more complex, as is also the case after infarction in parenchymal organs.
• In second-intention healing, also known as healing by secondary union,
– The inflammatory reaction is more intense,
– There is abundant development of granulation tissue, and the wound
contracts by the action of myofibroblasts.
– This is followed by accumulation of ECM and formation of a large scar.
CONT
 CONT

• Secondary healing differs from primary healing in several

respects:
– A larger clot or scab rich in fibrin and fibronectin forms at
the surface of the wound.
– Inflammation is more intense because large tissue defects
have a greater volume of necrotic debris, exudate, and
fibrin that must be removed. Consequently, large defects
have a greater potential for secondary, inflammation-
mediated, injury.
– Much larger amounts of granulation tissue are formed.
Larger defects require a greater volume of granulation
tissue to fill in the gaps and provide the underlying
framework for the regrowth of tissue epithelium. A greater
volume of granulation tissue generally results in a greater
mass of scar tissue.
 CONT

– Secondary healing involves wound contraction. Within 6 weeks, for example,

large skin defects may be reduced to a fraction of their original size by
contraction.
– This process has been ascribed to the presence of myofibroblasts, which are
modified fibroblasts exhibiting many of the ultrastructural and functional features
of contractile smooth muscle cells.
 Wound Strength

• Well sutured wounds have about 70% of the strength of normal skin.
• After removal of sutures seven days later, wound strength is down to
about 10% but this increases rapidly over the next 4 weeks.
• Increased tensile strength results from collagen synthesis exceeding
degradation in the first 2 months, and from structural modifications of
collagen (such as cross-linking and increased fiber size).
• Wound strength reaches approximately 70% to 80% by 3 months but
usually does not improve much beyond that point.
• Basis for health education to our patients post surgery
 Factors that influence wound healing

• A number of factors can alter the rate and efficiency of

healing. These can be classified in to those which act locally,
and those which have systemic effects. Most of these factors
have been established in studies of skin wound healing but
many are likely to be of relevance to healing at other sites.
• Local Factors
• Type, size, and location of the wound
• A clean, aseptic wound produced by the surgeon’s scalpel
heals faster than a wound produced by blunt trauma, which
exhibits aboundant necrosis and irregular edges. Small blunt
wounds heal faster than larger ones.Injuries in richly
vascularized areas (e.g., the face) heal faster than those in
poorly vascularized ones (e.g., the foot). In areas where the
skin adheres to bony surfaces, as in injuries over the tibia,
wound contraction and adequate apposition of the edges are
difficult. Hence, such wounds heal slowly.
 CONT

• Vascular supply
• Wounds with impaired blood supply heal slowly. For example, the
healing of leg wounds in patients with varicose veins is prolonged.
Ischemia due to pressure produces bed sores and then prevents their
healing. Ischemia due to arterial obstruction, often in the lower
extremities of diabetics, also prevents healing.
• Infection
• Wounds provide a portal of entry for microorganisms. Infection delays
or prevents healing, promotes the formation of excessive granulation
tissue (proud flesh), and may result in large, deforming scars.
 CONT

• Movement
• Early motion, particularly before tensile strength has been established,
subjects a wound to persistent trauma, thus preventing or retarding
healing.
• Ionizing radiation
• Prior irradiation leaves vascular lesions that interfere with blood supply
and result in slow wound healing. Acutely, irradiation of a wound blocks
cell proliferation, inhibits contraction, and retards the formation of
granulation tissue.
 Systemic Factors

• Circulatory status
• Cardiovascular status, by determining the blood supply to the
injured area, is important for wound healing. Poor healing
attributed to old age is often due, largely, to impaired
circulation.
• Infection
• Systemic infections delay wound healing.
• Metabolic status
• Poorly controlled diabetes mellitus is associated with delayed
wound healing.
• The risk of infection in clean wound approaches fivefold the
risk in non- diabetics. In diabetic patients, there can be
impaired circulation secondary to arteriosclerosis and impaired
sensation due to diabetic neuropathy. The impaired sensation
renders the lower extremity blind to every day hazards. Hence,
in diabetic patients, wounds heal the very slowly.
 Nutritional deficiencies

• Protein deficiency
• In protein depletion there is an impairment of granulation tissue and
collagen formation, resulting in a great delay in wound healing.
• Vitamin deficiency
• Vitamin C is required for collagen synthesis and secretion. It is required
in hydroxylation of proline and lysine in the process of collagen
synthesis. Vitamin C deficiency (scurvy) results in grossly deficient
wound healing, with a lack of vascular proliferation and collagen
deposition.
 CONT

• Trace element deficiency

• Zinc (a co-factor of several enzymes) deficiency will
retard healing by preventing cell proliferation. Zinc is
necessary in several DNA and RNA polymerases and
transferases; hence, a deficiency state will inhibit mitosis.
Proliferation of fibroblasts (fibroplasia) is, therefore,
retarded.
• Hormones However, these hormones have many other
effects, including anti-inflammatory actions and a general
depression of protein synthesis. It also inhibits fibroplasia
and neovascularization.
• Both epithelialization and contraction are impaired. It is,
therefore, difficult to attribute their inhibition of wound
healing to any one specific mechanism.
 CONT

• Thyroid hormones, androgens, estrogens and growth

hormone also influence wound healing.
• This effect, however, may be more due to their regulation
of general metabolic status rather than to a specific
modification of the healing process.
• Anti-inflammatory drugs
• Anti-inflammatory medications do not interfere with
wound healing when administered at the usual daily
dosages. Asprin and indomethalin both inhibit
prostaglandin synthesis and thus delay healing.
 Complications of Wound Healing
• Abnormalities in any of the three basic healing processes –
contraction, repair, and regeneration result in the
complications of wound healing.
• 1. Infection
• A wound may provide the portal of entry for many organisms.
Infection may delay healing, and if severe stop it completely.
• 2. Deficient Scar Formation
• Inadequate formation of granulation tissue or an inability to
form a suitable extracellular matrix leads to deficient scar
formation and its complications. The complications of
deficient scar formation are:
• a. Wound dehiscence & incisional hernias
• b. Ulceration
 CONT

• a. Wound Dehiscence and Incisional Hernias:

• Dehiscence (bursting of a wound) is of most concern after
abdominal surgery.
• If insufficient extracellular matrix is deposited or there is
inadequate cross-linking of the matrix, weak scars result.
• Dehiscence occurs in 0.5% to 5% of abdominal operations.
• Inappropriate suture material and poor surgical techiniques are
important factors.
• Wound infection, increased mechanical stress on the wound
from vomiting, coughing, or ileus is a factor in most cases of
abdominal dehiscence.
 CONT

• Systemic factors that predispose to dehiscence include poor

metabolic status, such as vitamin C deficiency,
hypoproteinemia, and the general inanition that often
accompanies metastatic cancer.
• Dehiscence of an abdominal wound can be a lifethreatening
complication, in some studies carrying a mortality as high as
30%.
• An incisional hernia, usually of the abdominal wall, refers to a
defect caused by poor wound healing following surgery into
which the intestines protrude.
 CONT

• b. Ulceration:
• Wounds ulcerate because of an inadequate intrinsic blood supply or
insufficient vascularization during healing.
• For example, leg wounds in persons with varicose veins or severe
atherosclerosis typically ulcerate.
• Nonhealing wounds also develop in areas devoid of sensation because of
persistent trauma.
• Such trophic or neuropathic ulcers are occasionally seen in patients with
leprosy, diabetic peripheral neuropathy and in tertiary syphilis from spinal
involvement (in tabes orsalis).
 CONT
• 3. Excessive Scar Formation
• An excessive deposition of extracellular matrix at the wound
site results in a hypertrophic scar or a keloid.
• The rate of collagen synthesis, the ratio of type III to type I
collagen, and the number of reducible cross-links remain high,
a situation that indicates a “maturation arrest”, or block, in the
healing process.
• Keloid Formation
• An excessive formation of collagenous tissue results in the
appearance of a raised area of scar tissue called keloid.
• It is an exuberant scar that tends to progress and recur after
excision.
• The cause of this is unknown. Genetic predisposition, repeated
trauma, and irritation caused by foreign body, hair, keratin,
etc., may play a part.
• It is especially frequent after burns. It is common in areas of
the neck & in the ear lobes.
 CONT

• Hypertrophic Scar
• Hypertrophic scar is structurally similar to keloid.
• However, hypertrophic scar never gets worse after 6 months
unlike keloid, which gets worse even after a year and some
may even progress for 5 to 10 years.
• Following excision keloid recurres, whereas a hypertrophic
scar does not.
• 4. Excessive contraction
• A decrease in the size of a wound depends on the presence of
myofibroblasts, development of cell-cell contacts and
sustained cell contraction.
• An exaggeration of these processes is termed contracture
(cicatrisation) and results in severe deformity of the wound
and surrounding tissues.
• Contracture (cicatrisation) is also said to arise as a result of
late reduction in the size of the wound.
 CONT

• Interestingly, the regions that normally show minimal wound

contraction (such as the palms, the soles, and the anterior
aspect of the thorax) are the ones prone to contractures.
• Contractures are particularly conspicuous in the healing of
serious burns.
• Contractures of the skin and underlying connective tissue can
be severe enough to compromise the movement of joints.
• Cicatrisation is also important in hollow viscera such as
urethra, esophagus, and intestine.
• It leads to progressive stenosis with stricture formation. In the
alimentary tract, a contracture (stricture) can result in an
obstruction to the passage of food in the esophagus or a block
in the flow of intestinal contents.
 CONT

• Several diseases are characterized by contracture and irreversible fibrosis of

the superficial fascia, including Dupuytren disease (palmar contracture),
plantar contracture (Lederhosen disease), and Peyronie disease (contracture of
the cavernous tissues of the penis).
• In these diseases, there is no known precipitating injury, even though the basic
process is similar to the contracture in wound healing.
• 5. Miscellaneous
• Implantation (or epidermoid cyst: Epithelial cells which flow into the healing
wound may later sometimes persist, and proliferate to form an epidermoid
cyst.
 Fracture Healing

• The basic processes involved in the healing of bone fractures bear many
resemblances to those seen in skin wound healing.
• Unlike healing of a skin wound, however, the defect caused by a fracture is repaired
not by a fibrous “scar” tissue, but by specialized bone forming tissue so that, under
favorable circumstances, the bone is restored nearly to normal.
 Structure of bone

• Bone is composed of calcified osteoid tissue, which consists of

collagen fibers embedded in a mucoprotein matrix (osteomucin).
• Depending on the arrangement of the collagen fibers, there are two
histological types of bone:
• Woven, immature or non-lamellar bone.
• This shows irregularity in the arrangement of the collagen bundles and
in the distribution of the osteocytes. The osseomucin is less abundant
and it also contains less calcium.
• Lamellar or adult bone. In this type of bone, the collagen bundles are
arranged in parallel sheets.
Stages in Fracture Healing (Bone Regeneration)

• Stage 1: Haematoma formation. Immediately following the

injury, there is a variable amount of bleeding from torn
vessels; if the periosteum is torn, this blood may extend into
the surrounding muscles. If it is subsequently organized and
ossified, myositis ossificans results.
• Stage 2: Inflammation. The tissue damage excites an
inflammatory response, the exudates adding more fibrin to the
clot already present. The inflammatory changes differ in no
way from those seen in other inflamed tissues. There is an
increased blood flow and a polymorphonuclear leucocytic
infiltration. The haematoma attains a fusiform shape.
 CONT
• Stage 3: Demolition. Macrophages invade the clot and
remove the fibrin, red cells, the inflammatory exudate, and
debris. Any fragments of bone, which have become detached
from their blood supply, undergo necrosis, and are attacked by
macrophages and osteoclasts.
• Stage 4: Formation of granulation tissue. Following this
phase of demolition, there is an ingrowth of capillary loops
and mesenchymal cells derived from the periosteum and the
endosteum of the cancellous bone. These cells have osteogenic
potential and together with the newly formed blood vessels
contribute to the granulation – tissue formation.
 CONT

• Stage 5: Woven bone and cartilage formation. The mesenchymal

“osteoblasts” next differentiate to form either woven bone or cartilage.
• The term “callus”, derived from the Latin and meaning hard, is often used to
describe the material uniting the fracture ends regardless of its consistency.
• When this is granulation tissue, the “callus” is soft, but as bone or cartilage
formation occurs, it becomes hard.
 CONT

• Stage 6: Formation of lamellar bone. The dead calcified cartilage or woven

bone is next invaded by capillaries headed by osteoclasts.
• As the initial scaffolding (“provisional callus”) is removed, osteoblasts lay
down osteoid, which calcifies to form bone.
• Its collagen bundles are now arranged in orderly lamellar fashion, for the most
part concentrically around the blood vessels, and in this way the Haversian
systems are formed.
• Adjacent to the periosteum and endosteum the lamellae are parallel to the
surface as in the normal bone.
• This phase of formation of definitive lamellar bone merges with the last stage.
 CONT

• Stage 7: Remodelling. The final remodeling process involving the

continued osteoclastic removal and osteoblastic laying down of bone
results in the formation of a bone, which differs remarkably little from
the original tissue.
• The external callus is slowly removed, the intermediate callus becomes
converted into compact bone containing Haversian systems, while the
internal callus is hollowed out into a marrow cavity in which only a few
spicules of cancellous bone remain.
***NORMAL AND ALTERED ACID BASES
BALANCE*****
 Normal Acid-Base Balance

• Function;-
– Maintains an equilibrium of the chemical composition (ion) of extra cellular fluid
to provide an optimal environment for cell functioning.
– Acid-base balance is necessary for normal body functioning.
– Uncontrolled alterations in normal acid-base balance can be inconsistent with life.
Illustration
 Hydrogen ion.

– Most precisely regulated ion concentration.

– Normal serum value is 37 – 43 mEq/L.
– Normal extra cellular concentration is essential for normal body function.
– Concentration is determined by types and amount of acids and bases.
– H+ (hydrogen ion) concentration determines the acidity or alkalinity (base) of a
solution.
Illustration
 Electrolytes.

• Substance that dissociates and forms electrically charged ions when mixed with
water.
• Form two types of ions;
– Cations (positively charged )
– Anions (negatively charged).
Illustration
Illustration
Illustration
 Acid.

• Electrolyte that forms hydrogen ion and anions in water.

• Hydrogen ion donor
• Increases H+ concentration of a solution.
Illustration
 Weak acid.

– Partially ionizes in water.

– Does not freely give up all its H+.
– H2 CO3 ( carbonic acid). Weak acid.
 Strong acid.

– Completely ionizes in water

– Liberates H+ readily.
– HCL (hydrochloric acid) Strong acid.
 Base.

• Substance that can bind hydrogen ions.

– Alkali. Substance that contains a base.
– Hydrogen ion acceptor.
– Lower s H+ concentration of a solution.
 CONT

• Weak base.
– Binds less readily with hydrogen ion.
– Bicarbonate ion. Weak base.
• Strong base.
– Binds readily with the hydrogen ion.
– Hydroxyl (OH) ion. Strong base.
• PH and Hydrogen ion.
• pH is a chemical shorthand symbol that indicates the hydrogen. Ion (H+)
concentration of a solution. Negative relationship;
– As the H+ concentration increases ----, the pH decreases. H+ = Ph
– As the H+ concentration decreases ……, the pH increases.
Illustration
Illustration
 CONT

• Numerical values.
• pH is between 0 and 14.
• pH 7 is neutral hydrogen.
– The number of hydrogen (H+) ions is balanced with an
equal number of hydroxyl (OH) ions.
• pH 0- 7 indicates acid solutions.
• Ph 7-14 indicates alkalotic (base) solutions.
• PH 7.35 – 7, 45 is the normal range of blood Ph.
– Normal blood pH is slightly alkaline.
– Blood pH below 7.35 indicates acidosis.
– Blood pH above 7.45 indicates alkalosis.
• pH 6.8-7,8 is compatible with life.
CONT
 CONT
• Hydrogen sources.
– Cellular metabolism produces acids. Two types pf acid—
volatile and nonvolatile.
– Acids produced are hydrogen ion donors.
– Body must eliminate excess H+ ion to maintain normal
pH.
• Metabolism. Volatile and Nonvolatile Acids.
• Volatile acids.
– An acid that can be excreted from the body as a gas.
– Carbonic Acid.
– Volatile acid produced by cellular metabolism.
– Lungs excrete carbon dioxide to decrease carbonic acid in
the body
– H2CO3-------- CO2 + H.2
Illustration
 CONT
• Nonvolatile acids.
– A fixed acid can not b eliminated from the lungs and must
be eliminated by the kidney.
– Types. All body metabolic acids except carbonic acid. They
include
• sulfuric acid,
• lactic acid,
• phosphoric acid,keto acids, and inorganic and organic
acids.

• Regulation of Body Fluid Ph.

• Chemical buffers.
– Mixture of two chemicals that minimize changes in the PH
of a solution when either an acid or a base is added.
Consists of a weak acid or weak base paired with a fully
ionized salt.
 CONT

• Function.
– Maintains PH of body fluid by reacting quickly with added acids or bases
to minimize changes in the Ph .
– Converts strong bases into weak bases, increasing H+ ion concentration.
• Reaction time.
– React immediately.
– Short acting. Once reactions occurs, they are used up.
– Unable to maintain pH over prolonged periods of excess acid or base.
 CONT

• Major buffer systems.

• Bicarbonate buffer system.
– Most important extra cellular buffer system
– Can be regulated by lungs and kidneys.
• The lungs excrete or retain carbon dioxide as needed.
• The Kidneys excrete or retain bicarbonate as needed.
• Consists of H2CO3 (carbonic acid and HCO3 (bicarbonate in
the same solution.
• The ratio of carbonic acid to bicarbonate must be maintained
at 1 acid to 20 bicarbonate for pH to be constant.
– If the amount of carbonic acid increases in the same ratio as
the bicarbonate, the pH will remain constant.
– Two parts to 40 parts bicarbonate = 2;20 ratio
Illustration
 CONT
• Phosphate buffer system.
– Important buffer system of the intracellular fluid.
– Similar to the bicarbonate buffering mechanism
• Protein buffer system.
– Buffer system of the intracellular fluid and plasma
– Hemoglobin, a protein buffer of the red blood cell,
maintains pH balance by affecting the chloride shift.
– CL- shifts in and out of the red blood cells depending on
the blood plasma level of oxygen. Each CL- ion that leaves
the cell is replaced by a HCO3 – ion.
• Respiratory regulation of plasma PCO2.
• Function.
• To maintain pH by controlling the partial pressure of carbon
dioxide PCO2 in the arterial blood.
• Partial pressure of a gas = pressure exerted by that gas in a
mixture of other gases.
 CONT

• PCO2 arterial blood is 38 – 42 mm Hg.

• Process.
– CO2 produced by cellular metabolism combines with H2O
to form carbonic acid.
– CO2 + H2O……….h2co3
– Transported to lungs through plasma.
– CO2 + H20 is excreted from alveoli into the atmosphere.
– When there is increased acid in the body, the respiratory
rate increases to remove the excess CO2.
– Acid = RR = CO2 removal = PCO2 = balance
– When there is decreased acid in the body, the respiratory
rate slows and deepens to build up carbonic acid level.
– Acid = RR = CO2 removal = PCO2 = ratio of acid to
base balanced.
 CONT

• Reactions.
– Response in 20 – 30 minutes.
– Quickly shifts blood pH toward normal
• Regulation of the plasma HCO3
• Function.
– Maintains acid – base balance by regulating bicarbonate
level and execrating nonvolatile H+
• Renal control processes.
• Resorption of the filtered bicarbonate.
– Primary mechanism in renal regulation.
 CONT

• Bicarbonate ions are selectively resorbed back into plasma from the renal
tubules.
– H2CO3 dissociates into H+ and Hco3.
– Na+ is reabsorbed from urine filtrate to exchange places with H+.
• H+ joins with HCO3 to form NaHCO3 and reenters the extra cellular fluid.
– H+ is excreted in urine.
• Increased resorption of HCO3 will maintain acid- base balance.
CONT
 CONT

• During an excess of H+ ions a decrease in HCO3 ions

excretion of intractable acid.
– Titratable acid. Secreted H+ that combines with buffers in
the tubular fluid and is excreted in urine.
– Most common buffer. Phosphate buffer HP04.
– Increased removal of H= ions will maintain acid – base
balance during an excess of H+ ions on a decrease in
bicarbonate ions.
• Excretion of ammonia.
– Renal tubules synthesize ammonia NH3 from amino acids.
– Combine with excess H+ ions excreted by renal tubules.
– The formed NH4 + joins with anions, CL – OR SO4 - , and
together they are excreted in the urine.
 CONT

– Able to eliminate large amounts of H+ ions from the body.

• Reaction time.
– Slower than chemical buffer or respiratory regulation.
– More complete compensation for acid-base imbalance. It can neutralize any
excess or base and eliminate it from the body.
 Altered Acid – Base Balance.

• Acidosis. An increase in the H+ concentration of body

fluids above normal levels or a decrease in the HCO3 –
below normal.
– pH below 7.35.
– Cause can be respiratory or metabolic alterations.
• Alkalosis. A decrease in the H+ concentration of body
fluids below normal levels or an increase in the HCO3
level.
– Ph above 7.45.
– Cause can be respiratory or metabolic alterations.
Normal blood gas values.
• Arterial blood is utilized for assessing acid-base balance.
Illustration
Illustration
 CONT

• Normal arterial blood gas values.

– Ph; 7.4.
– Pco2; 35-45mm Hg pressure.
– HCO3 - ; 24 mEq/L.
Etiology of Acidosis and Alkalosis.
• Respiratory acidosis.
– A condition in which there is increased carbonic acid level
caused by retention of carbon dioxide through
hypoventilation.
– Cause. Hypoventilation due to the following;
– Obstructive lung disease (e.g., emphysema)
• Emphysema.
• Asthma.
• Ateleclasis.
Illustration
Illustration
Illustration
 CONT

– Pulmonary fibrosis.
– Impaired neuromuscular function and chest movement
(e.g., kyphoscoliosis).
– Decreased activity of the respiratory center ( medulla) (e.g.,
narcotics).
• Symptoms.
– Respiratory system include cyanosis, shallow breathing,
and dyspnea.
– Neuromuscular system include disorientation, headache,
and blurred vision.
– Cardiac system include tachycardia, dysrhythmias, and
hypotension.
 CONT

• Lab values.
– pH ^ 7.35.
– PCO2 ^ 45mm Hg pressure.
– (HCO3 - ) unchanged.
• Respiratory alkalosis.
• A condition in which there is a decreased carbonic acid level
caused by an excessive amount of carbon dioxide exhaled due
to hyperventilation.
• Causes.
– Hyperventilation (e.g., anxiety).
– Increased respiratory center activity (e.g., fever).
 CONT

• Symptoms.
• Neuromuscular system include;
– Light headedness, altered consciousness, and convulsions.
– Parenthesis, twitching. And hyperreflexia.
– Positive Chvostek’s sigh and Trousseau’s sign.
• Lab values.
– pH ^ 7.45 .
– Pco2^ 35 mm Hg pressure.
– (HCO3 - ) unchanged.
 CONT

• Metabolic acidosis.
• Condition in which there is either an abnormal accumulation
of fixed acids or a loss of base.
• Cause.
• Renal insufficiency.
– Unable to excrete fixed acids adequately.
– Unable to retain adequate bicarbonate to balance the acid –
base ratio.
• Overproduction of metabolic acid.
– Diabetes mellitus. Increased production of keto acid due to
incomplete oxidation of fats.
– Hyperthyroidism, high fever, and trauma accelerate
metabolism.
 CONT

• Increased acid ingestion/production.

– Acetylsalicylic acid.
– Paraldehyde.
– Methyl alcohol.
– Ammonium chloride.
• Anaerobic metabolism. Increased lactic acid (e.g., strenuous
exercise, shock, or anemia).
• Increased loss of base (e.g., diarrhea, and prolonged vomiting).
 CONT

• Symptoms.
– Neuromuscular system include disorientation, weakness,
stupor and coma.
– Respiratory system include Kussamaul’s breathing and
deep, rapid respirations.
– Lab values.
• PH < 7.35.
• [ HCO3- ] < 22 mEq/L.
 CONT

• Metabolic alkalosis.
• A condition in which there is an abnormal increase in the base (HCO3 - ) or a
decrease in the H+ ion concentration.
• Causes.
– Ingestion of sodium bicarbonate (baking soda).
– Intravenous administration of sodium bicarbonate during cardiac arrest.
– Vomiting gastric contents. Loss of H+ and CL-.
– Diuretics (thiazide).
 CONT

Symptoms.
– Neuromuscular system include agitation, weakness, light – headedness, cramps
and convulsions.
– Respiratory system include shallow, slow respirations and apnea.
– Lab values.
• p H > 7.45.
• [ HCO3 - ] > 26 mEq/L.
 CONT

• Effects of Ph changes on Potassium, Calcium and Magnesium

Balance.
• Potassium imbalances.
• Kidneys regulation.
– Excessive H+ cation is exchanged for K+ cation in the
kidneys.
– Excessive H+ is excreted and K+ retained.
– Increased K+ produces hyperkalemia.
• Chemical buffer regulation.
– H+ is buffered intracellularly.
– Increased K+ cation exchanges with excessive H+ cation in
the cell.
– Increased K+ in extra cellular fluid produces
hyperkalemia.
• . Acidosis = hyperkalemia
Illustration
 CONT

• Alkalosis. Decreased H+ ion or increased base.

• Kidney regulation.
– More H+ cation is retained to balance the decrease.
– More K+ cation is excreted in the kidneys.
– Decreased K+ produces hypokalemia.
• Chemical buffer regulation.
– More H+ cation moves from within the cell to extra cellular
fluid.
– More K+ cation is held intracellularly.
– Decreased K+ in extra cellular fluid produces hypokalemia.
– Alkalosis = hypokalemia.
 CONT

• Calcium imbalances.
• Acidosis.
– Causes increased release of Ca+ fom plasma proteins.
– Increased Ca+ in extra cellar fluid produces hypokalemia.
– Alkalosis = hypocalemia.
 CONT

• Magnesium Imbalances
– Acidosis = hypomagnesaemia.
– Alkalosis = hypomagnesaemia.
– Acidosis pH
– ↓K ↓K
– ↓Ca ↓Ca
– ↓Mg ↓Mg
 CONT

• Compensation.
• Correction of abnormal arterial PH.
• The disease or disorder causing alteration in pH is corrected.
– Respiratory acidosis correction. Eliminates the cause pf the
hypoventilation.
– Respiratory alkalosis correction. Eliminates the cause of the
hyperventilation.
– Metabolism acidosis correction. Eliminates the cause of the
increased acid or decreased base.
– Metabolic alkalosis correction. Eliminates the cause of the
decreased H+ ion level.
 CONT

• Compensation.
• Physiologic adjustments made by systems not responsible for
the acid-base imbalance.
• Respiratory acidosis (high PCO2 ).
– The kidneys are the major compensatory mechanism.
– The kidneys retain increased bicarbonate HCO3 - , above
26 mEq/L.
– Increased HCO3 balances the ratio of HCO3 to H=.
– PCO2 + HCO3 = normal Ph.
– Ph returns to normal level..
Illustration
 CONT

• Respiratory alkalosis (low PCO2 ).

– The kidneys are the major compensatory mechanism.
– The kidneys excrete more bicarbonate.
– Decreased bicarbonate HCO3 – 22 mEq/l balances the acid-base ratio.
– PCO2 + HCO3 - = normal Ph.
 CONT

• Metabolic acidosis (low HCO3 - ).

– The respiratory system is the major compensatory
mechanism.
– Hyperventilation increases removal of carbon, dioxide.
– HCO3 – is balanced with CO2 (35 mm Hg ) and the acid-
base ratio is maintained.
– pH returns to normal.
• Metabolic alkalosis (increased HCO3 – or decreased H+
Ions ).
– The respiratory system is the major compensatory
mechanism.
– Hypoventilation increases retention of carbon dioxide.
– HCO3 - + H+ = normal acid-base ratio.
CONT
CONT
 CONT

• X. Interpretation of blood Gas Data

• A. Arterial pH.
– Indicates acidosis or alkalosis.
– Normal ph is 7.35-7 .45.
– pH < 7.35 = acidosis.
– pH > 7.45 = alkalosis.
– Compensated acid-base imbalance have pH levels near
normal.
 CONT

• Arterial PCO2 and HCO3 concentration.

• Indicates;
– Metabolic or respiratory cause of imbalance.
– Compensatory mechanism.
• Normal PCO2 is 35-45 mm Hg.
• Normal HCO3 IS 22-26 mEq/L.
• C. Step to interpret lab data.
• 1. Determine if pH indicates;
• a. Acidosis.
• b. Alkalosis.
• c. Compensated acidosis or alkalosis.
• 2. Determine if the PCO2 level is above or below the normal level.
• 3. Determine if the HCO3 level is above or below the normal level.
 CONT

• Examples pf lab data interpretation.

• Case 1—Respiratory acidosis.
– pH; 7.32 Decreased acidosis
– pCO2; 52 mm increased respiratory
– HCO3; 24 mEq/L normal
• Case 2—Respiratory acidosis Compensated
– pH; 7.35 near normal acidosis compensated
– pCO2; 50mm increased respiratory
– HCO3; 36 mEq/L increased kidney compensated
– Resorb HCO3
 CONT

• Case 3—Respiratory alkalosis.

– pH; 7.51 increased alkalosis
– pCO2; 32 mm decreased respiratory
– HCO3; 24 mEq/L normal
• Case 3—Respiratory alkalosis Compensated.
– pH; 7.45 mear normal alkalosis, compensated
– pCO2; 30mm decreased respiratory
– HCO3; 18 mEq/L decreased kidney compensation
– excrete more HCO3
 CONT

• Case 5--- Metabolic Acidosis.

– pH; 7.30 decreased acidosis
– pCO2; 38 mm normal
– HCO3; 16 mEq/L decreased metabolic
• Case 6---Metabolic Acidosis Compensated.
– pH; 7.40 near normal acidosis, compensated
– pCO2; respiratory compensation,
– lower PCO2- CO2
– execration
 CONT

• Case 5--- Metabolic Acidosis.

– pH; 7.30 decreased acidosis
– pCO2; 38 mm normal
– HCO3; 16 mEq/L decreased metabolic
• Case 6---Metabolic Acidosis Compensated.
– pH; 7.40 near normal acidosis, compensated
– pCO2; respiratory compensation,
– lower PCO2- CO2
– HCO3; 20 mm metabolic
execration
 CONT

• Case 7---Metabolic Alkalosis.

– pH; 7.50 increased alkalosis
– pCO2; 38 mEq/L normal
– HCO3; 38 mEq/L increased metabolic
• Case 8—Metabolic Alkalosis Compensated.
– pH; 7.40 near normal alkalosis compensated
– pCO2; 50 mm increased respiratory
– compensation, retain
– more CO2
– HCO3; 38 mEq/L increased metabolic
 CONT

• The Anion Gap.

– The difference between the cation concentration (sodium)
and the sum of the measured anions (CI- and HCO3 ).
– The difference indicates the extra cellular concentration of
other anions, phosphates, sulfates, organic acids and
proteins.
• Function.
– Used in the differential diagnosis of metabolic acidosis.
• Normal anion gap value.
– 12 + 4 mEq/L.
– 16 + 4 mEq/L if K is used in the computation of cations.
 SHOCK

• A condition in which there is an overall.

• Generalized reduction of adequate blood flow throughout the vasculature of the body.
• There is compromised or inadequate tissue and organ perfusion (low cardiac output).
• Which may result in multisystem deterioration and related loss of function
 Stages of shock

• Non-progressive shock. In the early phase. Many

compensatory mechanisms are activated in response to the
initial insult.
– Decreased tension on the stretch receptors (bar receptors
located in the aortic arch and carotid sinuses) stimulates the
automatic nervous system.
– Total peripheral resistance is decreased through
vasoconstriction.
– cardiac output is increased by sympathetic inhabitation of
vagal tone.
– ADH is secreted, causing water conservation and arterial
vasoconstriction.
 CONT

• The rennin-aniotensin-aldosterone system (RAA system) is

activated in response to low renal perfusion.
• Through a series of response, total peripheral resistance and
circulating intravascular fluid volume are increased.
 Clinical manifestations.

• General appearance. The person is awake but anxious. My complain of

thirst.
• Skin. Pale, moist and cool (due to vasoconstriction).
• Lungs. Shallow respirations,tachypnea.
• Heart. Elevated heart rate; normotensive.
• Genitourinary system. Reduced urinary output due to decreased renal
perfusion and ADH and aldosterone activity.
• Gastrointestinal system. Hypoactive bowl sounds due to vasoconstriction
and a decrease in blood flow to nonessential organs such as the
intestines.
 CONT

• Course.
• Usually either resolves in a few hours or progresses.
• Progressive shock. Uncompensated shock in which
compensatory mechanisms fail to restore blood volume and
tissue perfusion leading to deterioration in the clinical picture.
• Effects on organisms.
– Oxygen deprivation causes the modularly vasomotor center
to decrease its activity.
– Heart. The myocardium begins to fail, due to inadequate
coronary perfusion and its attempt to maintain cardiac
output. Lactic acid is released in response to oxygen
deprivation and is a potent depressor of myocardial
contractility.
 CONT

– Kidneys. Continuing effects of sympathetic

vasoconstriction may lead to acute tubular necrosis
secondary to ischemia and renal failure.
– Ischemic deterioration in lung tissue may progress to adult
respiratory distress syndrome, or shock lung.
– Gastrointestinal system. Ischemia in the gastrointestinal
tract causes the release of end toxins (vasodilating
substances). Which may further compound shock. Liver
function deteriorates.
 CONT

• Clinical manifestations include those findings associated with

shock, as well as severe laryngeal spasm, edema, and
bronchoconstriction, which may precede respiratory arrest.
• Clinical manifestations are related to organ failure
– General appearance. Decrease in level of consciousness.
– Skin. Cold, ashen, and diaphoretic.
– Lungs. Tachypnea with dyspnea.
– Heart. Progressive bradycaedia and hypotension with the
development of pulmonary and peripheral edema. Central
venous pressure and pulmonary artery pressures are
increased.
– Kidneys. Urinary output ceases.
• Course. Recovery depends on the underlying condition and
the effectiveness of therapeutic management.
 CONT

• Irreversible shock. The final progression, at which the

individual becomes unresponsive to all therapeutic
interventions and dies.
• Classifications of shock.
• Hypovolemic shock.
– A shock state resulting from a decreased circulatory fluid
pressure/volume.
– Cause. Hypovolemic shock is caused by any condition that
significantly depletes normal volumes of whole blood,
plasma, or water.
– Pathogenesis. A decreased volume causes a decrease in
venous return, a decrease in cardiac output, and a
consequent lowering of blood pressure, which may
eventually lead to shock.
 CONT

• Course. Shock is resolved if the underlying mechanism that initially reduced the
blood volume is treated and corrected. It may progress to the irreversible stage.
• Various forms include the following.
• Hemorrhagic shock. Hemorrhagic shock occurs as a result of massive up to 45% of
the total volume) loss of whole blood 9 e.g., gastrointestinal bleeding, postoperative
hemorrhage).many humoral substances are released, causing many complex
mechanisms.
 CONT

• Dehydration.
– Extensive and profound loss of body fluid (e.g., profuse
sweating; extensive gastro-intestinal fluid loss related to
diarrhea, vomiting).
– Fluid loss diminishes vascular volume, blood pressure falls,
and tissue and organ perfusion declines.
• Burns.
– Burns especially third-degree burns, cause hypovolemic
shock.
– Loss of plasma proteins decreases colloidal osmotic
pressure, causing water to leave the vascular space and
enter the interstitium.
– Intravascular volume decreases and progresses, as
previously described, to shock.
 Cardiagenic shock.

• A shock state directly attributable to impaired or compromised cardiac output

due to pump failure or decreased venous return.
• Clinical manifestations and diagnosis.
• Criteria for the diagnosis of caediogenic shock have been established by the
myocardial Infarction Research units (MIRU) of the National Heart, Lung, and
Blood Institute (NHLBI).
• Cardiogenic shock is characterized by the following.
– Systolic arterial pressure less than 90 mm Hg or 30 to 60 mm Hg below the
previous baseline level.
 CONT

• Evidence of decreased blood flow to major organ systems;

– Urine output less than 20ml/hour, usually with decreased
sodium content.
– Peripheral vasoconstriction associated with cold, clammy
skin.
– Impaired mental function.
• Cardiac index less than 2.1 leters/(minute/m2) (cardiac output
in liters per minute per square meter of body surface area.).
• Evidence of left-sided heart failure with LVEDP/PCWP
greater than 18 to 21 mm Hg.
 CONT

• Course treatment may preclude it development.

• If shock is related to myocardial infarction, the prognosis is
related to the extensiveness of the infarct.
• Vasogenic shock.
– A shock state attributable to profound and massive
vasodilatation related to vasomotor center depression.
Sepsis, and anaphylaxis.
– Pathogenesis. Blood volume itself is not actually reduced,
but rather the circulatory capacity to accommodate that
volume is increased.
 CONT

• Sequence of events.
– There is a profound relaxation of total peripheral resistance,
resulting in a decrease in blood volume returning to the
heart. The larger the vessel diameter, the less forceful,
therefore slower, is the blood flowing through it.
– There is decreased filling pressure in the chambers,
decreasing the stretch of heart muscle fiber (Frank-Starling
law;
– This decrease in preload lowers stroke volume, impairing
perfusion to those tissues and organs which were already
affected by vasodilation.
• Clinical manifestations include those related to hypotension
and shock.
• Course. Many of the compensatory mechanisms normally.
Restorative in shock are inadequate, due to the nature of the
primary defect.
 CONT

• Neurogenic shock.
• A vasogenic shock state resulting from loss of vasomotor tone that induces
generalized arteriolar and venous dilation. This leads to hypotension and the
pooling of blood.
• Causes.
– Conditions that depress modularly function or spinal cord integrity and
intervention (the normal mediators of vasomotor tone ) may precipitate
neurogic shock (e.g., deep general anesthesia, drug overdose, and head
trauma ).
– Spinal cord injury or high spinal anesthesia results from interference of
sympathetic pathways to blood vessels promoting vasodilatation.
 CONT

• Septic shock.
• A vasogenic shock state in which there is a severe and
profound condition pf generalized vascular collapse secondary
to a systematic infection.
• Pathogenesis.
– Gram-negative organisms (viruses,fungi,and gram-positive
bacilli0 release endotoxins from the bacterial cell wall.
– Gram-positive organisms (Escherichia coli, Klebsiella sp. )
produce exotoxins, causing exotoxic shock.
 CONT

• Sequence of events.
– In extreme infections, the release of large quantities of endotoxins overwhelms
the defense system.
– Once liberated into systematic circulation, endotoxins trigger and promote the
activation of noxious substances such as histamine, lysosomal enzymes,
bradykinnis, and serotin, compromising capillary wall integrity.
– Plasma leaks through the damaged capillaries, producing marked fluid volume
loss resulting in hypotension.
– Release of lactic acid further depresses myocardial contractility and total
peripheral resistance.
 CONT

• Stages of septic shock.

– Hyper dynamic stage. This stage presents with chills, fever,
and warm, dry, flushed skin.
– Tachycardia, tachypnea, with respiratory alkalosis, and
some alteration in blood pressure occur.
– Cardiac output I high( heperdynamic) due to an intact and
functional compensational sympathetic response to
decreased peripheral resistance.
– Normodynamic stage. A transitional period between the
first and third stages. Endotoxin liberation manifests itself
by symptoms of hypotension. Tachycardia persists in an
attempt to restore blood pressure.
– Hypo dynamic stage is similar to the irreversible state of
hemorrhagic shock.
– The person is acutely ill, and survival is doubtful.
 CONT

• Anaphylactic shock (anaphylaxis).

– A shock state in which there is a drastic and profound
peripheral vascular collapse occurring in only a few
minutes.
– Without immediate treatment, irreversible shock develops
and death occurs in an hour or so.
– The shock state develops as a result of profound
vasodilatation and low cardiac output secondary to a central
fluid volume deficit.
– This results from increased capillary permeability and
peripheral pooling of blood.
– Compensatory mechanisms are usually not adequate to
reverse such a rapid form or shock.
EDEMA FORMATION

WILSON A.L
 EDEMA

• Oedema is the abnormal collection of fluid in the tissues, which can occur in the interstitial or intracellular spaces.
• It can be the result of two processes;
– An increase in hydrostatic pressure
– Reduced oncotic pressure (oncotic pressure is osmotic pressure exerted by proteins).
 Pathogenesis of edema

• Edema occurs due to increased vascular permeability.

• In the early phase of inflammation, arteriolar vasodilation and increased volume of
blood flow lead to a rise in intravascular hydrostatic pressure,
• Resulting in movement of fluid from capillaries into the tissues.
• This fluid is called a transudate, and is essentially an ultrafiltrate of blood plasma that
contains little protein.
 CONT

• Transudation is soon eclipsed by increasing vascular permeability that allows

the movement of protein-rich fluid and even cells (called an exudate) into the
interstitium.
• The loss of protein-rich fluid into the perivascular space reduces the
intravascular osmotic pressure and increases the osmotic pressure of the
interstitial fluid.
• The net result is outflow of water and ions into the extravascular tissues.
• Fluid accumulation in extravascular spaces is called edema.
• Whereas exudates are typical of inflammation, transudates accumulate in
various non-inflammatory conditions
 Factors that cause edema formation

• The balance between filtration and absorption can be altered as a result of everyday
occurrences or as part of a disease process.
• Increase in hydrostatic pressure
– Oedema forms when there is an increase in hydrostatic pressure either at the
arterial end of the capillary or at the venous end.
– This raises the pressure of blood in the capillary and causes an increase in the rate
of filtration, precipitating edema.
 CONT
• Immobility
– When a person stands up, capillary hydrostatic pressure
increases in the lower parts of the body because the column
of blood raises hydrostatic pressure in the lower arteries
and veins.
– When someone stands very still the problem is exacerbated
because the inactivity minimises the action of the skeletal
muscle pump, causing pressure in the lower veins to rise
further, owing to venous pooling, in turn augmenting an
increase in capillary hydrostatic pressure.
• Hypertension –
– When blood pressure increases, the individual is at risk of
developing oedema, as the increase in blood pressure is
reflected through the circulatory system at the capillaries as
the hydrostatic pressure.
– As such, this increases filtration and reduces absorption
processes.
 CONT
• Peripheral vascular disease
– When the pressure increases in the legs as a result of PVD-
leading to oedema and serious swelling of the legs.
– An increase in swelling can lead to hypoxic cell damage or
stimulation of the inflammatory response.
• Heart failure –
– The pressure can increase in either the systemic veins or
pulmonary veins, depending on which side of the heart is
affected.
– Failure of the left ventricle will cause pressure to rise in the
pulmonary veins and can lead to oedema formation in the
lungs, known as pulmonary oedema.
– Right-sided heart failure (complete heart failure) is
characterised by a rise in hydrostatic pressure in the vena
cava and other systemic veins.
– This tends to cause oedema in systemic tissues, and
oedema will form in areas such as the wrists and ankles.
 CONT

• Renal failure
– Certain types of damage to the kidneys will interfere with
their ability to eliminate excess water and solutes into
urine, resulting in build up of excess fluid in the body.
– Blood volume increases and blood pressure rises
throughout the cardiovascular system.
– The increase in pressure raises capillary hydrostatic
pressure, in turn increasing filtration and decreasing
absorption processes, leading to oedema.
• Reduced oncotic pressure
– Edema also forms when there is a reduction in plasma
proteins in the extracellular fluid.
– Any condition that leads to a reduction in plasma proteins
will promote changes in capillary absorption
 CONT

• Liver failure
– The liver manufactures plasma proteins.
– Liver damage can cause plasma protein concentration to decrease, lowering
plasma oncotic pressure.
– This can lead to formation of ascites.
• Renal disease
– Kidney damage can increase elimination of plasma proteins in the urine -
nephrotic syndrome.
– This loss of protein triggers a reduction in capillary absorption because of the
drop in plasma oncotic pressure.
 CONT

• Malnutrition –
– Malnutrition causes inadequate amounts of proteins to be digested through the
gastrointestinal tract.
– If the malnourished state is allowed to continue, the proteins stored in the body
are broken down by the liver and used as a source of energy to maintain cellular
and organ function.
– This leaves inadequate amounts of protein in the plasma to produce effective
plasma oncotic pressure.
 CONT
• Inflammatory response
– Oedema can occurs with tissue injury as well as when there
is an infection.
– Their pathogenesis varies.
– The tissue injury leads to cellular changes, which cause a
severe inflammatory response that ends with repair to
damaged cells and tissue.
– Following damage, the injured endothelium releases
mediators and stimulates the clotting cascade.
– The mediators of inflammation are histamine, kinins,
prostaglandins, complement and the cytokines.
– They act as a signalling system - chemotaxis - to attract
nutrients, fluids, clotting factors and neutrophils and
macrophages to the damaged site.
– The mediators cause a localised increase in capillary
permeability, leading to swelling, oedema, redness, heat
and pain - classic signs of inflammation.
 CONT

• The tissue swelling observed in inflammation occurs due to a

reversal of normal capillary absorption processes.
• This is because the damaged capillaries and injured tissues
release mediators, allowing protein-rich fluid to leak out from
the plasma into the interstitial fluid.
• As a result, the concentration of proteins in the interstitial fluid
rises to a greater level than in the capillaries, increasing
oncotic pressure in the tissues.
• In this way absorption occurs outward - from the plasma into
the interstitial space - resulting in edema.
 CONT

• Lymphatic obstruction
– The lymphatic system normally absorbs interstitial fluid and the few proteins that
normally pass across the capillary membrane.
– When the lymphatic channels are blocked by infection or neoplasms, or are
surgically removed, proteins and fluid accumulate in the interstitial space.
– For example, lymphoedema of the arm or leg occurs after surgical removal of
axillary and femoral lymph nodes for treatment of carcinoma.
 Intracellular oedema

• Occurs due
– Hypoxic injury, when the blood flow falls below a certain
critical level required to maintain cell membrane viability.
– Swelling from interstitial oedema becomes so great that it
cuts off blood supply.
• In this instance, the interruption in the supply of oxygenated
blood to cells can result in cellular changes, which in turn can
stimulate the inflammatory response.
 CONT

• Intracellular oedema can also occur as a result of:

– Generalised ischaemia (hypovolaemia)
– Ischaemia of an organ (acute tubular necrosis, myocardial
infarction)
– Breakdown in skin integrity (pressure ulcers).
• The above will all lead to hypoxic injury.
• The consequence of the interrupted supply of oxygenated
blood to cells results in:
– Anaerobic metabolism and reduced stores of adenosine
triphosphate (ATP), a substance that releases energy when
it is broken down
– Cellular membrane disruption, which causes sodium and
water to move into the cell.
 Review questions

• List the five Rs of the inflammatory response.

• State the three steps of phagocytosis.
• List and briefly describe the four possible outcomes of acute inflammation.
• Differentiate between acute and chronic inflammation.
• Differentiate between first and second intention in wound healing.
NEOPLASM

WILSON A.L
 NEOPLASM

• "new growth."
• Abnormal mass of tissue,growth of which exceeds and is uncoordinated with
that of the normal tissues and persists in the same excessive manner after the
cessation of the stimuli which evoked the change.
• Common medical terms, a neoplasm is often referred to as a tumor,
• Study of tumors is called oncology (from oncos, "tumor," and logos, "study
of").
 CONT

• Neoplasia = new growth

• Neoplasm = tumor
• Tumor = swelling
• The study of tumors = Oncology
– Oncos = tumor + ology = study of
 Definition

– is an abnormal mass of tissue,

– the growth of which is uncoordinated with that of normal tissues,
– and that persists in the same excessive manner after the cessation of the
stimulus which evoked the change“
– With the loss of responsiveness to normal growth controls

– Different from hyperplasia, metaplasia and dysplasia.

399
 CONT

• Neoplastic cells are altered from normal cell behaviour because they
continue to replicate, irrespective of the regulatory influences that
control normal cell growth.
• Neoplasms enjoy autonomy and increase in size regardless of their
local environment and nutritional status of the host.
• Depend on host for their nutrition and blood supply.
• Some require endocrine support, and such dependencies can be
exploited to the disadvantage of the neoplasm.
• Division of neoplasms into benign and malignant categories.
• Based on a judgment of a neoplasm's potential clinical behavior.
 Regulation of Cell division

• Cells normally differentiate, grow, mature and divide.

• These are regulated processes, balanced in a healthy system such that
cell birth is nearly equal to cell death

401
 CONT

• Regulation of cell division includes:

– Signaling by biochemicals released from one cell that interact with other cells
growth factors or cytokines
– Other external factors , such as contact inhibition
– Genes and internal factors that promote and regulate cell division-genes and
chromosomal factors - telomeres, braking proteins – Rb proteins

402
 Neoplasia Classification

• Benign Tumours
– A tumor is said to be benign when its features show that it will remain localized,
and is amenable to local surgical removal.
– Patient generally survives.
– Can produce more than localized lumps, and sometimes they are responsible for
serious disease.
 CONT

Benign tumors :
– Will remain localized
– Cannot spread to distant sites
– Generally can be locally excised
– Patient generally survives
– grow slowly
– low mitotic rate
– well differentiated
– not invasive; well-defined borders
 Malignant

• Cancer – from Latin for crab

• Grow rapidly;
• High mitotic index,
• Poorly differentiated;
• Do not have a capsule; invade surrounding structures;
• Metastasize from the primary to a secondary site (metastasis).
 Clinical features of tumors

• Benign and malignant tumors can be distinguished on the basis

of;
– Degree of differentiation,
– Rate of growth,
– Local invasiveness,
– Distant spread as shown in the following table
CONT
 Components of a tumor

• All tumors have two basic :

– Parechyma: made up of neoplastic cells
– Stroma: made up of non-neoplastic, host-derived
connective tissue and blood vessels

The parenchyma: The stroma:

Determines the Carries the blood
biological behavior of supply
the tumor Provides support for
From which the tumor the growth of the
derives its name parenchyma
 CONT

• Stroma, made up of;

– Connective tissue,
– Blood vessels,
– Host-derived inflammatory cells.
– Crucial to the growth of the neoplasm, since it carries the blood supply and
provides support for the growth of parenchymal cells
• Parenchyma of the neoplasm largely determines its biologic behavior, and it is this
component from which the tumor derives its name.

409
 Neoplasia Nomenclature

• Generally, benign tumors are designated by attaching the suffix -oma to the
cell type from which the tumor arises.
• A benign tumor arising in
– Fibrous tissue is a fibroma;
– Cartilaginous tumor is a chondroma.
• Nomenclature of benign epithelial tumors is more complex.
• Classified sometimes on
– Basis of their microscopic pattern
– Basis of their macroscopic pattern.
• Others are classified by their cells of origin
 CONT

• Adenoma is applied to benign epithelial neoplasms producing gland

patterns and to neoplasms derived from glands but not necessarily
exhibiting gland patterns.
• Papillomas are benign epithelial neoplasms, growing on any surface,
that produce microscopic or macroscopic finger-like fronds.
• Polyp is a mass that projects above a mucosal surface, as in the gut, to
form a macroscopically visible structure, some malignant tumors also
may appear as polyps.
• Cystadenomas are hollow cystic masses; typically they are seen in the
ovary.
 CONT

• Examples:
– Benign tumor arising in fibrous tissue:
Fibro + oma = Fibroma

Benign tumor arising in fatty tissue:

Lipo + oma = lipoma
 CONT

• Benign tumor arising in cartilage; chondro + oma = chondroma

• Benign tumor arising in smooth muscle; Leiomyo + oma = leiomyoma
• Benign tumor arising in skeletal muscle; Rhabdomyo + oma =
rhabdomyoma
 CONT

• Epithelial benign tumors are classified on the basis of :

– The cell of origin
– Microscopic pattern
– Macroscopic pattern
 CONT

– Adenoma : benign epithelial neoplasms producing gland

pattern….OR … derived from glands but not necessarily
exhibiting gland pattern
– Papilloma : benign epithelial neoplasms growing on any
surface that produce microscopic or macroscopic finger-like
pattern
 CONT

• Polyp : a mass that projects above a mucosal

surface to form a macroscopically visible
structure.
e.g. - colonic polyp
- nasal polyp
 CONT

• Examples :
– Respiratory airways: Bronchial adenoma
– Renal epithelium: Renal tubular adenoma
– Liver cell : Liver cell adenoma
– Squamous epithelium: squamous papilloma
 Malignant tumors:
Nomenclature

• Collectively referred to as cancers, derived from Latin word crab-that is, they
adhere to any part that they seize in an obstinate manner, similar to a crab's
behavior.
• Malignant, as applied to a neoplasm, implies that the lesion can invade and
destroy adjacent structures and spread to distant sites (metastasize) to cause
death.
• Not all cancers pursue so deadly a course.
• Some are less aggressive and are treated successfully, but the designation
malignant constitutes a red flag.
 CONT

• Neoplasms arising in mesenchymal tissue or its derivatives -sarcomas.

• Cancer of fibrous tissue origin-fibrosarcoma,
• Malignant neoplasm of chondrocytes -chondrosarcoma.
• Sarcomas are designated by their histogenesis (that is, the cell type of
which they are composed).
• Neoplasms of epithelial cell origin are called carcinomas.
 CONT

• Epithelia of body are derived from three germ-cell layers;

• Malignant neoplasm in renal tubular epithelium (mesoderm) -carcinoma, as are
cancers in skin (ectoderm) and lining epithelium of the gut (endoderm).
• It is evident that mesoderm may give rise to carcinomas (epithelial) and sarcomas
(mesenchymal).
 CONT

• Carcinomas may be qualified further.

• Carcinomas that grow in a glandular pattern are called adenocarcinomas,
• Those that produce squamous cells are called squamous cell carcinomas.
• Sometimes the tissue or organ of origin can be identified, as in the designation
of renal cell adenocarcinoma or cholangiocarcinoma, which implies an origin
from bile ducts.
 NB
• Sometimes tumor shows little or no differentiation and must be
called poorly differentiated or undifferentiated carcinoma.
• In some instances the tumor cells may undergo divergent
differentiation, creating so-called mixed tumors, example is
mixed tumor of salivary gland.
• These tumors have obvious epithelial components dispersed
throughout a fibromyxoid stroma, sometimes harboring islands
of cartilage or bone.
• All of these diverse elements are thought to derive from
epithelial cells, myoepithelial cells, or both in the salivary
glands, and the preferred designation of these neoplasms is
pleomorphic adenoma.
• Fibroadenoma of the female breast is another common mixed
tumor.
• This benign tumor contains a mixture of proliferated ductal
elements (adenoma) embedded in a loose fibrous tissue
(fibroma).
 CONT

• Multifaceted mixed tumors should not be confused with a teratoma, which

contains recognizable mature or immature cells or tissues representative of
more than one germ-cell layer and sometimes all three.
• Teratomas originate from potential stem cells such as those normally present
in the ovary and testis and sometimes abnormally present in sequestered
midline embryonic rests.
• Such cells have the capacity to differentiate into any of the cell types found in
the adult body and so, not surprisingly, may give rise to neoplasms that mimic,
in a helter-skelter fashion, bits of bone, epithelium, muscle, fat, nerve, and
other tissues.
 CONT

• Some glaring inconsistencies may be noted.

• For example, the terms lymphoma, mesothelioma, melanoma, and seminoma are
used for malignant neoplasms.
• These inappropriate usages are firmly entrenched in medical terminology.
 CONT

– Malignant tumor arising in mesenchymal tissue : SARCOMA

• From fibrous tissue: Fibrosarcoma
• From bone : Osteosarcoma
• From cartilage : chondrosarcoma
 CONT

• Malignant tumors arising from epithelial origin :

CARCINOMA
– Squamous cell carcinoma
– Renal cell adenocarcinoma
– cholangiocarcinoma
 CONT

• Exceptions
• Melanoma ( skin )
• Mesothelioma (mesothelium )
• Seminoma ( testis )
• Lymphoma ( lymphoid tissue )
 CONT

• Based on the biological behavior :

– Benign and malignant
• Based on the cell of origin :
– One neoplastic cell type : lipoma, adenocarcinoma
– More than one neoplastic cell type : fibroadenoma
– More than one neoplastic cell type derived from more than
one germ-cell layer: teratoma
– Derived from embryonic tissue: blastoma (could be
benign e.g. osteoblastoma, or malignant e.g.
neuroblastoma)
 CONT

Hamartoma: a mass composed of cells native to the organ

e.g. pulmonary hamartoma.
Choristoma: a mass composed of normal cells in a wrong
location e.g. pancreatic choristoma in liver or stomach.
• Malformation and not neoplasm.
 Genesis of Cancer

• Several cellular control pathways must be altered to produce

cancer:
– Autonomy – proliferate in the absence of external growth
signals
– Autocrine stimulation
– Increase in growth factor receptors
– Post-receptor signal cascade inside the cell stuck in
the “on” position

430
 CONT

• Overcome antigrowth signals:

• Contact with basement membrane, other cells
• Inactivation of tumor suppressor genes or activation of the cyclindependent
kinases that drive the cell
• Prevention of apoptosis

431
 Oncogenes

• Non-mutant state called proto-oncogenes

• Stimulate cell growth and replication when turned “on” by
mutation
• Cause uncontrolled growth

432
 Tumor suppressor genes

• Negatively regulate proliferation-antioncogenes

• Want these to remain intact takes two “hits” to remove both
genes

433
434
 Gene silencing

• Regions of genes normally turned off can spread without

mutation and turn off tumor suppressor genes drugs that
demethylate DNA may turn genes back on

435
 Loss of caretaker genes
Chromosomal instability

436
 Genesis of Cancer
• Angiogenesis
• angiogenic factors or vascular endothelial
growth factor (VEGF)
• possible source of new therapies

437
 Genesis of Cancer
• Telomerase
• Other factors:
• decreased cell-to-cell adhesion
• secretions of proteases
• ability to grow in new locations

438
 Causes of Cancer

• Genetics and cancer prone families

– To be passed down, mutations must occur in germ cells inherited
mutations almost always in tumor suppressor genes these
individuals are targets for cancer screening

439
 CONT

• Viral causes of cancer:

– viruses assoc. with about 15 % of cancers world wide – us. Cervix or liver
– Hepatitis B or C in chronic form
– Human papilloma virus; spread through sexual contactHPV integrates into DNA
and uses viral oncogenes

440
 CONT

• Epstein-Barr and Kaposi sarcoma -both herpes viruses

• Human T cell leukemia-lymphoma virus; blood transfusions,
needles, sex and breast feeding

441
 CONT

• Bacterial causes of Cancer

– Helicobacter pylori infects >1/2 world’s population assoc. with B cell lymphomas
of the stomach
– Treatment with antibiotics can cause regression of lymphoma
– Tumors arise in MALT -MALTomas

442
 Environmental factors

• Tobacco use
• Diet
• Alcohol use
• Sexual and reproductive behavior
• Air pollution
• Occupation hazards – asbestos
• UV radiation and other radiation
• hormones

443
 Gene-Environment Interactions:
• Exposure to environmental agents can cause increased risk
of cancer
• cancer in lab animals – carcinogens
• Comparisons of populations
• genetics vs. lifestyle
• “Genetics loads the gun; the environment pulls the trigger.”

444
 Diagnosis:
Screening procedures and blood tests:
Tumor markers
substances on plasma membranes
in blood, spinal fluid or urine
hormones, genes antigens or
antibodies

445
Markers can be used:
To screen and identify individuals at
high risk
Help diagnose the specific type of
tumor
Follow the course of the cancer

446
 Tumor spread

• Local spread
– Cellular multiplication
• Function of generation time
• Growth if cell reproduction > cell death
• Mechanical invasion
– along path of least resistance
– compresses blood vessels, leading to tissue death and
increased space
447
 CONT

Lytic enzymes
– proteases, collagenases, plasminogen activators, lysosomal
enzymes
– some involved in producing new blood vessels
Decreased cell adhesion
– loss of anchoring molecules allows cancer to slip
between normal cells

448
 CONT

– Increased motility
– essential for metastasis
– intravasation
– extravasation
– may secrete autocrine motility factor
– extend psuedopodia
– three step hypothesis:
– attachment to the matrix
– dissolution of the matrix
– locomotion through the matrix 449
 Staging

• Staging is the extent of spread of the tumour within the body and it can
be assessed in three ways;
– Clinical Examination
– Investigations
– Pathological examination of tissues
• There are two current staging systems:
 TNM staging (Primary Tumour, Nodal Involvement, Distant
Metastases)

• For each of the three components, numbers are added to indicate extent of
involvement:
– T0 to T4: In situ lesion to largest and most extensive primary tumour
– N0 to N3: No nodal involvement to widespread lymph node involvement
– M0 to M2: No metastasis to disseminated haematogenous metastases
 AJC staging (American Joint Committee)

• Takes into account all the components of TNM staging, and divides all cancers into
stage 0 to IV.
– Stage 1 – confined to site of origin
– Stage 2- cancer is locally invasive
– Stage 3 – cancer has spread to regional structures
– Stage 4- cancer has spread to distant sites

452
 Grading

• Grading and staging help to determine prognosis and treatment of malignant

tumours.
• Grading is the macroscopic and microscopic degree of differentiation of a
tumour.
• Gross features like exophytic or fungating appearance are indicative of less
malignant growth, as compared to diffusely infiltrating tumours.
• Grading is based on two histologic features that is,
– Degree of anaplasia
– Rate of growth.
 CONT

• Categorized from grade I-IV:

– Grade I – Well differentiated (<25% anaplastic cells)
– Grade II – Moderately differentiated (25%-50% anaplastic
cells)
– Grade III – Moderately differentiated (50%-75% anaplastic
cells)
– Grade IV – Poorly differentiated or anaplastic (>75%
anaplastic cells)
• Grading is subjective and degree of differentiation may vary
from one section of a tumour to another.
• Tumours are graded in descriptive terms such as;
– Well differentiated,
– Undifferentiated,
– Keratinizing,
– Non-keratinizing
 Patterns of spread: Metastasis

A metastasis grows when:

vascular network is developed
host defenses are evaded
a compatible environment is available
• Direct or continuous extension
• By lymphatics or blood stream
– As clumps or as single cells
– Lymphatics most common

455
 CONT

• Angiogenesis
– Due to production of angiogenic factors
– Due to drop in antiangiogenic factors

456
Distribution and common sites of distant
metastases
• often occurs in the first capillary bed
encountered
•Others show “organ tropism”
•Due to:
•Local growth factors or hormones
•Preferential adherence to the surface
•Presence of chemotactic factors

457
 Clinical manifestations of Cancer

• Pain
– Usually not in early stages
– 60 – 80 % of terminally ill
– Psychogenic, cultural and physiologic components
– Due to pressure, obstruction, stretching, tissue damage or
inflammation

458
 CONT

Fatigue
sleep disturbances
biochemical changes
loss of muscle function

459
 CONT

Cachexia – wasting
anorexia
early satiety
weight loss
anemia
marked weakness
taste alterations
altered metabolism

460
 CONT
Anemia
chronic bleeding
malnutrition
medical therapies
malignancy in blood forming organs
Administer erythropoietin
461
 CONT

Leukopenia and thrombocytopenia

tumor invasion of bone marrow
chemotherapy or radiation

462
 CONT

• Paraneoplastic Syndromes
– Release of hormones by cancer cells
– Hematological complications such as
procoagulation factors
– Causes weakness by attacking neuromuscular
junction (similar to myasthenia gravis)

463
 CONT

• Infection
• most significant cause of complications
and death

• Assignment
• Discuss the Genetic basis of Cancer

464
 Carcinogenic agents

• Carcinogens. substances capable of producing neoplastic

growth.
• They are known to increase the likelihood that exposed
individuals will develop a neoplasm.
• There are three types of carcinogens.
• Chemical carcinogens (eight types).
– Polycyclic aromatic hydrocarbons include tobacco smoke,
exhaust fumes, and products of combustion.
– They may cause cancers of the lip. tongue. oral cavity.
head. neck, larYnX. lungs. and bladder.
 CONT

• Aromatic amines and azodyes include certain foods;

naphthalene (used in some moth repellants and insecticides).
They may cause cancer of the bladder.
• Alkylating agents include nitrogen mustard and mustard gas.
• They may cause leukemia or lymphoid neoplasms.
• Nitrosamines include food converted to nitrosamines gastric
carcinoma.
 CONT

• Naturally occurring products such as Aflatoxin B,

(Aspergillus fLavus) found on corn, barley, peas, milk, and
cheddar cheese, may cause cancer of the nuts may cause
cancer of the oral cavity.
• Several drugs, such as griseofulvin and flagyl, may affect
certain carcinomas as shown in laboratory rats.
– DES may cause cancer of the vagina in female offspring
and testicular cancer in male offspring.
– Alcohol may cause cancers of the mouth, pharynx,
esophagus. larynx, and liver.
 CONT

• Metals such as asbestos, cadmium, chromium. and nickel may

cause cancer of the lung. nasal cavity, prostate, pleural cavity,
and gastrointestinal tract.
• Industrial compounds such as polyvinylchloride (used to
manufacture plastics) may cause angiosarcoma of the liver.
 Physical carcinogens (five types).

• Ionizing radiation from the atomic bomb may cause direct or indirect damage to
DNA. resulting in leukemia.
• Ultraviolet radiation from sun exposure may cause skin cancer.
• Schistosoma haematobium infestations, found in some foreign countries, may cause
squamous cell cancer of the bladder.
 CONT

• Injections of mineral oil into the peritoneal cavity may cause

granulomatous inflammation, which may be followed by
plasma cell tumors.
• Asbestos fibers.
– Cigarette smoking may cause bronchogenic or gastric
carcinoma with continuous exposure.
– Pipe smoking may cause oral cancer.
 CONT

• Oncogenic viruses. Viruses implicated in human cancers.

There are two types.
– DNA. Epstein-Barr vI'rus I'S l' k d In e to Burkitt's
lymphoma and cancer of the nasopharynx.
– RNA.; C-type is linked to certain types of leuk and B-type i
l'nk d emla. . . s 1 e to breast and cervical cancer
• Other: Factors In Carcinogenesis.
• Diet .
– High-fat and low-fiber diets are linked to cancers of the
colon and breast.
– Some food preservatives (e.g., those used for salting
,drying or charring) may increase the risk of stomach
cancer .
 CONT

• Sexualty. cancer.
– Women who become sexually active at an early age or who
have multiple sexual partners are at an Increased risk of
developing cervical cancer.
– This type of cancer is lowest among nuns, virgins, and
jewish women.
– The low incidence among Jewish women. of Jewish men.
may be due to circumcision
– Jewish men, circumcized shortly after birth, have low rates
of cancer of the penis.
– Early menarche, nulli-gravida, or late menopause may
increase the risk of breast cancer in women
 CONT

Habits.
– Heavy drinkers have an increased risk of cancer of the
esophagus.
– Cigarette smokers have an increased risk of lung cancer.
Hormones.
– Increased hormone levels over a period of time may cause
cancer of the breast. endometrium. vagina, prostate,
thyroid, or adrenal cortex.
• Predisposing lesions.
– Fibrocystic disease of the breast may increase the risk of
breast cancer.
 CONT

– Adenomatous colon and rectal polyps may be

precancerous.
– Growth of the Primary Tumor. Tumor growth rate is
affected by blood supply. nutrition, immune
responsiveness, and. in some case, endocrine support.
– Benign tumors grow more slowly than malignant ones.
– A malignant tumor's growth rate correlates with its
differentiation level. The more undifferentiated a tumor, the
greater its growth and dissemination.
– A primary tumor usually grows for years before producing
a palpable or symptomatic mass.
– Each time a cell reproduces, it doubles the tumor mass. A
typical tumor has doubled 30 times before it is clinically
observed.
 Chemical Carcinogens
• More than 200 years ago, the London surgeon Sir Percival Pott
correctly attributed scrotal skin cancer in chimney sweeps to
chronic exposure to soot. Based on this observation, the
Danish Chimney Sweeps Guild ruled that its members must
bathe daily. No public health measure since that time has
achieved so much in the control of a form of cancer.
Subsequently, hundreds of chemicals have been shown to be
carcinogenic in animals.
• Some of the major agents are presented in the table below.
ILLUSTRATION
 Diagnosis

• Diagnosis of tumors can be done

– Clinically,
– Radiological,
– Biochemically
– Microscopic examination.
• Depending on the procedure used to get a sample to be examined,
– Whole lesion,
– Large or small sample
– Few cells may be studied.
 Biopsies for histopathologic assessment

• Biopsies allow for assessment of tissue morphology (appearance of

architecture):
– Excisional Biopsy – small tumors, whole lesion is removed and
examined.
– Incisional Biopsy – Fairly large, representative wedge of tissue is
removed and examined immediately or by frozen section after a day
or so.
– Needle Biopsy – Thin core of tissue is removed, done for many tumors
including deep seated ones under radiological control. Specimen not
representative-potential for sampling error.
 Cytology

• Relies on interpretation of appearance of individual cells, although

degree of cohesion of tumour cells can also be assessed.
• Specimens obtained from body fluids, through fine needle
aspiration.
• Relatively simple, atraumatic and does not require an anaesthetic.
• Deeply located lesions can be sampled under imaging control.
Conventional diagnosis and additional techniques

• Tumor Markers
– Biochemical assays enzymes associated with tumors,
hormones, and other tumor markers in the blood cannot be
utilized for definitive diagnosis of cancer;
– Contribute to finding cases
– Some instances are useful in determining effectiveness of
therapy or the appearance of a recurrence.
– Prostate-Specific Antigen (PSA), a tumor marker, is used to
screen for prostatic adenocarcinoma,
– One of the most used, and most successful, tumor markers
in clinical practice.
– Prostatic carcinoma can be suspected when elevated levels
of PSA are found in the blood.
 CONT

• PSA screening also highlights problems encountered by virtually

every tumor marker.
• Although PSA levels are often elevated in cancer, PSA levels also
may be elevated in benign prostatic hyperplasia.
• Furthermore, there is no PSA level that ensures that a patient does
not have prostate cancer.
• PSA test suffers from both low sensitivity and low specificity.
 Other markers

– Carcinoembryonic antigen (CEA), -evident in carcinomas

of the colon, pancreas, stomach, and breast,
– α-fetoprotein-produced by hepatocellular carcinomas, yolk
sac remnants in the gonads, and occasionally
teratocarcinomas and embryonal cell carcinomas.
– Can be produced by a variety of non-neoplastic conditions
as well hence lack both specificity and sensitivity required
for the early detection of cancers.
– Useful in the detection of recurrences after excision.
– With successful resection of the tumor, these markers
disappear from the serum.
– Reappearance almost always signifies the beginning of the
end.
 Molecular Diagnosis

• Diagnosis of malignancy –
– Each T and B cell has unique rearrangement of its antigen receptor genes,
polymerase chain reaction (PCR) - based detection of T-cell receptor or
immunoglobulin genes allows distinction between monoclonal (neoplastic) and
polyclonal (reactive) proliferations.
– Many blood-based neoplasms, and a few solid tumors, are defined by particular
translocations.
– Diagnosis by fluorescence in situ hybridization (FISH) or PCR can be used to
detect translocations characteristic of Ewing sarcoma and several leukemias and
lymphomas.
– PCR-based detection provides the molecular diagnosis of chronic myeloid
leukemia.
 CONT

• Prognosis and behaviour –

– Certain genetic alterations are associated with a poor prognosis,
– Presence of these alterations determines the patient's subsequent
therapy.
– FISH and PCR methods can be used to detect amplification of
oncogenes which provide prognostic and therapeutic information for
breast cancers and neuroblastomas.
• Detection of minimal residual disease –
– Detection of minimal residual disease after treatment.
 Molecular Profiling of Tumors

• Possible by DNA-microarray analysis.

• Technique allows simultaneous measurements of expression
levels of several thousand genes, and by using bio-informatic
tools, the relative levels of gene expression in different
samples can be compared.
• In essence, a molecular profile is generated for each tissue
analyzed.
• Clusters of gene expression patterns can be detected that allow
segregation of phenotypically similar tumors into distinct
subcategories with dramatically different survival rates.
• Currently available morphologic and molecular tools are
insufficient for stratification of tumors into prognostically
different subgroups.
 CONT

• Analyses have been performed on breast cancers and melanomas.

• Although the data currently available have to be validated by prospective
analysis of a larger cohort of patients, the proof of principle has been obtained.
• In the near future, molecular profiling will become part of diagnosis,
classification, and management of cancer.
• This type of analysis may also reveal novel gene targets for development of
new drugs.
• Thus, therapy may be tailored to the specific genes dysregulated in a given
tumor.
PATHOLOGICAL PROCESSES THAT AFFECT
SELECTED ORGANS

WILSON A.L
 Pathogenesis of disease

• Disease-an abnormality in structure or function within a single cell, eg, in cancer,

• Manifests itself because of the way in which other cells and tissues are affected and
take part in the response to the original cause.
Liver disease (Patterns of injury and causes of
liver disease)

• More consequences,
• Due to dependence of other organs on the metabolic
function of the liver.
• Major causes
– Toxins
– Viruses
– Autoimmune disease
– Metabolic disorders
– Congenital malformations may also be a source
of liver dysfunction.
 CONT

• Categories of liver disease by presentation:

– Cholestasis
– Acute Hepatitis
– Chronic Hepatitis
– Cirrhosis
– Fulminant Hepatic Failure
– Focal or extrinsic diseases with variable manifestations in the liver
 CONT

• Liver disease can be ;

– Acute or chronic,
– Focal or diffuse,
– Mild or severe,
– Reversible or irreversible.
• Acute liver disease,
– Patient may die from hepatic failure, require a liver
transplant or recover completely.
 Chronic disease,

– Gradual inflammation and scarring

– Accompanied by regeneration
– Results in cirrhosis, which in turn puts the patient at
risk of developing a malignant tumor (hepatocellular
carcinoma).
• Liver disorders/injury through necrosis and apoptosis is
irreversible.
• Massive cell necrosis, no enough healthy cells to repopulate.
• Minimal cell loss, surviving epithelial cells regenerate.
• In persistent injury and inflammation fibrosis occurs.
 Liver Cirrhosis

Chronic degenerative disease of the liver characterized by

normal hepatic tissue being replaced with connective tissue.
Clinical Manifestations
• Fatigue, loss of vigor, and weight loss;
• Gastrointestinal; signs ;
– Nausea, vomiting, jaundice, and tender hepatomegaly;
• Extra-hepatic; signs
– Palmar erythema, spider angiomas, muscle wasting,
parotid and lacrimal gland enlargement, gynecomastia
and testicular atrophy in men, menstrual irregularities
in women, and coagulopathy.
• Portal hypertension ;
– Ascites, portosystemic shunting, encephalopathy,
splenomegaly, and esophageal and gastric varices with
intermittent hemorrhage.
 Etiology

• Infections -viral hepatitis (Types B,C and D and

toxoplasmosis),
• Genetic diseases (such as Wilson’s disease and cystic
fibrosis),
• Drugs and poisons (alcohol)
• Miscellaneous (diabetes mellitus and sarcoidosis).
 N/B

• Chronic and progressive.

• Common causes include: Alcohol abuse and Infectious agents (particularly hepatitis
B virus (HBV) and hepatitis C virus (HCV)
• Other causes include:
– Chronic biliary obstruction
– Drugs
– Metabolic disorders
– Chronic congestive heart failure
– Primary (autoimmune) biliary cirrhosis
 Pathogenesis

• Increased or altered synthesis of collagen and other

connective tissue or basement membrane components of
the extracellular matrix is implicated in hepatic fibrosis
hence pathogenesis of cirrhosis.
• Extracellular matrix is involved in modulating the
activities of the cells with which it is in contact.
• Fibrosis affect blood flow through the liver and cell
function.
• Hepatic fibrosis appears to occur in three situations:
– As an immune response,
– As part of the process of wound healing
– In response to agents that induce primary fibrogenesis.
• Hepatitis B Virus and Schistosoma species are examples
of immunologic agents producing fibrosis.
 CONT

• Agents such as carbon tetrachloride attack and kill

hepatocytes directly can produce fibrosis as part of wound
healing.
• In both immune responses and wound healing, the fibrosis is
triggered indirectly by the effects of cytokines released from
inflammatory cells.
• Agents eg ethanol and iron cause primary fibrogenesis by
directly increasing collagen gene transcription and thus
increasing amount of connective tissue secreted by cells.
• Actual culprit in increased fibrogenesis may be the fat-storing
stellate cells of the hepatic reticulo-endothelial system.
 CONT

• In response to cytokines, they differentiate from

quiescent stellate cells in which vitamin A is stored
into myofibroblasts, which lose their vitamin A
storage capacity and become actively engaged in
extracellular matrix production.
• In addition to the stellate cells, fibrogenic cells are
also derived from portal fibroblasts, circulating
fibrocytes, bone marrow, and epithelial-mesenchymal
cell transition.
 Hepatic fibrosis stages:

– First stage
• Reversible
• Characterized by change in extracellular matrix composition from
non-cross-linked, non-fibril-forming collagen to collagen that is
more dense and subject to cross-link formation.
 The second stage

– Involves formation of sub-endothelial collagen

cross-links, proliferation of myoepithelial cells,
and distortion of hepatic structure with the
appearance of regenerating nodules.
 NB
• Cirrhosis remains a dynamic state
• Certain interventions, even at advanced stages, may yield
benefits such as regression of scar tissue and improvements in
clinical outcomes.
• Not well understood how alcohol causes chronic liver disease
and cirrhosis.
• Chronic alcohol abuse is associated with;
– Impaired protein synthesis and secretion,
– Mitochondrial injury,
– Lipid peroxidation,
– Formation of acetaldehyde and its interaction with cellular
proteins and membrane lipids,
– Cellular hypoxia, and both cell-mediated and antibody-
mediated cytotoxicity.
• Genetic, nutritional, and environmental factors also influence
the development of liver disease in chronic alcoholics
 Cirrhosis Diagnosis

• Liver has a firm consistency-liver biopsy definitive method

• Histologically, all forms of cirrhosis are characterized by three
findings:
– Marked distortion of hepatic structures
– Scarring as a result of increased deposition of fibrous tissue
and collagen,
– Regenerative nodules surrounded by scar tissue.
 CONT

• Cirrhosis-alcohol abuse-micronodular/ macronodular or

both.
• Micronodular cirrhosis-nodules less 3 mm/uniform in
size,
• Macronodular cirrhosis-nodules larger 3 mm /variable
size.
• Scarring-most severe in central regions, or dense bands of
connective tissue may join portal and central areas.
• Specific histopathologic findings may help to establish
the cause of cirrhosis.
• Eg alcoholic hyalin and infiltration with
polymorphonuclear cells suggest alcoholic cirrhosis.
 Kidney disease (Uremia, glomerulonephritis)

• Patients renal disease have abnormalities of urine

– Volume
– Composition-presence-red blood cells/protein.
• Systemic symptoms
– Edema,
– Fluid overload,
– Electrolyte abnormalities,
– anemia
• Lack of pain receptors within kidney,
• Pain-prominent complaint where there is involvement of the
ureter or the renal capsule eg nephrolithiasis.
• Due to role of kidney in filtering blood, a wide range of
systemic diseases manifested most prominently in the kidney
 CONT

• Renal disease-prominent presentation of ;

– Long-standing diabetes mellitus,
– Hypertension,
– Autoimmune disorders such as systemic lupus
erythematosus.
• Renal disease may result in sufficient loss of kidney
function to be incompatible with life.
 CONT

• Not all renal disease is terminal.

• Some are
– Temporary,
– Self-limited
– Reversible with no permanent consequences.
• Other progress to renal failure, associated;
– Metabolic and hemodynamic consequences.
– Disordered regulation of body electrolyte and volume
status
– Loss of non-excretory renal functions such production of
erythropoietin-anemic
 Chronic Renal Failure

• Occurs when functions of kidneys have been reduced by chronic disease, to a point
there is retention of nitrogenous waste products normally excreted in the urine.
• Reduction in glomerular filtration rate (GFR) can be detected by measuring;
– Urea
– Creatinine in the blood
– Creatinine clearance
• From the blood and 24-hour urine samples
 Clinical Presentation

• Patient newly diagnosed with renal failure will have typical

initial findings that suggest chronic disease:
– Osteodystrophy,
– Neuropathy,
– Bilateral small kidneys shown by abdominal
ultrasonography, and anemia.
• Etiology
• Common causes of chronic renal failure ;
– Diabetes mellitus,
– Hypertension
– Glomerulonephritis.
– Polycystic kidney disease,
– obstruction, and infection
 Pathology & Pathogenesis of Chronic Renal Failure

• Acute injury to kidney results in death and sloughing of tubular epithelial cells, often
followed by their regeneration,
• Chronic injury results in irreversible loss of nephrons, leading to a greater functional
burden by fewer nephrons.
• Manifested as;
– Increase in GFR
– Hyperfiltration.
• Compensatory hyperfiltration, predisposes to fibrosis and scarring (glomerular
sclerosis).
• Rate of nephron destruction and loss increases, speeding the progression to uremia.
 Uremia

• Complex of symptoms and signs that occurs when residual

renal function is inadequate.
• 50% of nephrons can be lost without functional impairment i.e
individuals are able to donate.
• 20% of initial renal capacity, patients may be largely
asymptomatic because a new steady state is achieved in which
blood levels of these products are not high enough to cause
overt toxicity.
• At this stable level of renal function, hyperfiltration-
accelerated evolution to end-stage chronic renal failure is in
progress, and the little functional reserve can lead to uremia
with any added stress (for example, infection, obstruction,
dehydration, or nephrotoxic drugs) or with any catabolic state
associated with increased turnover of nitrogen-containing
products with reduction in GFR.
 Pathogenesis of Uremia

• Pathogenesis of chronic renal failure derives in part from

a combination of the toxic effects of:
– Retained products excreted by kidneys (nitrogen-
containing products of protein metabolism)
– Normal products such as hormones now present in
increased amounts
– Loss of normal products of the kidney (for instance,
loss of erythropoietin).
• Excretory failure results also in fluid shifts, with
increased intracellular Na+ (Sodium) and water and
decreased intracellular K+ (Potassium).
• Alterations contribute to alterations in kidney function
 Clinical Manifestations

• Na+ (Sodium) Balance and Volume Status;

– Degree of Sodium Na+ and water excess.
– Reflects loss of renal route of salt and water excretion.
– Moderate degree of Na+ and water excess may occur
without signs of extracellular fluid excess.
– Continued excessive Na+ ingestion contributes to
congestive heart failure, hypertension, ascites, peripheral
edema, and weight gain.
– On the other hand, excessive water ingestion contributes to
hypo-natremia.
 CONT
– Avoid excess salt intake and restrict fluid intake to equals
urine output plus 500 ml (insensible losses).
– Further volume control through diuretics (patient who still
makes urine) or at dialysis.
• Impaired renal salt and water conservation mechanisms,
– Very sensitive to sudden extra-renal Na+ and water losses
occur through, vomiting, diarrhea, and increased sweating
with fever.
– Easily leads to ECF depletion, further deterioration of renal
function (which may not be reversible), and even vascular
collapse and shock.
– Dry mucous membranes, dizziness, syncope, tachycardia,
and decreased jugular venous filling suggest progression of
volume depletion.
 K+ (Potassium) Balance

• Hyperkalemia (excessive potassium)-serious problem in CRF, especially

patients whose GFR below 5 ml/min.
• GFR falls, aldosterone-mediated K+ transport in the distal tubule increases in
a compensatory fashion.
• Patient whose GFR is between 50 ml/min and 5 l/min is dependent on tubular
transport to maintain K+ balance.
• Treatment with drugs that may impair aldosterone-mediated K+ transport e.g.
K+-sparing diuretics, ACE inhibitors, or blockers, can therefore precipitate
dangerous hyperkalemia in a patient with CRF.
 CONT

• Patients with DM (leading cause of CRF) may have a

syndrome of hyporeninemic hypoaldosteronism.
• Lack of renin production by kidney diminishes levels
of angiotensin II and, therefore, impairs aldosterone
secretion.
• Patients are unable to compensate for falling GFR by
enhancing their aldosterone-mediated K+ transport
hence relative difficulty handling K+.
• Usually manifested as hyperkalemia even before GFR
has fallen below 5 ml/min.
• Other secondary and systemic clinical
manifestations include:
 Metabolic Acidosis

• Reduced capacity to excrete acid and generate base results in metabolic

acidosis.
• GFR is above 20 ml/min, only moderate acidosis develops before re-
establishment of a new steady state of buffer production and
consumption.
• Fall in blood pH in these individuals can usually be corrected with 20–30
mmol (2–3 g) of sodium bicarbonate by mouth daily.
• Highly susceptible to acidosis in the event of a sudden acid load or the
onset of disorders that increase the generated acid load.
 Mineral and Bone

• Several disorders of phosphate, Ca2+, and bone metabolism are

observed in CRF.
• Key factors in the pathogenesis of these disorders include
– Diminished absorption of Ca2+ from the gut
– Overproduction of parathyroid enzyme (PTH)
– Disordered vitamin D metabolism
– Chronic metabolic acidosis
• All of these factors contribute to enhanced bone resorption.
 CONT

• Hypophosphatemia and hypermagnesemia can occur

through overuse of phosphate binders and
magnesium-containing antacids, although
hyperphosphatemia is more common.
• Hyperphosphatemia contributes to the development
of hypocalcemia and thus serves as an additional
trigger for secondary hyperparathyroidism, elevating
blood PTH levels.
• The elevated blood PTH further depletes bone Ca2+
and contributes to osteomalacia of chronic renal
failure.
Cardiovascular and Pulmonary Abnormalities

• Congestive heart failure and pulmonary edema ; in the

context of volume and salt overload.
• Hypertension;
– On the basis of fluid and Na+ overload.
– Hyperreninemia syndrome in which falling renal perfusion
triggers the failing kidney to overproduce renin and thereby
elevate systemic blood pressure.
• Pericarditis ;resulting from irritation and inflammation of the
pericardium by uremic toxins
• Cardiovascular risk in CRF remains leading cause of
mortality in
• Results in myocardial infarction, stroke, and peripheral
vascular disease.
• Risk factors in these patients include hypertension,
hyperlipidemia, glucose intolerance, chronic elevated cardiac
output, and valvular and myocardial calcification.
 Hematologic Abnormalities

• CRF patients have marked abnormalities in RBC count, wbc function, and
clotting parameters.
• Normochromic, normocytic anemia, with symptoms of Restlessness ,easy
fatigability and hematocrit levels 20–25%,.
• Anemia is due chiefly to lack of production of erythropoietin and loss of its
stimulatory effect on erythropoiesis.
• Patients CRF regardless of dialysis status, show a dramatic improvement in
hematocrit when treated with erythropoietin (epoetin alpha).
 Additional causes of anemia

• Bone marrow suppressive

– Effects of uremic poisons,
– bone marrow fibrosis due to elevated blood PTH,
– Toxic effects of aluminum (from phosphate-binding antacids and
dialysis solutions),
– Hemolysis and blood loss related to dialysis (while the patient is
anticoagulated with heparin).
 CONT

• CRF Patients display abnormal hemostasis manifested as ;

– Increased bruising,
– Increased blood loss at surgery,
– Increased incidence of spontaneous gastrointestinal and
cerebrovascular hemorrhage (including both hemorrhagic
strokes and subdural hematomas).
• Laboratory abnormalities include ;
– Prolonged bleeding time,
– Decreased platelet factor III,
– Abnormal platelet aggregation and adhesiveness,
– Impaired prothrombin consumption, none of which are
completely reversible even in well-dialyzed patients.
 CONT

• Uremia is associated with increased susceptibility to infections,

• Believed to be due to leukocyte suppression by uremic toxins.
• Suppression seems greater for lymphoid cells than neutrophils and
affect chemotaxis, acute inflammatory response, and delayed
hypersensitivity more than other leukocyte functions.
• Acidosis, hyperglycemia, malnutrition, and hyperosmolality also
contribute to immunosuppression
• Invasiveness of dialysis and the use of immunosuppressive drugs in
renal transplant patients also contribute to an increased incidence of
infections.
 Neuromuscular Abnormalities

• CNS symptoms and signs may range from;

• Mild sleep disorders
• Impairment of mental concentration,
• Loss of memory,
• Errors in judgment,
• Neuromuscular irritability (manifested as hiccups, cramps,
fasciculations, and twitching) to asterixis, myoclonus, stupor,
seizures, and coma in end-stage uremia.
• Asterixis is manifested as involuntary flapping motions seen
when the arms are extended and wrists held back.
• It is due to altered nerve conduction in metabolic
encephalopathy from a wide variety of causes, including renal
failure.
 CONT

• Peripheral neuropathy (sensory greater than motor, lower

extremities greater than upper),
• Restless legs syndrome (poorly localized sense of
discomfort and involuntary movements of the lower
extremities), indication for starting dialysis.
• Patients on hemodialysis can develop aluminum toxicity,
characterized by speech dyspraxia (inability to repeat
words), myoclonus, dementia, and seizures.
• Aggressive acute dialysis can result in a disequilibrium
syndrome characterized by nausea, vomiting, drowsiness,
headache, and seizures.
• Presumably, this is an effect of rapid pH or osmolarity
change in extra cellular fluid (ECF), resulting in cerebral
edema
 Gastrointestinal (GI) Abnormalities

• Nonspecific uremic patients include;

– Anorexia,
– Hiccups,
– Nausea,
– Vomiting, and diverticulosis.
• Improve with dialysis.
 Endocrine and Metabolic Abnormalities

• Women with uremia have low estrogen levels, which perhaps explain the high
incidence of amenorrhea and the observation that they rarely are able to carry
a pregnancy to term.
• Regular menses (but reduced rate of successful pregnancies) typically return
with frequent dialysis.
• Low testosterone levels, impotence, oligospermia, and germinal cell dysplasia
• CRF eliminates kidney as a site of insulin degradation, thereby increasing the
half-life of insulin.,typically has a stabilizing effect on diabetic patients whose
blood glucose was previously difficult to control.
 Dermatologic Abnormalities

• Patients with CRF display pallor because of anemia,

• Skin color changes related to accumulated pigmented metabolites
• Gray discoloration resulting from transfusion-mediated hemochromatosis,
ecchymoses and hematomas as a result of clotting abnormalities, and pruritus and
excoriations as a result of Ca2+ deposits from secondary hyperparathyroidism.
• Urea concentrations are extremely high, evaporation of sweat leaves a residue of urea
termed "uremic frost."
 Glomerulonephritis

• Structural alterations of the glomerulus and present :

– Hematuria,
– Proteinuria,
– Reduced GFR, and hypertension.
• Some of these disorders are specific to the kidney, whereas others are systemic
diseases in which the kidney is primarily or prominently involved.
 Clinical Presentation of glomerulonephritis

• Disorders fall into five categories:

• Acute glomerulonephritis,
– An abrupt onset of hematuria and proteinuria with reduced GFR and renal salt and
water retention,
– Recovery of renal function.
– Subset of those with an intra-renal cause of acute kidney injury.
• Rapidly progressive glomerulonephritis,
– Recovery from acute disorder does not occur.
– Worsening renal function results in irreversible and complete renal failure over
weeks to months
 CONT
• Chronic glomerulonephritis,
– Renal impairment after acute glomerulonephritis progresses
slowly over a period of years and eventually results in
chronic renal failure.
• Nephrotic syndrome,
– Marked proteinuria, particularly albuminuria (24-hour
urine protein excretion > 3.5 gms), hypoalbuminemia,
edema, hyperlipidemia, and fat bodies in the urine.
– May be either isolated (eg, minimal change disease) or part
of some other glomerular syndrome (for example, with
hematuria and casts).
• Asymptomatic urinary abnormalities,
– Hematuria and proteinuria (usually in amounts below that
seen in nephrotic syndrome) but no functional
abnormalities associated with reduced GFR, edema, or
hypertension.
– Many patients with these findings will develop CRFslowly
over decades.
 Etiology

• AG occurs most typically in infectious diseases,

• classically pharyngeal or cutaneous infections with
certain "nephritogenic" strains of group A beta-hemolytic
streptococci but also other pathogens.
• Rapidly progressive glomerulonephritis -heterogeneous
group of disorders, display pathologic features common
to various categories of necrotizing vasculitis.
• Chronic glomerulonephritis and nephrotic syndrome -
unclear origin.
• Progressive renal deterioration in chronic
glomerulonephritis proceeds slowly but irreversibly,
resulting in CRF as many as twenty years after initial
discovery of an abnormal urinary sediment.
 CONT

• Some cases of nephrotic syndrome are variants of acute

glomerulonephritis, rapidly progressive glomerulonephritis, or chronic
glomerulonephritis in which massive proteinuria is a presenting feature.
• Other cases of nephrotic syndrome fall into the category of minimal
change disease, in which many of the pathologic consequences are due to
proteinuria.
• Common cause of asymptomatic urinary abnormalities is
Immunoglubulin A (IgA) nephropathy, an immune complex disease
characterized by diffuse mesangial IgA deposition.
 Pathology & Pathogenesis

• Different forms of glomerulonephritis and nephrotic syndrome represent

differences in the nature, extent, and specific cause of immune-mediated
renal damage.
• Cytokines (in particular transforming growth factor-1 (TGF-1) and
platelet-derived growth factor (PDGF) are synthesized by mesangial
cells, inciting an inflammatory reaction in some forms of glomerular
disease.
• It is not known exactly how the various forms of immune-mediated renal
damage occur.
 Acute Glomerulonephritis

• Post-infectious acute glomerulonephritis is due to immune attack on

the infecting organism in which there is cross-reactivity between an
antigen of the infecting organism (for example, group A beta-
hemolytic streptococci) and a host antigen.
• Result is deposition of immune complexes and complement in
glomerular capillaries and the mesangium.
• Symptoms and signs typically occur 7–10 days after onset of for
example, acute pharyngeal or cutaneous infection and resolve over
weeks after treatment of the infection.
 Rapidly Progressive Glomerulonephritis

• Linear immunoglobulin deposits suggest antiglomerular basement membrane (GBM)

antibody, which may coincident with pulmonary hemorrhage.
• Immunofluorescence studies permit distribution into subgroups correlating with other
features of the disease.
• From 5% to 20% of patients have linear anti-GBM antibody deposits in glomeruli
and a tendency to hemoptysis suggestive of Good pasture's syndrome.
 CONT

• Granular immunoglobulin deposits are suggestive of immune

complexes due to an underlying systemic disease,
• Such as IgA nephropathy, postinfectious glomerulonephritis, lupus
nephritis, or mixed cryoglobulinemia.
• 30–40% have granular immunoglobulin deposits and an autoantibody
pattern typical of Wegener's granulomatosis (antineutrophil
cytoplasmic antibody - ANCA).
• These patients are typically older, with more systemic constitutional
symptoms.
 Chronic Glomerulonephritis

• Some patients with acute glomerulonephritis develop chronic renal failure

slowly over a period of 5–20 years.
• Cellular proliferation, in either the mesangium or the capillary, is a pathologic
structural hallmark in some of these cases,
• Whereas others are notable for obliteration of glomeruli and yet others display
irregular sub-epithelial protein deposits with uniform involvement of
individual glomeruli.
 Activity 4.3

• Describe in your note book the etiology and pathology for each of the five clinical
presentations of glomerulonephritis.
 CYSTS

• A cyst is an abnormal, closed, saclike tissue containing fluid, gas, or semisolid

material.
• Cysts are common
• Occur anywhere in the body in people of any age.
• Vary in size and may be detectable only under a microscope or they can grow
so large that they displace normal organs and tissues.
• Outer wall of a cyst is called the capsule.
 CONT

• Cysts can arise as a result of:

– "wear and tear" or simple obstructions to the flow of fluid
– Infections
– Tumors
– Chronic inflammation
– Genetic conditions
– Defects during embryogenesis.
• Cysts are only preventable to the extent that the underlying cause is
preventable.
 Types of cysts

• Cysts in the breast which are part of benign proliferative ("fibrocystic")

disease
• Ovarian cysts-dermoid cysts, a specific type of ovarian tumor that often
contains cysts and other tissues
• Cysts within the thyroid gland
• Baker cyst (popliteal) behind the knee
• Ganglion cysts of the joints and tendons
 CONT

• Cysts of the glands within the eyelid, termed chalazions

• Sebaceous cysts of the small glands in the skin
• Epidermal cysts of the skin, sometimes known as epidermal inclusion
cysts, that are frequently found on the face, scalp, neck, and trunk
• Bartholin cysts, enlargement of small glands near the vaginal opening
• Pineal cysts, cysts within the pineal gland of the brain
 CONT

• Pancreatic cysts are collections of fluid within the pancreas.

– Some pancreatic cysts are true cysts that are lined by cells that secrete
fluid.
– Other pancreatic cysts are pseudocysts and do not contain specialized
lining cells.
• Polycystic kidney disease, an inherited condition in which the kidneys
contain multiple cysts
• Tarlov cysts, also known as meningeal or perineural cysts, are located in
the sacrum, the fused bones at the base of the spine.
 CONT

• Infections and inflammation, such as abscesses and boils on the skin, can also be
causes of cysts.
• Arachnoid cysts are located between the brain or spinal cord and the arachnoid
membrane, one of the three membranes that cover the brain and spinal cord.
• Majority of cysts are benign, but some may produce symptoms due to their size
and/or location.
• Rarely are cysts associated with malignant tumors or serious infections.
SYSTEMIC PATHOLOGY

WILSON A. L
 Cardiovascular System

• Anatomy & Histology

– Blood vessels
• Closed system of various conduits
• Carry blood from heart to tissues through lungs and
back to heart.
• Lined by a layer of endothelial cells which secretes
substances that
– Affect diameter of vessels
– Provide for growth, repair and formation of new
vessels that carry blood to tissues.
• Vessels vary in;
– Diameter,
– Thickness
– Length.
 Arterial Vessels

• Various layers of tissue that make up blood vessels are

structured in circular rings.
• Aorta, large arteries, and arterioles are made up of;
– Outer layer of connective tissue, -adventitia;
– Middle layer of smooth muscle-media;
– Inner layer, -intima, containing layer of endothelial cells
and some sub endothelial connective tissue.
• Walls of aorta and large arteries contain ;
– Abundant elastic tissue, much concentrated in
• Internal elastic lamina-prominent band between intima
and media,
• External elastic lamina, between the media and the
adventitia.
 CONT

• Vessels stretch by force of cardiac ejection during systole, and elastic tissue
permits them to recoil during diastole.
• This maintains diastolic pressure and aids the forward motion of the blood.
• Walls of arterioles contain less elastic tissue but more smooth muscle
innervated by constrictor noradrenergic nerve fibers.
• In some instances, there is vasodilator cholinergic innervation.
• Arteries and arterioles offer considerable resistance to blood flow and are
known as resistance vessels.
 Capillaries

• Terminal portions of arterioles drain into capillaries.

• On upstream side, openings of the capillaries are surrounded by smooth muscle pre-
capillary sphincters.
• Capillaries themselves are made up of a single layer of endothelial cells.
• Capillaries anastomose extensively, and although each capillary is only 5–9 mm in
diameter, there are so many of them that the total cross-sectional area of all
capillaries is about 4500 cm2.
 Venules & Veins

• Venules
– Similar to capillaries and are their approximate total
cross-sectional area is 4000 cm2.
– Drain into veins, which drain into the superior and
inferior vena cavae, and which in turn drain into the
right atrium of the heart.
– Walls of veins, unlike those of arteries and arterioles,
are easily distended and can expand to hold more
blood without much increase in intravascular pressure.
– Known as capacitance vessels.
– Innervated, and their smooth muscles respond to
noradrenergic stimulation, pushing blood into the heart
and arterial side of circulation.
– Intima of the limb veins is folded at intervals to form
the venous valves that prevent retrograde flow.
 Lymphatics

• Lymphatic vessels
– Made up of endothelial tubes.
– Fluid enter them through loose junctions between endothelial cells.
– Drain into larger endothelial tubes that have valves and contractile walls
containing smooth muscle, so that the fluid they contain moves centrally.
– Central lymphatics drain into the right and left subclavian veins.
– Lymphatic system drains excess fluid in tissues back into the vascular
system.
 Physiology

• In supine position.
– Systolic and diastolic pressures in aorta and large arteries are stable, and
there is a large pulse pressure.
– Normal blood pressure is about 120/80 mm Hg in healthy young adults.
– In arterioles there is a sharp drop which falls steadily in venous system to
about 5 mm Hg at the entrance of vena cavae into right atrium.
– Blood velocity falls in arterioles and is low in capillaries due to large total
cross-sectional area.
– It increases again in large veins.
– The pressures mentioned so far are those recorded
 CONT

• Because of weight of blood, there is a pressure increase in standing position in

both arteries and veins of 0.77 mm Hg for each centimeter below heart it is
measured and a corresponding decrease above the heart.
• Thus,
– When mean arterial pressure at level of heart is 100 mm Hg,
– Mean arterial pressure in a large artery in foot of a standing averaged-sized
adult is about 180 mm Hg;
– In head, it is about 62 mm Hg.
 Measurement of Arterial Pressure

• Arterial pressure can be measured directly by;

– Inserting a needle into an artery,
– Auscultation using a sphygmomanometer.
• Normal Arterial Pressure in brachial artery at heart level in healthy young
adults is about 120/80 mm Hg.
• Affected by many factors, including;
– Emotion and anxiety.
– Systolic and diastolic pressures normally fall by as much as 20 mm Hg
during sleep.
– In individuals with hypertension, the fall during sleep is reduced or absent.
 CONT

– Blood pressure rises with advancing age, but there has been
uncertainty about magnitude of rise because hypertension is
a common disease whose incidence increases with
advancing age.
– Individuals who have systolic blood pressures < 120 mm
Hg at age 50–60 years and never develop clinical
hypertension still have systolic pressures that rise
throughout life.
– Individuals with mild hypertension that is untreated show a
more rapid rise in systolic pressure.
– In both groups, diastolic pressure also rises but then starts
to fall in middle age as the stiffness of arteries increases.
– Consequently, pulse pressure rises with advancing age.
 Capillary Circulation

• In capillaries, speed of blood flow is decreased because of the

large total cross-sectional area.
• Obviously, most of net movement of substances out of a
capillary occurs at its arteriolar end, where net pressure
gradient is outward primarily because hydrostatic pressure in
capillary (about 37 mm Hg) is greater than oncotic pressure.
• As capillary resistance and filtration progressively cause a
decrease in hydrostatic pressure along length of vessel, the
inwardly directed oncotic pressure gradient becomes greater
than hydrostatic pressure gradient so that, at venular end, fluid
is reabsorbed.
• Any excess solute and solvent in the tissues is picked up by the
lymph vessels and moved to the venous circulation by the
main lymphatic ducts.
 Hypertension

• Hypertension is not a single disease but a syndrome with multiple causes.

• In most instances, cause remains unknown,
• Cases are lumped together under;
– Essential hypertension
– Primary hypertension.
• Hypertension-cause is known -secondary hypertension,
 Pathogenesis
• Normal blood pressure as systolic pressure of < 120 mm Hg
and diastolic pressure of < 80 mm Hg.
• Hypertension -arterial pressure greater than 140/90 mm Hg in
adults on at least three consecutive visits
• Bood pressure -between normal and 140/90 mm Hg are
considered to have pre-hypertension -should appropriately
modify their lifestyle to lower their blood pressure to below
120/80 mm Hg.
• Systolic pressure normally rises throughout life, and diastolic
pressure rises until age 50–60 years but then falls, so that pulse
pressure continues to increase.
• Common cause of hypertension is increased peripheral
vascular resistance.
• Other causes include ;
– Prolonged increases in cardiac output,
– Increased blood volume
– Increased blood viscosity.
 Clinical Presentation
• Hypertension by itself does not cause symptoms-discovered during routine
screening or when patients seek medical advice for its complications.
• Complications are serious and potentially fatal;
– myocardial infarction,
– congestive heart failure,
– thrombotic and hemorrhagic strokes,
– hypertensive encephalopathy, and renal failure.
• "the silent killer."
• Observable changes are generally found in advanced cases;
– Hypertensive retinopathy,
– Retinal hemorrhages and exudates
– Swelling of optic nerve head (papilledema),
– left ventricular hypertrophy,
– cardiac enlargement.
• It is important to listen with the stethoscope over the kidneys because in
renal hypertension, narrowing of the renal arteries may cause bruits.
• In many patients with hypertension, the condition is benign and progresses
slowly; in others, it progresses rapidly. Actuarial data indicate that on
average untreated hypertension reduces life expectancy by 10–20 years.
Atherosclerosis is accelerated, and this in turn leads to ischemic heart
disease with angina pectoris and myocardial infarctions, thrombotic
strokes and cerebral hemorrhages, and renal failure . Another complication
of severe hypertension is hypertensive encephalopathy, in which there is
confusion, disordered consciousness, and seizures.
• In malignant hypertension, there is widespread fibrinoid necrosis of the
media with intimal fibrosis in arterioles, narrowing them and leading to
progressive severe retinopathy, congestive heart failure, and renal failure.
If untreated, malignant hypertension is usually fatal in 1 year.
 Management
• In all forms of hypertension modern treatment with adrenergic
blocking drugs, inhibitors of the renin-angiotensin system, Ca2+
channel inhibitors, and diuretics reduce blood pressure, usually to
normal levels. In addition, these treatments delay or prevent
complications and lengthen life expectancy. However, they are not
curative and must be continued indefinitely. Thus, essential
hypertension is like diabetes mellitus: It can be controlled but not
cured. If a cause of hypertension can be identified, its treatment
may result in a cure. Consequently, it is important to identify such
cases.
 Etiology
• 6.4.3 Management
• In all forms of hypertension modern treatment with adrenergic blocking drugs,
inhibitors of the renin-angiotensin system, Ca2+ channel inhibitors, and diuretics
reduce blood pressure, usually to normal levels. In addition, these treatments
delay or prevent complications and lengthen life expectancy. However, they are
not curative and must be continued indefinitely. Thus, essential hypertension is
like diabetes mellitus: It can be controlled but not cured. If a cause of
hypertension can be identified, its treatment may result in a cure. Consequently,
it is important to identify such cases.

• 6.4.4 Etiology
• Activity 6.1

• a. Coarctation of the Aorta

• Congenital narrowing of the aorta usually occurs just distal to the origin of the
left subclavian artery. Peripheral resistance is increased above the constriction.
Therefore, blood pressure is elevated in the arms, head, and chest but lowered
in the legs. However, because the constriction is proximal to the renal arteries,
renin secretion is increased in most cases of coarctation as a result of the
reduction in arterial pressure in the renal arteries. This tends to increase blood
pressure throughout the body. Elimination of the constriction by resecting the
narrowed segment of the aorta usually cures the condition.
• b.
• Salt Sensitivity
• About 30% of whites with normal renal function and normal blood pressure are salt sensitive
compared with 55% of whites with essential hypertension. For unknown reasons, a larger percentage
of black hypertensives are salt sensitive. These figures have obvious significance in terms of
recommendations about salt intake in hypertension.
• c. Renal Abnormalities
• Renal artery constriction increased blood pressure. Renal hypertension resulting from constriction of
one or both renal arteries accounts for only 2% of cases of clinical hypertension. The narrowing can
be due to atherosclerosis, fibroelastic overgrowth of the wall of the renal artery, or external pressure
on the vessel. The initial constriction decreases renal arteriolar pressure, and this leads to increased
renin secretion. However, in many cases, some other mechanism takes over chronically to maintain
the hypertension. The nature of this other mechanism is unknown.
• In rare instances, hypertension can be caused by tumors of the renin-secreting juxtaglomerular cells.
• d. Acute and chronic glomerulonephritis and other forms of diffuse kidney disease can cause
hypertension when loss of the ability to excrete salt is severe enough that Na+ and water are
retained and blood volume is expanded.
• e. In Liddle's syndrome, there is abnormal sodium retention by the kidneys with expanded
extracellular fluid volume, producing hypertension but no increase in circulating mineralocorticoids.
• A mutation in the mineralocorticoid receptor that causes renal Na+ retention and hypertension has
also been described. This mutation makes the receptor constitutively active and causes progesterone
and related steroids to act as agonists. The result is early-onset hypertension, which is markedly
exacerbated during pregnancy.
• f. Abnormalities of the Renin-Angiotensin System
• Increased secretion of angiotensinogen from the liver can cause hypertension. Secretion of this
angiotensin precursor is under endocrine control and is stimulated by estrogens. Consequently, it is
increased in women taking contraceptive pills containing large amounts of estrogens. When
circulating angiotensinogen is increased, more angiotensin II is formed and blood pressure rises. The
normal compensation for this response is decreased secretion of renin because angiotensin II feeds
back directly on the juxtaglomerular cells to reduce renin secretion.
• g.
• Adrenal Gland Disorders
• A remarkable number of adrenal abnormalities cause hypertension. These
include mainly conditions in which mineralocorticoids are secreted in excess, but
excess secretion of cortisol also causes hypertension, as does excess secretion of
catecholamines by tumors of the adrenal medulla.
• h. Glucocorticoid Excess
• The incidence of hypertension is greater than normal in Cushing's syndrome,
indicating that cortisol as well as mineralocorticoids can cause hypertension. The
mechanism involved is unsettled, although there are a number of possibilities.
First, glucocorticoids stimulate angiotensinogen secretion by the liver, and as
noted, this increases circulating angiotensin II unless the feedback inhibition of
renin secretion is able to compensate for the rise.
• i.
• Excess Secretion of Catecholamines
• Increases in adrenal medullary secretion of norepinephrine elevate systolic and diastolic
pressure, and increases in epinephrine secretion may have the same effect. Tumors of the
adrenal medulla (pheochromocytomas) cause hypertension. Norepinephrine-secreting
tumors usually produce sustained hypertension, as do epinephrine-secreting tumors.
However, about 15% of the tumors secrete episodically, producing intermittent bouts of
palpitations, headache, glycosuria, and extreme systolic hypertension. The same symptoms
are produced by acute injection of a large dose of epinephrine.
• j. Neurologic Disorders
• The nervous system plays a key role in maintaining blood pressure in normal individuals.
Clonidine and other drugs lower blood pressure by acting on the brain to decrease
sympathetic discharge, and several of the most effective treatments for chronic
hypertension act peripherally to reduce the effect of vasomotor sympathetic discharge to
the blood vessels and heart. These and other observations suggest that clinical
hypertension could be caused by CNS abnormalities.
Nursing care of patient suffering from hypertension
 GENETIC DISORDERS
• genetic disorders. Your knowledge of Cell biology and Genetics,
and embryology that you covered in Unit One will come in
handy as you read through this section. Therefore, it will be
prudent for you to revise the Unit.
 Introduction to genetics
• Genetics is the branch of biology that deals with heredity,
especially the mechanisms of hereditary transmission and the
variation of inherited characteristics among similar or related
organisms. A gene is a molecular unit of heredity of living
organisms. It is a name given to some stretches of DNA and RNA
that code for a polypeptide or for an RNA chain that has a function
in the organism. Living beings depend on genes, as they specify all
proteins and functional RNA chains. Genes hold the information to
build and maintain an organism's cells and pass genetic traits to
offspring, although
• some organelles (for example, the mitochondria) are self-
replicating and are not coded for by the organism's DNA. All
organisms have many genes corresponding to various
biological traits, some of which are immediately visible, such as
eye color, number of limbs, complexion, hair texture and some
of which are not, such as blood type or increased risk for
specific diseases, or the thousands of basic biochemical
processes that comprise life. From the Cell biology unit, i hope
you remember DNA carries the
• genetic code. It is a double stranded helical structure. It is made of
nucleotides. Each nucleotide consists of a 5-carbon sugar
(deoxyribose), a nitrogen containing base attached to the sugar,
and a phosphate group. There are four different types of
nucleotides found in DNA, differing only in the nitrogenous base.
The four nucleotides are given one letter abbreviations as
shorthand for the four bases (Fig 13). These are; A is for adenine, G
is for guanine, C is for cytosine and T is for thymine. Adenine and
guanine are also known as purines whereas cytosine and thymine
are pyrimidines.
• RNA is also called ribonucleic acid. It consists of a long, usually
single-stranded chain of alternating phosphate and ribose units
with the bases adenine, guanine, cytosine, and uracil bonded
to the ribose. RNA molecules are involved in protein synthesis
and sometimes in the transmission of genetic information.
• The basic components of RNA are the same as those for DNA
with two major differences. The pyrimidyne base uracil replace
thymine and ribose replace deoxyribose. Adenine and Uracil
are formed by two hydrogen bonds.
• Having reviewed some concepts in genetics, let us proceed and look at more
concepts at greater depth.
• The mechanism of cellular and tissue dysfunction in genetic diseases are as
varied as the organs they affect. To some extent, these mechanisms are similar
to those that occur in non-heritable disorders. For example, a fracture resulting
from decreased bone density in osteoporosis heals in much the same way as one
caused by a defective collagen gene in osteogenesis imperfecta, and the
response to coronary atherosclerosis in most individuals does not depend on
whether they have inherited a defective low-density lipoprotein (LDL) receptor.
Thus, the pathophysiologic principles that distinguish genetic disease focus not
so much on the affected organ system as on the mechanisms of mutation (see
section on mutation), inheritance, and molecular pathways from genotype to
phenotype.
• Humans only have approximately 30,000 genes. The unraveling of
our "genetic architecture" promises to unlock secrets of inherited
as well as acquired human disease, since ultimately all diseases
involve changes in gene make-up or expression. Powerful
technologies now allow applications of the human gene sequences
to the analysis of human diseases. For example, DNA and RNA
microarrays ("gene chips") can be used to simultaneously screen
for the expression of thousands of genes in diseased tissues. Such
"molecular profiling" has become an important tool in the study of
malignant diseases
• Take Note 5.1
• It is worth noting that until recently the major focus of gene
hunting has been discovery of structural genes whose products
encode proteins. It has been found however, that a very large
number of genes do not encode proteins. Instead, their
products play important regulatory functions.
• By current estimates, there are approximately 1000 genes in humans that encode miRNAs,
accounting for about 3% of the human genome. Transcription of miRNA genes produces
primary microRNA transcript (pri-miRNA), which is processed within the nucleus to form
another structure, called pre-miRNA. With the help of specific transporter proteins, pre-
miRNA is exported to the cytoplasm. Additional "cutting" by an enzyme, appropriately
called Dicer, generates mature miRNAs that are about 21 to 30 nucleotides in length (hence
the name "micro"). Next, the miRNA unwinds its double strand, and single strands of this
duplex are incorporated into a multiprotein complex called RNA-induced silencing complex
(RISC). Base pairing between the miRNA strand and its target mRNA directs the RISC to
either cause mRNA cleavage or repress its translation. Given that the numbers of miRNA
genes are far fewer than those that encode proteins, it follows that a given miRNA can
silence many target genes. The precise mechanism by which the target specificity of miRNA
is determined remains to be fully elucidated.
• Another species of gene-silencing RNA, called small interfering RNAs (siRNAs),
works in a manner quite similar to that of miRNA. Unlike miRNA, however, siRNA
precursors are introduced by investigators into the cell. Their processing by Dicer
and functioning via RISC are essentially similar to that described for miRNA.
siRNAs are becoming powerful tools for studying gene function and may in the
future be used therapeutically to silence specific genes, such as oncogenes,
whose products are involved in neoplastic transformation.
• With this background of developments in human genetics, we can now turn to
the classification of human diseases into three categories:
• 1. Those that are genetically determined
• 2. Those that are almost entirely environmentally determined
• 3. Those to which both nature and nurture contribute
• However, progress in understanding the molecular basis of many so-called
environmental disorders has tended to blur these distinctions. At one time,
microbial infections were cited as examples of disorders arising wholly from
environmental influences, but it is now known that an individual's genetic
makeup considerably influences his or her immune response and susceptibility
to microbiologic infections. In fact, the genetic contribution even in common
diseases is far greater than is commonly appreciated.
• Surveys indicate that as many as 20% of the pediatric inpatients in university
hospitals in the USA suffer from disorders of genetic origin. These data describe
only the tip of the iceberg. Chromosomal aberrations have been identified in as
many as 50% of spontaneous abortions during the first trimester and many more
probably had gene mutations. Only those mutations compatible with
independent existence constitute the reservoir of genetic disease in the
population at large.
• Several pediatric disorders are of genetic origin, however, it must be borne in mind that not
all genetic disorders present in infancy and childhood, and conversely, many pediatric
diseases are not of genetic origin. To the latter category belong diseases resulting from
immaturity of organ systems.
• In this context it is helpful to clarify three commonly used terms:
• • Hereditary
• • Familial
• • Congenital
• Hereditary disorders, by definition, are derived from one's parents, are transmitted in the
gametes through the generations, and therefore are familial. The term congenital simply
implies "present at birth." It should be noted that some congenital diseases are not genetic
(for example, congenital syphilis). On the other hand, not all genetic diseases are congenital;
the expression of Huntington disease, for example, begins only after the third or fourth
decade of life.
 Mutations
• The term mutation refers to permanent changes in the DNA. Those that affect germ cells are
transmitted to the offspring and may give rise to inherited diseases. Mutations in somatic cells are
not transmitted to the children but are important in the causation of cancers and some congenital
malformations.
• Details of specific mutations and their effects are discussed along with the relevant disorders
throughout this text.
• Here we cite only some common examples of gene mutations and their effects.
• Point mutations result from the substitution of a single nucleotide base by a different base, resulting
in the replacement of one amino acid by another in the protein product. The mutation giving rise to
sickle cell anemia is an excellent example of a point mutation that alters the meaning of the genetic
code. Such mutations are sometimes called missense mutations. On the contrary, certain point
mutations may change an amino acid codon to a chain termination codon, or stop codon. Such
mutations interrupt translation, and the resultant truncated proteins are rapidly degraded.
• Frameshift mutations occur when the insertion or deletion of one or two base pairs alters the
reading frame of the DNA strand.
• Trinucleotide repeat mutations belong to a special category, because these
mutations are characterized by amplification of a sequence of 3 nucleotides.
Although the specific nucleotide sequence that undergoes amplification differs
in various disorders, all affected sequences share the nucleotides guanine (G)
and cytosine (C). For example, in fragile X syndrome, prototypical of this category
of disorders, there are 200 to 4000 tandem repeats of the sequence CGG within
a gene called FMR1. In normal populations, the number of repeats is small,
averaging 29. The expansions of the trinucleotide sequences prevent normal
expression of the FMR1 gene, thus giving rise to mental retardation. Another
distinguishing feature of trinucleotide repeat mutations is that they are dynamic
(that is, the degree of amplification increases during gametogenesis). These
features, discussed in greater detail later in this section, influence the pattern of
inheritance and the phenotypic manifestations of the diseases caused by this
class of mutations.
• Activity 5.1
• Before moving on, describe when the following gene
mutations occur and their effects:
• 1. Point mutations
• 2. Frameshift mutations
• 3. Trinucleotide repeat mutations
• With this brief review of the nature of mutations, we can turn our attention to the three major
categories of genetic disorders:
• 1. Those related to mutant genes of large effect
• 2. Diseases with multifactorial (polygenic) inheritance
• 3. Those arising from chromosomal aberrations.

• The first category, sometimes referred to as mendelian disorders, includes many uncommon
conditions, such as the storage diseases and inborn errors of metabolism, all resulting from single-
gene mutations of large effect. Most of these conditions are hereditary and familial.
• The second category includes some of the most common disorders of humans, such as hypertension
and diabetes mellitus. Multifactorial, or polygenic, inheritance implies that both genetic and
environmental influences condition the expression of a phenotypic characteristic or disease.
• The third category includes disorders that are the consequence of numeric or structural
abnormalities in the chromosomes.
 Single-gene disorders - Structural and biochemical
disorders in single gene disease
• Single-gene defects (mutations) follow the well-known mendelian patterns
of inheritance. Thus, the conditions they produce are often called
mendelian disorders. Although individually each is rare, altogether they
account for approximately 1% of all adult admissions to hospitals and
about 6% to 8% of all pediatric hospital admissions.

• Mutations involving single genes follow one of three patterns of

inheritance:
• • Autosomal dominant
• • Autosomal recessive
• • X-linked
Examples of disorders caused by single-gene defects
• A single-gene mutation may lead to many phenotypic effects
(pleiotropy), and conversely, mutations at several genetic loci
may produce the same trait (genetic heterogeneity).

• Before we continue and to reinforce understanding, it is

prudent that you make sure you work on the following
assignment.
• Assignment 5.1

• Explain in detail the pathogenesis, chromosomal alterations in

the following diseases;
• 1. Sickle cell disease
• 2. Hemophilia
• 3. Polycystic kidney disease
 Multi-factorial inheritance
• Multifactorial (also called polygenic) inheritance is involved in
many of the physiologic characteristics of humans (such as,
height, weight, blood pressure, hair color). A multifactorial
physiologic or pathologic trait may be defined as one governed
by the additive effect of two or more genes of small effect,
conditioned by environmental, non-genetic influences.
• Even monozygous twins reared separately may achieve
different heights because of nutritional or other environmental
influences.
 Disorders with multifactorial inheritance
• Presumably, there is some threshold effect, so that a disorder becomes
manifest only when a certain number of effector genes, as well as
conditioning environmental influences, are involved. The threshold effect
also explains why parents of a child with a polygenic disorder may
themselves be normal. Once the threshold value is exceeded, the severity
of the disease is directly proportional to the number and the degree of
influence of the pathologic genes.
• The following features characterize multifactorial inheritance. These have
been established for the multifactorial inheritance of congenital
malformations and, in all likelihood, obtain for other multifactorial
diseases.
• A multifactorial disorder may occur based on the number of mutant genes
inherited. The risk is therefore greater in siblings of persons having severe
expressions of the disorder. The rate of recurrence of the disorder is the same for
all first-degree relatives (that is, parents, siblings, and offspring) of the affected
individual. Thus, if parents have had one affected child, the risk that the next
child will be affected is between 2% and 7%. The likelihood that identical twins
will both be affected is significantly less than 100% but is much greater (20% to
40%) than the chance that non-identical twins will both be affected.
• In pregnancy, when one child is affected, there is as high as a 7% chance that the
next child will be affected, but after two affected siblings, the risk rises to about
9%.
• Please attempt the following activity before we proceed.
• This form of inheritance underlies common diseases such as
diabetes mellitus, hypertension, gout, schizophrenia, bipolar
disorder, and certain forms of congenital heart disease, as well
as some skeletal abnormalities. Hypertension provides an
excellent example of multifactorial inheritance. At some
arbitrary level of blood pressure, hypertension is said to exist,
because pressures above this level are associated with a
significant disadvantage to the individual
 Cytogenetic disorders and normal karyotype
• Cytogenetics is a branch of genetics that is concerned with the
study of the structure and function of the cell especially the
chromosomes. It includes the routine analysis of the G-Banded
chromosomes, other cytogenetic banding techniques as well as
molecular cytogenetics such as FISH as well as Comparative
genomic hybridization (CGH).
• It is estimated that approximately one of 200 newborn infants has
some form of chromosomal abnormality. The figure is much higher
in fetuses that do not survive to term. It is estimated that in 50% of
first-trimester abortions, the fetus has a chromosomal abnormality.
 Definition of terms
• Cytogenetic disorders may result from alterations in the number or structure of
chromosomes and may affect autosomes or sex chromosomes.
• Karyotyping
• Before discussing chromosomal abnormalities, we need to know that
karyotyping is the basic tool of the cytogeneticist. Karyotyping is the number and
appearance of chromosomes in the nucleus of eukaryotic cells. The term is also
used for the complete set of chromosomes in a species, or an individual
organism. Karyotypes describe the number of chromosomes, and what they look
like under a light microscope. Attention is paid to their length, the position of
the centromeres, banding pattern, any differences between the sex
chromosomes and any other physical characteristics. The preparation and study
of karyotypes is part ot cytogenetics.
• Another definition of a karyotype is a photographic illustration of a
stained metaphase spread in which the chromosomes are arranged
in order of decreasing length. Many techniques for staining
chromosomes have been developed. With the widely used Giemsa
stain (G banding) technique, each chromosome set can be seen to
possess a distinctive pattern of alternating light and dark bands of
variable widths. The use of banding techniques allows certain
identification of each chromosome, as well as of structural changes
in the chromosomes.
• Let us now look at some terminologies used in relation to
chromosome numbers.
• In human beings, the normal chromosome count is 46, that is, 2n = 46. Any
exact multiple of the haploid number (n) is called euploid, whereas,
chromosome numbers such as 3n and 4n are called polyploid. Polyploidy
generally results in a spontaneous abortion.
• Any number that is not an exact multiple of n is called aneuploid. The chief
cause of aneuploidy is non disjunction of a homologous pair of
chromosomes at the first meiotic division or a failure of sister chromatids
to separate during the second meiotic division. The latter may also occur
during somatic cell division, leading to the production of two aneuploid
cells. Failure of pairing of homologous chromosomes followed by random
assortment (anaphase lag) can also lead to aneuploidy.
 Monosomy and Trisomy
• When nondisjunction occurs at the time of meiosis, the
gametes formed have either an extra chromosome (n + 1) or
one less chromosome (n - 1). Fertilization of such gametes by
normal gametes would result in two types of zygotes: trisomic,
with an extra chromosome (2n + 1), or monosomic (2n - 1).
Monosomy involving an autosome is incompatible with life,
whereas trisomies of certain autosomes and monosomy
involving sex chromosomes are compatible with life. These, as
we shall see, are associated with variable degrees of
phenotypic abnormality.
 Mosaicism
• This term is used to describe the presence of two or more
populations of cells in the same individual. In the context of
chromosome numbers, postzygotic mitotic nondisjunction
would result in the production of a trisomic and a monosomic
daughter cell; the descendants of these cells would then
produce a mosaic. As discussed later, mosaicism affecting sex
chromosomes is common, whereas autosomal mosaicism is
not.
 Structural Chromosomal Abnormalities
• Structural changes in the chromosomes usually result from
chromosomal breakage with loss or rearrangement of material.
A cytogenetic shorthand is used to select the changes in which
p (petit) denotes the short arm of a chromosome, and q, the
long arm. Each arm is then divided into numbered regions (1,
2, 3, and so on) from centromere outward, and within each
region the bands are numerically ordered. See Figure 13.
• Translocation involves the transfer of a part of one chromosome to
another in a reciprocal process, where fragments are exchanged between
two chromosomes. In genetic shorthand, translocations are indicated by t
followed by the involved chromosomes in numeric order, for example,
46,XX,t(2;5)(q31;p14). This would indicate a reciprocal translocation
involving the long arm (q) of chromosome 2 at region 3, band 1, and the
short arm of chromosome 5, region 1, band 4.
• When the complete broken pieces are exchanged, the resulting balanced
reciprocal translocation is not harmful as the carrier has the normal
number of chromosomes and the full complement of genetic material.
However, during gametogenesis, the formation of unbalanced gametes
result in abnormal zygotes.
• Translocation involving two acrocentric chromosomes is called centric fusion type, or
robertsonian, translocation where the breaks occur close to the centromere, affecting the
short arms of both chromosomes. Transfer of the segments leads to one very large
chromosome and the other extremely small. The short fragments are lost, leaving the
carrier with 45 chromosomes. The short arms of all acrocentric chromosomes carry highly
redundant genes (for example, ribosomal RNA genes), therefore the loss is compatible with
survival. However gametogenesis could lead to abnormal offspring.
• Isochromosomes result when the centromere divides horizontally rather than vertically. One
of the two arms of the chromosome is then lost, and the remaining arm is duplicated,
resulting in a chromosome with two short arms only or two long arms only. The most
common isochromosome present in live births involves the long arm of the X chromosome
and is designated i(Xq). When fertilization occurs by a gamete that contains a normal X
chromosome, there is monosomy for genes on Xp and trisomy for genes on Xq.
• Deletion involves loss of a portion of a chromosome. A single break
may delete a terminal segment. Two interstitial breaks, with
reunion of the proximal and distal segments, may result in loss of
an intermediate segment. The isolated fragment lacks a
centromere and almost never survives.
• Inversions happen when there are two interstitial breaks in a
chromosome, and the segment reunites after a complete
turnaround.
• A ring chromosome is a variant of a deletion. After loss of distal
segments of each chromosome, the arms unite to form a ring.
• Before we proceed, attempt the following activity.
 Selected Genetic Disorders
• Cytogenetic Disorders Involving Autosomes
• Three autosomal trisomies (21, 18, and 13) and one deletion syndrome (cri
du chat syndrome), which results from partial deletion of the short arm of
chromosome 5, were the first chromosomal abnormalities identified. Only
trisomy 21 and 22q11.2 deletion occur with sufficient frequency to merit
further consideration. Here we briefly consider trisomy 21.
• Trisomy 21 (Down Syndrome)
• Down syndrome is the most common of the chromosomal disorders.
About 95% of affected persons have trisomy 21, so their chromosome
count is 47. As mentioned earlier, the most common cause of trisomy, and
therefore of Down syndrome, is meiotic nondisjunction. The parents of
such children have a normal karyotype and are normal in all respects.
• Maternal age is a significant factor on the incidence of Down syndrome. It
occurs in 1 in 1550 live births in women younger than 20 years, compared
to 1 in 25 live births in women older than 45 years. The correlation with
maternal age suggests that the meiotic nondisjunction of chromosome 21
occurs in the ovum and the extra chromosome is mostly of maternal origin.
• In about 4% of all patients with trisomy 21, the extra chromosomal
material is present not as an extra chromosome but as a translocation of
the long arm of chromosome 21 to chromosome 22 or 14. Such cases are
frequently familial, and the translocated chromosome is inherited from
one of the parents. Approximately 1% of trisomy 21 patients are mosaics,
usually having a mixture of 46- and 47-chromosome cells. Symptoms in
such cases depend on the proportion of abnormal cells.
• Characteristic clinical features of Down syndrome include; epicanthic folds and flat facial
profile, mental retardation, congenital malformations which are responsible for most of the
deaths in early childhood. Serious infections are another important cause of morbidity and
mortality. As with most other clinical features, the basis of increased susceptibility to
infection is not clearly understood. The chromosomal imbalance, in some undefined
manner, also increases the person's risk of developing acute leukemias, particularly acute
megakaryocytic leukemia.
• The overall prognosis for individuals with Down syndrome has improved as a result of better
control of infections. Currently, the median age at death is 47 years. Most of those who
survive into middle age develop histologic, metabolic, and neurochemical changes of
Alzheimer disease. Many develop frank dementia. The basis of this association is being
actively investigated, with the hope of finding clues to the pathogenesis of Alzheimer
disease.
• Although the karyotype of Down syndrome has been known for decades, the molecular
basis of this disease remains elusive.
 Cytogenetic Disorders Involving Sex Chromosomes
• A number of abnormal karyotypes involving the sex chromosomes, ranging
from 45,X to 49,XXXXY, are compatible with life. Indeed, phenotypically
normal males with two and even three Y chromosomes have been
identified. Such extreme karyotypic deviations are not encountered with
the autosomes. In large part this latitude relates to two factors:
• 1. Lyonization of X chromosomes and
• 2. The small amount of genetic information carried by the Y
chromosome.
• The consideration of lionization, began with Mary Lyon (1962). She
proposed that in females only one X chromosome is genetically active. So a
48,XXXX female has only one active X chromosome.
• This phenomenon explains why normal females do not have a double dose
(compared with males) of phenotypic attributes coded by the X chromosome.
The Lyon hypothesis also explains why normal females are in reality mosaics,
containing two cell populations: one with an active maternal X, the other with an
active paternal X. Modifications of this hypothesis is found in diseases like Turner
Syndrome, which affects females.
• Extra Y chromosomes are readily tolerated because the only information known
to be carried on the Y chromosome seems to relate to male differentiation. It
should be noted that whatever the number of X chromosomes, the presence of a
Y invariably dictates the male phenotype. The gene for male differentiation (SRY,
sex-determining region of Y chromosome) is located on the short arm of the Y.
• The Klinefelter syndrome arising in aberrations of sex chromosomes is described
briefly.
 Klinefelter Syndrome
• This syndrome is best defined as male hypogonadism that develops
when there are at least two X chromosomes and one or more Y
chromosomes. Most people with the syndrome are 47,XXY. This
karyotype is the result of non disjunction of sex chromosomes
during meiosis. The extra X chromosome may be of either maternal
or paternal origin. Factors contributing to this meiotic error include
advanced maternal age and a history of irradiation of either parent.
Approximately 15% of the patients show mosaic patterns, including
46,XY/47,XXY, 47,XXY/48,XXXY, and variations on this theme. The
presence of a 46,XY line in mosaics is usually associated with a
milder clinical condition.
• The clinical manifestations of Klinefelter syndrome include;
hypogonadism, an increase in length between the soles and
the pubic bone, eunuchoid body habitus, reduced facial, body,
and pubic hair, gynecomastia, testicular atrophy, low serum
testosterone levels and elevated urinary gonadotropin levels.
Associated disorders include infertility, mental retardation,
breast cancer (20 times more common than in normal males),
extragonadal germ cell tumors, and autoimmune diseases such
as systemic lupus erythematosus
 Single-gene disorders with atypical patterns of
inheritance
• There are three groups of diseases resulting from mutations
affecting single genes that do not follow the mendelian rules of
inheritance. These include diseases caused by:
• 1. Triplet-repeat mutations
• 2. Mutations in mitochondrial genes
• 3. Genomic imprinting.
 Triplet-Repeat Mutations: Fragile X Syndrome
• Fragile X syndrome is the prototype of diseases in which the mutation is
characterized by a long repeating sequence of 3 nucleotides. Other
examples of diseases associated with trinucleotide repeat mutations
include Huntington disease and myotonic dystrophy, and all disorders
discovered so far are associated with neurodegenerative changes.
• Fragile X syndrome is characterized by mental retardation and an
abnormality in the X chromosome. It is one of the most common causes of
familial mental retardation. The cytogenetic alteration, referred to as
Fragile X, is induced by certain culture conditions and is seen as a
discontinuity of staining or constriction in the long arm of the X
chromosome.
• Clinically affected males have moderate to severe mental retardation. They express a
characteristic physical phenotype that includes a long face with a large mandible, large
everted ears, and large testicles (macro-orchidism). Although characteristic of fragile X
syndrome, these abnormalities are not always present or may be quite subtle. The only
distinctive physical abnormality that can be detected in at least 90% of postpubertal males
with fragile X syndrome is macro-orchidism.

• Fragile X syndrome results from a mutation in the FMR1 gene, which maps to Xq27.3. Like
all X-linked recessive disorders, this disease affects males. However 20% of "carrier males",
who may be clinically and cytogenetically normal can transmit the disease to their
grandsons through their phenotypically normal daughters.
• Another peculiarity is the presence of mental retardation in 50% of carrier females. These
unusual features have been related to the dynamic nature of the mutation (See Fig. 5-3).
• Take Note 5.2
• Note that in the first generation all sons are normal and all
females are carriers. During oogenesis in the carrier female,
premutation expands to full mutation; hence, in the next
generation all males who inherit the X with full mutation are
affected. However, only 50% of females who inherit the full
mutation are affected, and only mildly.
• The molecular basis of fragile X syndrome is not yet very clear but is beginning to
be understood. The CGG repeats are located in 5' untranslated region of the
FMR1 gene. In patients with this disease, the expanded CGG repeats are
hypermethylated. Methylation then extends up-stream into the promoter
region, resulting in transcriptional silencing of the FMR1 gene. The product of
the FMR1 gene, called FMR protein (FMRP), is widely expressed in normal
tissues, but higher levels of transcripts are found in the brain and the testis.
Current evidence suggests that FMRP is an RNA-binding protein that is
transported from the cytoplasm to the nucleus, where it binds specific mRNAs
and transports them to the axons and dendrites. It is in the synapses that FMRP-
mRNA complexes perform critical roles in regulating the translation of specific
mRNAs. The absence of this finely coordinated "shuttle" function seems to
underlie the causation of fragile X syndrome”.
• In all cases of other neurodegenerative diseases related to trinucleotide-repeat
expansions, gene functions are altered by an expansion of the repeats, but the
precise threshold at which premutations are converted to full mutations differs
with each disorder. While the expansion in fragile X syndrome occurs during
oogenesis, in other disorders such as Huntington disease, premutations are
converted to full mutations during spermatogenesis. The expansion may involve
any part of the gene and can be grouped into two broad categories, those that
affect untranslated regions (as in fragile X syndrome) or coding regions (as in
Huntington disease). When mutations affect noncoding regions, there is "loss of
function," since protein synthesis is suppressed (for example, FMRP). By
contrast, mutations involving translated parts of the gene give rise to abnormal
proteins that interfere with function of normal proteins (for example, Huntington
disease).
 Diseases Caused By Mutations in Mitochondrial
Genes
• Mitochondria contain several genes that encode enzymes involved in
oxidative phosphorylation. Inheritance of mitochondrial DNA is associated
with maternal inheritance compared to that of nuclear DNA. This
peculiarity is due to the fact that ova contain abundant mitochondria
within their cytoplasm, whereas spermatozoa contain few, if any.
• Diseases caused by mutations in mitochondrial genes are rare and affect
organs most dependent on oxidative phosphorylation (skeletal muscle,
heart, brain). Leber hereditary optic neuropathy is the prototypical
neurodegenerative disorder in this group, which manifests itself as
progressive bilateral loss of central vision that leads to blindness.
 Genomic Imprinting: Prader-Willi and Angelman
Syndromes
• All humans inherit two copies of each gene, carried on homologous maternal and paternal
chromosomes. It has usually been assumed that there is no difference between normal
homologous genes derived from the mother or the father. However, it has been established
that in some genes, functional differences exist between the paternal and the maternal
genes. These occur from an epigenetic process called genomic imprinting, whereby certain
genes are differentially ‘inactivated’ during gametogenesis. Thus, maternal imprinting refers
to transcriptional silencing of the maternal allele, whereas paternal imprinting implies that
the paternal allele is inactivated. Imprinting occurs in ovum or sperm and is then stably
transmitted to all somatic cells derived from the zygote.
• Let us illustrate Genomic imprinting by considering two uncommon genetic disorders:
• 1. Prader-Willi syndrome
• 2. Angelman syndrome.
• Prader-Willi syndrome is characterized by mental retardation, short stature, hypotonia,
obesity, small hands and feet, and hypogonadism. In 60% to 75% of cases, an interstitial
deletion of band q12 in the long arm of chromosome 15 [that is, del(15)(q11;q13)] can be
detected. In many patients without a detectable cytogenetic abnormality, FISH analysis
reveals smaller deletions within the same region. It is striking that in all cases the deletion
affects the paternally derived chromosome 15.
• In contrast with Prader-Willi syndrome, patients with the phenotypically distinct Angelman
syndrome are born with a deletion of the same chromosomal region derived from their
mothers. Patients with Angelman syndrome are also mentally retarded, but in addition they
present with ataxic gait, seizures, and inappropriate laughter. Because of the laughter and
ataxia, this syndrome is also called the happy puppet syndrome.
• A comparison of these two syndromes clearly demonstrates the "parent-of-origin" effects
on gene function. If all the paternal and maternal genes contained within chromosome 15
were expressed in an identical fashion, clinical features resulting from these deletions would
be expected to be identical regardless of the parental origin of chromosome 15.
• The molecular basis of these two syndromes can be understood in the context of imprinting.
It is believed that a set of genes on maternal chromosome 15q12 is imprinted (and hence
silenced), and thus the only functional alleles are provided by the paternal chromosome.
When these are lost as a result of a deletion (in the paternal chromosome), the patient
develops Prader-Willi syndrome. Conversely, a distinct gene that also maps to the same
region of chromosome 15 is imprinted on the paternal chromosome. Only the maternally
derived allele of the gene is normally active. Deletion of this maternal gene on chromosome
15 gives rise to the Angelman syndrome. Molecular studies of cytogenetically normal
patients with Prader-Willi syndrome have revealed that in some cases both of the
structurally normal chromosome 15s are derived from the mother. Inheritance of both
chromosomes of a pair from one parent is called uniparental disomy. The net effect is the
same (i.e., the patient does not have a functional set of genes from the [nonimprinted]
paternal chromosome 15). Angelman syndrome, as might be expected, can also result from
uniparental disomy of parental chromosome 15.
• Review questions
• 1. Give three examples of diseases with multifactorial inheritance as an
underlying factor.
• 2. Which three groups of diseases that result from mutations affecting single
genes that do not follow the mendelian rules of inheritance? Give an example of
a disorder in each group.
• 3. What are the genetic alterations in Hemophilia and Sickle cell disease?
• 4. Differentiate between the terms polyploidy and euploid as applied in
cytogenetics.
• 5. State the clinical features of a child having Down syndrome.
• 6. State the differences between Prader-willis syndrome and Angelman
syndrome.