LESSON 1: GENERAL PATHOLOGY Difference between Signs and Symptoms

Pathology • Signs
o Objective
• From Greek “pathos” (suffering) and
o Observable phenomenon that can be
“logos” (study)
identified by another person
• Study of structural, biochemical and o It is manifested physically
functional changes in cells, tissues, and
• Symptoms
organs that underlie diseases
o Subjective
• Uses molecular, microbiologic, o It cannot be identified by anyone else
immunologic, and morphologic techniques to o It is what the patient feels
attempt to explain the signs and symptoms
manifested by the patient Example:
• Serves as the bridge between the basic
55/M: Classic Pneumonia
sciences and clinical medicine
• Scientific foundation for all of medicine • Etiology: Acquired – Infectious – Bacteria
• Pathogenesis:
Division of Pathology
o Edema
• General Pathology – reactions of cells and o Red Hepatization
tissues to abnormal stimuli and inherited o Gray Hepatization
defects o Resolution (healing)
o Such reactions are often not tissue – • Morphologic Changes:
specific o Stage of Congestion: active
▪ Acute inflammation – in hyperemia and edema
response of bacterial infection o Stage of Red Hepatization:
• Special or Systematic Pathology – specific neutrophils, congestion, fibrin
responses in specialized organs and tissues o Stage of Gray Hepatization:
that are responsible for disorders that involve degradation of red blood cells, Fibrin
these organs – supp. Exudate
o Organ disorders o Stage of Resolution: healing
• Clinical Manifestations:
4 Aspects of Disease Process
o Cough
• Etiology o Tachypnea – increase of respiration
o Cause/origin of the disease rate
o Origin of disease, which may be o Fever
intrinsic/ genetic or acquired: o Abnormal Chest Finding
infectious, nutritional, chemical, Importance of knowing the 4 Aspects of Disease
physical Process:
o Intrinsic/ Genetic – inherited
mutation (disease – associated gene • To be able to diagnose our patient correctly
variance)
3 Parameters in diagnosing the patient
• Pathogenesis
o Development of the disease • History
o Mechanism of its development or • Physical Examination
sequence of events in the response of • Diagnostics (laboratory, x-ray, etc.)
cells or tissues to the etiologic agent;
spectrum of disease
• Morphologic Changes
o Structural, functional, or biochemical
changes brought by pathogenesis
o These changes will result into a
dysfunction leading to clinical
manifestations
o Biochemical and structural alterations
induced in the cell/ organs that are
characteristic or diagnostic of an
etiologic process
• Clinical Manifestations
o Signs and symptoms manifested by
the patient
o Functional consequences and
derangements of the morphologic
changes
LESSON 1: CELLULAR INJURY AND DEATH Causes of Cellular Injury
Overview of Cellular Responses to Stress and • Hypoxia and Ischemia are among the most
Noxious Stimuli common causes of cell injury
o Hypoxia – oxygen deficiency
o Ischemia – reduced blood supply;
most common cause of hypoxia;
results from arterial obstruction
Ischemia is under Hypoxia; it is the most common
cause of Hypoxia.
• Toxins
o Potentially toxic agents are
encountered daily in the environment;
these include air pollutants,
insecticides, CO, asbestos, cigarette
smoke, ethanol, and drugs.
• Infectious Agents
o All types of disease – causing
pathogens, including viruses,
Your cells actively interact with their environment. It bacteria, fungi, and protozoans, injure
is constantly adjusting their structures and functions cells.
to accommodate changing demands and extracellular • Immunologic Reactions
stresses. o Autoimmune reactions against one’s
Your cell or the intracellular milieu of your cells are own tissues, allergic reactions against
normally or tightly regulated such that it remains environmental substances, and
fairly constant a state referred to as your excessive or chronic immune
HOMEOSTASIS. responses to microbes
• Genetic Abnormalities
It has to maintain an intracellular milieu; so, it is very o Genetic aberrations can result in
much regulated to maintain homeostasis of the pathologic changes as conspicuous as
normal cell. the congenital malformations
associated with Down Syndrome or
However, our normal cell is continuously exposed to
as subtle as the single amino acid
different stresses. That’s why our cells need to
substitution in hemoglobin giving rise
ADAPT because of the presence of these stresses.
to sickle cell anemia.
However, if our cell cannot adapt or there is an • Nutritional Imbalances
inability to adapt, there will be CELL INJURY. o Protein – calorie insufficiency among
impoverished populations remains a
If that cellular injury is only mild or transient, it is
major cell injury, and specific vitamin
going to be a REVERSIBLE INJURY and the cell
deficiencies are not uncommon even
can go back to a normal cell or in its homeostatic
in developed countries with high
state.
standards of living
If the cell is exposed to injurious stimuli, it will lead o Excessive dietary intake may result in
directly to CELL INJURY and this injury will obesity and also an important
become severe and progressive. underlying factor in many diseases
such as in type 2 diabetes mellitus and
When this cellular injury is severe or progressive, it
arthrosclerosis
will lead to IRREVERSIBLE INJURY which will
• Physical Agents
lead to cell death: NECROSIS or APOPTOSIS.
o Trauma, extremes of temperature,
radiation, electric shock, and sudden
changes in atmospheric pressure all
have wide – ranging effects on cells
• Aging
o Cellular senescence results in a
diminished ability of cells to respond
to stress and, eventually, the death of
cells and of the organism
An RBC has a lifespan of around 90-120 days. When
it comes senescent it will not be able to do its function
to transfer oxygen all throughout the body
General Principles of Cellular Injury If there is persistent or severe hypoxia or ischemia,
it will lead to the failure of ATP generation and
• The cellular response to injurious stimuli depletion of your ATP in the cells.
depends on the type of injury, its duration,
and its severity Without ATP, cells will not be able to do its function
o Low dose of toxin or brief period of and the cell will eventually die.
ischemia – leads to reversible cell
Loss of this critical energy store has deleterious
injury
effects on many cellular systems:
o Higher dose of toxin or longer period
of ischemia – leads to irreversible cell • Reduced activity of plasma membrane ATP –
injury dependent sodium pumps
• The consequences of an injurious stimulus • Increase in anaerobic glycolysis
also depend on the type, status, adaptability, o Not enough production of ATP
and genetic makeup of the injured cell o Increase of lactate/lactic acid which
o Striated skeletal muscle on the leg can will further affect the blood pH
tolerate ischemia for 2 to 3 hours environment and may cause cellular
(there will be no irreversible injury) injury and death
▪ If this happens on the cardiac • Structural disruption of the protein synthetic
muscle, the cell will die after apparatus
20 to 30 minutes of ischemia
• Cell injury usually results from functional
and biochemical abnormalities in one or more
of a limited number of essential cellular
components
Mechanisms of Cell Injury and Death
• Hypoxia and Ischemia
o Deficiency of oxygen leads to failure
of many energy – dependent
metabolic pathways, and ultimately to
death of cells by necrosis

Where sodium goes, water follows.

• Ischemia – Reperfusion Injury

Under certain circumstances, the restoration of blood
flow to ischemic but viable tissues results,
How does Hypoxia and Ischemia affect the cell and
paradoxically, in increased cell injury.
cause cellular injury or death?
Since that the ATP provided by Glycolysis is not • New damage may be initiated during
enough, the glucose will be converted into pyruvate. reoxygenation by increased generation of
However, pyruvate cannot enter the mitochondria so ROS – Reactive Oxygen Species which can
it has to be converted into Acetyl CoA so that it will cause injury.
undergo the Citric Acid Cycle. From this, it will • The inflammation that is induced by
produce a lot of energy but is still not enough. This ischemic injury may increase with
will lead to Oxidative phosphorylation. reperfusion because it enhances the influx of
leukocytes and plasma proteins which may
Oxidative phosphorylation requires oxygen. ATP is lead to further injury.
produced from your ADP through oxidative
phosphorylation during the reduction of your oxygen
in your electron transport system in your
mitochondria.
Deficiency of oxygen will lead to the absence of
Aerobic Respiration and Oxidative Phosphorylation.
 Free Mechanisms of Mechanisms Pathologic
• Oxidative Stress Radical Production of Removal Effects
Superoxide Incomplete Conversion to Direct
Oxidative stress refers to cellular abnormalities that reduction of O2 H2O2 and O2 damaging
are induced by ROS, which belong to a group of during by effects on lipids
mitochondrial superoxide (peroxidation),
molecules known as free radicals.
oxidative dismutase proteins, and
Free radicals are chemical species, extremely phosphorylation DNA
by phagocyte
unstable, and readily react with inorganic and oxidase in
organic molecules; when generated in cells, they leukocytes
avidly attack nucleic acids as well as a variety of Hydrogen Mostly from Conversion to Can be
peroxide superoxide by H2O2 and O2 converted to
cellular proteins and lipids. action of by catalase, OH and OCl-,
superoxide glutathione which destroy
dismutase peroxidase microbes and
cells
Hydroxyl Produced from Conversion to Direct
radical H2O, H2O2, O2- H2O by damaging
by various glutathione effects on
chemical peroxidase lipids, proteins,
reactions and DNA
Peroxynitrite Interaction of Conversion to Direct
O2- and NO nitrite by damaging
mediated by enzymes in effects on
NO synthase mitochondria lipids, proteins,
and cytosol and DNA
The production of your ROS is increased by many
injurious stimuli such as radiation, toxins, and
• Cell Injury caused by Toxins
reperfusion.
Toxins, including environmental chemicals and
The free radicals are removed by spontaneous decay
substances produced by infectious pathogens, induce
and by specialized enzymatic enzymes, enzymatic
cell injury that culminates primarily in necrotic cell
systems. ROS: Superoxide, Hydrogen peroxide, and
death
Hydroxyl radical is being removed by the enzymatic
systems and remove the free radicals. Two general mechanisms:
To compensate with the toxic substance in the body, • Direct – acting toxins
ROS is being converted by the enzymatic system by o Some toxins act directly by
superoxide, glutathione peroxidase, catalase. combining with a critical molecular
If the enzymatic system fails to remove the free component or cellular organelle
radicals, it will lead to the accumulation of your free • Latent toxins
radicals – increase of free radicals. o Not intrinsically active toxins
o Must be converted to reactive
Pathologic effects: metabolites which then act on the
target cells
• Lipid peroxidation → Membrane damage
o Carbon tetrachloride will be
• Protein modifications → Breakdown,
converted by the liver into free
misfolding
radicals
• DNA damage → Mutations
ROS are produced by 2 major pathways:
• Endoplasmic Reticulum Stress
• ROS are produced normally in small amounts
in all cells during the reduction – oxidation The accumulation of misfolded proteins in a cell can
(redox) reactions stress compensatory pathways in the ER and lead to
• ROS are produced in phagocytic leukocytes, cell death by apoptosis
mainly neutrophils and macrophages.
Intracellular accumulation of misfolded proteins may
o Produced in minimal amount that the
be caused by abnormalities that increase the
body can be able to still remove it
production of misfolded proteins or reduce the
o However, in different injurious
ability to eliminate them
stimulus such as having radiation,
toxins, and reperfusion, there will be
greater ROS production
 Misfolded proteins are toxic to our body and leads to • DNA Damage
different disorders or diseases.
Exposure of cells to radiation or chemotherapeutic
Mild ER Stress: Adaptive Unfolded Protein agents, intracellular generation of ROS, and
Response acquisition of mutations may all induce DNA
damage, which if severe may trigger apoptotic
• Misfolded proteins will attach to the sensor
death.
of misfolded proteins (IRE1) – receptors or
the sensor of the ER • Inflammation
• This will cause a signal:
Inflammatory cells, including neutrophils,
o To increase the synthesis of the
macrophages, lymphocytes, and other leukocytes,
chaperones
secrete products that evolved to destroy microbes but
o To reduce protein synthesis
also may damage host tissues
o To increase protein degradation
• Reduced load of misfolded proteins Common Events in Cell Injury from Diverse
Causes
Severe ER Stress: Terminal Unfolded Protein
Response: Apoptosis • Mitochondrial Dysfunction
The body was not able to adapt to stress: irreversible
cell injury
• Misfolded proteins will attach to the sensor
of misfolded proteins (IRE1) – receptors or
the sensor of the ER
• This will cause a signal:
o Activation of BH3 proteins →
Activation of caspases
▪ BH3 opposes the action of the
BCL
Diseases Caused by Misfolded Proteins
Disease Affected Pathogenesis
Protein
Diseases Caused by Mutant Proteins That Are Degraded,
Leading to their Deficiency
Cystic fibrosis CFTR Loss of CFTR leads to defects • Defects in Membrane Permeability
in chloride transport and death
of affected cells Increased membrane permeability leading
Familial LDL receptor Loss of LDL receptor leads to
ultimately to overt membrane damage is a feature of
hypercholester hypercholesterolemia
olemia most forms of cell injury that culminate in necrosis
Tay-Sachs Hexosaminidase Lack of the lysosomal enzyme
disease β subunit leads to storage of GM2 SEQUENCE OF EVENTS IN CELL INJURY
gangliosides in neurons AND CELL DEATH
Diseases Caused by Misfolded Proteins That Result in ER Stress
– Induced Cell Loss
Retinitis Rhodopsin Abnormal folding of rhodopsin
pigmentosa causes photoreceptor loss and
cell death, resulting in
blindness
Creutzfeldt – Prions Abnormal folding of PrPsc
Jacob disease causes neuronal cell death
Alzheimer’s A β peptide Abnormal folding of A β
disease peptide causes aggregation
within neurons and apoptosis
Diseases Caused by Misfolded Proteins That Result from Both
ER Stress – Induced Cell Loss and Functional Deficiency of the
Protein
Alpha – I – anti – α – I anti - trypsin Storage of
trypsin deficiency nonfunctional
protein in
hepatocytes causes
apoptosis; absence
of enzymatic activity
in lungs causes
destruction of elastic
tissue giving rise to
emphysema
REVERSIBLE INJURY
Reversible injury is the stage of cell injury at which
the deranged function and morphology of the injured
cells can return to normal if the damaging stimulus is
removed

Normal kidney tubules: Simple cuboidal

epithelium with microvilli
Reversible: increased eosinophilia in cells; swelling;
surface blebs are present; distortion of microvilli

IRREVERSIBLE INJURY
Irreversible injury invariably leads to cell death,
which goes as either apoptosis or necrosis.
• Necrosis
Morphologic characteristics: o Major pathway of cell death in many
• Cellular swelling commonly encountered injuries
• Fatty change o Ischemia, exposure to toxins,
infections, trauma
Cellular Swelling o Always due to pathologic process
(disease)
• First manifestation of cell injury; not
clearly seen in microscope; but apparent at • Apoptosis – programmed cell death
o Cell kills itself
the level of the whole organ
o Caused by
• Result of failure of energy – dependent ion
▪ Deprivation of growth factors
pumps in the plasma membrane, leading to
in cells
the inability of maintaining ionic and fluid
▪ DNA is beyond repair
homeostasis
o Nuclear dissolution without complete
• Causes pallor (paleness), increased turgor
loss of membrane integrity
(degree of elasticity of skin), and an increase
o Active, energy – dependent, tightly
in organ weight
regulated cell death
Fatty Change
In comparison to Necrosis, Apoptosis is not only all
• Occurs in hypoxic injury and various forms the time physiologic but can also be pathologic.
of toxic or metabolic injury
Features of Necrosis and Apoptosis
• Manifested by the appearance of small or
large lipid vacuoles in the cytoplasm Feature Necrosis Apoptosis
• Occurs mainly in cells involved in and Cell size Enlarge Reduced
dependent on fat metabolism: hepatocytes (swelling) (shrinkage)
and myocardial cells Nucleus Pyknosis → Fragmentation into
Karyorrhexis nucleosome – sized
• Appearance of triglyceride containing lipid
→ Karyolysis fragments
vacuoles in the cytoplasm
Plasma Disrupted Intact; altered
Other intracellular changes associated with cell membrane structure, especially
injury include: orientation of lipids
Cellular Enzymatic Intact; may be
• Plasma membrane alterations such as contents digestion; may released in
blebbing, blunting, or distortion of microvilli leak out of cell apoptotic bodies
and loosing of intercellular attachments Adjacent Frequent No
• Mitochondrial changes such as swelling and inflammation
the appearance of phospholipid – rich Physiologic or Invariably Often physiologic
amorphous densities Pathologic role pathologic means of
(culmination eliminating
• Dilation of the ER with detachment of
of irreversible unwanted cells;
ribosomes and dissociation of polysomes
cell injury) may be pathologic
• Nuclear alterations such as clumping of after some forms of
chromatin, “Myelin figures” which are cell injury,
simple collections of phospholipids especially DNA and
resembling myelin sheaths protein damage
 • Pyknosis – shrinkage Cerebral vascular disease infarct versus
• Karyorrhexis – fragmentation hemorrhage/ bleeding
• Karyolysis – dissolution Infarct and bleeding leads to hypoxic cell death
NECROSIS Infarct – like ischemia, there is blockage in the blood
Necrosis is a form of cell death in which cellular vessel; decreased blood flow
membranes fall apart, and cellular enzymes leak out Bleeding – leakage of blood from the blood vessel;
and ultimately digest the cell the blood cannot go directly to the brain; brain will
The biochemical mechanisms of necrosis: not receive oxygen

• Failure of energy generation in the form of

ATP because of reduced oxygen supply or
mitochondrial damage
• Damage to cellular membranes, including the
plasma membrane and lysosomal
membranes, which results in leakage of
cellular contents including enzymes
• Irreversible damage to cellular lipids,
proteins, and nucleic acids which may be
caused by reactive oxygen species (ROS)
Types of Necrosis
Coagulative Necrosis
• Characterized by the preservation of the Gangrenous Necrosis
architecture/outline of the coagulated cells
• The denaturation of proteins is the primary • Not specific pattern of cell death, but
mechanism, which create a delineation of the usually applied to a limb that lost its blood
necrotic tissue in gross examination supply that has undergone coagulative
• Coagulative necrosis is characteristic of necrosis (dry gangrene)
hypoxic death of cells in all tissues except the • Particularly in limb and extremities
brain • Patient with a diabetic foot infection can
develop into gangrenous necrosis
• Wet gangrene – coagulative necrosis plus
superimposed bacterial infection
(liquefactive necrosis) because of actions of
degradative enzymes in the bacteria

Liquefactive Necrosis
• Characteristic of focal bacterial, or
occasional fungal infections
• Complete digestion of cells
• Transformation of cells into liquid viscous
mass due to the inflammatory response
elicited by the microbes
• Necrotic material becomes creamy yellow
(pus) due to presence of dead leukocytes
• Seen in the hypoxic death of cells in the
nervous system

Infarct or bleeding
Caseous Necrosis Fibrinoid Necrosis
• Distinctive form of coagulative necrosis • Special form of necrosis usually seen in
often seen in TB infection immune reactions involving blood vessels
• Characterized by cheesy white gross • Occurs when complexes of antigens and
appearance of necrotic area (hence antibodies are deposited in the wall of arteries
“caseous”) • The immune complexes along with leaked
• On microscopic examination, caseous fibrin forms fibrinoid (fibrin – like),
necrosis exhibit a granulomatous reaction: amorphous and bright – pink structures
o Amorphous granular debris
composed of fragmented coagulated
cells
o The granular debris is enclosed within
a distinct inflammatory border
• Unlike in coagulative necrosis, the tissue
architecture is obliterated
• Caseous Necrosis is surrounded by
granuloma which is composed of:
o Epithelioid cells
o Giant cells
o Lymphocytes
APOPTOSIS
Apoptosis is a pathway of cell death in which cells
activate enzymes that degrade the cells’ own nuclear
DNA and nuclear and cytoplasmic proteins
• Process that eliminates cells with a variety of
intrinsic abnormalities and promotes
clearance of the fragments of the dead cells
without eliciting inflammation
• Little leakage of cellular contents hence no
inflammatory reaction
Physiologic Apoptosis vs Pathologic Apoptosis
Physiologic Apoptosis
Death of cells that are no longer needed; to
maintain a steady number of various cell populations
in tissues
• Normally happening
Fat Necrosis
Pathologic Apoptosis
• Not specific pattern but denoting descriptive
focal areas of fat destruction due to release of Eliminates cells that are genetically altered or injured
pancreatic lipases beyond repair without eliciting severe host reaction,
o The pancreatic enzymes that have keeping the damage as contained as possible
leaked out of the acinar cells liquified • Abnormally happening
the membrane of the fats in your
peritoneum and lipases and split your Mechanism of
Condition
triglycerides or esters contained Apoptosis
within the fat Physiologic Apoptosis
o Lipases will degrade the different During embryogenesis Loss of growth factor
areas in the body signaling (presumed
o Acute pancreatitis mechanism)
Turnover of Loss of growth factor
• Release fatty acids combine with calcium
proliferative tissues signaling (presumed
visible chalky white areas – shadowy outlines (e.g., intestinal mechanism)
of necrotic fat cells with basophilic calcium epithelium,
deposits plus surrounding inflammatory cells lymphocytes in bone
marrow, and thymus)
Involution of hormone Decreased hormone
– dependent tissues levels lead to reduced
(e.g., endometrium) survival signals
 Decline of leukocyte Loss of survival signals The normal cell lives because of the survival signal
numbers at the end of as stimulus for (e.g., growth factor).
immune and leukocyte activation is
inflammatory responses eliminated The growth factor attaches to the receptor and will
Elimination of Strong recognition of yield to the production of your anti – apoptotic
potentially harmful self self-antigens induces protein (BCl2)
– reactive lymphocytes apoptosis by both the
BCl2 will inactivate the BAX/BAK channel through
mitochondrial and
blocking it to avoid the leakage of Cytochrome C
death receptor
pathways (activates caspase, triggers apoptotic death)
Pathologic Apoptosis During Apoptosis, there could be lack of survival
DNA Damage Activation of signal (physiological) or brought by irradiation
proapoptotic proteins
(pathologic) that leads to DNA damage.
by BH3 – only sensors
Accumulation of Activation of Both of these will lead to the activation of the sensor
misfolded proteins proapoptotic proteins (BH3 – only protein)
by BH3 – only sensors,
possibly direct BH3 – only protein antagonizes BCl2 which makes
activation of caspases BCl2 unable to do its function
Infections, especially Activation of the
certain viral infections mitochondrial pathway With the activation of the BAX/BAK channel, it will
by viral proteins be pro – apoptotic.
Leakage of Cytochrome C occurs which activates
Killing of infected cells the caspases and triggers apoptotic death.
by cytotoxic T
lymphocytes, which Death Receptor Pathway (Extrinsic)
activate caspases
• Many cells express surface molecules called
death receptors that trigger apoptosis
Mechanisms of Apoptosis • Most are members of the tumor necrosis
Apoptosis is regulated by biochemical pathways that factor family which contain in their
control the balance of death and survival – inducing cytoplasmic regions a conserved “death
signals and ultimately the activation of enzymes domain”
called caspases (cysteine proteases that cleave • It mediates interaction with other proteins
proteins after aspartic acid residues) involved in cell death
• Involved in the elimination of self – reactive
Two distinct pathways converge on caspase
lymphocytes and in the killing of target cells
activation:
by some cytotoxic T lymphocytes (CTLs)
➔ Mitochondrial Pathway that express FasL
➔ Death Receptor Pathway
Mitochondrial Pathway (Intrinsic)
• Responsible in most physiologic and
pathologic situations
• Cytochrome c
o Protein in mitochondria that is
capable of inducing apoptosis
o Leak out into the cytoplasm when
mitochondrial membrane becomes
permeable FasL molecules are being cross – linked with the Fas
o Activate caspase, triggers apoptotic molecule and they will bind to an adopter protein via
death. your death domain.
With this, caspases are activated and triggers
apoptosis.