ADNAN PATHOLOGY book for medical students.pdf

Adnan S. Chaudhary
Nida Rehman Alvi NB

Adnan‟s Human Pathology
Adnan S. Chaudhary | Nida Rehman Alvi NB 1

bi-smi llāhi r-raḥmāni r-raḥīm
ِِ‫م‬ْ‫ي‬ِ‫ح‬ َّ‫ر‬‫ل‬‫ا‬ ِ‫ن‬ٰ ْ
‫ْح‬ َّ‫ر‬‫ل‬‫ا‬ِ‫هلل‬‫ا‬ ِ‫م‬ْ‫س‬ِ‫ب‬
IN THE NAME OF GOD, THE MOST
GRACIOUS, THE MOST MERCIFUL

Dedications
Dedicated to sweet Allah, the Holy Prophet (PBUH), my husband (Behzad) and my parents who have always supported
me, guided me, loved me, and inspired me to never give up and always provided me confidence , motivation, and care to reach
new height in the life.
Nida Rehman Alvi NB
To my RAB, His Prophet (SWT) and all important persons of my life who are praying for me continuously.
Adnan S. Chaudhary

Adnan‟s Human Pathology Dedications
Table of Contents
Pathology _____________________________________________________________________________4
Branches of Pathology ___________________________________________________________________4
Types of specimens used in clinical pathology...................................................................................................1
Importance of Pathology _________________________________________________________________3
Role of Pathology Technician______________________________________________________________3
Scope of Pathology ______________________________________________________________________3
Disease _______________________________________________________________________________3
Classifying Diseases _____________________________________________________________________4
Etiology_______________________________________________________________________________5
Pathology _____________________________________________________________________________5
Pathophysiology ________________________________________________________________________6
Pathogenesis ___________________________________________________________________________6
Clinical Features _______________________________________________________________________6
Signs vs Symptoms ______________________________________________________________________6
Investigations __________________________________________________________________________7
Management and treatment _______________________________________________________________7
Cell Adaptations ________________________________________________________________________8
Hyperplasia____________________________________________________________________________8
Hypertrophy ___________________________________________________________________________9
Atrophy _______________________________________________________________________________9
Metaplasia ____________________________________________________________________________9
Intracellular Accumulation_______________________________________________________________10
Aplasia ______________________________________________________________________________11
Hypoplasia ___________________________________________________________________________11
Hemorrhage __________________________________________________________________________11
Thrombosis ___________________________________________________________________________11
Thrombotic disorders ___________________________________________________________________13
Morphologic Characteristics of Thrombi And Clots ___________________________________________15
Embolism ____________________________________________________________________________15
Infarction ____________________________________________________________________________16
Hyperemia / congestion _________________________________________________________________16
Ischemia _____________________________________________________________________________18
Hypoxia______________________________________________________________________________18
Anaplasia ____________________________________________________________________________19
Edema _______________________________________________________________________________19
Definition ____________________________________________________________________________20

Types (Reversible and Irreversible Injury)___________________________________________________20
Causes of cell injury (Etiology) ___________________________________________________________22
The Morphology of Injury________________________________________________________________23
Patterns of Tissue Necrosis_______________________________________________________________24
Mechanisms of Cell Injury (Necrosis) ______________________________________________________26
Apoptosis_____________________________________________________________________________29
Fatty change __________________________________________________________________________30
Pigmentation__________________________________________________________________________30
Pathologic Calcification_________________________________________________________________31
Inflammation__________________________________________________________________________33
Acute Inflammation_____________________________________________________________________33
Chemical mediators and regulators of inflammation___________________________________________37
Outcomes of Acute Inflammation __________________________________________________________38
Morphologic Patterns Of Acute Inflammation ________________________________________________39
Chronic inflammation___________________________________________________________________39
Etiological factors______________________________________________________________________39
Chronic Inflammatory Cells and Mediators __________________________________________________40
Chronic Inflammation Types _____________________________________________________________40
Morphologic Patterns Of Chronic Inflammation ______________________________________________41
Healing and Repair_____________________________________________________________________43
Restoration Of Normal Structure __________________________________________________________44
SCAR FORMATION ____________________________________________________________________45
Factors That Influence Tissue Repair_______________________________________________________46
The Immune System: Innate And Adaptive Immunity ___________________________________________48
Immunopathology ______________________________________________________________________53
Amyloidosis___________________________________________________________________________58
Allergy_______________________________________________________________________________59
Dysplasia ____________________________________________________________________________60
Neoplasms____________________________________________________________________________60
Classification and nomenclature of tumors __________________________________________________60
Properties of Neoplasms_________________________________________________________________61
Carcinogenesis and etiology______________________________________________________________64
. Grading and staging___________________________________________________________________66
Diagnosis ____________________________________________________________________________66
Different Modes of Metastasis ____________________________________________________________68
TNM Staging System____________________________________________________________________68
Prognosis with Tumors__________________________________________________________________68

Survival & Treatment of Cancer In General _________________________________________________68
Leukemia or Blood Cancer_______________________________________________________________69
____________________________________________________________________________________71
Ulcer (Peptic, Duodenal) ________________________________________________________________71
Hypertension__________________________________________________________________________73
Shock________________________________________________________________________________75
Reference ____________________________________________________________________________78
Authors ______________________________________________________________________________80

Adnan‟s Human Pathology Pathology
Pathology
Patho is a Greek word /term which mean deep,
emotion, passion, Suffering or disease and Logy the
Greek word traditionally mean word, thought,
principle, Speech or study.
“The scientific study of disease is called
pathology.”
Or
“The study of Gross and microscopic patterns of
disease is called pathology.”
Or
“Pathology is the study of essential nature of
disease, disease process and functional changes in
cells, tissues or organs that are caused by disease is
called pathology”
Branches of Pathology
Following are some major branches of pathology.
1. General medical pathology
2. Systemic pathology
3. Cytopathology
4. Anatomical pathology
5. Dermatopathology
6. Forensic pathology
7. Histopathology
8. Neuropathology
9. Pulmonary Pathology
10. Renal pathology
11. Surgical Pathology
12. Clinical pathology
13. Hematopathology/Haematopathology
14. Immunopathology
15. Molecular Pathology
16. Oral/Maxillofacial pathology
General Pathology
It is the branch of pathology deals with very
basic concept of various disease process in the
animal/human body we see the progression of
disease, cause and mechanism of disease and the
associated alteration in the structure and function.
Another definition of general pathology the study
of general reactions of cells and tissues to insults
and injuries that are basis to all disease progress.
Systemic Pathology
The study of the specific disease processes or
reactions as they affect particular organs systems.
For example disease of CNS and GIT etc.
Cytopatopathology
Cyto means cell, Patho means disease logy
means studies Cytology/cytopathology is a very
important topic in the medicine as many diseases
can be diagnosed by studying cells. Cells are
removed from patient are sent for cytological
examination to hospital cytology lab/medical lab
where cells are examined under microscope.
Anatomical Pathology
Anatomical pathology is also called as
anatomic pathology is a medical specialty in which
we study about diagnosis and progression of
disease based on the macroscopic, microscopic,
biochemical, Immunological, and biochemical
examination of organs and tissues. Or Anatomic
pathology is concerned with the diagnosis of
diseases based on the gross, microscopic, and
molecular examination of organs tissues and whole
bodily Autopsy. The anatomical pathologists report
to doctors he/she doesn‘t usually see the patients.
Dermatopathology
Derma means Skin, Patho mean disease and
logy means study. Dermatopathology is a joint sub
specialty of dermatology and pathology in which
deal with the study analysis of the potential cause
of skin diseases at a basic level.
Dermatopathologist work in close association with
clinical/consultant dermatologist.
Dermatopathologist diagnose the cause of
infected/diseased skin tissues by analysis in the
medical laboratory.
Or
Dermatopathology from Greek word derm
that mean skin, pathos mean fate, harm,/disease is a
joint subspecialty of dermatology and pathology
and to a lesser extent of surgical pathology that
focuses on the study of cutaneous disease at a
microscopic and molecular level.
Forensic pathology
Forensic pathology is also an important type
of pathology that focus on finding/determining the
INTRODUCTION TO PATHOLOGY
1

Adnan‟s Human Pathology Branches of Pathology
actual cause of death by examining corps.‫الشیں‬
Forensic mean forum (court of law) Pathology
(study of disease) Application of knowledge of
pathology/medicine to aid in the administration of
justice (in relation to court of law) Forensic
pathology lab is a legal organization of seeking help
from expert in medical profession.
Histopathology
Histo mean tissues Patho mean
disease/suffering Logy mean study. Histopathology
means refers to the microscopic examination of
tissues in order to study the manifestation of
disease.
or
Histopathology refers to the examination of a
biopsy/surgical specimen by a pathologist.
or
Histopathology the microscopic study of
diseased tissue is an important tool of anatomical
pathology since an accurate diagnosis of cancer
and other diseases usually requires
histopathological examination of samples.
Neuropathology
Neuro mean Brain, Patho mean study and
logy mean disease. It is the study of disease of
nervous system tissues usually in the form of either
small surgical biopsy/whole body autopsy.
Neuropathology is the subspecialty of anatomic
pathology, Neurology and Neurosurgery.it shouldn't
be confused with Neuropathy which refers to the
disorder of nervous system.
The work of neuropathologist consists of
largely of examining biopsy tissue from the brain
and spinal cord to diagnose of disease. The biopsies
usually requested if the mass is detected to
checkout for an abnormality.
Pulmonary Pathology
Pulmo mean Lungs and pulmonary means
related to lungs Patho mean disease logy mean
study. In pulmonary pathology we study about
diseases related to lungs and respiratory system,
neoplastic and non-neoplastic diseases of lungs and
thoracic pleura when lung disease occur that
prevent the lung from working properly.
Renal Pathology
Renal mean kidneys Pathology mean study of
diseases. Renal pathology is the study of
cells/tissues damage due to injury /disease. Renal
pathologist works closely with Nephrologists and
Kidneys transplant surgeons. Renal pathologist
obtain specimen via percutaneous renal biopsy.
Specimen of kidneys is examined under light
microscope, electron microscope and
immunofluorescence to obtain a definitive
diagnosis.

Surgical Pathology
Surgical pathology is the branch of pathology
in which we deal with the study of tissues which are
removed from the living bodies‘ patients‘ pre and
post-surgery to check out the abnormality and
determine the treatment plan. Often two major
types of specimen submitted for surgical pathology
analysis. Most often in order to render a definitive
diagnosis.
Clinical Pathology
Clinical pathology is the diagnosis of disease
through the study of bodily fluids, such as blood
,urine, tissues, Saliva, semen, vaginal discharge.
Clinical pathologists are
specialized
physician/medical lab
scientist who diagnose
diseases examining and
testing cells/bodily
fluids and tissues.
Types of specimens
used in clinical pathology
Blood
Blood is used in many tests. Blood
can either be examined as a "whole,"
as plasma (the fluid left when red and
white blood cells are removed), or as
serum (a clear fluid that separates
from blood when it clots).
Blood is usually drawn with a needle
from a vein, usually in the forearm.

Adnan‟s Human Pathology Branches of Pathology
(This is also called venipuncture).
Sometimes, the tip of the finger is
pricked and then squeezed to draw
blood (called a finger stick).
Urine
Urine is also used for a wide range of
tests. Urine specimens can be obtained
by:
 Random method. The patient
urinates in a cup.
 Clean catch specimen. The outer
genital area has been cleaned
before urinating in a cup.
 Sterile urine test. This needs
catheterization (a tube is put into
the urethra and goes to the bladder
to obtain urine).
Sometimes, a healthcare provider will
need the patient to do a timed test to
measure substances excreted into the
urine over several hours.
Sputum
(also
called
phlegm)
Sputum can be coughed into a clean
container.
Feces
Feces or stool is usually collected by
the patient in a clean cardboard or
plastic container.
Other
body
fluids
Other body fluids collected for testing
may include the following:
 Spinal fluid
 Pleural fluids. These fluids are
around the lungs and/or in the
pleural cavity (the space between
the two membranes that surround
the lungs).
 Belly fluids
 Joint fluids
 Bone marrow
Hemato/Haematopathology
Haem = Blood, pathology=study of disease
It is the study of disease/diorders related to blood,
abnormal growth and appearance of blood cells,
their production, and other organs/tissues that are
involved in the haematopoiesis such as bone
marrow, spleen, thymus, etc. the blood abnormal
cells (WBC) can be seen very high in numbers in
leukemia (a type of blood cancer).
Immunopathology
Immunopathology is the branch of
pathology/medicine in which we deal study about
immune responses associated with disease it
includes the study of diseases of organisms, organ
system, diseases with respect to immune response
/system while immunopathogenesis is the process
of disease development involving an immune
response /components thereof.
Radiation Pathology
Radiation pathology is the study of the interaction
between human tissues and radiations and problems
that can be rise from the use of radiations. The
tissue can be genetically deform in result this can
lead to variety of illnesses, that could be
minor/deadly
Molecular Pathology
Molecular pathology is the branch of pathology that
deals with the study of diagnosis of disease through
the examination of molecules with in the
organs, tissues/bodily fluids (such as urine, sputum,
semen, vaginal discharge etc.
Oral And Maxillofacial pathology
Oral and maxillofacial pathology is one of the
dental specialties and is sometimes consider
specialty of both dentistry and pathology.
Oral and maxillofacial pathology also termed as
oral pathology) stomatoganthic disease, dental
disease, or mouth disease refers to the disease of
mouth.(oral cavity/stomata)jaws(maxillary or
gnath) and related structure such as salivary glands,
tempomandibular joints, facial muscles and perioral
skin.in this we study about diseases of oral cavity
and jaws.

Adnan‟s Human Pathology Importance of Pathology
Importance of Pathology
Pathology has an importance of backbone
.as without backbone we can‘t perform our daily
activities we can‘t stand/sit. Similar without
pathology we can‘t find out the cause of any
disease. The whole essence of any medicine lies in
physiology, pathology, and pharmacology etc. If a
person is a master of these areas medicine he can
understand medical issues well coming to
pathology it is the key of our field, the mechanism
of disease progress, vital to understand the disease.
If we don‘t know how a disease occur than we
cannot treat the ideal way to treat is to know the
normal physiology followed by pathology and its
treatment (pharma).
Pathology is the branch of medical sciences
primarily concerned with the examination of
organs, tissues, and bodily fluids, blood, saliva,
bone marrow, urine. for example an order to
diagnose a specific condition or disease. Typically
laboratories will process the sample provided and
analysis the result which are given to the patient's
doctor.
A general pathologist/lab scientist is a
physician who is trained in clinical chemistry,
microbiology, and hematology and is familiar with
all aspects of laboratory analysis.it is possible to
overemphasize the importance of pathology in
modern medicine. Pathology is used in the
diagnosis, treatment and management of an
increasing range of clinical conditions and studies
show that 70-80% of all health care decisions
diagnosis /treatments depend upon pathological
investigations.it use in equally significant in the
investigation of male and female infertility.
Role of Pathology Technician
Pathology technician also plays an
important role in medical laboratory diagnosis.
They examine dead bodies during Autopsies and
assist doctor during autopsies .they also assist
doctors during lab work analysis. The pathology
technician/diploma holders are responsible to assist
their doctors/lab scientist by preparing, examining,
and processing tissues and
bodily fluids specimen in medical laboratories.
Pathology technology concern the test
chemical, procedure and laboratory machinery used
to analyze biological Samples.
Scope of Pathology
Pathology has a wide scope if you have
completed your beginner certificate /diploma in
pathology. You can begin work in medical
laboratories. You can study further more in medical
lab sciences to earn your bachelor/Master‘s degree
you can continue your studies till PHD in lab
sciences.
After getting your degrees you can work as a
pathologist/lab scientist. Join as an assistant
professor in medical college and work there as a
pathology teacher/lecturer. There are several
advantages of joining a medical institute which
include seeing a wide range of cases and getting
experience in different subspecialties.
The pay scale is decent and work is not so
tough so you can have a balanced work and family
life. Pathology field may not be suitable for those
who don‘t like to follow instructions or want to
peruse something of their own.
Disease
A disease in any change in structure or function of
cells, tissues/organs of human /animal other than
injury that disrupts the normal function of the body
is called disease.
Disease is a change in a body that disturbs the
normal functioning of body's system.
Definition of disease: Resulting from a
pathophysiological response to external or internal
factors.
Definition of disorder: A disruption of the disease
to the normal or regular functions in the body or a
part of the body.
Disorders can be classified into the following areas:
 Mental
 Physical
 Genetic
 Emotional
 Behavioural

Adnan‟s Human Pathology Classifying Diseases
 Structural
Definition of syndrome: A collection or set of
signs and symptoms that characterize or suggest a
particular disease.
Down syndrome is a well-known genetic syndrome.
Classifying Diseases
A disease is the modification of the structure and
function where it affects the body from working
normally in the body‟s system. The characteristics
of a disease can be shown from particular signs
and symptoms. These diseases are classified into
different types.
Acquired disease
This is where the disease is not present from birth
therefore it is not inherited. These factors can occur
from the external environment. These are diseases
that can be passed on through communicable and
non-communicable means.
Acquired disease corresponds with infectious
disease as it is non-genetic. An example of an
acquired disease is HIV. HIV is a sexual
transmitted disease that can be passed from
unprotected sex, contaminated blood transfusions
etc. This disease is classified to be acquired.
Congenital disease:
This is where the disease is present from birth. This
can be genetic or non-genetic. There are many
conditions that can be passed in this way. One of
them like sickle cell anemia is an inherited lifelong
disease. The sickle cells are sticky and stiff so they
block the blood flow in the blood vessels. The
blood flow that is blocked can cause pain and organ
damage. This is more likely to develop into heart
disease.
Infectious diseases
This can be caused from harmful microorganisms
such as bacteria, viruses, fungi or parasites.
Infectious diseases can be transferred from person
to person. Basically the diseases a person can
‗catch‘. The spread of diseases can be categorized
into direct contact (person to person) and indirect
contact (spread through the air or touching an
infected surface).
Direct contact
Direct contact happens when the infected person
transmits the microorganisms to another person
without a contaminated object or person. Person to
person contact: Direct contact through
person to person contact can occur by touching the
infected person or from the secretion of bodily
fluids.
Another way is the spray of droplets that can spread
an infectious disease which can occur from
coughing and sneezing. The common cold is one
example of the spread of an infectious disease.
If the spread of droplets from an infected person
reaches the eyes, nose or mouth of a normal person,
it can cause symptoms of the illness. The droplets
can move up to three feet as they‘re large in size of
10 micrometers allowing them to stay in the air for
along. Droplet transference can develop from
packed environments of which it clarifies in why
respiratory infections are common during the
months of winter. Infectious diseases can be spread
directly from animal to person. This can happen
from being bitten or scratched from the contact of
the infected animal. It can make you sick but in
extreme cases could cause death.
One other way it is spread is from Mother to unborn
child. The pathogens can pass through the placenta
like the AIDS virus and the toxoplasmosis parasite.
Indirect contact
Indirect contact is the transfer of infectious particles
from person to person by an intermediate carrier.
These pathogens can stay onto inanimate objects
which include table tops, doorknobs etc. Other
infections come from the organisms that live
within the environment but are not passed from
person to person. Examples include fungal
infections like histoplasmosis, with some bacterial
infection like anthrax. Airborne transmission
happens from indirect contact where they travel
through the air in miniature sized particles. These
miniature sized particles ejected out in the air for
even long periods of time.
Some disease can be transferred by bites and stings
where the germs use the insect carriers. This can be
mosquitos, fleas etc. The carriers are also known as
vectors. Mosquitos are an example of carrying the
malaria parasite. The vector pathogen spreads when
the insect encounters that microorganism on its
body or in its intestinal tract to where it land on the
person and bites them. The insect‘s body can be
used to multiply the pathogen in order for it to
infect a new host.
Other diseases by indirect contact can happen from
food contamination. This can include food and
water that is contaminated. Or also known as
common vehicle transmission that lets germs spread
and cause the illness. Food can be called a vehicle
if the germs spread in causing an illness like the
contamination of E.coli.

Adnan‟s Human Pathology Etiology
A fomite is another indirect transmission of where
the substance or the object is carrying
microorganisms. These can be germs or parasites
that transfer from one individual to the next. A
fomite can be anything like a dirty cloth. These
objects can assist in the spread of pathogenic
organisms.
Diseases with environmental
causes
This is due to environmental factors that can be a
part of forming a disease. This affects individuals
that have a particular condition that is already
genetically inherited. This can include diet, stress,
physical and mental abuse, exposure to pathogens,
toxins, radiation and chemicals. One example is
asbestos that was used to insulate
houses, factories and schools. Then it was realised
of how dangerous the insulation can be where it
was found to cause a type of cancer in the lungs
called mesothelioma.
Degenerative diseases
The structure or function deteriorating over time
affecting the tissues or organs. It can take effect
from body wear or your choice of regime like
eating patterns or exercise. It often comes from the
ageing process of the body wearing down as
damages occur that can sometimes lead to pain or
loss of use. An example can be osteoarthritis.
Another example of degenerative diseases is
Alzheimer‘s where their ability is limited in
perform daily activities without support.
The above describes each different types of
diseases and infections. These groups are used by
health professional to identify its relevance to its
respective disease.
Classifying diseases provides an order of
investigation and representation of the group the
disease falls into.The infectious diseases are most
common and present in most human beings. They
are regularly treated through vaccines. They
sometimes referred as protozoal. With this in mind
Infectious diseases have other ways
of ‗infection‘ and terms are used to classify the rate
and/or action of infectious diseases. Putting
diseases especially infectious diseases in to
informative system of understanding and its actions
can be overlapped with different meanings but by
labeling them in sub-category will help
professionals to develop diagnosis to the problem.
Also diseases have different - rates, period it takes
and area of spreading.
Terms used are either
1. Acute disease
2. Chronic disease
3. Subacute disease
4. Latent disease
5. Communicable
6. Contagious diseases
Remember
 A disease is a pathophysiological response
to internal or external factors.
 A disorder is a disruption to regular bodily
structure and function.
 A syndrome is a collection of signs and
symptoms associated with a specific
health-related cause.
 A condition is an abnormal state of health
that interferes with normal or regular
feelings of wellbeing.
Etiology
Etiology is concerned with general causes of a
disease and the circumstances (‗risk factors‘) that
predispose an individual to suffer
from its effects: it may be thought of as answering
the question, ‗why?‘
Aetiology makes no assumptions or assertions
about the processes by which these factors bring
about the condition. Thus, the aetiology of
tuberculosis (TB) involves poor public and
domestic hygiene, reduced patient immune status
and the mycobacterium; that of cancer may include
genetic predisposition, viral infection and
environmental toxins; that of essential hypertension
involves obesity, salt intake and stress, etc.
Etiology is the origin of a disease, including the
underlying causes and modifying factors. It is now
clear that most common diseases, such as
hypertension, diabetes, and cancer, are caused by a
combination of inherited genetic susceptibility and
various environmental triggers. Understanding the
genetic and environmental factors underlying
diseases is a major theme of modern medicine.
Pathology
Pathology is concerned with the mechanisms
of the disease process, what the disease does, and
how it does so. It answers the question, ‗how did
it cause the observed symptoms?‘ Ideally it will
explain the steps by which the aetiological risk
factors lead to the malfunction. It then describes

Adnan‟s Human Pathology Pathophysiology
the changes caused in body function resulting
from the disease and the body‘s response to this
Pathophysiology
The pathophysiology of a disease relates its
effects to the disruption of normal physiological
functions, e.g. the pathophysiology of essential
hypertension involves a raised peripheral vascular
resistance and possibly an expansion of
the intravascular fluid volume.
Pathogenesis
Pathogenesis describes the development or
progression of the disease process. Thus, the
pathogenesis of rheumatoid arthritis (RA) involves
synovial hyperplasia followed by inflammatory cell
infiltration, then articular erosion. Where
immunological processes are known to be involved
in the disease, e.g. the autoimmune pancreatic
destruction in type 1 diabetes mellitus, the term
immunopathology is used.
There are a few general pathogenic mechanisms,
such as inflammation and ischaemia, that occur as
fundamental bodily responses to very many
diseases.
Pathogenesis refers to the steps in the development
of disease. It describes how etiologic factors trigger
cellular and molecular changes that give rise to the
specific functional and structural abnormalities that
characterize the disease. Whereas etiology refers to
why a disease arises,
pathogenesis describes how a disease develops.
Clinical Features
Signs and symptoms, often thought to be
synonymous, are distinct terms. Symptoms are
subjective; they are noticed by the patient and
either reported – the things a patient complains
of – or elicited on questioning. Signs are usually
found objectively on examination by the clinician,
although occasionally may be noticed by
the patient. Both are important: the former
emphasize what are likely to be the patient‘s
major concerns; the latter aid precise diagnosis.
The typical pattern of clinical features
caused by a disease is called its presentation. Many
diseases have such consistent presentations as to be
almost diagnostic, e.g. a spiking fever, stiff neck
and photophobia in meningitis; such
definitive features are called pathognomonic. A
well-defined group of clinical features that
commonly occur together is sometimes called a
syndrome, e.g. proteinuria, hypoproteinaemia
and oedema together are known as the ‗nephrotic
syndrome‘
Signs vs Symptoms
Basis for
comparison
Signs Symptoms
Meaning The sign is an
objective
evidence of a
disease which
means others
observe it.
The symptom
is a subjective
evidence of a
disease which
means it's only
what a person
can feel.
Example Asthma,
tuberculosis,
cancer, AIDS
have few signs
which can be
specifically
diagnosed by
health care
professionals
Itching, body
pain, nausea,
headache are
the symptoms
felt only by the
person or the
patients.
How to
observe
Signs can be
visible and
observable by
the health care
professionals
The sufferer or
patients can
only feel
symptoms.
Way to check Signs are
measurable by
monitoring
pulse rate,
temperature, X-
ray, Laboratory
test, and other
machines.
Symptoms
cannot be
measure; they
are only felt.
Types Medical signs
are of three
Medical
Symptoms are

Adnan‟s Human Pathology Investigations
Basis for
comparison
Signs Symptoms
types:
Anamnestic
signs
Prognostic signs
Diagnostic
signs
of three types:
Chronic
symptoms.
Relapsing
symptoms.
Remitting
symptoms.
Investigations
In describing a disease it is helpful to include the
tests or procedures used to confirm a diagnosis,
distinguishing between closely related conditions
(the differential diagnosis) or monitoring
progress. For example, although the measurement
of urinary glucose is a poor method of
assessing control in a patient with diabetes
mellitus, it is quite useful for screening large
groups for possible diabetes.
Management and treatment
Management embraces all the decisions made to
deal with the patient‘s complaint; it describes
the strategy. Its first task is to decide realistic
aims, based on a knowledge of the presentation,
investigations and natural history. Within the
broad area of management, treatment comprises
the range of interventions, like drugs, surgery or
physiotherapy, that can be used to achieve these
aims. Of course, this can include doing very little if
the condition is self-limiting. On the other
hand, in very advanced or incurable disease,
management might involve no more than symptom
control, nursing care, simple reassurance
and appropriate counseling, i.e. palliative care.
The assessment of the balance of harms and
benefits of different treatments (the risk-to benefit
or harm-to-benefit ratio) must be based
on knowledge of the severity and mortality of
the condition, the risks of not treating and the
toxicity of the treatment.

Adnan‟s Human Pathology Cell Adaptations
Cell Adaptations
Cells normally maintain a steady state called
homeostasis in which the intracellular milieu is kept
within a fairly narrow range of physiologic
parameters. As cells encounter physiologic stresses
or pathologic stimuli, they can undergo adaptation,
achieving a new steady state and preserving
viability and function. The principal adaptive
responses are hypertrophy, hyperplasia, atrophy,
and metaplasia. If the adaptive capability is
exceeded or if the external stress is inherently
harmful, cell injury develops.
Physiologic adaptations
Physiologic adaptations usually represent responses
of cells to normal stimulation by hormones or
endogenous chemical mediators (e.g., the hormone-
induced enlargement of the breast and uterus during
pregnancy).
Pathologic adaptations
Pathologic adaptations are responses to stress that
allow cells to modulate their structure and function
and thus escape injury. Such adaptations can take
several distinct forms.
Hyperplasia
Hyperplasia is an increase in the size of an organ
or tissue caused by an increase in the number of
cells.
Hyperplasia is an adaptive response in cells
capable of replication, hyperplasia takes place if
the tissue contains cell populations capable of
replication; it may occur concurrently with
hypertrophy and often in response to the same
stimuli.
It is exemplified by glandular proliferation in the
breast during pregnancy.
In some cases, hyperplasia occurs together with
hypertrophy. During pregnancy, uterine
enlargement is caused by both hypertrophy and
hyperplasia of the smooth muscle cells in the
uterus.
Hyperplasia can be physiologic or pathologic. In
both situations, cellular proliferation is stimulated
by growth factors that are produced by a variety of
cell types.
Physiologic hyperplasia
The two types of physiologic hyperplasia.
1. Hormonal hyperplasia
2. Compensatory hyperplasia
Hormonal hyperplasia exemplified by the
proliferation of the glandular epithelium of the
female breast at puberty and during pregnancy.
Compensatory hyperplasia in which residual
tissue grows after removal or loss of part of an
organ. For example, when part of a liver is resected,
mitotic activity in the remaining cells begins as
early as 12 hours later, eventually restoring the liver
to its normal weight. The stimuli for hyperplasia in
this setting are polypeptide growth factors produced
by uninjured hepatocytes as well as non-
parenchymal cells in the liver. After restoration of
the liver mass, cell proliferation is ―turned off‖ by
various growth inhibitors
Pathologic hyperplasia
Pathologic hyperplasia is caused by
excessive hormonal or growth factor stimulation.
For example, after a normal menstrual period there
is a burst of uterine epithelial proliferation that is
normally tightly regulated by stimulation through
pituitary hormones and ovarian estrogen and by
inhibition through progesterone. However, a
disturbed balance between estrogen and
progesterone causes endometrial hyperplasia,
which is a common cause of abnormal menstrual
bleeding.
An important point is that in all of these
situations, the hyperplastic process remains
controlled; if the signals that initiate it abate, the
hyperplasia disappears. It is this responsiveness
to normal regulatory control mechanisms that
distinguishes pathologic hyperplasia from cancer, in
which the growth control mechanisms become
deregulated or ineffective.
CELL ADAPTATIONS & TERMINOLOGIES
2

Adnan‟s Human Pathology Hypertrophy
Hypertrophy
Hypertrophy is an increase in the size of an organ
or tissue due to an increase in the size of
cells.
Hypertrophy is an increase in the size of cells
resulting in increase in the size of the organ.
Other characteristics include an increase in
protein synthesis and an increase in the size or
number of intracellular organelles. A cellular
adaptation to increased workload results in
hypertrophy, as exemplified by the increase in
skeletal muscle mass associated with exercise and
the enlargement of the left ventricle in hypertensive
heart disease.
Types of Hypertrophy
Hypertrophy can be physiologic or pathologic and
is caused either by increased functional demand or
by growth factor or hormonal stimulation.
Physiologic hypertrophy enlargement of the uterus
during pregnancy occurs as a consequence of
estrogen stimulated smooth muscle hypertrophy.
Increased demand the striated muscle cells in both
the skeletal muscle and the heart can undergo only
hypertrophy because adult muscle cells have a
limited capacity to divide.
Pathologic cellular hypertrophy is the cardiac
enlargement that occurs with hypertension or
aortic valve disease.
Atrophy
Atrophy is a decrease in the size of an organ or
tissue and results from a decrease in the mass of
preexisting cells.
Shrinkage in the size of the cell by the loss of cell
substance is known as atrophy.
Causes of atrophy
1. Decreased workload
2. Nutritional or oxygen deprivation
3. Diminished endocrine stimulation
4. Aging
5. Denervation (lack of nerve stimulation in
peripheral muscles caused by injury to
motor nerves).
Characteristic features often include the presence of
autophagic granules, which are intra cytoplasmic
vacuoles containing debris from degraded
organelles.
The mechanisms of atrophy consist of a
combination of decreased protein synthesis and
increased protein degradation in cells.
In some instances, atrophy is thought to be
mediated in part by the ubiquitin proteasome
pathway of protein degradation. In this pathway,
ubiquitin-linked proteins are degraded within the
proteasome, a large cytoplasmic protein complex.
Figure Atrophy of the brain
Metaplasia
Metaplasia is the replacement of one differentiated
tissue by another.
Metaplasia is a reversible change in which one
adult cell type (epithelial or mesenchymal) is
replaced by another adult cell type.
1. Squamous metaplasia

Adnan‟s Human Pathology Intracellular Accumulation
Squamous metaplasia is exemplified by the
replacement of columnar epithelium at the
squamocolumnar junction of the cervix by
squamous epithelium.
It can also occur in the respiratory epithelium of
the bronchus, in the endometrium, and in the
pancreatic ducts.
Associated conditions include chronic irritation
(e.g., squamous metaplasia of the bronchi with
long-term use of tobacco) and vitamin A
deficiency.
This process is often reversible.
2. Osseous metaplasia
Osseous metaplasia is the formation of new bone at
sites of tissue injury. Cartilaginous metaplasia may
also occur.
3. Myeloid metaplasia
Myeloid metaplasia (extramedullary hematopoiesis)
is proliferation of hematopoietic tissue at sites other
than the bone marrow, such as the liver and spleen.
Intracellular Accumulation
Parenchymal cells may accumulate normal (water,
proteins, etc.) or abnormal (mutated proteins,
infectious agents, etc.) substances in their nuclei or
cytoplasm (typically in phago-lysosomes). These
substances can be produced by the cell
(endogenous) or elsewhere but stored in the cell
(exogenous). This can be harmless for the cell or
toxic. Here are some examples of accumulations.
1. Fatty Change or Steatosis
2. Cholesterol & Cholesteryl esters
3. Proteins
4. Glycogen
5. Pigments
Mechanisms of intracellular
accumulation
Accumulate in the cell via 4 main pathways
1. Abnormal metabolism (can't remove
endogenous substance) - e.g. fatty change in
liver and heart
2. Abnormal folding, transport, or degradation
of endogenous proteins - e.g. α1-antitrypsin
in liver cells
3. Storage diseases: Defect in enzymes that
metabolize lipids and carbs -> accumulation
of endogenous lipids and carbohydrates in
usually lysozymes
4. Ingestion of indigestible materials - cell
takes in exogenous substances that it can't
metabolize or transport elsewhere.
1. Normal cellular constituents
1)Rate of synthesis increased (e.g. Russell bodies
in plasma cells)
2)Rate of metabolism is inadequate to remove a
normal substance (e.g. fatty liver, lipid
accumulation in heart from prolonged moderate
hypoxia causing tigered myocardium,
atherosclerosis, xanthomas, foamy
macrophages, cholesterolosis, and protein
resorption droplets in renal tubules in
proteinuria)
3)Genetic defects in metabolism, transport,
packaging or secretion (e.g. in a-1-antitrypsin
deficiency there is a slow-folding protein and
accumulation of partially folded intermediates,
glycogen accumulation in renal epithelium,
liver and heart of diabetics or in glycogenoses)
2. Abnormal substance
1.Abnormal exogenous particle (e.g. carbon
pigment - anthracosis, tattooing)
2.Hyaline change (intracellular protein or
extracellular collagen, BM material or amyloid)
3.Calcification (dystrophic, metastatic -
hypercalcemia)
3. Pigment
Endogenous pigments (e.g. lipofuscin is a
combination of lipids and phospholipids. It is
yellow-brown and accumulates in liver and heart
with aging. EM: perinuclear electron-dense
aggregate; melanin, hemosiderin).

Adnan‟s Human Pathology Aplasia
Figure Mechanisms of intracellular accumulation
Aplasia
Aplasia is a failure of cell production.
During fetal development, aplasia results in
agenesis, or absence of an organ due to failure of
production. Later in life, it can be caused by
permanent loss of precursor cells in proliferative
tissues, such as the bone marrow.
Hypoplasia
Hypoplasia is a decrease in cell production that is
less extreme than in aplasia.
It is seen in the partial lack of growth and
maturation of gonadal structures in Turner
syndrome and Klinefelter syndrome.
Hemorrhage
Hemorrhage is the escape of blood from the
vasculature into surrounding tissues, a hollow
organ or body cavity, or to the outside.
Hemorrhage is most often caused by trauma.
Hemorrhage, defined as the extravasation of blood
from vessels, occurs in a variety of settings.
1) Hematoma
This localized hemorrhage occurs within a tissue or
organ.
2) Hemothorax,
hemopericardium,
hemoperitoneum, and
hemarthrosis
Hemorrhage may occur in the pleural cavity,
pericardial sac, peritoneal cavity, or a synovial
space, respectively. Extensive hemorrhages can
occasionally result in jaundice from the massive
breakdown of red cells and hemoglobin.
3) Petechial hemorrhages,
petechiae, or purpura
These small, punctate hemorrhages occur in
the skin, mucous membranes, or serosal surfaces.
4) Ecchymosis
This diffuse hemorrhage is usually in skin and
subcutaneous tissue.
Thrombosis
Thrombosis is intravascular coagulation of blood,
often causing significant interruption of
blood flow.
It is pathologically predisposed by many
conditions, including venous stasis, usually from
immobilization; CHF; polycythemia; sickle cell
disease; visceral malignancies; and the use of oral
contraceptives, especially in association with
cigarette smoking.
Thrombogenesis

Adnan‟s Human Pathology Thrombosis
This process results from the interaction of
platelets, damaged endothelial cells, and the
coagulation cascade.
Platelets
a) Platelet functions
i. Maintain the physical integrity of the
vascular endothelium
ii. Participate in endothelial repair through the
contribution of platelet-derived growth
factor (PDGF)
iii. Form platelet plugs
iv. Promote the coagulation cascade through
the platelet phospholipid complex
b) Reactions involving platelets
(1) Adhesion
i. Vessel injury exposes subendothelial
collagen, leading to platelet adhesion
(adherence to the subendothelial
surface).
ii. Interaction of specific platelet-surface
glycoprotein receptors and
subendothelial collagen is mediated by
von Willebrand factor.
(2) Release reaction
Soon after adhesion, platelets release adenosine
diphosphate (ADP), histamine, serotonin, PDGF,
and other platelet granule constituents.
(3) Activation of coagulation cascade
Conformational change in the platelet membrane
makes the platelet phospholipid complex available,
thus contributing to the activation of the
coagulation cascade, leading to the formation of
thrombin.
(4) arachidonic acid metabolism
Arachidonic acid, provided by activation of the
platelet membrane phospholipase, proceeds through
the cyclooxygenase pathway to the production of
thromboxane a2 (txa2). Platelet TxA2 is a potent
vasoconstrictor and platelet aggregant. The
inhibition of cyclooxygenase by low-dose aspirin is
the basis of aspirin therapy for prevention of
thrombotic disease.
(5) Platelet aggregation
i. Platelets stick to each other (as contrasted to
adhesion, the adherence of platelets to the
underlying subendothelium).
ii. Additional platelets are recruited from the
circulation to produce the initial hemostatic
platelet plug
iii. The process is mediated by the glycoprotein
IIb-IIIa complex on the surface of the
platelets that is required for the linking of
platelets by fibrinogen bridges.
iv. Agonists that promote aggregation include
aDP, thrombin, and txa2, as well as
collagen, epinephrine, and platelet-
activating factor, derived from the granules
of basophils and mast cells.
(6) Stabilization of the platelet plug.
Fibrinogen bridges bind the aggregated platelets
together. The platelet mass is stabilized by fibrin.
(7) Limitation of platelet plugs formation.
Prostacyclin (PGI2), another product of the
cyclooxygenase pathway, is synthesized by
endothelial cells. Endothelial PGI2 is antagonistic
Sto platelet TxA2 and limits further platelet
aggregation. Fibrin degradation products are also
inhibitors of platelet aggregation.
Endothelial cells
a. These cells are resistant to the thrombogenic
influence of platelets and coagulation proteins.
Intact endothelial cells act to modulate several
aspects of hemostasis and oppose coagulation
after injury by thromboresistance.
b. Some functions of endothelial cells include:
i. Producing heparin-like molecules,
endothelial proteoglycans that activate
antithrombin III, which neutralizes thrombin
and other coagulation factors, including
factors IXa and Xa
ii. Secreting plasminogen activators, such as
tissue plasminogen activator (tPa)
iii. Degrading ADP
iv. Taking up, inactivating, and clearing
thrombin.
v. Synthesizing thrombomodulin, a cell-surface
protein that binds thrombin and
converts it to an activator of protein C, a
vitamin K-dependent plasma protein.
Activated protein C (APC) cleaves factors
Va and VIIIa, thus inhibiting coagulation.
vi. Synthesizing protein s, a cofactor for APC
vii. Synthesizing and releasing PgI2
viii. Synthesizing and releasing nitric oxide,
which has actions similar to those of PGI2.
Coagulation cascade
This has been classically described as following
two distinct, but interconnected, pathways.

Adnan‟s Human Pathology Thrombotic disorders
a. Extrinsic pathway of coagulation is initiated
by tissue factor, which activates factor VII and
forms a tissue factor–factor VIIa complex. The
complex initiates coagulation through the
activation of factor X to factor Xa (and
additionally factor IX to factor IXa). Factor Xa
converts prothrombin (factor II) to thrombin
(factor IIa). factor Va is a cofactor required in
the conversion of prothrombin to thrombin.
Thrombin converts fibrinogen to fibrin.
(1) The prothrombin-mediated cleavage of
fibrinogen results in a fibrin monomer,
which is polymerized and stabilized by
factor XIII, thus forming the fibrin clot.
(2) The action of the tissue factor–factor VIIa
complex is limited by tissue factor
pathway inhibitor.
(3) The extrinsic pathway is clinically
evaluated by the prothrombin time (Pt),
which is a measure of factors II, V, VII,
X, and fibrinogen.
Intrinsic pathway of coagulation involves the
activation of all clotting factors with the exception
of factors VII and XIII.
(1) This pathway may involve contact activation
with interactions of the so-called contact factors:
factor XII (Hageman factor), prekallikrein, and
high-molecularweight kininogen, as well as
factor XI. Contact activation is important in in
vitro clotting in glass containers and in laboratory
testing, but its physiologic role has been questioned
because a deficiency of the contact factors is not
associated with abnormal bleeding.
(2) It is probably initiated by the tissue factor–
factor VIIa complex (from the extrinsic pathway),
activating factor IX to factor IXa. Factor IXa, in
turn, leads to the conversion of factor X to factor
Xa, catalyzed by factor VIIIa. It can also be
activated by the platelet phospholipid complex,
which becomes available through conformational
changes in the platelet membrane.
3) Thrombin production further stimulates the
pathway by the activation of factor XI to factor
XIa and by the activation of the cofactors, factor V
to factor Va and factor VIII to factor VIIIa.
(4) The intrinsic pathway can be evaluated by the
partial thromboplastin time (Ptt), which is a
measure of factors II, V, VIII, IX, X, XI, XII, and
fibrinogen.
Fibrinolysis (thrombus
dissolution)
This is concurrent with thrombogenesis and
modulates coagulation. It restores blood flow in
vessels occluded by a thrombus and facilitates
healing after inflammation and injury.
1. The proenzyme plasminogen is converted by
proteolysis to plasmin, the most important
fibrinolytic protease.
2. Plasmin splits fibrin.
3. It is a classic teaching that factor XII to XIIa
activation links the fibrinolytic system, coagulation
system, complement system, and kinin system.
Thrombotic disorders
Classification
a. Thrombotic disorders can be antithrombotic
(hemorrhagic), leading to pathologic bleeding states
such as hemophilia and von Willebrand disease.
b. They can also be prothrombotic, leading to
hypercoagulability with pathologic thrombosis.
Hereditary thrombophilia
General considerations
Hereditary thrombophilia is a prothrombotic
familial syndrome occurring most often in
adolescents or young women.
(1) Characteristic features include recurrent venous
thrombosis and thromboembolism.

Adnan‟s Human Pathology Morphologic Characteristics of Thrombi And Clots
(2) The syndrome can be caused by deficiency of a
number of antithrombotic proteins, including
antithrombin III, protein C, and protein s.
Factor V Leiden
(1) This is the most frequent cause of hereditary
thrombophilia.
(2) This is an abnormal factor V protein with a
specific mutation that alters the cleavage site
targeted by APC. The mutation prevents the
cleavage and inactivation of the mutant factor Va
by APC, a phenomenon referred to as ―hereditary
resistance to activated protein C.‖
Prothrombin 20210a transition
(1) This is the second most common cause of
hereditary thrombophilia (as of this writing).
(2) This G-to-A mutation in the 3'-untranslated
region of the prothrombin gene is associated with
elevated plasma prothrombin levels and an increase
in venous thrombosis.
Methylene tetrahydrofolate reductase mutation
(mtHfr C677t)
(1) This results in a moderate increase in serum
homocysteine, which is associated with both
arterial and venous thrombosis. The increased
homocysteine can be reduced by dietary
supplementation with folic acid and vitamins B6
(pyridoxine) and B12 (cobalamin).
(2) This is also associated with an increased risk of
neural tube defects and possibly a number of
diverse neoplasms.
Increased levels of factor VIII, factor IX, factor
XI, or fibrinogen are also associated with
increased venous thrombosis.
antiphospholipid antibody
syndrome
a. This prothrombotic disorder is characterized by
autoantibodies directed against a number of
protein antigens complexed to phospholipids.
It is further characterized by recurrent venous
and arterial thromboembolism, fetal loss,
thrombocytopenia, and a variety of neurologic
manifestations.
b. This syndrome is most often diagnosed
because of an incidental finding of a prolonged
PTT. This is a paradoxical abnormality,
because a prolonged PTT is usually
considered to be an indicator of antithrombotic
or hemorrhagic syndromes, just the reverse of
the prothrombotic characteristics of the
antiphospholipid antibody syndrome. The
prolonged PTT is thought to be an in vitro
artifact caused by interaction of the
antiphospholipid antibodies with the
phospholipid reagent used in
the PTT test.
c. Sometimes (but not always), this syndrome is
associated with systemic lupus erythematosus
(SLE). For this reason, an antiphospholipid
antibody that prolongs the PTT is sometimes
referred to as the lupus anticoagulant.
Another antiphospholipid antibody associated
with SLE is the anticardiolipin antibody, which
can cause a falsepositive serologic test for
syphilis.
Disseminated intravascular
coagulation (DIC)
DIC is both a prothrombotic and antithrombotic
disorder characterized by widespread thrombosis
and hemorrhage resulting from the consumption
of platelets and coagulation factors.
Heparin-induced
thrombocytopenia (HIt) syndrome
a. This syndrome is characterized by heparin-
induced thrombocytopenia (and thrombosis) and
is a consequence of therapy with high molecular-
weight heparin.
b. There are two types:
(1) type I HIt results in a mild to moderate
drop in platelets. It occurs in about 5%
of heparinized platelets and can appear within a
day of heparinization. It is not immune-mediated
and is not a contraindication to future heparin use.
(2) type II HIt leads to a severe drop in
platelets (often <50% of baseline) and imparts
a high risk of thrombosis. It usually manifests 5 to
10 days after heparin therapy and occurs in ∼1%
of heparinized patients. It is thought to be caused
by antibodies to the complex of heparin and
platelet factor 4 (Pf4). However, identification
of anti-PF4 antibodies is not diagnostic of Type II
HIT as they can be seen in
nonthrombocytopenic heparinized patients. The
gold standard for diagnosis is the serotonin-
release assay, although this test is rarely used in
practice and presumptive diagnosis is often made
based on clinical factors and the presence of PF4
antibodies. Once Type II HIT has been diagnosed,
further heparin treatment is contraindicated.

Adnan‟s Human Pathology Morphologic Characteristics of Thrombi And Clots
Morphologic Characteristics
of Thrombi And Clots
1. Arterial thrombi
a. These thrombi are formed in areas of active
blood flow.
b. When mature, they demonstrate alternate dark
gray layers of platelets interspersed with lighter
layers of fibrin. This layering results in the lines of
Zahn.
c. Eventually they liquefy and disappear or are
organized with fibrous tissue formation.
Recanalization, new blood vessel formation within
a thrombus, restores blood flow.
2. Venous thrombi
(phlebothrombosis)
a. These thrombi are formed in areas of less
active blood flow, most often in the veins of
the lower extremities and in the
periprostatic or other pelvic veins.
b. They are predisposed by venous stasis, with a
high incidence occurring in hospitalized patients on
bed rest.
c. They are dark red with a higher concentration of
red cells than arterial thrombi. Lines of Zahn are
not prominent or are absent.
d. They are often associated with concurrent venous
inflammatory changes. Inflammation of veins with
thrombus formation is referred to as
thrombophlebitis.
3. Postmortem clots
a. These clots appear soon after death and are not
true thrombi. In contrast to true thrombi, they are
not attached to the vessel wall.
b. Settling of red cells results in a two-layered
appearance: currant jelly appearance in the red
cell-rich lower layer and a chicken fat appearance
in the cell-poor upper layer.
Embolism
This is the passage and eventual trapping within the
vasculature of any of a wide variety of mass
objects.
a. thromboembolism. Embolism of
fragments of thrombi is the most
frequent form of embolism.
1. Pulmonary emboli
a. These emboli are an important cause of sudden
death, usually occurring in immobilized
postoperative patients and in those with CHf.
b. Immobilization leads to venous thrombosis in
the lower extremities. Portions of the friable
thrombus break away, travel through the venous
circulation, and lodge in branches of the pulmonary
artery.
Figure Pulmonary embolus
c. Pulmonary emboli vary in size from saddle
emboli obstructing the bifurcation of the
pulmonary artery, which can produce sudden death,
to less clinically significant small emboli. Emboli
of intermediate size can cause pulmonary
hypertension and acute right ventricular failure.
d. Obstruction of the pulmonary artery leads to
pulmonary infarction, a term often used
interchangeably with pulmonary embolism.
Hemorrhagic pulmonary infarcts result.
These are characteristically wedge shaped and
located just beneath the pleura.
2. Arterial emboli
a. sites of origin. Arterial emboli usually arise from
a mural thrombus, a thrombus that adheres to one
wall of a heart chamber or major artery.
(1) Mural thrombi in the left atrium are associated
especially with mitral stenosis with atrial
fibrillation.
(2) Mural thrombi in the left ventricle are caused by
myocardial infarction.

Adnan‟s Human Pathology Infarction
3) Thrombi at the junction of the internal and
external carotid arteries are a cause of thrombotic
brain infarcts and can also be a site of origin of
emboli.
b. sites of arrest
(1) Branches of the carotid artery, most
frequently the middle cerebral artery, leading to
cerebral infarction
(2) Branches of the mesenteric artery, leading to
hemorrhagic infarction of the intestine
(3) Branches of the renal artery, producing
characteristic wedge-shaped pale infarcts of the
renal cortex
3. Paradoxical emboli are left-sided emboli that
originate in the venous circulation but gain access
to the arterial circulation through a right-to-left
shunt, most often a patent foramen ovale or an atrial
septal defect
B. other forms of embolism
1. Fat emboli
a. These emboli are particles of bone marrow and
other fatty intraosseous tissue that enter the
circulation as a result of severe (often multiple)
fractures.
b. They lodge in the lungs, brain, kidneys, and
other organs.
c. They may be asymptomatic or may be manifest
clinically by the potentially fatal fat embolism
syndrome, characterized by pulmonary distress,
cutaneous petechiae, and various neurologic
manifestations.
2. Air emboli
a. These emboli result from the introduction of air
into the circulation, most often by a penetrating
chest injury or as a consequence of a clumsily
performed criminal abortion.
b. They can occur as decompression sickness,
observed in deep-sea divers who return to the
surface too rapidly. Bubbles of relatively insoluble
nitrogen come out of solution and
obstruct the circulation, producing musculoskeletal
pain (“the bends”) and small infarcts (caisson
disease) in the central nervous system, bones, and
other tissues. Because nitrogen has an affinity for
adipose tissue, obese persons are at increased risk
for this disorder.
3. Amniotic fluid emboli
a. These emboli are caused by escape of amniotic
fluid into the maternal circulation.
b. They can activate the coagulation process,
leading to DIC.
c. They can cause maternal death.
4. miscellaneous sources of emboli include
fragments of atherosclerotic plaques, clumps of
inflamed, infected tissue, and tumor fragments.
Infarction
Definition
Infarction is necrosis resulting from ischemia
caused by obstruction of the blood supply; the
necrotic tissue is referred to as an infarct.
Anemic infarcts
1. These infarcts are white or pale infarcts.
2. They are usually caused by arterial occlusions in
the heart, spleen, and kidney.
Hemorrhagic infarcts
1. These infarcts are red infarcts, in which red cells
ooze into the necrotic area.
2. They occur characteristically in the lung and
gastrointestinal tract as the result of arterial
occlusion. These sites are loose, well-vascularized
tissues with redundant arterial blood supplies (in
the lung, from the pulmonary and bronchial
systems; in the gastrointestinal tract, from multiple
anastomoses between branches of the mesenteric
artery), and a hemorrhage into the infarct occurs
from the non obstructed portion of the vasculature.
3. They can also be caused by venous occlusion.
This is an important contribution to infarcts
associated with volvulus, incarcerated hernias, and
postoperative adhesions.
Hyperemia / congestion
Hyperemia is an increased amount of blood in the
vessels of an organ or tissue in the body.
It can affect many different organs, including the:
 liver
 heart
 skin
 eyes
 brain
Types of hyperemia
There are two types of hyperemia:
Active hyperemia happens when there‘s an increase
in the blood supply to an organ. This is usually in

Adnan‟s Human Pathology Hyperemia / congestion
response to a greater demand for blood — for
example, if you‘re exercising.
Passive hyperemia is when blood can‘t properly
exit an organ, so it builds up in the blood vessels.
This type of hyperemia is also known as
congestion.
Causes of hyperemia
Each type of hyperemia has a different cause.
Active hyperemia is caused by an increased flow of
blood into your organs. It usually happens when
organs need more blood than usual. Your blood
vessels widen to increase the supply of blood
flowing in.
Causes of active hyperemia include:
 Exercise. Your heart and muscles need more
oxygen when you‘re active. Blood rushes to
these organs to supply extra oxygen. Your
muscles need up to 20 times their normal
supply of blood during a workout.
 Heat. When you‘re running a high fever or
it‘s hot outside, extra blood flows to your
skin to help your body release heat.
 Digestion. After you eat, your stomach and
intestines need more blood to help them
break down foods and absorb nutrients.
 Inflammation. During an injury or infection,
blood flow to the site increases.
 Menopause. Women who are
in menopause often have hot flashes, which
cause a rush of blood to the skin —
especially of the face, neck, and chest.
Blushing is a similar response.
Release of a blockage. Hyperemia can happen
following ischemia, which is poor blood flow to an
organ. Once ischemia is treated, blood rushes to the
area.
Passive hyperemia happens when blood can‘t
properly drain from an organ and begins to build up
in the blood vessels.
Causes of passive hyperemia include:
 Heart failure or ventricular failure. The left
and right ventricles are the two main
pumping chambers of the heart. The right
ventricle pumps blood to the lungs, and the
left ventricle pumps oxygen-rich blood to
the body. When the heart can‘t beat well
enough to push blood through the body,
blood begins to back up. This backup causes
swelling, or congestion, in organs like the
liver, lungs, spleen, and kidneys.
 Deep vein thrombosis (DVT). DVT is
caused by a clot in one of the deep veins —
often in your lower legs. The clot can break
free and get lodged in a vein in your lung,
called a pulmonary embolism.
 Hepatic vein thrombosis (HVT), also called
Budd-Chiari syndrome. HVT is a blockage
in the veins of the liver caused by a blood
clot.
Symptoms
The main symptoms of hyperemia are:
 redness
 warmth
Other symptoms depend on the cause of the
problem.
Heart failure symptoms include:
 shortness of breath
 coughing or wheezing
 swelling in the belly, legs, ankles, or feet
caused by fluid buildup
 fatigue
 loss of appetite
 nausea
 confusion
 fast heartbeat
DVT symptoms include:
 swelling and redness in the leg
 pain
 warmth
HVT symptoms include:
 pain in the upper right side of your abdomen
 swelling in your legs and ankles
 cramps in your legs and feet
 itching
Treatment options
Hyperemia itself isn‘t treated, because it‘s just a
sign of an underlying condition. Active hyperemia
caused by exercise, digestion, or heat doesn‘t need
to be treated. The blood flow will slow down once
you stop exercising, your food is digested, or you
get out of the heat.
Causes of passive hyperemia can be treated.
Doctors treat heart failure by addressing the cause
of the disease, such as high blood
pressure and diabetes.
Treatments include:
 a heart-healthy diet

Adnan‟s Human Pathology Ischemia
 exercise
 weight loss, if you‘re overweight
 medicines such as ACE inhibitors and beta-
blockers to lower blood pressure, or digoxin
to strengthen your heartbeat
DVT is treated with blood thinners such as heparin
or warfarin (Coumadin). These drugs stop the blood
clot from getting bigger, and prevent your body
from making new clots. If these drugs don‘t work,
you might get clot-busting drugs called
thrombolytics to quickly break up the clot. You can
also wear compression stockings to stop the
swelling in your legs from DVT.
HVT is also treated with blood thinners and clot-
busting drugs. You might need medication to treat
liver disease, too.
Complications and associated
conditions
Hyperemia itself doesn‘t cause complications.
Conditions that cause hyperemia can have
complications like:
 heart valve problems
 kidney damage or failure
 heart rhythm problems
 liver damage or failure
 pulmonary embolism — a blood clot that
becomes lodged in a blood vessel in the
lung
Outlook and prognosis
The outlook depends on the cause of increased
blood in the blood vessels.
Heart failure is a chronic condition. Although you
can‘t cure it, you can manage its symptoms with
medication and changes to your lifestyle. DVT can
be treated, but you‘ll need to watch for symptoms
because it can come back in the future.
Ischemia
Hypoxia
Hypoxia, in medicine, condition of the body in
which the tissues are starved of oxygen. In its
extreme form, where oxygen is entirely absent, the
condition is called anoxia.
Types of hypoxia
There are four types of hypoxia:
(1) The hypoxemic type, in which the
oxygen pressure in the blood going to the tissues is
too low to saturate the hemoglobin;
(2) The anemic type, in which the amount of
functional hemoglobin is too small, and hence the
capacity of the blood to carry oxygen is too low;
(3) The stagnant type, in which the blood is or may
be normal but the flow of blood to the tissues is
reduced or unevenly distributed; and
(4) The histotoxic type, in which the tissue cells are
poisoned and are therefore unable to make proper
use of oxygen. Diseases of the blood, the heart and
circulation, and the lungs may all produce some
form of hypoxia.
Mechanisms
The hypoxemic type of hypoxia is due to one of
two mechanisms:
(1) A decrease in the amount of breathable
oxygen—often encountered in pilots, mountain
climbers, and people living at high altitudes—due
to reduced barometric pressure (see altitude
sickness)
(2) cardiopulmonary failure in which the lungs are
unable to efficiently transfer oxygen from the
alveoli to the blood.
In the case of anemic hypoxia, either the total
amount of hemoglobin is too small to supply the
body‘s oxygen needs, as in anemia or after severe
bleeding, or hemoglobin that is present is rendered
nonfunctional. Examples of the latter case
are carbon monoxide poisoning and
acquired methemoglobinemia, in both of which the
hemoglobin is so altered by toxic agents that it
becomes unavailable for oxygen transport, and thus
of no respiratory value.
Stagnant hypoxia, in which blood flow through
the capillaries is insufficient to supply the tissues,
may be general or local. If general, it may result
from heart disease that impairs the circulation,
impairment of veinous return of blood, or trauma
that induces shock. Local stagnant hypoxia may be
due to any condition that reduces or prevents the
circulation of the blood in any area of the body.
Examples include Raynaud syndrome and Buerger
disease, which restrict circulation in the extremities;
the application of a tourniquet to control

Adnan‟s Human Pathology Anaplasia
bleeding; ergot poisoning; exposure to cold; and
overwhelming systemic infection with shock.
In histotoxic hypoxia the cells of the body are
unable to use the oxygen, although the amount in
the blood may be normal and under normal tension.
Although characteristically produced by cyanide,
any agent that decreases cellular respiration may
cause it. Some of these agents
are narcotics, alcohol, formaldehyde, acetone, and
certain anesthetic agents.
Anaplasia
Anaplasia, in which tumor cells are very poorly
differentiated and exhibit pleomorphism,
hyperchromatism (dark-staining nuclei), an
increased nuclear-cytoplasmic ratio, abnormal
mitoses, cellular dyspolarity, and often prominent
nucleoli, is a common feature.
In general, highly anaplastic tumors are very
aggressive, and well-differentiated tumors are less
aggressive. Paradoxically, the most aggressive
tumors often respond well to chemotherapy and
radiotherapy, because these modalities are most
effective with rapidly dividing cells
Edema
This is an abnormal accumulation of fluid in
interstitial tissue spaces or body cavities.
Causes of edema
1. Increased hydrostatic pressure is exemplified by
CHF.
a. Right-sided heart failure results in
peripheral edema.
b. Left-sided heart failure results in
pulmonary edema.
2. Increased capillary permeability occurs in
inflammation or with injury to capillary
endothelium, as may occur in burn injury.
3. Decreased oncotic pressure is from
hypoalbuminemia caused by:
a. Increased loss of protein, for example, by
renal loss in the nephrotic syndrome
b. Decreased production of albumin in
cirrhosis of the liver
4. Increased sodium retention can occur as either a
primary or secondary phenomenon.
a. Primary sodium retention, associated with
renal disorders
b. Secondary sodium retention, such as
occurs in CHf
(1) Decreased cardiac output results in
decreased renal blood flow, which activates
the renin-angiotensin system.
(2) In turn, this activates aldosterone
production, with resultant retention of sodium
and water.
5. Blockage of lymphatics results in lymphedema
Types of edema
1. anasarca is generalized edema.
2. Hydrothorax is an accumulation of fluid in the
pleural cavity.
3. Hydropericardium is an abnormal accumulation
of fluid in the pericardial cavity.
4. Hydroperitoneum (ascites) is an abnormal
accumulation of fluid in the peritoneal cavity.
5. transudate
a. This non inflammatory edema fluid
results from altered intravascular hydrostatic or
osmotic pressure.
b. It has a low protein content and a specific
gravity less than 1.012.
6. exudate
a. This edema fluid results from increased
vascular permeability caused by inflammation.
b. It has a high protein content, a specific
gravity exceeding 1.020, and characteristically
contains large numbers of inflammatory
leukocytes. Because the metabolically active
leukocytes consume glucose, the glucose content is
often greatly reduced.

Adnan‟s Human Pathology Definition
Definition
Cell injury results when cells are stressed so
severely that they are no longer able to adapt or
when cells are exposed to inherently damaging
agents or suffer from intrinsic abnormalities (e.g.,
in DNA or proteins).
Types (Reversible and
Irreversible Injury)
Reversible cell injury
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.
As noted above some of the changes that occur in
cell injury are thought to be potentially reversible.
Several manifestations of this sublethal injury can
be recognizing histologically; some of these may in
fact be adaptive responses of the cell. One of the
earliest changes detected is swelling of the
cytoplasm. The cells may become vacuolated
(hence the term vacuolar degeneration). This is a
reflection of the inability of the cell to regulate the
ionic and fluid balance across the plasma
membrane reflecting ATP depletion. There is
electron microscopic evidence of
disruption of the membranes; blebs are seen and
points of contact with adjacent cells become
loosened. Mitochondria may also be swollen and
there may be subtle changes in the nuclear
structure. Another common manifestation of
sublethal injury is the accumulation of triglycerides
in the cell – fatty change or steatosis. This is most
commonly seen in liver injury but can occur at
other sites such as heart and skeletal muscle. The
mechanisms for the accumulation are complex but
include impairment of fatty acid oxidation,
increased generation of free fatty acids and
reduction in apolipoprotein production.
Irreversible cell injury
With continuing damage, the injury becomes
irreversible, at which time the cell cannot recover
and it dies. The precise point beyond which
reversible injury becomes irreversible is not yet
fully defined.
There are two types of cell death—necrosis and
apoptosis—which differ in their mechanisms,
morphology, and roles in disease and physiology.
Necrosis
Necrosis is always a consequence of injury and is
associated with loss of membrane integrity.
Necrosis is the death of cells with loss of membrane
integrity and with enzymatic destruction of the
cellular constituents. This leads to leakage of cell
constituents into the surrounding tissue and the
circulation. There is an inflammatory response to
these cellular constituents and the initiation of a
repair process.
When damage to membranes is severe, enzymes
leak out of lysosomes, enter the cytoplasm, and
digest the cell, resulting in necrosis.
Necrosis is the major pathway of cell death in
many commonly encountered injuries, such as
those resulting from ischemia, exposure to toxins,
various infections, and trauma.
Apoptosis
When a cell is deprived of growth factors, or the
cell‟s DNA or proteins are damaged beyond repair,
typically the cell kills itself by
another type of death, called apoptosis, which is
characterized by nuclear dissolution without
complete loss of membrane integrity.
Whereas necrosis is always a pathologic process,
apoptosis serves many normal functions and is not
necessarily associated with pathologic cell injury.
Furthermore, in keeping with its role in certain
physiologic processes, apoptosis does not elicit an
inﬂammatory response.
CELL INJURY
3

Adnan‟s Human Pathology Types (Reversible and Irreversible Injury)
Feature Necrosis Apoptosis
Cell size
Enlarged
(swelling)
Reduced
(shrinkage)
Nucleus
Pyknosis →
karyorrhexis →
karyolysis
Fragmentation
into
nucleosome
size fragments
Plasma
membrane
Disrupted
Intact; altered
structure,
especially
orientation of
lipids
Cellular
contents
Enzymatic
digestion; may
leak out of cell
Intact; may be
released in
apoptotic
bodies
Etiology
Gross
irreversible
cellular injury
Subtle cellular
damage,
physiologic
programmed
cell removal
Adjacent
inﬂammation
Frequent No
Physiologic or
pathologic role
Invariably
pathologic
(culmination of
irreversible cell
injury)
Often
physiologic;
means of
eliminating
unwanted cells;
may be
pathologic after
some forms of
cell injury,
especially
DNA and
protein damage
Morphologic
changes
Involves many
contiguous
cells
Increased
cytoplasmic
eosinophilia
due to
denaturation of
proteins
Progressive
nuclear
condensation
and
fragmentation
with eventual
disappearance
of nuclei
Preservation of
tissue
architecture in
early stages of
coagulative
necrosis
Involves single
cells or small
clusters of cells
Cytoplasmic
shrinking and
increased
eosinophilic
staining
Chromatin
condensation
and
fragmentation
Fragmentation
into membrane-
bound
apoptotic
bodies
Biochemical
changes
Passive form of
cell death not
requiring gene
involvement or
new protein
synthesis
DNA
fragmentation
is haphazard
rather than
Active form of
cell death
requiring gene
expression,
protein
synthesis, and
energy
consumption
DNA
fragmentation

Adnan‟s Human Pathology Causes of cell injury (Etiology)
regular,
resulting in an
electrophoretic
smudge pattern
is regular at
nucleosomal
boundaries,
resulting in an
electrophoretic
―laddered‖
pattern
Causes of cell injury (Etiology)
There are many diverse causes of cell injury, from
subtle changes occurring because of a genetic
mutation leading to a single amino acid change in a
polypeptide chain to massive burns:
1. Hypoxia (deficiency of oxygen)
2. Chemical agents and poisons
3. Infectious agents
4. Immune-mediated processes
5. Genetic abnormalities
6. Nutritional imbalances
7. Physical agents
8. Aging
1) Oxygen Deprivation
The commonest cause in clinical practice is
hypoxia where the cell is damaged because aerobic
respiration is diminished. Hypoxia can occur when
there is a reduction in the blood supply to a tissue,
as occurs in myocardial infarction for example.
Such impairment in blood supply, ischaemia,
clearly leads to a reduction in the availability of key
substances other than oxygen (e.g. glucose).
Hypoxia can also occur when there is a reduction in
the overall oxygenation of the blood as occurs in
cardiorespiratory failure and in carbon monoxide
poisoning.
2) Chemical agents and poisons
glucose, salt, or even water, if absorbed or
administered in excess, can so derange the osmotic
environment that cell injury or death results. Agents
commonly known as poisons cause severe damage
at the cellular level by altering membrane
permeability, osmotic homeostasis,
or the integrity of an enzyme or cofactor, and
exposure to such poisons can culminate in the death
of the whole organism. Other potentially toxic
agents are encountered daily in the environment;
these include air pollutants, insecticides, CO,
asbestos, and ―social stimuli‖ such as ethanol.
Therapeutic drugs can cause cell or tissue injury in
a susceptible patient or if used excessively or
inappropriately
Chemical cell injury is illustrated by the model of
liver cell membrane damage induced by carbon
tetrachloride (CCl4). In this model, CCl4 is
processed by the P-450 system of mixed function
oxidases within the SER, producing the highly
reactive free radical CCl3·.
CCl3 diffuses throughout the cell, initiating lipid
peroxidation of intracellular membranes.
3) Infectious agents
Agents of infection range from submicroscopic
viruses to meter-long tapeworms; in between are
the rickettsiae, bacteria, fungi, and protozoans.
4) Immune-mediated processes
Immunological reactions are also a cause of cell
injury when there is an exaggerated response to a
foreign protein (anaphylaxis) or when there is
breakdown of the normal tolerance mechanisms to
self-antigens (autoimmune disease).
5) Genetic abnormalities
Genetic diseases can lead to cell injury by a variety
of mechanisms. At one extreme there are gross
chromosomal abnormalities which lead to major
congenital malformations (e.g. trisomy 21) and at
the other extreme, single base mutations in a gene
leading to a protein product which is abnormally
folded and which cannot be exported from the cell
(e.g. α1-antitrypsin deficiency). Many inherited
metabolic abnormalities are caused by there being a
genetically determined enzyme defect or
deficiency; these may have consequences for only
one tissue or organ system but most commonly
have systemic effects.
6) Nutritional imbalances
Nutritional imbalances can also be gross, such as
that seen in protein-calorie malnutrition
(kwashiorkor) which sadly remains a common
condition in certain parts of the world, or more
subtle, for example a vitamin deficiency. It is
important to recognize, however, that nutritional

Adnan‟s Human Pathology The Morphology of Injury
imbalances are not always due to a lack of nutrients
but increasingly common is the cell injury
associated with excess of nutrients. Obesity and the
associated metabolic syndrome are a major cause of
serious disease.
Moreover, diets rich in animal fat are strongly
implicated in the development of atherosclerosis as
well as in increased vulnerability to many disorders,
including cancer.
7) Aging
Cellular senescence leads to alterations in
replicative and repair abilities of individual cells
and tissues. All of these changes result in a
diminished ability to respond to damage
and, eventually, the death of cells and of the
organism.
8) Physical agents
Physical agents which cause cell injury include
extremes of temperature and atmospheric pressure,
radiation, direct and indirect mechanical trauma and
electrical currents.
The Morphology of Injury
All stresses and noxious inﬂuences exert
their effects first at the molecular or biochemical
level. Cellular function may be lost long before cell
death occurs, and the morphologic changes of cell
injury (or death) lag far behind both.
For example, myocardial cells become non
contractile after 1 to 2 minutes of ischemia,
although they do not die until 20 to 30 minutes of
ischemia have elapsed. These myocytes may not
appear dead by electron microscopy for 2 to 3
hours, or by light microscopy for 6 to 12 hours
The cellular derangements of reversible
injury can be corrected, and if the injurious
stimulus abates, the cell can return to normalcy.
Persistent or excessive injury, however, causes cells
to pass the nebulous ―point of no return‖ into
irreversible injury and cell death.
There are no definitive morphologic or biochemical
correlates of irreversibility, two phenomena
consistently characterize irreversibility: the
inability to correct mitochondrial dysfunction (lack
of oxidative phosphorylation and ATP generation)
even after resolution of the original injury, and
profound disturbances in membrane function.
Morphology of reversible injury
The two main morphologic correlates of reversible
cell injury are cellular swelling and fatty change.
Cellular swelling is the result of failure of energy-
dependent ion pumps in the plasma membrane,
leading to an inability to maintain ionic and ﬂuid
homeostasis.
Cellular swelling the first manifestation of almost
all forms of injury to cells, is a reversible alteration
that may be difficult to appreciate with the light
microscope, but it may be more apparent at the
level of the whole organ.
When it affects many cells in an organ, it causes
some pallor (as a result of compression of
capillaries), increased turgor, and increase in weight
of the organ. Microscopic examination
may reveal small, clear vacuoles within the
cytoplasm; these represent distended and pinched-
off segments of the endoplasmic reticulum (ER).
This pattern of nonlethal injury is sometimes called
hydropic change or vacuolar degeneration.
Fatty change occurs in hypoxic injury and in
various forms of toxic or metabolic injury and is
manifested by the appearance of small or large lipid
vacuoles in the cytoplasm.
Fatty change is manifested by the appearance of
lipid vacuoles in the cytoplasm. It is principally
encountered in cells participating in fat metabolism
(e.g., hepatocytes, myocardial cells) and is also
reversible. Injured cells may also show increased
eosinophilic staining, which becomes much more
pronounced with progression to necrosis.
The intracellular changes associated with reversible
injury include
1. Plasma membrane alterations such as
blebbing, blunting, or distortion of microvilli,
and loosening of intercellular attachments;
2. mitochondrial changes such as swelling and
the appearance of phospholipid-rich
amorphous densities;
3. dilation of the ER with detachment of
ribosomes and dissociation of polysomes;
4. Nuclear alterations, with clumping of
chromatin. The cytoplasm may contain
phospholipid masses, called myelin figures,
which are derived from damaged cellular
membranes.
Morphology of irreversible injury

Adnan‟s Human Pathology Patterns of Tissue Necrosis
Necrosis is characterized by changes in the
cytoplasm and nuclei of the injured cells .
Cytoplasmic changes
Necrotic cells show increased eosinophilia (i.e.,
pink staining from the eosin dye—the E in the
hematoxylin and eosin [H&E] stain), attributable
in part to increased binding of eosin to denatured
cytoplasmic proteins and in part to loss of the
basophilia that is normally imparted by the
ribonucleic acid (RNA) in the cytoplasm
(basophilia is the blue staining from the
hematoxylin dye—the H in ―H&E‖). Compared
with viable cells, the cell may have a more glassy,
homogeneous appearance, mostly because of the
loss of glycogen particles.
Myelin fgures are more prominent in necrotic cells
than during reversible injury. When enzymes have
digested cytoplasmic organelles, the cytoplasm
becomes vacuolated and appears ―moth-eaten.‖ By
electron microscopy, necrotic cells are
characterized by discontinuities in plasma and
organelle membranes, marked dilation of
mitochondria with the appearance of large
amorphous densities, disruption of lysosomes, and
intra cytoplasmic myelin figures.
Nuclear changes.
Nuclear changes assume one of three patterns, all
due to breakdown of DNA and chromatin. The
basophilia of the chromatin may fade (karyolysis),
presumably secondary to deoxyribonuclease
(DNase) activity. A second pattern is pyknosis,
characterized by nuclear shrinkage and increased
basophilia; the DNA condenses into a solid
shrunken mass. In the third pattern, karyorrhexis,
the pyknotic nucleus undergoes fragmentation. In 1
to 2 days, the nucleus in a dead cell may completely
disappear. Electron microscopy reveals profound
nuclear changes culminating in nuclear dissolution.
Fates of necrotic cells
Necrotic cells may persist for some time or may be
digested by enzymes and disappear.
Dead cells may be replaced by myelin figures,
which are either phagocytosed by other cells or
further degraded into fatty acids. These fatty acids
bind calcium salts, which may result in the dead
cells ultimately becoming calcifed.
Patterns of Tissue Necrosis
There are several morphologically distinct patterns
of tissue necrosis, which may provide clues about
the underlying cause. Although the terms that
describe these patterns do not reﬂect underlying
mechanisms, such terms are in common use, and
their implications are understood by both
pathologists and clinicians. Most of these types of
necrosis have distinct gross appearance; fibrinoid
necrosis is detected only by histologic examination.
Leakage of intracellular proteins through the
damaged cell membrane and ultimately into the
circulation provides a means of detecting tissue-
specifc necrosis using blood or serum samples.
Cardiac muscle, for example, contains a unique
isoform of the enzyme creatine kinase and of the
contractile protein troponin, whereas hepatic bile
duct epithelium contains a temperature-resistant
isoform of the enzyme alkaline phosphatase, and
hepatocytes contain transaminases. Irreversible
injury and cell death in these tissues result in
increased serum levels of such proteins, and
measurement of serum levels is used clinically to
assess damage to these tissues.
Coagulative necrosis
Coagulative necrosis is a form of necrosis in which
the underlying tissue architecture is preserved for at
least several days. The affected tissues take on a
firm texture. Presumably the injury denatures not
only structural proteins but also enzymes, thereby
blocking the proteolysis of the dead cells; as a
result, eosinophilic, anucleate
cells may persist for days or weeks. Leukocytes are
recruited to the site of necrosis, and the dead cells
are digested by the action of lysosomal enzymes of
the leukocytes. The cellular debris is then removed
by phagocytosis. Coagulative necrosis is
characteristic of infarcts (areas of ischemic
necrosis) in all of the solid organs
except the brain.

Adnan‟s Human Pathology Patterns of Tissue Necrosis
Figure Coagulative necrosis. A, A wedge-shaped kidney infarct
(yellow) with preservation of the outlines. B, Microscopic view of the
edge of the infarct, with normal kidney (N) and necrotic cells in the
infarct (I).
Liquefactive necrosis
Liquefactive necrosis is 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. For obscure reasons, hypoxic death of
cells within the central nervous system often evokes
liquefactive necrosis.
Whatever the pathogenesis, the dead cells are
completely digested, transforming the tissue into a
liquid viscous mass.
Eventually, the digested tissue is removed by
phagocytes. If the process was initiated by acute
inflammation, as in a bacterial infection, the
material is frequently creamy yellow and is called
pus.
Figure Liquefactive necrosis. An infarct in the brain showing
dissolution of the tissue.
Gangrenous necrosis
Although gangrenous necrosis is not a distinctive
pattern of cell death, the term is still commonly
used in clinical practice. It usually refers to the
condition of a limb, generally the lower leg, that
has lost its blood supply and has undergone
coagulative necrosis involving multiple tissue
layers. When bacterial infection is superimposed,
coagulative necrosis is modifed by the liquefactive
action of the bacteria and the attracted leukocytes
(resulting in so-called wet gangrene).
Caseous necrosis
Caseous necrosis is encountered most often in foci
of tuberculous infection. Caseous means ―cheese-
like,‖ referring to the friable yellow-white
appearance of the area of necrosis. On microscopic
examination, the necrotic focus appears as a
collection of fragmented or lysed cells with an
amorphous granular pink appearance
in the usual H&E-stained tissue. Unlike with
coagulative necrosis, the tissue architecture is
completely obliterated and cellular outlines cannot
be discerned. The area of caseous necrosis is often
enclosed within a distinctive inflammatory border;
this appearance is characteristic of a focus of
inflammation known as a granuloma.
Figure Caseous necrosis. Tuberculosis of the lung
Fat necrosis
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. This occurs in the
calamitous abdominal emergency known as acute
pancreatitis. In this disorder, pancreatic enzymes
that have leaked out of acinar cells and ducts
liquefy the membranes of fat cells in the
peritoneum, and lipases split the triglyceride esters
contained within fat cells. The released fatty acids
combine with calcium to produce grossly visible

Adnan‟s Human Pathology Mechanisms of Cell Injury (Necrosis)
chalky white areas (fat saponifcation), which enable
the surgeon and the pathologist to identify the
lesions. On histologic examination, the foci of
necrosis contain shadowy outlines of necrotic fat
cells with basophilic calcium deposits, surrounded
by an inflammatory reaction.
Figure Fat necrosis in acute pancreatitis
Fibrinoid necrosis
Fibrinoid necrosis is a special form of necrosis,
visible by light microscopy, usually in immune
reactions in which complexes of antigens and
antibodies are deposited in the walls of arteries. The
deposited immune complexes, together with fbrin
that has leaked out of vessels, produce a bright pink
and amorphous appearance on H&E preparations
called fbrinoid (fbrin-like) by pathologists.
Figure Fibrinoid necrosis in an artery in a patient with
polyarteritis
Mechanisms of Cell Injury
(Necrosis)
The biochemical mechanisms linking any given
injury with the resulting cellular and tissue
manifestations are complex, interconnected, and
tightly interwoven with many intracellular
metabolic pathways.
Several general principles are relevant to most
forms of cell injury:
1. The cellular response to injurious stimuli
depends on the type of injury, its duration,
and its severity.
2. The consequences of an injurious stimulus
depend on the type, status, adaptability, and
genetic makeup of the injured cell
3. Cell injury results from functional and
biochemical abnormalities in one or more of
several essential cellular components.
i. Mitochondria and their ability to
generate ATP and ROS under
pathologic conditions;
ii. Disturbance in calcium homeostasis;
iii. Damage to cellular (plasma and
lysosomal) membranes;
iv. Damage to DNA and misfolding of
proteins.
4. Multiple biochemical alterations may be
triggered by any one injurious insult.
Depletion of ATP
Causes of ATP depletion are reduced supply of
oxygen and nutrients, mitochondrial damage, and
the actions of some toxins (e.g., cyanide).
Significant depletion of ATP has widespread effects
on many critical cellular systems.
i. The activity of plasma membrane ATP-
dependent sodium pumps is reduced,
resulting in intracellular accumulation of
sodium and efflux of potassium. The net
gain of solute is accompanied by iso-
osmotic gain of water, causing cell swelling
and dilation of the ER.
ii. There is a compensatory increase in
anaerobic glycolysis in an attempt to
maintain the cell‘s energy sources. As a
consequence, intracellular glycogen stores
are rapidly depleted, and lactic acid
accumulates, leading to decreased
intracellular pH and decreased activity of
many cellular enzymes.
iii. Failure of ATP-dependent Ca2+
pumps leads
to influx of Ca2+
, with damaging effects on
numerous cellular components, described
later.

Adnan‟s Human Pathology Mechanisms of Cell Injury (Necrosis)
iv. Prolonged or worsening depletion of ATP
causes structural disruption of the protein
synthetic apparatus, manifested as
detachment of ribosomes from the rough
ER (RER) and dissociation of polysomes
into monosomes, with a consequent
reduction in protein synthesis Ultimately,
there is irreversible damage to
mitochondrial and lysosomal membranes,
and the cell undergoes necrosis.
Mitochondrial Damage and
Dysfunction
Mitochondria are sensitive to many types of
injurious stimuli, including hypoxia, chemical
toxins, and radiation. Mitochondrial damage may
result in several biochemical abnormalities:
i. Failure of oxidative phosphorylation leads
to progressive depletion of ATP,
culminating in necrosis of the cell, as
described earlier.
ii. Abnormal oxidative phosphorylation also
leads to the formation of reactive oxygen
species, which have many deleterious
effects, described below.
iii. Damage to mitochondria is often associated
with the formation of a high-conductance
channel in the mitochondrial membrane,
called the mitochondrial permeability
transition pore. The opening of this channel
leads to the loss of mitochondrial membrane
potential and pH changes, further
compromising oxidative
phosphorylation.
iv. The mitochondria also contain several
proteins that, when released into the
cytoplasm, tell the cell there is internal
injury and activate a pathway of apoptosis.
Inﬂux of Calcium
The importance of Ca2+ in cell injury was
established by the experimental fnding that
depleting extracellular Ca2+
delays cell death after
hypoxia and exposure to some toxins. Cytosolic
free calcium is normally maintained by ATP-
dependent calcium transporters at concentrations as
much as 10,000 times lower than the concentration
of extracellular calcium or of sequestered
intracellular mitochondrial and ER calcium.
Ischemia and certain toxins cause an
increase in cytosolic calcium concentration, initially
because of release of Ca2+ from the intracellular
stores, and later resulting from increased inﬂux
across the plasma membrane. Increased cytosolic
Ca2+ activates a number of enzymes, with potentially
deleterious cellular effects.
These enzymes include phospholipases (which
cause membrane damage), proteases (which break
down both membrane and cytoskeletal proteins),
endonucleases (which are responsible for DNA and
chromatin fragmentation), and adenosine
triphosphatases (ATPases) (thereby hastening ATP
depletion). Increased intracellular Ca2+ levels may
also induce apoptosis, by direct activation of

ADNAN PATHOLOGY book for medical students.pdf

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