general-pathology-lecture-notes-1-12.pdf

Pathology Exam 1 Study Guide
Cellular Injury and Adaptation
- Intro to Pathology
o The term pathology is derived from 2 Greek words
§ Pathos = disease
§ Logos = study
o Etiology – the origin of disease including the underlying causes and modifying
factors
o Pathogenesis – the steps in the development of a disease
§ Etiology refers to why a disease arises, while pathogenesis refers to how a
disease develops
o Pathology Divisions
§ Anatomic Pathology
• Autopsy Pathology – dissection and microscopic exam of tissues
removed from cadavers at postmortem exam
• Surgical Pathology – dissection and microscopic exam of biopsies
and surgical specimens removed from living patients to diagnose
tumors or other diseases
§ Clinical Pathology (Laboratory Medicine)
• Clinical chemistry
• Microbiology
• Immunopathology
• Hematology / Hematopathology
• Blood Banking
• Transfusion Medicine
- Intro to Pathology
o Rudolph Virchow (1821-1902)
§ German scientist who introduced the idea that the cell represented the
basic functional unit of the body (cellular pathology)
§ FATHER OF PATHOLOGY
o Sir William Osler (1849-1919)
§ Famous clinician who worked in Baltimore, Philadelphia and Boston – early
1900s
§ Noted that our clinical practice is only as good as our understanding of
pathology
- Overview of Cell Injury and Cell Death
o Homeostasis
§ Homoios – steady
§ Stasis -state
§ The state of balance between 2 opposing pressures operating in and around
a cell or tissue
§ Steady state – when an equilibrium between the cells and their
environment is achieved and maintained

§ External stimuli may alter this equilibrium
• Demands are increased – cell metabolism shifts to a higher level
achieving a new steady state
• Demands are decreased – cell metabolism shifts to a lower steady
state
o Either way, the adaptation is temporary, and the cell may
revert to the original steady state after the external
demands terminate
- Cellular Adaptations
o Prolonged exposure of cells to adverse or exaggerated normal stimuli evokes
various adaptations at the level of individual cells, tissues or organs
o Once the cause is removed, most cells revert to a normal state again
o Cellular adaptations include:
§ Atrophy
• Denotes a decrease in the size of a cell, tissue, organ or the entire
body
• Classifications of atrophy:
o Physiologic atrophy
§ Decreased Work Load
• Immobilization of a limb due to injury
§ Aging
• Certain numbers of brain cells are lost every
day from birth onward, which results in a
decrease in the entire brain
• Bones of elderly people are thin and more
prone to fracture
• Atrophic muscles are thin and weak in the
elderly
• Thymus
§ Loss of Endocrine Stimulation
• Ovaries, uterus and breasts following
menopause
o Pathologic atrophy
§ Inadequate nutrition
§ Diminished blood supply (ischemia)
• Kidneys affected by nephoangiosclerosis
§ Loss of Innervation
• De-inervated muscles after a spinal cord
injury or in muscular dystrophy
• The fundamental cellular changes are identical
o Decreased protein synthesis
o Increased protein degradation (ubiquitin-proteasome
pathway)

§ Hypertrophy
• An increase in size of tissues or organs owing to an enlargement of
individual cells
• Hypertrophy occurs in cells that have a limited capacity to divide
o Pure hypertrophy only occurs in heart and other muscle
• May be physiologic or pathologic
• Limit will be reached beyond which increased size can no longer
compensate for increased burden
o Opposite of atrophy
• Physiologic Hypertrophy
o Caused by increased functional demand or hormonal
stimulation (ex-skeletal muscles in body builders or the
uterus in pregnancy)
§ The uterus during pregnancy (white arrow)
increases in size mainly due to estrogen acting on
smooth muscle estrogen receptors leading to the
increase in smooth muscle cell size (figure C)
compared to smooth muscle cells in a normal
uterus (blue arrow and figure B)
• Cell size increases
• Pathologic Hypertrophy
o Hypertrophy of the heart
§ Increased pressure in the outflow side of the left
ventricle requires more force to be overcome and
its achieved by hypertrophy of cardiac muscle fibers
(ex – hypertensions, aortic stenosis, endocarditis)
• Concentrated myocardial hypertrophy of
the left ventricle wall in a pt with long-
standing hypertension
o Heart cannot make more cells, so
cell size increases
§ Hyperplasia
• An increase in the size of tissues and organs caused by an increased
number of cells
• Occurs in cell populations capable of replication
• Typically occurs as a result of hormonal stimulation (growth factors)
• May occur as a response to chronic injury
• Physiologic Hyperplasia
o Hormonal – female breast at puberty
o Compensatory – resected liver = liver regrows after being
partially removed
• Pathologic Hyperplasia
o Excessive growth factor or hormone stimulation

§ *important point* - the hyperplastic process
remains controlled – if cause is removed the
hyperplasia disappears!!
§ Neoplasia – increased number of cells à tumor, but
even with removal of cause, cells still increase
o Chronic Injury – Induced Hyperplasia
§ Hyperplasia is secondary to chronic injury
• Inflammatory papillary hyperplasia due to
ill-fitting dentures
o Inflammation of tissue – tries to
make denture fit by growing around
the denture!
§ Metaplasia
• A form of adaptation characterized by the change of one normal
cell type into another normal cell type
• One cell type is replaced by another type that is more capable of
handling a particular stress
• Reprogramming of the stem cell to differentiate along a new
pathway**
• Reversible change - when harmful stimulus is discontinued
metaplasia will go away!
• Examples: intestinal metaplasia in Barrett’s Esophagus
o Squamous mucosa transforms into columnar epithelium of
intestinal type
§ Difficult swallowing – squamous epithelium for
protection (white / pale tissue)
• GERD – acid breaks down esophageal walls
à transforms into columnar – lower part of
esophagus changed from squamous to
columnar – can lead to cancer – but should
be reversible
o Ciliated pseudostratified columnar epithelium of bronchial
mucosa changes into squamous epithelium – cigarette
smoke irritant
§ Irritant causes squamous metaplasia to develop in
order to protect the lungs from irritants
• Metaplasia may have some disadvantages
o Important protective mechanisms may be lost – ex – loss of
mucous secretion and ciliary movement in bronchial
epithelium
o Changes that induce metaplastic changes may lead to
malignant transformation
orGERD

• Metaplasia may occur in mesenchymal cells (fibrous tissue, muscle
and fat) but it is generally a pathologic alteration and not an
adaptation to stress
- Categories of Cell Injury
o Overview of Cell Injury and Cell Death
§ Important points:
• Cellular function may be lost long before cell death occurs, and the
morphologic changes of cell injury (death) lag far behind both.
• The events that determine when reversible cell injury progresses to
irreversible injury and then to death are poorly understood
• The 2 events that consistently characterize irreversible cell injury
are the inability to correct mitochondrial dysfunction and inability
to control what comes in and out of cell due to irreversible
damage to the cell membrane
o Ultrastructural – visible with electron microscope
o May not see effect of myocardial infarction until days after
event – will just see plaques not cell death
o Reversible Cell Injury
§ Reversible cell injury – if the adverse environmental influences evoke a
cellular response that remains within the range of homeostasis
• Cessation of injury results in the return of the cell to the original
steady state
• Typically mild or short lived
§ The two main morphologic characteristics of reversible cell injury are
cellular swelling and fatty change
§ Morphologic alterations
• Cellular swelling (hydrophobic- droplets of water in cell or vacuolar
change)
o First manifestation of almost all forms of cellular injury
o Increased influx of water into the cytoplasm
o Membrane bound vacuoles formed from the invaginations
of the plasma membrane and ER
• Plasma membrane – blebbing, blunting and loss of microvilli
• Cytoplasm – myelin figures, lipid vacuoles in the cytoplasm (fatty
change)
• Mitochondrial changes – swelling and the appearance of small
amorphous deposits
• Dilation of ER – detachment of ribosomes and disassociation of the
ribosomes
• Nuclear alteration – clumping of the chromosomes
• Ultrastructural electron micrographs:
o Normal proximal kidney tubule epithelium with microvilli
(top)

o Microvilli are lost and incorporated into apical cytoplasm
(middle)
o Mitochondria were swollen and have undergone
condensation and become electron dense (middle)
o Late injury with markedly swollen mitochondria with
electron-dense deposits of precipitated calcium and
proteins (last)
§ Pathogenesis of Cellular Swelling
• Plasma membranes are selectively permeable membranes that
maintain the gradient in the concentration of minerals (Na, K, CL)
inside and outside the cells
o This is achieved through Na/K ATPase pumps fueled by ATP
• Anoxia (no oxygen) or other forms of energy deprivation cause
dysfunction of these enzyme pumps leading to an influx of Na and Cl
into the cell due to a higher gradient extracellularly
o Water influx follows the Na and Cl leading to cellular
swelling
• Restoration of ATPase function:
o Na and water are pumped out
o Swelling disappears
§ Pathogenesis of Other Functional Alterations
• Swollen mitochondria
o Generates less energy
§ Instead of oxidative ATP production, the cell reverts
to less efficient glycolysis
§ Excessive production of lactic acid
• Cell becomes acidic, which further slows
down cell metabolism
• Dilation and Fragmentation of ER
o RER loses membrane attached ribosomes
§ Decreased protein synthesis
• Swollen Organelles Disintegrate
o Organelle membranes curl up into concentric bodies
(myelin figures)
o Hydrolytic lysosomal enzymes leak from overdistended
phagosomes into the acidic cytoplasm extensively damaging
other cellular components
• Hydropic change is reversible
• Cell will revert to its normal steady state
o Energy source is restored
o Toxic injury is neutralized
o Irreversible Cell Injury
§ Cells exposed to heavy doses of toxins, severe hypoxia or anoxia, or other
overwhelming insults cannot recover from the injury

• Energy production in mitochondria has fallen below the essential
minimum necessary for cell function that cannot be restored to
normal levels
• Plasma membrane functions are irrevocably lost
• Nuclear functions have been disrupted
§ Morphologic Alterations
• Characteristic morphologic changes of the nucleus
o Pyknosis – marked by the condensation of the chromatin
(pyknos = dense)
o Karyorrhexis – chromatin fragmentation into smaller
particles (karyon = nucleus, rrhexis = disruption)
o Karyolysis – dissolution of nuclear structure and lysis of
chromatin by enzymes such as DNAase and RNAase
§ Irreversible Cell Injury à Cell Death
• Dead cells release their contents into the extracellular fluid, reach
the circulation an are washed away
o Cytoplasmic enzymes such as aspartate aminotransferase
(AST- common liver enzyme) and lactate dehydrogenase
(LDH), which are released from dead cells, can be measured
in the clinical chemistry lab and serve as useful signs of cell
injury à determines cell death in body
§ Must look at released enzymes to make a diagnosis
- Cell Death
o All cells in the human body have a finite life span that ends in death
o Some cells may be replaced from stem cells (hepatocytes, epithelium) whereas
others are irreplaceable (cardiac myocytes, neurons)
o Cell death occurs in several forms
§ Necrosis – exogenously induced cell death from toxins or anoxia (necros =
dead) – something kills the cell à inflammation!
• Patterns of Necrosis
o Coagulative*most common*
§ Coagulative – tissue looks like a solid mass of boiled
meat in which the proteins are coagulated by heat
§ The injury denatures structural proteins and
enzymes which blocks the proteolysis of the dead
cells
§ Characteristics of infarctions (ischemic necrosis) in
all solid organs *except the brain*
• Nucleus is gone, red color but cells maintain
their shape
§ Form of necrosis in which the architecture of dead
tissues are preserved for some days
§ The affected tissues exhibit a firm texture

§ Microscopically, eosinophilic (red), anucleate cells
persist for days and weeks
§ More red, inflammation and neutrophils in 2nd
pic!
Cannot see nuclei anymore
o Liquefactive* most common*
§ Characterized by the complete digestion of the
dead cells. The tissue becomes a viscous liquid mass
§ Local bacteria or fungal infections
§ Infarction of the brain
§ Typical of a brain infarct that gets transformed into
a fluid-filled cavity after an ischemic event (stroke)
§ Also seen in focal bacterial and fungal infections
• Microbes stimulate the accumulation of
leukocytes with the liberation of enzymes
from these cells
• Necrotic material is usually creamy yellow
due to the presence of dead leukocytes
(pus)
o Gangrenous
§ This is not a specific pattern of cell death, but the
term is commonly used in clinical practice
§ This usually applies to a limb (lower leg typically)
that has lost its blood supply
§ It undergoes coagulative necrosis; however, it
involves several tissue planes
§ When bacterial infection is superimposed, there is
more liquefactive necrosis due to the actions of the
degradative enzymes in the bacteria and the
attracted leukocytes
§ Wet Gangrene – bacterial infection of coagulated
tissue leads to inflammation and a secondary
liquefaction
§ Dry Gangrene – necrotic tissue dries out and
becomes dark black and mummified.
o Caseous – “cheese” necrosis
§ Typically found in tuberculosis (microbacterial) and
histoplasmosis (fungal)
§ The necrotic tissue is grossly friable, yellow-white
and cheesy
§ The area of caseous necrosis is surrounded by a
distinctive pattern of inflammation known as a
granuloma
• In lung here

§ Granuloma – typical tuberculosis granuloma with
an area of central necrosis surrounded by multiple
Langerhans-type giant cells (arrow), epithelial cells
and lymphocytes
§ Granuloma – a cimcumscribed collection of
epithelial histiocytes (classic definition)
• Barrier around something that the body has
trouble eliminating
o Fat
§ Special form of liquefactive necrosis caused by the
action of lipolytic enzymes
§ It is limited to adipose tissue, usually around the
pancreas
• Occurs in acute pancreatitis
§ Pancreatic enzymes released into the adjacent
adipose tissue degrade the fat into glycerol and free
fatty acids
§ Saponification
• Free FAs rapidly bind with calcium, forming
calcium soaps
• Area of fat necrosis appears like liquefied
fat with white-ish specks of calcium soaps
scattered about.
o Fibrinoid
§ Special form of necrosis usually seen in immune
rxns involving blood vessels
§ Occurs when complexes of antigens and antibodies
are deposited in the walls of arteries
§ Deposits of immune complexes and fibrin that has
leaked from the vessels result in a bright pink,
amorphous appearance to the vessel walls on HE
staining
§ Seen in immunologically mediated vasculitis
syndromes
§ Apoptosis – endogenously programmed cell death (dropping out) – cell is
unnecessary or has injury or genetic change à losing control à suicide
§ Autolysis – death of cells and tissues in a dead organism as a result of
cessation of respiration and heath beat ( autos = self , lysis = dissolution
- General Principles of Cellular Injury
o The cellular response depends on the type of injury, duration and severity
o The consequences of an injurious stimulus depend on the type, status, adaptability
and genetic makeup of the injured cell
o Cell injury results from the functional and biochemical abnormalities in one or more
of several essential cellular components

o Multiple biochemical alterations may be triggered by any 1 insult
§ (Striated muscle will accommodate complete ischemia for 2-3 hours while a
cardiac muscle cell will die in 20-30 minutes.
§ A glycogen rich hepatocyte will tolerate ischemia much longer than one that
is depleted of glycogen.
§ Different variants of cytochrome P-450 will metabolized a toxin at different
rates.)
- Principal Mechanisms of Cell Injury
o Depletion of ATP
§ Major causes:
• Reduced O2 supply
• Mitochondrial damage / dysfunction
o Causes: hypoxia, chemical toxins and radiation
o Results: depletion of ATP due to failure of oxidative
phosphorylation
o Abnormal oxidative phosphorylation leads to formation of
reactive oxygen species (ROS)
o Release of proteins that can activate apoptosis
• Actions of some toxins
§ Widespread effects on many critical cellular systems
• Activity of Na pumps in plasma membrane is reduced resulting in
cellular swelling – more Na and Ca in cell followed by h2O
• Decreased pH due to increase in anaerobic glycolysis (lactic acid)
caused decreased enzyme activity and clumping on nuclear
chromatin – more acidic environment
• Influx of Ca into the cell – swelling
o Influx of calcium
§ Cytosolic free calcium is maintained by ATP-
dependent transporters at 10,000 times lower than
extracellular calcium or calcium sequestered in
mitochondria or ER
§ Increased cytosolic calcium activated a number of
enzymes including:
• Phospholipases – damage membranes
• Proteases – damage membranes and
cytoskeletal proteins
• Endonucleases – DNA and chromatin
fragmentation
• ATPases – hastens ATP depletion
§ Can induce apoptosis
• Decrease protein synthesis
• Accumulation of Oxygen-Derived Free Radicals
o Free radicals are chemical species with a single unpaired
electron in the outer orbital

§ Attack nucleic acids as well as a variety of cellular
proteins and lipids
§ Reactive oxygen species (ROS) – oxygen derived
free radical whose role in cell injury is well
established
§ Balance between free radical production and
removal
o Generation of free radicals is increased by
§ Absorption of radiant energy
• UV light and X-rays
• Enzymatic metabolism of exogenous
chemicals
• Inflammation
o ROS cause injury by 3 main mechanisms
§ Lipid peroxide of membranes
§ Cross-linking and other changes in proteins
§ DNA damage
o Defects in Membrane Permeability
§ Consistent feature in most forms of cell injury that lead to necrosis
§ Important targets:
• Mitochondrial membranes
• Plasma membrane
• Lysosomal membranes
o Need control of what enters/exits the cell or will die!!
o Damage to DNA and Proteins
§ Cells can repair damage to DNA
§ Accumulation of improperly folded proteins
• Both lead to cell death via apoptosis
o Tumor suppressor genes à induce apoptosis! If they are
lost, cancer starts
- Cell Death
o Apoptosis
§ Pathway of cell death in which cells activate enzymes that degrade the cells
own nuclear DNA
§ Energy dependent and requires activation of a specific set of genes and
enzymes (suicide genes)
§ Programmed cell death**
§ The dead cell is rapidly cleared and does not ilicit an inflammatory
response*
§ Initial event could be endogenous or exogenous
• Long-lasting viral infection – chronic viral hep C – exogenous
• Lack of necessary growth factors in a brain cell – endogenous
§ Physiologic Cause of Apoptosis

• Apoptosis occurs in many normal situations and serves to eliminate
potentially harmful cells and cells that have outlived their
usefulness
• Examples – embryogenesis, involution of hormone dependent
tissues upon hormone deprivation
• Cell loss in proliferating cell populations – blood or epithelial
• Elimination of cells that have served their useful purpose
• Elimination of potentially self-reactive lymphocytes à auto immune
diseases
• Cell death by cytotoxic T lymphocytes
§ Pathologic Causes of Apoptosis
• Apoptosis eliminates cells that are genetically altered or injured
beyond repair, it does so without eliciting an inflammatory
response, keeping the extent of tissue damage to a minimum
• Examples
o DNA damage
o Accumulation of misfolded proteins
o Cell injury in certain infections (usually viral)
o Pathologic atrophy in organs after duct obstruction
- Intercellular Accumulations and Calcification
o Intracellular Accumulations
§ Cells may accumulate abnormal amounts of various substances
• Can be harmless or associated with injury
• Can be in many locations in the cell
• May be exogenous or produced by the cell
§ 4 Main Pathways
• Inadequate removal of a normal substance
• Accumulation of an abnormal substance
• Failure to degrade a metabolite
• Deposition and accumulation of an abnormal exogenous substance
§ Fatty Change (Steatosis)

• Abnormal accumulations of TAGs most often in liver cells
§ Cholesterol
• Ex-atherosclerosis
§ Proteins
• Russel Bodies (immunoglobulins) in plasma cells, neurofibrillary
tangles in neurons
§ Glycogen
• Poorly controlled diabetes, glycogen storage, diseases
§ Pigments
• Carbon – coal dust (antheacosis) – dark lungs for smokers
• Lipofuscin – wear and tear pigment, accumulates in a variety of
tissues (heart, liver, brain) as a function of age or atrophy
• Melanin – pigment that acts as a screen for harmful radiation
• Hemosiderin – aggregates of ferritin micelles when iron levels are
elevated
§ Types of Calcification
• Dystropic Calcification
o Calcification of necrotic tissue with normal calcium levels –
dead tissue
o Neucrotic tissues attract calcium salts and often undergo
calcification
o Seen in artherosclerotic arteries, damaged heart valves or
necrotic tumors
• Metastatic Calcification
o Deposition of calcium salts in normal tissue the presence of
abnormal calcium metabolism – live tissue
o Feature of metabolic hypercalcemia secondary to
hyperparathyroidism, vitamin D toxcicity, increased
destruction of bone or renal failure
- Cellular Aging
o Individuals age because their cells age
o Cellular aging is the result of a progressive decline in the life span and the functional
capacity of cells
o Main mechanisms
§ Accumulation of DNA damage
§ Decreased cellular replication
• Normal cells have a limited capacity for replication – replicative
senescence – eventually will stop dividing – malignant cells don’t
have replicative senescence and will continue to grow
• Telomeres are short repeated sequences on the end of linear
chromosomes
• Telomeres shorten with each cell division
o Mutated in malignant cells = just keeps being regenerated
• Defective protein homeostasis

Inflammation
- Overview
o A protective response
§ Eliminate the cause of injury (like germs)
§ Eliminate dead cells
o Can cause tissue injury:
§ Severe infection
§ Prolonged cause of inflammation
§ Inappropriate inflammation
• Autoimmunity
• Hypersensitivity
o Components of Inflammation
§ Leukocytes – eliminates microbes or dead tissue
§ Plasma – complement: mediators of inflammation, elimination of microbes
/ clotting factors and kininogens – mediators of inflammation
§ Mast cells – source of mediators
§ Lymphocytes – immune response
§ Monocytes (in vessel) / macrophage (outside of vessel) – elimination of
microbes and dead tissue, source of mediators and role in immune response
§ ECM – repairs the area
o Acute vs. Chronic Inflammation
§ Acute
• Rapid onset and short duration (minutes to days)
• Usually neutrophil-rich inflammatory infiltrate
§ Chronic
• Insidious onset and long duration (days to years)
• Usually mononuclear inflammatory infiltrate
o Signs of Inflammation
§ Rubor (redness)
§ Tumor (swelling)
§ Calor (heat)
§ Dolor (pain)
§ Function laesa = loss of function
o Steps of Inflammation
§ Recognition of injurious agents
§ Recruitment of leukocytes
§ Removal of agent
§ Regulation of response
§ Resolution / repair
- Acute Inflammation
o Vascular and Cellular response
o Rapid response
o Delivers leukocytes and plasma proteins

o Vascular changes
§ Vasodilation (causes rubor – vessels carry more blood) and increased
vascular permeability (vessel leaks out – warmth and swelling)
o Cellular events
§ WBCs (neutrophils) recruited
§ WBCs are activated
o Stimuli for Acute Inflammation
§ Infections
§ Trauma
§ Necrosis
§ Foreign bodies
§ Hypersensitivity reactions
o Vascular Flow in Acute Inflammation
§ Vasoconstriction (seconds)
§ Arteriolar dilation à erythema
§ Increased permeability à fluid in ECM à increased blood viscosityà
decreased blood flow à statis
• Hydrostatic pressure pushes fluid out and osmotic pressure pulls
fluid in
§ Neutrophil margination – as vessel get bigger, neutrophils will go to the
perimeter of the vessel
o Vascular Permeability in Acute Inflammation
§ Increased hydrostatic pressure à transudate (edema – water rich liquid)
§ Endothelial leakage à exudate (protein rich residue)
• Causes of endothelial leakage:
o Cell contraction à intercellular gaps
o Cell injury
§ From original cause of injury
§ From effect of activated WBCs
o Mediator-induced transcytosis of proteins
o Angiogenesis – new blood vessel formation – vessels leak as
they are forming
o Leukocyte Recruitment
§ Margination
• Laminar flow pushes larger WBCs to outside of stream
o Cellular part of inflammation
o Dilated pipe = larger particles (WBCs) go to the perimeter of
the stream
§ Rolling
• Due to selectins
o The WBCs bind to blood vessel walls and roll
o Then, via integrins, WBCs adhere to the vessel wall and then
go through vessel wall via transmigration
§ Adhesion and Transmigration

• Due to integrins on WBCs interacting with ligand on endothelial cell.
§ Migration (chemotaxis – cell motility along a concentration gradient)
• Bacterial products
• Cytokines
• Complement components
• Lipoxygenase and arachidonic and acid metabolites
o Timeline for Acute Inflammation
§ Neutrophils dominate for 6-24 hours
• Very numerous in circulation
• Short-lived
§ Monocytes dominate at 24-48 hours
• Longer survival than neutrophils
§ Very rapid and edema is due to leakage of vessels
o Receptors on Leukocytes
§ Toll-like receptors
• For LPS
• For other bacterial products
§ 7-transmembrane receptors
• For bacterial peptides
• For mediators
§ Cytokine receptors
§ Phagocyte receptors – FYI
o Results of Leukocyte Activation
§ Phagocytosis with intracellular destruction of microbes and dead cells
§ Release of microbicidal substances
§ Production of mediators to amplify reaction
• Neutrophil is activated, eats microbe and leaks mediators –
increases inflammatory / immune response
o Phagocytosis
§ Recognition and attachment of particle to WBC
• Receptors on WBC recognize opsonins (antibodies that coat the
germ) on surface of particle
o Opsonins = IgG, C3 (complement) or collectins
§ Engulfment via a phagocytotic vesicle
o Killing and Degradation
§ Lysosomes fuse with phagosomes
§ Oxidative burst à ROS à kill microorganism
§ Degradation by lysosomal acid hydrolases
• NADPH oxidase makes radicals that will kill the germ in the
phagolysosome
o Secretion of Microbicidal Substances
§ Granules of leukocytes = lysosomes containing:
• Elastase (degrades elastins) or antimicrobial peptides
§ Mechanism of cellular release

• Regurgitation during phagocytosis
• Frustrated phagocytosis à extracellular release
• Membrane damage
o Lysosomes leak out and cause damage in the area
- Pathology of Acute Inflammation
o Mechanisms to kill microorganisms also injure normal cells and tissues
§ Neutrophil Extracellular Traps (NETs)
• Response to: bacteria, fungi or mediators
• Nuclear chromatin and embedded granule proteins leave cell à
trapping of microorganisms
o Neutrophil poops out its nucleus and forms a net that traps
bacterial cocci
o Defective Acute Inflammation
§ Leukocyte (WBCs) adhesion deficiencies (LADs)
• Type 1 and type 2
§ Defective microbicidal activity
• Chronic granulomatous disease
§ Defect in phagolysosome formation
• Chediak-higashi (AR)
o Chronic granulomatous disease = enzyme complex needed
to kill a germ is not there = so never causes germ death à
granuloma
§ Toll-like receptor pathway mutations
- Outcome of Acute Inflammation
o Resolution
o Progression to chronic inflammation – if it failed to kill all of the germs
o Scarring = fibrosis
- Morphology of Acute Inflammation
o Serous inflammation – when transducent (watery) dominates
§ Watery, protein poor fluid accumulation (edema)
• Vesicle (blister)
• Effusion (if inside body cavity)
o Fibrinous inflammation
§ Protein-rich exudate (more vascular permeability than in serous)
§ Fibrinolysis à resolution
• If resolution fails, exudate is organized (fibroblasts enter and make
collagen à adhesions appear between heart and pericardium)
o Ingrowth of blood vessels and fibroblasts
§ Fibrin comes out in the exudate!
§ Bread and butter pericarditis
o Suppurative (purulent) inflammation
§ Neutrophils dominate morphology
§ Large focus = abscess

• PUS = liquefactive necrosis and dead neutrophils make up the
abscess
§ Abscess – large focus of Suppurative inflammation with necrosis due to
impaired drainage
• Must be drained – will not heal without draining because it is dead
tissue and pus!
o Ulcers
§ Loss of epithelium and inflammatory response
• Road rash will be an ulcer
• Can be chronic
• Neutrophils dominate
• Gastric or peptic ulcer – stomach contents eat stomach
- Chemical Inflammatory Mediators
o Produced locally
§ Some sequestered in WBC intracellular granules (histamine)
§ Others synthesized de novo (when needed) at site (prostaglandins and
cytokines)
o Circulating (usually produced by liver)
§ Circulate as inactive form
§ Proteolytic cleavage à activation
o Usually bind receptors on target cells
o Stimulate target cells to release secondary effector molecules
o Under strict and complex regulation
- Cell Derived Mediators (probably no questions about mediators)
o Vasoactive amines = histamine or serotonin
o Arachidoic acid metabolites = prostaglandins, leukotrienes, lipoxins
o Platelet activating factor
o Cytokines = TNF, IL-1, chemokines
o ROS
o Nitric oxide
o Lysosomal enzymes
o Neuropeptides
- Plasma Protein-Derived Mediators
o Circulating mediators
§ Complement system – includes all of these mediators – used to increase
inflammation and to destroy cells
§ Coagulation proteins -
§ Kinins – with complement, overlap with the coagulation cascade – coagulate
blood
• *Some mediators overlap with coagulative system
• Enzyme cascades – used to amplify a cellular signal and thus,
amplify the cellular response – enzymes lower activation energy and
are not consumed so can activate several proteins quickly
o Mediators of Vasodilation

§ Prostaglandins
§ Nitric oxide
§ Histamine
o Mediators of Vascular Permeability
§ Histamine, serotonin, C3a, C5a, bradykinin, leukotrienes C4, D4 and E4, PAF,
Substance P
• Causes leaky vessels
o Mediators of WBC Recruitment and Activation
§ TNF, IL-1, chemokines, C3a, C5a, leukotriene B4, bacterial products
o Mediators of Fever
§ IL-1 - interleukin
§ TNF – tumor necrosis factors
§ Prostaglandins
o Mediators of Pain
§ Prostaglandins
§ Bradykinin
§ Neuropeptides
o Mediators of Tissue Damage
§ WBC lysosomal enzymes
§ ROS
§ Nitric Oxide
o Major Cytokines – guess TNF, then IL-1, then IL-6
§ TNF is in everything but the liver
§ IL-1 is in everything but the endothelium and heart
- Chronic Inflammation
o Prolonged duration (weeks to years)
§ Acute inflammation
§ Tissue injury
§ Healing
o Characterized by:
§ Mononuclear (lymphocytes, plasma and macrophages) inflammatory
infiltrate
§ Tissue destruction
§ Repair (angiogenesis and fibrosis)
o Setting of Chronic Inflammation
§ Persistent infections
§ Immune-mediated diseases (hypersensitivity)
§ Prolonged exposure to toxic agents
o Chronic Inflammatory Cells
§ Macrophages (derived from monocytes)
§ Lymphocytes
• T and B cells
§ Plasma cells
§ Eosinophils (usually IgE mediated inflammation)

• Not always considered a chronic inflammation cell
§ Mast cells (usually IgE mediated inflammation) – don’t care right now
o Granulomatous Inflammation
§ Specialized subtype of chronic inflammation
§ Defined by presence of granuloma
• Granuloma = circumscribed collection of epithelioid histiocytes
o Can have multinucleated giant cells
o Can have peripheral cuff of lymphocytes
§ Small collections of activated macrophages
(cytoplasm is huge and nucleus is smaller so it looks
like squamous epithelium)
§ Causes of Granulomatous Inflammation:
• Mycobacteria
• Many fungi** (not all)
• Foreign bodies
• Sarcoidosis – not well understood, pt has granulomas but has ruled
out everything that typically causes granulomas = idiopathic
granulomas
§ Pic = well-formed caseous granuloma
• Middle = dead caseous necrosis
• Histocytes – blobs
• Blue = cuff of lymphocytes around histocytes
• 3-4 cells hugging = granuloma
• Red is dead = necrotic tissue picks up eosinophil well
• Blue is bad = neoplasia – nucleus gets bigger in cancer cells
- Systemic Effects of Inflammation
o Acute-phase reaction = systemic inflammatory response system
o Largely mediated by cytokines
§ TNF, IL-1 and IL-6
• All from the liver!
o Acute Phase Response
§ Fever
§ Increased levels of plasma “acute phase” proteins
§ Leukocytosis
§ Increased heart rate
§ Increased blood pressure
§ Decreased swelling
§ Chills and rigors (shivering)
§ Anorexia – no appetite
§ Malaise and somnolence
• Increases WBCs
o Severe Acute-Phase Responses
§ Cachexia (wasting of tissues)
• Largely due to TNF (aka cahexin)

o Can happen in cancer or severe inflammatory response
§ Septic shock
• Shock = blood isn’t flowing
o Due to heart not pumping, no fluid or vessels are too dilated
• DIC
o Disseminated intravascular coagulation – small blood clots
everywhere but mainly in capillaries – exhausted the
coagulation proteins and now will bleed to death with
minor trauma
• Hypoglycemia – low blood sugar
• Hypotensive shock – vessels are too dilated
Repair (wound healing)
- Overview
o Regeneration
§ Proliferation of uninjured cells
§ Typical of epithelia and liver
o Scarring (Fibroplasia)
§ Replacement of cells by collagen
§ Typical of
• Severe damage and many solid organs
o *both processes require close interaction between cells and ECM***
- Cell and Tissue Regeneration
o Proliferating Cells in Repair
§ Remnants of injured tissue - to restore normal structure
§ Endothelial cells – to make new blood vessels
§ Fibroblasts – to make collagen
o Cell Cycle
§ Growth factors drive transitions
§ Cyclins regulate progression
• Labile = cells that constantly divide (skin, gut, marrow)
• Quiescent = stable cells, usually in G0
• Permanent = cells incapable of regeneration, will only heal by
scarring – neurons, and striated cardiac muscle
o Stem Cells
§ Important properties
• Asymmetric replication
o Division à differentiated cell and stem cell
• Self-renewal
§ Types
• Embryonic stem cells (ES cells) – can become any type of cell
• Adult stem cells (aka tissue stem cells)
o Regenerative Medicine

§ Introduce genes from stem cells into patient’s cells à induced pluripotent
stem cells (iPS cells)
• Can grow a new liver if you need one
o Growth Factors: Functions
§ Promote entry of cell to cell cycle
§ Relieve block on cell cycle progression (stimulate G0 cells to go to M cycles)
§ Prevent apoptosis
§ Enhance synthesis of proteins for mitosis
o Growth Factors in Repair
§ VEGF (vascular endothelial growth factor) and FGF (fibroblast growth factor)
• Both involved in wound healing and will make new blood vessels via
angiogenesis
o Growth Factor Effects
§ Autocrine – GF signals the same cell that produced it
§ Paracrine – GF signals cell nearby
§ Endocrine – GF signals cell far away
o Types of GF Receptors
§ Receptors with intrinsic kinase activity
• Ligand binds receptor à dimerizes and receptor subunit is
phosphorylated = creates an enzyme cascade by binding and
activating intracellular proteins
§ G-protein-coupled receptors (7 transmembrane receptors)
• Ligand binds receptor à associate with G-proteins, GDP is replaced
by GTP à activation
§ Receptors without intrinsic enzyme activity
• Ligand binds extracellular part of receptor à conformational
change of intracellular part
• Intracellular part associated with Janus kinases (JAKs)
o Extracellular Matrix in Repair
§ Regulates cells proliferation, movement and differentiation by:
• Providing substrate for cell adhesion and migration
• Sequester water à turgor pressure
• Sequester minerals à tissue rigidity
• Serves as a GF reservoir
o ECM is needed for wound healing – reservoir and scaffold
for regenerating cells and repair
o If ECM is damaged or damage to heart or brain = scarring!
§ 2 forms of ECM
• Interstitial matrix
o 3D amorphous gel
§ Collagens, fibronectin, elastin, proteoglycans,
hyaluronate ect.
o Bulk of ECM
• Basement membrane

o Plate-like mesh
§ Collagen 4 (non-fibrillar) and laminin
o Located under epithelium usually
§ Major ECM components
• Structural proteins
o Tensile strength and recoil
§ Collagens – 30 types, rope-like triple helix that
provides tensile strength
• Fibrillar (1, 2,3,5)
• Non-fibrillar (4,7,9)
o Collagen 1 (wound healing) and 4
(basement membrane)
§ Elastin – provides elastic recoil – in aorta
• Hydrated gels
o Resilience and lubrication
§ Proteoglycans = glycosaminoglycan and protein
core
• Resilience, lubrication and GF reservoir
o Proteoglycans = look like cleaning
brushes = makes tissue resilient to
trauma
§ Hyaluronan (hyaluronic acid)
• Mucopolysaccharide without a protein core
o Binds with water to make gelatin-
like matrix
• Adhesive glycoproteins
o Connect ECM components to each other
o Connect ECM components to cells
o Fibronectin - binds many ECM components and attaches to
integrins
o Laminin – connects cells to type 4 collagen and heparin
sulfate
o Integrins – binds cells to ECM
§ ECM Functions
• Mechanical support
o For cell anchorage, migration and to maintain cell polarity
• Control of cell proliferation
o By binding and displaying GF and by integrin signaling
• Scaffolding for tissue renewal
o Basement membrane is required for regeneration
• Establishment of tissue microenvironments
o Regeneration in Repair
§ Labile tissues
• Regeneration if basement membrane scaffold is intact

§ Stable tissues
• Limited regeneration in many parenchymal organs
o Liver is excellent at regeneration!
§ Permanent tissues
• No regeneration
- Scar Formation
o Steps in Scar Formation
§ Inflammation – begin to clear dead cells
§ Angiogenesis – make new blood vessels from existing vessels
• Steps
o Vasodilation
o Separation of pericytes
o Migration of endothelial cells
o Proliferation of endothelial cells
o Remodeling into tubes
o Recruitment of pericytes and smooth muscle cells
o Suppression of proliferation and migration
o Deposition of basement membrane
• Angiogenesis Growth Factors
o VEGF family – migration and proliferation of endothelial
cells
o FGF family – proliferation of endothelial cells
§ Migration of: macrophages, fibroblasts and
epithelial cells
o Angiopoietins (Ang1 and Ang2) (don’t care yet)
§ Structural maturation of new vessels
§ Migration and proliferation of fibroblasts – make collagen!
• Driven by GFs (mostly from macrophages)
o PDGF, FGF-2 and TGF-beta***
§ Tell fibroblasts to divide and make ECM
• New blood vessels will go away after
healing
§ Collagen synthesis
• Fibroblasts synthesize ECM (especially collagen)
• Progressive regression of vessels
§ Remodeling (maturation and reorganization)
• Matrix metalloproteins (MMPs) degrade collagen and other ECM
components
• MMPs turned off by tissue inhibitors of metalloproteinases (TIMPs)
• Wound contraction (due to myofibroblasts)
o Making scar stronger!
§ * Angiogenesis and the migration and proliferation of fibroblasts form
granulation tissue!!!****
• Granulation tissue is the HALLMARK OF WOUND HEALING

o Scabs = blood leaking out of new vessels = healing
o Blue = collagen 1
• Left pic = still edema
• Right = later so some vessels and more
collagen
- Factors that Influence Tissue Repair
o Antagonists of Wound Healing
§ Infection – most important cause of delayed healing***
§ Inadequate nutrition (ex- lack of vitamin C = scurvy – hydroxylating collagen)
§ Mechanical forces (ex-causing dehiscence = when sutures are
broken/ripped out ) or need a cast
§ Poor perfusion (diabetics have crappy circulation)
§ Foreign bodies – no blood flow in foreign bodies
o Abnormal Wound Healing
§ Keloid = hypertrophic scar due to excessive collagen production
• More common in African Americans = will keep coming back and
needs plastic surgery
§ Proud Flesh – excessive granulation tissue – horses
§ Contracture – wound contraction reduces range of motion
• Myofibroblasts pull the wound together = lesion contracture
(sometimes from burns) – scars are pulled too tightly over a joint
and limits motion
§ Stricture – wound contraction in viscus à obstruction
• Lesion in pipes
- Clinical Examples of Repair
o Healing of skin wounds
o Fibrosis of parenchymal organs
o Healing by First Intention
o Healing of an incised wound with approximated edges
Primary = sew edges of wound together
• Day 0 = surgeon’s incision
• Day 1 = neutrophils appear, basal cells divide
• Day 2-3 = macrophages replace neutrophils, granulation tissue
invades wound space, vertical collagen fibers
• Day 4-5 = peak of neovascularization, collagen fibers bridge wound,
epithelium of normal thickness
• 2nd
week = continued collagen formation, regression of vascular
channels, dissipation of inflammation
• 1st
month = scar
o Healing by Second Intention
§ The healing of a wound without approximation of edges
• Same as healing by first intention but with the following differences:
o Larger amount of necrotic debris, exudate and fibrin to
remove

o Greater volume of granulation tissue leading to (early) large
scar
o Wound contraction* - due to myofibroblasts – can shrink
scar 90-95%
• Only difference is that the edges of the wound are not put together
– huge wound, so cannot put a timeline with it
• Wound contraction is primary but more obvious with a bigger
wound
o Wound strength
§ Sutured = 70%
§ 1 week (no suture) = 10%
§ 3 months = 70-80%
§ Will never go back to 100%***
o Parenchymal Organ Fibrosis
§ Same mechanisms as scar formation (including wound contraction)
Hemodynamic Disorders – bleeding issues
- Cardiovascular Disease
o Most important cause of morbidity and mortality in Western society
o Divided into diseases that affect the heart, the vessels and the blood components.
o Blood components: water, salt, protein, and elements of coagulation (platelets and
factors), WBCs and RBCs
o Disorders lead to adaptation and further abnormalities
§ Centrifuge blood
• RBCs
• Buffy coat? – WBCs and plasma
• Plasma – water and salt ect.
- Edema
o Normal hydrostatic pressure is equal to the plasma colloid osmotic pressure
o Net fluid into interstitial drains into lymphatic returns to blood stream via thoracic
duct
o Elevated hydrostatic pressure or diminished colloid osmotic pressure = increased
movement of fluid out of vessels
§ Hydrostatic = pushes water out
§ Osmotic = caused by proteins pulling water in
o Edema – fluid in the tissue (swelling)
§ Increased hydrostatic pressure and low osmotic pressure
o Effusion – fluid in body cavities
- Edema (cont)
o Non-inflammatory
o Inflammatory
o Exudate (opaque)
§ Protein rich plasma inflammatory mediators
§ Local vs. sepsis

§ Generally high values
o Transudate (translucent)
§ Protein-poor plasma
§ Heart failure, liver failure, severe nutritional disorders
§ Generally low values
§ Pitting edema à
- Renin – Angiotensin System
o Prominent for hypertension
o Kidneys sense low blood volume or pressure due to severe blood loss (trauma) and
secretes renin which converts angiotensin to angiotensin 1 which is converted to
angiotensin 2 in the lung which stimulates the adrenal gland to make aldosterone
which tells kidney to absorb salt and water follows to increase blood pressure
o Sodium and Water Retention
§ Increased salt retention with associated water – at kidney with renin-
angiotensin pathway
§ Increased hydrostatic pressure and decreased colloid pressure
§ Decreased renal perfusion
- Increased Hydrostatic Pressure
o Disorders that impair venous return
o Localized – deep vein thrombosis
o Systemic – congestive heart failure
§ Increased blood pressure and hydrostatic pressure = liver disease
- Reduced Plasma Osmotic Pressure (comes from proteins)
o Albumin – half of the total plasma protein – low albumin = liver disease, liver makes
albumin
o Inadequate synthesis or increased loss
o Severe liver disease
o Nephrotic syndrome – holes in glomerulus so peeing out proteins!
o Secondary hyperaldosteronism
- Lymphatic Obstruction
o Disruption of lymphatic drainage
§ Trauma
§ Fibrosis
§ Invasive Tumors
§ Infectious agents – parasitic filariasis
• Lymph edema – parasite gets into lymphatic system and obstructs
the flow of the lymph
• Breast cancer – metastasizes to the lymph nodes and causes edema
- Edema and Effusions
o Edema = fluid build-up in skin
o Effusion = fluid build-up in organs – fluid in interstitial space of organs
§ Heart = pericardial effusion
§ Lungs = pleural effusion
§ Abdomen = ascites

- Hyperemia and Congestion
o Hyperemia (active)
§ Arteriolar dilation
§ Erythema
§ Inflammation
§ Skeletal muscle during exercise*
o Congestive (passive)
§ Reduced outflow
§ Systemic – CHF
§ Localized – Isolated venous obstruction
• Liver with chronic passive congestion = nutmeg liver (left)
• Centrilobular necrosis with degenerating hepatocytes and
hemorrhage = liver disease and failure
- Hemostasis
o Hemostasis – process blood clots form at sites of vascular injury
o Hemostatic Abnormalities:
§ Hemorrhagic Disorders –excessive bleeding
§ Thrombotic Disorders – blood clots form within vessels in cardiac chambers
o Arteriolar Vasoconstriction
§ Mediated by neurogenic mechanisms
§ Endothelium
o Primary Hemostasis
§ Formation of the platelet plug*
§ Exposure of vWF
§ Shape changes
§ Release of granules
§ Aggregation
o Secondary Hemostasis – need more than just a platelet plug
§ Formation of fibrin clot*
§ Coagulation cascade
§ Thrombin cleaves fibrinogen into fibrin
• If bleeds, then stops then bleeds again may have disorder of
secondary hemostasis
o Clot Stabilization and Resorption
§ Polymerized fibrin and platelet aggregated a solid, permanent plug
§ Tissue plasminogen activator, t-PA – limits clot and leads to resorption and
repair
• Can have issues if clot doesn’t dissolve
o Platelets
§ Platelets play an integral role in hemostasis
§ Anucleate fragments shed from megakaryocytes
§ Platelet adhesion – vWF and GpIb
§ Contractile cytoskeleton
§ Secretion of granule content

§ Platelet aggregation
o Coagulation Cascade
§ Thrombin activates the cleavage of fibrinogen to fibrin to form clots!
• 2 Hemostasis = ends with fibrin clot from coagulation cascade
§ Intrinsic vs extrinsic
§ Enzyme – substrate – cofactor à coagulation test?
§ Prothrombin time (PT) – measure extrinsic
§ Partial thromboplastin time (PTT) – measures intrinsic
§ Thrombin
• Thrombin is most important
• Conversion of fibrinogen into crosslinked fibrin*
• Platelet activation
• Pro-inflammatory effects
• Anticoagulation effects – breaks the clot!
o Fibrinolysis
§ Counter regulatory mechanisms
§ Fibrinolytic cascade
§ Enzymatic activity of plasmin, generated by activated plasminogen*
• Breaks down fibrin*
• Fibrin split products (D-dimers) *
• Factor XII-dependent pathway
• Plasminogen activators – t-PA**
o Given to pts within 30 min of a stroke to break the clot – if
later then angioplasty – but cannot administer both!
o Anticoagulant Effects
§ Antithrombotic effects
• Platelet inhibitory: prostacyclins*, nitric oxide, adenosine
diphosphotase
• Binds and alters activity of thrombin*
§ Anticoagulant effects
• Thrombomodulin*
• Endothelial protein C receptor – protein C/protein S complex ** -
breaks down clots!
• Heparin-like molecules
• Tissue factor pathway inhibitor
§ Fibrinolytic effects
• t-PA
- Hemorrhagic Disorders
o Abnormal bleeding
§ Massive bleeding secondary to rupture - dissection
§ Subtle defects in clotting – vWF defects
§ Coagulation factor hemophilias
o Defect of primary hemostasis – cannot make platelet plug! Issues with platelets!
§ Platelets of vWF

§ Petechiae or purpura (minute hemorrhages) – tiny bruising – platelets are
used and small clots everywhere!
§ Epistaxis, GI bleed or menorrhagia, intracerebral hemorrhage
• Hemorrhagic stroke – vessels burst open due to hypertension!
• TIA = clot!
o Defects of secondary hemostasis – issues with proteins of clotting cascade – cannot
clot!
§ Coagulation factors
§ Hemarthorosis following minor trauma
- Thrombosis
- Virchow’s Triad:
- Endothelial Injury
o Injury may trigger thrombosis exposure of vWF and tissue factor
o Prothrombotic environment – promotes thrombosis including infectious agents,
metabolic abnormalities, toxins absorbed in cigarettes: “endothelial activation or
dysfunction”
§ Trauma, infection, autoimmunity or diabetes
§ Hypercholesterolemia
§ Vessels rupture and clot forms
- Abnormalities in Blood Flow
o Atherosclerotic narrowing
o Statis – clot formation
o Atrial fibrillation, bed rest, airplanes
o Turbulence
o Artherosclerotic vessel narrowing
- Hypercoagulability
o Thrombophilia
o Disorder of the blood that predisposes to thrombosis
o Primary or Secondary
o Factor V Leiden (**MOST COMMON**) **
§ Single-nucleotide mutation in factor V
§ Factor V resistant to cleavage and inactivation of Protein C à cannot break
clot!!**
§ Heterozygotes have a 5x increase of thrombosis and homozygotes have a
50x increase
§ Inherited
§ Acquired = disseminated cancer – a lot of clots – can cause edema and
embolism
- Heparin-Induced Thrombocytopenia (low platelets)
o Follows administration of unfractionated heparin*
o Induce antibodies that bind to heparin and platelet factor 4 on the surface of
platelets or endothelial cells
o Platelet activation, aggregation and consumption
o Prothrombotic state (while on heparin)

o Low-molecular weight heparin – less frequent HIT
- Antiphospholipid Antibody Syndrome
o Previously called Lupus Anticoagulant syndrome*
o Recurrent thrombosis, repeated miscarriages, cardiac valve vegetations,
thrombocytopenia*
o PE (pulmonary embolisms), pulmonary hypertension, stroke, bowel infarct,
renovascular hypertension
o Antibody targets β2-glycoprotein* I, protein that associated with the surfaces of
endothelial cells and trophoblasts and thrombin
§ In vivo – induce hypercoagulable state
§ In vitro – induce prolonged coagulation antibodies interfere with
phospholipids
§ False-positive for syphilis because the antigen in assay is embedded in
cardiolipin
- Thrombi
o Arterial thrombi tend to grow retrograde - develop on endothelium
o Venous thrombi extend in the direction of blood flow – blow propagate to heart à
lungs**
o Clots have Lines of Zahn*** – pale platelet and fibrin deposits with alternating
darker red cell-rich layers
o Postmortem clots: gelatinous and dark red dependent portion, “chicken fat” upper
portion, usually not attached to underlying vessel wall
o Pic à clot made with blood and laminar flow, post-mortem clots don’t have this or
lines**
- Fate of a Thrombus
o Propagation
o Embolization à systemic!
o Dissolution
o Organization and recanalization
§ Make a new, reduced, lumen of the vessel
- Clinical Features of a Thrombus
o Venous thrombosis
o Arterial and cardiac thrombosis
- Embolism
o Embolus is a detached intravascular solid, liquid or gaseous mass carried by the
blood from its point of origin to a distant site**
o Can cause tissue dysfunction or infarction
o Types of Embolism
§ Thromboembolism: Pulmonary and Systemic
• Pulmonary Embolism
o Dislodged thrombi
o Causes 100,00 deaths a year
o Originates from deep venous thrombosis to the right heart
and into the right pulmonary artery

o One large – saddle embolus or multiple emboli ** stuck in
bifurcation of lung! = sudden death!
§ Pic = saddle embolism caused via DVT to lungs
o Usually clinically silent however sudden death, right heart
failure occurs with 60% obstruction
o Vascular rupture results in pulmonary hemorrhage but not
usually cause pulmonary infarction due to dual blood supply
• Systemic Thromboembolism
o 80% arise from intracardiac mural thrombi: 2/3rds from left
ventricular wall infarcts, 1/4th atrial fibrillation
o Emboli lodge into various sites – lower extremities (75%),
brain (10%), intestines, kidneys, spleen &upper extremities
§ Heart à arterial fibulation and turbulent flow or
erythema all can cause clots that go everywhere!
§ DVT à embolism à lung BUT, if there is a hole in
the heart, DVT can go to brain via paradoxical
embolism**
o Consequences depend on
§ Vulnerability of tissue ischemia
§ Caliber of occluded vessel
§ Collateral circulation **kidney doesn’t have this!**
§ Fat and Marrow Embolism – usually trauma from broken bones
• Fat globules found in the pulmonary vasculature after fracture of
long bones, trauma or burns*
• Fat embolism syndrome: minority of symptomatic patients
o Pulmonary insufficiency, neurologic symptoms, anemia and
thrombocytopenia
o Fatal in 5-15% of cases
o 1-3 days after injury, develop tachypnea, dyspnea,
tachycardia, irritability and restlessness
o Diffuse petechial rash*
§ Amniotic Fluid Embolism – rare, mom fatality
• 5th most common cause of maternal mortality worldwide*
• Ominous complication of labor and immediate postpartum period
• 1/40,000 deliveries – 80% mortality
• Infusion of amniotic fluid or fetal tissue in the maternal circulation
via a tear in the placental membranes or rupture of uterine veins
• Sudden severe dyspnea (difficult breathing), cyanosis (blue) and
shock followed headache to seizures and coma
• Pulmonary edema and disseminated intravascular coagulation
• Biochemical activation of coagulation factors rather than
mechanical obstruction
§ Air Embolism

• Gas bubbles within the circulation can coalesce to form froth
masses that obstruct flow and cause ischemic injury
• Decompression sickness: sudden decreases in atmospheric pressure
• High pressures, increased nitrogen gas is dissolved in blood and
tissue, if ascend to rapidly, the nitrogen can form gas bubble within
skeletal muscle – “the bends”
o Scuba divers, or air in IV system
• Treatment in a decompression chamber
§ Others: cholesterol, tumor fragments, foreign bodies
- Infarct
o Area of ischemic necrosis caused by occlusion of arterial supply or venous drainage*
o Classified according to color and +/- infection
o Red infarcts
§ Venous occlusion*
§ Loose, spongy tissues where blood can collect
§ Tissues with dual circulations à GI and Lungs!
§ Tissues previously congested by venous overflow
§ Flow is reestablished to a previous site of occlusion and necrosis
o White infarcts
§ Occlusion of end-arterial circulation*
§ Compact tissues
• Myocardial infarctions*
o Wedge shaped – occluded vessel at apex
o Microscopic- ischemic coagulative necrosis (MOST INFARCTS ARE COAGULATIVE)
§ <4 hours no changes
§ 4-12 hours’ frank necrosis, acute inflammation – increased neutrophils!
§ Most infarcts a replaced by scar
o Liquefactive necrosis – brain
o Septic infarcts – infected cardiac valve vegetations embolize or when microbes seen
necrotic tissue
o Factors that Influence Infarcts:
§ Anatomy of the vascular supply
§ Rate of Occlusion
§ Tissue vulnerability to hypoxia
• fibroblasts<cardiac myocytes<neuron
o fibroblasts handle hypoxia best!
o Pics = lung infarct, spleen infarct and kidney infarct (depressions = fibrous scar
tissue)
§ Hypoxemia
- Shock
o A state in which diminished cardiac output or reduced effective circulating blood
volume impairs tissue perfusion and leads to cellular hypoxia
§ Heart cannot pump fast enough to supply blood to body!
o Septic Shock – systemic inflammation

§ Incidence rising to improvements in life support and growing risks of
immunocompromised patients
§ Increase prevalence of multidrug resistant organisms*
• Bacteria cause vasodilation and activate clot cascade causing a lack
of blood to systemic vasculature and organs
• DIC = body uses all of clotting factors
§ Most frequently triggered by gram-positive bacterial infections, followed by
gram-negative bacteria and fungi**
§ Host response to bacterial, viral or fungal infections
§ Systemic inflammatory conditions
• Endothelial activation
• DIC
• Metabolic derangements
• Organ failure and death
o Stages of Shock
§ 1) Nonprogressive phase – reflex compensatory mechanisms with organ
perfusion maintained
• Neurohumoral mechanisms: tachycardia, peripheral
vasoconstriction, renal conservation of fluid
§ 2) Progressive stage – tissue hypoperfusion, lactic acidosis
• Widespread tissue hypoxia
§ 3) Irreversible stage
o Morphology of Shock
§ Hypovolemic and cardiogenic – hypotension; weak, rapid pulse; tachypnea
and cool clammy cyanotic skin
• MI or trauma with heart not working!
§ Septic shock – initially be warm and flushed because of peripheral
vasodilation
• Hypertension
§ Cardiac, cerebral and pulmonary dysfunction, followed by electrolyte
disturbances
§ Renal insufficiency and fall in urine output
§ Coagulopathy – DIC = disseminated intravascular coagulopathy = no
platelets and no coagulation
§ 90% survival of hypovolemic shock in young patients, worse mortality rates
with septic shock
o Clinical Consequences
§ Hypovolemic / Cardiogenic
• Hypotension with weak, rapid pulse, tachypnea and cool, clammy
cyanotic skin
§ Septic Shock
• Hypotension – warm and flushed

Disease of The Immune System
- Innate and Adaptive Immunity
o Innate
§ Natural or Naïve
• Includes: Epithelium, neutrophils, macrophages, NK cells and
Complement (drills holes in germs)
• Occurs within hours
o Adaptive
§ Acquired or Specified
• Humoral
o Attacks extracellular microbes
o Antibodies from B-Cells
• Cell-Mediated
o Attacks intracellular microbes
o T-Cells
- Cells and Tissues of the Immune System
o Lymphocytes
§ T-cells
• Mature in the Thymus
• Locations
o Blood (60-67% of blood lymphocytes)
o Spleen (periarteriolar)
o Lymph nodes (interfollicular)
o Tonsils (interfollicular)
• Surface T-Cell Receptor recognizes antigen displayed by APCs
o On T-cell surface
o Recognizes antigen on APCs
o Composition:
§ Alpha and beta heterodimer
§ Non-covalently linked to 5 other proteins for signal
transduction
• CD3 (y, s and e proteins)
• 2 C proteins
• 2 Subtypes
o CD4+ = T-helper cells
§ CD4 binds to MHC II on APC
§ Cytokine Secretion
• Stimulate B cells à antibody production*
cross-talk*
• Stimulate macrophages
o CD8+ = Cytotoxic T-cells
§ Binds to MCH I on APC
§ Cytokine secretion

• To kill cells!
• Major Histocompatibility Complex = MHC = all need APCs*
o MHC I
§ Encoded by HLA – A, B and C genes
• Human Leukocyte Antigen = HLA
§ On all nucleated cells
§ Binds to CD8 (on killer cells)
§ Favors peptides made within the cell
o MHC II
§ Encoded by: HLA – DP, DQ and DR genes
§ On APCs
§ Binds to CD4 (on helper cells)
§ Favors peptides made outside the cell
o MHC III
§ Complement proteins
• C2, C3 and Bf
§ Tumor necrosis factor (TNF)
§ Lymphotoxin
• HLA – Human Leukocyte Antigen
o Each person has 6 HLA I classes (3 maternal and 3 paternal)
o Each person has up to 20 HLA II classes (due to mixing of
alpha and beta chains)
o Haplotype
§ The combination of HLA alleles in each individual
§ Implicated in transplantation complications
(rejection)
• Stimulates the immune system to attack
transplants
o HLA and Disease
§ HLA-B27 associated with:
• Ankylosing spondylitis (joints)
• Several post-infectious arthropathies
§ Some HLA-DR alleles associated with autoimmune
diseases
§ B-cells
• Mature in Bone Marrow
• Location:
o Blood (10-20% of blood lymphocytes)
o Spleen (follicles)
o Lymph nodes (follicles)
o Tonsils (follicles)
o Mucosa (MALT)
• Surface IgM or IgD recognizes antigen

o Does not require antigen association with MHC molecule, in
contrast to TCR on T-cells
o Don’t need APC – can see naked antigen!
• Immunoglobulins (Ig)
o Some (IgM, IgD) expressed on B-cell membrane
o Most (all but IgD) secreted by plasma cells (terminally
differentiated B-cells)
o 5 Classes of Immunoglobulins (correlates with heavy chain)
§ IgG (in blood- can cross placenta) *
§ IgA (major secretions and blood) *
§ IgM (on B cells and in blood)
§ IgE (attached to mast cells and in blood)
§ IgD (only on B-cells, not secreted)
o Structure: 2 heavy chains and 2 light chains (kappa or
gamma) with FC region that is recognized by other cells
§ NK cells (innate)
• Natural Killer Cells
o Part of innate system
o Do not express highly variable antigen receptors
o Recognize cells with DNA damage, then kills them
o Antigen Presenting Cells (APCs)
§ Dendritic cells
• The major cells to display antigens to T-Cells
• 2 types
o Interdigitating dendritic cell (in T-cell zones of lymphoid
tissues – between germinal centers)
o Follicular dendritic cell (in B-cell zones of lymphoid tissue –
in germinal centers of follicles)
§ Others – macrophages and B-cells
o Effector Cells
§ Mature B and T cells
§ Plasma cells (terminally differentiated B-cells)
o Tissues
§ Lymphoid Tissues
• Generative (primary): where maturation occurs
o Thymus
o Bone marrow
§ Hematopoietic and adipose tissues
§ 100 – age = % of hematopoietic tissue you should
have
• Peripheral (secondary) – where adaptation develops
o Lymph nodes
o Spleen
o Tonsils

o MALT
- Overview of Normal Immune Response
o Innate immune response
§ Early
• Epithelia = 1st
line of defense
• Phagocytes
o Neutrophils and Macrophages
• NK cells
• Complement system
o Capture and display of antigens
§ Dendritic cells in epithelium capture microbes and their antigens
§ Dendritic cells with antigens travel to lymph nodes to serve as APCs to naïve
T-cells
• MHC 1 present to CD8
• MHC 2 presents to CD4
§ Antigens not in APCs are recognized by B-cells
§ APCs are in the lymph nodes*
o Cell-mediated immunity
§ Antigen presentation activates T-cells
• Activated T-cells proliferate, differentiate into effector and memory
cells, effector T-cells migrate to site of antigen, secrete cytokines
o Activated cells make more cells with receptors à leave cells
and go to circulation
o CD4 = helper – finds antigen on APC – innate immune
response will enter and kill antigen
§ Effector Functions of CD4 T-cells (helper)
• Secrete IL-2, express receptor for IL-2
• Interaction of IL-2 and its receptor à
proliferation of antigen specific T-cells
(effector and memory cells)
o TH1 and TH2 = subcategories of
CD4 T-cells = hypersensitivity
o TH1
§ Produces IFN-y à
§ Activation of macrophages
§ Stimulation of B-cells to
make antibodies
o TH2 (worms)
§ Produce IL-4 à stimulation
of B-cells to become IgE –
secreting plasma cells
§ Produce IL-5 à activation
of eosinophils

§ Produce IL-13 à mucous
secretion
o CD8 = kills cells with antigen stat
§ Effector functions of CD8 T cells
• Activated CD8 T-cells differentiated into
cytotoxic T lymphocytes (CTLs)
• CTLs kill cells containing microbes
§ Cytokines
• Polypeptide products of many cells (esp. activated lymphocytes and
macrophages)
• Mediate inflammation and immune responses
• Pleiotropic – one cytokine affects many cell types
• Redundant – many cytokines induce same response
• Cytokines of innate immunity and inflammation
o TNF, IL-1, chemokines, IL-12, IFN-y
• Cytokines regulating lymphocytes in adaptive immunity
o IL-2, IL-4, IFN-y, IL-5
• Cytokines stimulate hematopoiesis
o Colony stimulating factors (CSFs)
o Humoral immunity (B-cells)
§ IgM and IgD on naïve B-cell surface recognize antigen à activation of B-cell
§ Helper T-cells and activated B-cells à B-cell proliferation
§ B-cells differentiate into plasma cells
§ Plasma cells secrete Igs
§ Antibody actions
• Neutralize microbes by binding to them
• IgG coats (opsonizes – target for phagocytosis) microbes, targeting
them for phagocytosis
• IgG and IgM activate complement
• IgA in secretions neutralizes microbes in Lumina of gut, respiratory
tract et al
• IgG is the only antibody that can cross placenta
• IgE coats helminths (worms), allowing mast cells and eosinophils to
kill (IgE à TH2 à kill worms)
o Virus not attached to cell when attacked by B-cell – more B-
cells make antibodies – plasma cells secrete antibodies
•
o Immune decline and immune memory
§ Decline of Immune Response
• Infection eradicated à death (apoptosis) of effector cells
• Memory cells (antigen specific) persist à more rapid immune
response on next exposure (why vaccines work)
- Hypersensitivity Reactions
o Causes of Hypersensitivity

§ Reactions against self-antigens = autoimmunity (low self-tolerance)
§ Reactions to microbes
§ Reactions to environmental antigens
o Hypersensitivity = host injury due to mechanisms that normally work to eliminate
infections
o Types of Hypersensitivity
§ 1 = immediate
• Allergies
• Inherited propensity for increased TH2 response à IgE production
(worms)
• IgE binds mast cells (sensitization)
• On re-exposure to antigen, antigen binds IgE on mast cell surface à
activation of mast cells (allergic reaction)
o Antigen / Allergen à TH2 à B-cell à Plasma à IgE à
Mast Cell à allergic reaction
• Allergic Reaction – Type 1
o Vasodilation and increase vascular permeability due to:
§ Histamine, PAF, LT C4, D4, E4, proteases and PGD2
o Smooth Muscle Spasm due to:
§ LTC4, D4 and E4, histamine, PGs, PAF, adenosine
o Cellular Infiltration (late-phase reaction) due to:
§ Cytokines, LT B4, eosinophil and neutrophil
chemotactic factors
• Mast Cell Mediators (pic)
• Early Phase Reaction
o Starts within 5-30 minutes
o Ends by an hour
• Late Phase Reaction
o Starts 2-8 hours later
o Ends within several days
§ Neutrophils are recruited by chemokines
§ Lymphocytes (TH2)
§ Eosinophils are recruited by eotaxin et al
• Produce
o Major basic protein à epithelial
cell injury
o LTC4 à increased inflammation
o PAF à increased Inflammation
• Clinical Type 1 Hypersensitivity
o Systemic Reaction
§ Anaphylaxis à shock
o Local Reaction
§ Skin à urticaria (hives)
§ Gut à vomiting and diarrhea

§ Lung à bronchoconstriction = hay fever or asthma
§ 2 = antibody -mediated
• Antibodies vs. antigen or cell surface or ECM (ab against RBCs)
• Opsonization of cells àphagocytosis (often in spleen)
o Hemolytic anemia or thrombotic thrombocytopenic purpura
(TPP) = antibodies against platelets)
• Complement Activation à recruitment of inflammatory cells
o Goodpasture syndrome (lung and kidney), acute rheumatic
fever, ANCA vasculitis
• Antibody mediated enzyme activation
o Pemphigus vulgaris (blisters)
• Antibody Mediated Cellular Dysfunction
o Mysasthenia gravis, graves’ disease (increase thyroid) and
hashimoto thyroiditis (decrease thyroid) , insulin resistant
diabetes mellitus and pernicious anemia
§ 3 = immune-complex mediated
• Normally, antigen – antibody complexes are phagocytoses and
removed
• Type 3 hypersensitivity occurs when the # of antigen-antibody
complexes overwhelms the systems à deposition of complexes à
inflammatory response
o Systemic immune complex disease
§ Pathogenesis
• Formation of complexes in circulation
• Deposition of complexes in various tissues
(vessel walls)
• Inflammatory reaction to deposits
§ Prototype = acute serum sickness
o Local immune complex disease
§ Prototype = Arthus Reaction
• Pre-formed antibodies in circulation
• Injection of antigen to skin
• Antigen-antibody complexes form at
injection site and diffuse into vascular walls
• Peak inflammatory response within 4-10
hours
• Type 3 Hypersensitivity Diseases
o Systemic lupus erythematosus, Post-infection
glomerulonephritis, Membranous glomerulonephropathy,
IgA nephropathy, Polyarteritis nodosa, reactive arthritis,
serum sickness, arthus reaction
§ 4 = T-cell mediated
• CD4 T-cells à type 4 hypersensitivity, delayed
o Prior antigen exposure à memory CD4 TH1 cells

o Re-exposure à recruitment of memory TH1 cells
o TH1 cells secrete IFN-y à macrophage activation
§ Activate macrophages
• Have increased phagocytic activity
• Have increased microbicidal activity
• Secrete à PDGF and TGF-beta à fibrosis =
recruit fibroblasts
o TH1 cells also secrete
§ IL-2 à T-cell proliferation
§ TNF à various effects on endothelium
§ Lymphotoxin à various effects on endothelium
o If prolonged à granuloma formation*
§ Granuloma = circumscribed collection of *
histocytes
o Examples of delayed type 4
§ Tuberculin skin test (PPD), tuberculosis,
histoplasmosis, leprosy, contact dermatitis (poison
ivy and oak)
• CD8 T-cells type 4 hypersensitivity, cytotoxic
o Exaggerated CD8 cytotoxic T-lymphocyte (CTL) response
§ Type 1 diabetes mellitus
- Rejections of Allographs
o Mechanisms of Rejection
§ Direct
• Host T-cells recognize graft MHC molecules as foreign with graft
dendritic cells as APC
o Host CD4 T-cell and graft MHC II à delayed type 4
hypersensitivity reaction
o Host CD8 T-cell and graft MHC I à cytotoxic type 4
hypersensitivity reaction (T-cell differentiation to CTL)
§ Indirect
• Host T-cells recognize graft MHC molecules as foreign with host
dendritic cells as APC
o Effector Mechanisms of Graft Rejection
§ T-cell mediated
• CTLs kill graft cells (esp. endothelial cells à thrombosis and
ischemia)
• CD4 T-cell secretes cytokines à delayed type 4 hypersensitivity
reaction
§ Antibody Mediated
• Host antibody vs. graft MHC antigen (and others) à antibodies bind
to endothelium à complement activation and WBC recruitment à
injury (like type 2 hypersensitivity reaction)

• Can be hyperacute if antidonor antibodies are pre-formed (rejection
within minutes to hours)
o Hyperacute = host kills the graft
o Improving Graft Survival
§ HLA Matching
• Living-related donor kidney
§ Immunosuppression = increased risk of infection! = must take meds forever!
• Complications of immunosuppression
o Infection
§ Bacteria, including opportunists
§ Fungi, including opportunists
§ Viruses
o Cancer
§ Lymphoma (EBV-related)
§ SCCA (HPV-related)
§ Kaposi Sarcoma (KSHV-related)
o Allogenic Bone Marrow Transplantation
§ Chemotherapy and or radiation à death of tumor cells and marrow
§ Donor bone marrow or stem cells then transplanted
• Gives person a new immune system
o Autogenous – given back your own marrow
§ Bone Marrow transplantation complications
• Rejection
o Host T-cells and host NK cells resistant to radiation /
chemotherapy
• Graft vs. Host disease (graft rejects (kills) host) – liver transplants
o Not limited to bone marrow transplantation
• Prolonged immune deficiency = increased infections
- Autoimmune Diseases
o ß Immunologic Tolerance (avoiding autoimmune disease)
§ Central
• Apoptosis of T and B cells that recognize self-antigen (not 100%
effective)
o T cells receptors and antigen receptors of B cells – don’t
want them to recognize self – if they do = apoptosis
§ Peripheral
• Anergy – inactivation of offending T or B cell
• Suppression of offending T or B cell
o Mediated by regulatory T-cells
• Activation – induced cell death
o Mechanisms of Autoimmunity
§ Genetic – inheritance of certain MHC / HLA alleles à
• Associations with MLC and MHC
§ Infection – antibody vs. microbe antigen cross reacts with self-antigen

• Determines when it declares itself – acquired
o Autoimmune Diseases
§ Rheumatoid arthritis (RA), Seronegative spondyloarthropathies,
polyarthritis nodosa and other vasculitis
§ Systemic Lupus Erythematosus (SLE)
• Multisystem disease, affects:
o Skin, kidney, serosal membranes, joints and heart
• Widely variable signs and symptoms
• Unpredictable clinical course
• Incidence = 1 in 2500
• More women than men, more black than white*
• SLE Criteria for Diagnosis
o Not defined by appearance – A TON ON SLIDE
o *Need at least 4 criteria required for diagnosis (not
necessarily simultaneous)
o ANA is a screen for lupus – antinuclear antibodies à
• SLE Autoantibodies – detected in lab – type 2 or type 3
hypersensitivity!
o Antinuclear antibodies (ANA) vs.
§ DNA, Histones, Non-histones bound to RNA,
nucleolar antigens
o Other autoantibodies vs.
§ Blood cells, phospholipids (lupus anticoagulant)
*misnomer*
• Prothrombic state
• Antibodies against thrombus = makes them
more susceptible to blood clots!
• SLE Variables
o Genetic
§ 25% monozygotic twin concordance
§ 1-3% dizygotic twin concordance
§ Family members have increased risk
§ Association with HLA-DR2 and DR3 alleles
§ 10% with complement deficiency
o Non-genetic
§ UV light exacerbates skin lesions
§ Cigarette smoking
§ Can be drug-induced
• Procainamide, hydralazine or female
hormones
• ß SLE Morphology
o Acute necrotizing vasculitis
o Red is dead!
o Lupus patients have issues in kidney

o Glomerulonephritis * don’t memorize*
§ Class 1 – normal LM
§ Class 2 – mesangial
§ Class 3 – focal proliferative
§ Class 4 = diffuse proliferative
§ Class 5 – membranous
§ Class 6 – end-stage
§ Class 3 and 5
§ Class 4 and 5
o Skin
§ Malar rash (butterfly rash)
§ Discoid rash
§ Photosensitivity – UV light sensitivity
o Joints
§ Usually not striking morphology
o CNS
§ Small vessel angiopathy (intimal proliferation)
§ Thrombosis (antiphospholipid syndrome)
• Lupus anticoagulant
• If in brain = stroke
§ Microinfarcts
§ Premature atherosclerosis
o Spleen
§ Splenomegaly*, thickened capsule, follicular
hyperplasia, perivascular “onion skin” fibrosis ß
• Concentric layers of fibrosis
o Serosal Membranes
§ Effusions (too much fluid – pleural and peritoneal
caivities) and Exudates (protein-rich effusions)
o Heart
§ Pericarditis, myocarditis and or Libman -Sacks
Endocarditis – thrombi on surface of valves =
vegetations! Sterile endocarditis = no bacteria but
can embolize*
o Lung
§ Interstitial fibrosis
• SLE Clinical Course
o Highly variable – can have flare ups
§ Mild to death within months
o Usually remissions and relapses
o Survival
§ 90% 5-year survival
§ 80% 10-year survival
o Death usually due to: renal failure, infection or diffuse CNS

§ Sjogren syndrome disease
• Dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia)
• Due to immune-mediated destruction of lacrimal and salivary glands
o Destroy salivary and lacrimal glands*
• 2 forms
o Primary (sicca syndrome) – no salivary or lacrimal glands
o Secondary
§ Associated with: RA, SLE, polymyositis, systemic
sclerosis, vasculitis and thyroiditis
• Clinical Course
o About 90% in 35-45-year-old women* autoimmune = more
common with women!!
o About 60% with other autoimmune disorder
o Extra glandular manifestations
§ Synovitis, pulmonary fibrosis, peripheral
neuropathy
§ 40X increased risk of B-cell lymphoma (b-cell
cancer)
§ Systemic Sclerosis (Scleroderma) (SS)
• Excessive fibrosis throughout body (not just skin) – systemic!
o ß Diffuse atrophy!
o Limited (mostly skin, till late in course) = CREST syndrome*
§ Calcinosis
§ Raynaud phenomenon – response to cold air
§ Esophageal dysmotility – difficult swallowing
§ Sclerodactyly – hardness of fingers
§ Telangiectasia – vessels
• Systemic Sclerosis Morphology
o Skin
§ Diffuse sclerotic atrophy
§ Histology
• Edema, perivascular inflammation,
thickened vascular basement membranes
(capillaries and small arteries)
• Eventual replacement of edema by fibrosis
• Less glands, more fibrosis
o Alimentary Tract (in about 90%)
§ Atrophy and fibrous replacement of Muscularis
propria (drives peristalsis) à stiffness
§ Especially affects esophagus à GERD
o Musculoskeletal system
§ Synovial hyperplasia and inflammation
§ Subsequent fibrosis*

§ About 10% with myositis* - inflammation of skeletal
muscle
o Lungs (less than 50%)
§ Pulmonary hypertension, interstitial fibrosis
• High BP
o Kidneys (about 66%)
§ Interlobular artery intimal fibrosis, hypertension
• High BP
o Heart
§ Patchy myocardial fibrosis*, arteriolar thickening
o *sclerosis = made harder with deposition of collagen,
fibrosis = deposition of collagen*
• SS Clinical Course
o 1 men to 3 women = more women!
o 50s to 60s
o Most have Raynaud phenomenon
§ Cold-induced arterial reversible vasospasm
• Finger will change from White à blue à
red when cold
• No blood flow to digits
o Course difficult to predict
o 35-70% 10-year survival
§ Inflammatory Myopathies (don’t care)
• Polymyositis – skeletal muscle
• Dermatomyositis – skin and muscle
• Inclusion body myositis - common
§ Mixed CT Disease
• Presentation with features of SLE, polymyositis and SS
o Arthritis, hand edema, Raynaud phenomenon, esophageal
dysmotility, myositis, deceased RBC and WBC, fever,
lymphadenopathy, hypergammaglobulinemia
§ Polyarteritis Nodosa and other Vasculitides
• Necrotizing inflammation of blood vessels with probable immune
pathogenesis
• More to come (when blood vessel disease is covered)
- Immunodeficiency Diseases
o Primary – uncommon, inherited, typically present in childhood – iatrogenic = caused
by meds – meds to decrease immune system
§ X-linked agammaglobulinemia (XLA, Bruton Disease)
o Alpha beta and gamma regions of gel electrophoresis = no
gamma immunoglobulins or other gamma proteins in
blood! *
• Pre-B-cells cannot become B-cells
• No immunoglobulin production (agammaglobulinemia)

• Decreased B-cells in blood – not in lymphoid germinal centers
• Absent plasma cells
• Underdeveloped germinal centers
• Normal T-cell mediated responses
• Presents after 6 months of age (after mom’s abs are gone) passive
IgG is gone! Nursing = IgA passive after = unable to make own abs
o Recurrent bacterial infections
o Some viral infections
o Giardiasis
• X-linked Disease = so more men than women***
• Therapy – intravenous immunoglobulin
• 20% have associated autoimmune disease
• Genetic cause BTK mutation – single gene mutation***
§ Common variable immunodeficiency
• Heterogenous group of disorders with a low Ig production = not a
single gene = BTK is normal! – not making antibodies
• Men = women
• Presentation in teens or 20s*
• Clinical manifestations similar to XLA
• Associated with autoimmune disorders
• Associated with lymphoma
• Most with unknown genetic cause
§ Isolated IgA deficiency – cannot class switch*
• The most common primary immunodeficiency***
• MOST COMMON immunodeficiency is IgA deficiency******
o Incidence = 1 in 700 white
• Increased sinopulmary and GI infections
• Associated with autoimmune diseases
• Unknown genetic cause
§ Hyper IgM syndrome – IgM cannot change to IgG (targets cells for
phagocytosis)
• Impaired heavy-chain class (isotype) switching – failure of class
switching!
o Normal or increased IgM*
o Absent IgG à recurrent pyogenic infections (no
Opsonization)
o Absent IgA and IgE*
• About 70% X-linked (gene for CD40L)*
• Also decreased cell-mediated immunity à recurrent intracellular
pathogen infections
§ Thymic hypoplasia (DiGeorge)
• *Congenital defect in thymus development à absence of T-cells –
where T cells mature*

o B-cells and Ig are unaffected
• Can be parathyroid hypoplasia à decreased Ca+2
• CATCH-22***
o Cardiac abnormality (tetralogy of Fallot) – 4 probs in heart
o Abnormal facies
o Thymic aplasia *** main problem!
o Cleft palate
o Hypocalcemia / Hypoparathyroidism *
o 22q11.2 deletion – long arm of 22 chromosome
§ Severe combined immunodeficiency (SCID)*
• Genetically Heterogeneous – not single gene disorder – prevent
from cd8 or cd4 – combined because CD4 cant help B side – so,
hurts both sides of immune system
o About 50% are X-linked
§ Gene mutations for y chain of cytokine receptor
o 40-50% are autosomal recessive (AR)
§ Adenosine deaminase deficiency (50%)
§ Various other genetic causes (50%)
o Defects in humoral and cell mediated immunity
• Hypoplastic Lymphoid Organs
o Thymus, lymph nodes, tonsils, MALT
• Severe and recurrent infections
o Bacteria, viruses, fungi, protozoa
• Therapy: bone marrow transplantation*
§ Wiskott-Aldrich Syndrome exist
§ Innate immunity deficiencies
• Complements = drill holes in germs*
• Complement Abnormalities exist
• Phagocyte Deficiencies
o Chronic granulomatous disease***
§ NAPDH oxidase deficiency à impaired neutrophil
killing activity
§ Respiratory burst that releases free radicals –
neutrophil eats germ but cant kill it* pusà
granuloma!
o Leukocyte adhesion deficiencies à impaired phagocytosis
• Acquired Immune Deficiency Syndrome (AIDS)****
o Caused by human immunodeficiency virus (HIV) =
retrovirus*
§ Targets CD4+ cells! – assists T and B cells
o Infection of CD4 T-cells è decreased CD4 T-cells
o About 5,000,000 new cases each year
o 5th
most common cause of death in USA for 25 – 44 yr
olds**

o Transfusions = for hemophiliacs – need more proteins so
transfusions from more than one person
o Common in asia and Africa
o AIDS is decreasing = good therapy
o HIV Transmission
§ Sexual
• 75% of HIV infections are sexually
transmitted
• More male to male or male to female*
than female to male
o Harder for women to spread it!
• Virus in semen (lymphocytes and
extracellular) and vaginal and cervical cells
§ Parenteral
• Drug abuse – sharing needles
• Hemophiliacs receiving factor 8 or 9
concentrates
o Now we synthesize factors 8 and 9
• Blood product transfusion
o Risk = .00014% or 1 in 676,000 ****
• Needle stick injury
o Risk = .3% (1 in 3,300)
§ Hep B = 30%
§ Mother to infant
• Transplacental, intrapartum or breast milk
o Utero, delivery or nursing
o HIV genome
§ Retrovirus = so uses RNA à DNA with reverse
transcriptase enzyme
• Gp41 (stick) and gp120 (candy)
§ Viral polymerase makes mistakes (1/10^5
nucleotides)
• Mistake with outer coating
• A lot of errors with stick things – so virus is
hard!
§ Most mistakes in coding section for envelope
glycoproteins à variability of the envelope
• Since envelope is target of immune system,
vaccine is difficult
o HIV Subtypes / clades
§ Group M (Major)
• More common than group O
• Divided into subtypes called clades (A-J)
• Clade B = most common in Europe and USA

• Different clades have differing abilities to
infect dendritic cells à variable
transmission rates
§ Group O (outlier)
o HIV / AIDS Pathogenesis
§ Viral gp120 binds to host CD4 (receptor for this
virus!!)*** à gp120 changes conformation
§ Viral gp120 binds to CXCR4 (T-cells - coreceptor) or
CCR5 (macrophages)
§ Viral gp41 inserts into host cell membrane
§ Virus fuses with host cell membrane à viral
genome (RNA) enters cell – genome injected into
cell!
§ Reverse transcription* à proviral cDNA
• cDNA can remain in cytoplasm
• in dividing T-cells, cDNA is integrated into
host genome
o can remain latent (non-transcribed)
for months-years
o can be actively transcribed à
formation of new viruses
o Resistance to HIV
§ Defective CCR5 à decreased infectivity
• In USA
o 20% white are heterozygous for
defective CCR5 (co-receptor*) *
o 1% whites are homozygous for
defective CCR5
o HIV: Mechanisms for killing CD4 T-Cells
§ Viral replication à infected cell lysis
§ Infected T-cells killed by CTLs (CD8s kill CD4s)
§ HIV antigens cause activation (and subsequent
apoptosis) of uninfected T-cells
§ Uninfected T-cells bind soluble gp120 (candy) à
aberrant signaling à apoptosis
§ CD4 to CD8 goes from 2:1 to 1:2 **
§ Precursor T-cells can be infected and die à
decrease ability to replace lost cells
o HIV and Macrophages
§ HIV can replicate in nondividing macrophages (not
true in T-cells)
• Macrophages also have CD4s! and don’t
really lyse = so reservoir for more virus even
if all CD4s are killed!

§ Infected macrophages shed few virions but contain
many
• Also, resistant to lysis
o Macrophage serves as virus
reservoir
o HIV and Dendritic Cells
§ Infected mucosal (interdigitating) dendritic cells
transport virus to lymph node à
• Infection of CD4 T-cells
• Infection of follicular dendritic cells
o Follicular dendritic cells become
virus reservoirs
o Follicular dendritic cells infect CD4
T-cells
o HIV and B Cells
§ Polyclonal B-cell activation à
• Hypergammaglobulinemia** too many
abs!! – gel electrophoresis gamma
• Circulating immune complexes
§ Impaired B-cell response (mult. causes, including
decreased T-cell help) à increased infection with
encapsulated bacteria
o HIV CNS Pathogenesis
§ Poorly understood, morphology less striking than
clinical Sx
§ Main CNS cells infected: macrophage and
microglia**
o HIV Natural History
§ Acute Phase (in 50-70%)
• 3-6 weeks after infection
• Nonspecific viral illness
• Seroconversion (ex- detectable production
of anti-HIV abs) occurs 3-17 weeks after
exposure à end of acute phase ***
§ Chronic Phase (100%)
• Progressive CD4 T-cell loss
• Continued viral replication
• Can last several years
• Development of persistent
lymphadenopathy (enlarged lymph nodes –
immune system crashes) heralds evolution
to next phase
§ Crisis Phase (AIDS)*** name change!

• Decreased host defense à increased
infections
• Increased viremia
• CD4 count < 500
§ Most reach crisis phase (AIDS) in 7-10 years
§ Rapid progressors reach crisis phase in 2-3 years
§ Nonprogressors (<5%) are asymptomatic with
stable CD4 counts > 10 years
o CD4 Counts****
§ > 500 = usually asymptomatic
§ 200-500 = early symptoms
§ <200 = severe immunosuppression = AIDS defining
finding **** - CD8 plummets too!
o AIDS-Defining Illnesses in HIV and person
§ Protozoal and helminthic
• Cytosporidiosis, isosporidiosis,
pneumocystosis, toxoplasmosis
§ Fungal
• Candidias, crytococcosis (CNS),
coccidiomyocosis (disseminated),
histoplasmosis (disseminated)
§ Bacterial
• Mycobacteriosis, nocardiosis, Salmonella
infection – tuberculosis
§ Viral
• CMV, HSV- herpes simplex virus, VZV-
chicken pox, progressive multifocal
leukoencephalopathy (JC virus)
§ Neoplastic
• Kaposi sarcoma, Burkitt/immunoblastic
lymphoma, primary CNS lymphoma* only
happens here**, uterine cervical cancer
§ Laboratory Finding
• CD4 < 200 **** diagnosed as AIDS
o Secondary – common, often iatrogenic
§ Malnutrition, infection, cancer, renal disease, sarcoidosis, therapeutic, AIDs
- Amyloidosis
o Diverse group of diseases with extracellular deposition of amyloid à tissue damage
and decreased function
o Amyloid (means starch-like* misnomer)
§ misfolded proteins forming insoluble fibrils
§ > 20 different proteins can misfold to form amyloid
§ Randomly oriented, nonbranching fibrils**
§ Fibril diameter of 7.5 – 10 nm*

§ Fibrils = polypeptide chains (in beta pleated sheet formation) wound
together in groups up to 6
§ Staining characteristics led to the misnomer meaning starch like
o Amyloidosis Pathogenesis
§ High conc. Of misfolded forms – 20 proteins misfolding into beta sheets****
• With aging (senile amyloidosis)
• With increased production of the protein (chronic inflammation)
• With decreased excretion of the protein (dialysis associated)
• Mutation à protein with tendency to misfold (hereditary)
• Limited proteolysis à protein that misfolds (Alzheimer’s disease)
o Amyloid Morphology
§ Light Microscopy
• Extracellular hyaline, congophilic with apple green birefringence***
o Appear hyaline under LM = use congo red stain for
amyloids!
• Polarize filter = something in tissue rotate plane of polarization! –
rotate light and add green color****
§ Electron Microscopy
• Nonbranching, randomly oriented fibrils (pickup sticks), fibril
diameter = 7.5-10nm
§ Amyloid in the Kidney
• Mostly nodular glomerular deposition – pt keeps peeing proteins!
• Also interstitial and perivascular
§ Amyloid in the Spleen
• Moderate to marked splenomegaly
• 2 patterns
o Sago spleen = deposition in follicles (gross appearance is
tapioca granules)
o Lardaceous spleen = deposition in splenic sinuses
§ Amyloid in the Liver
• Massive hepatomegaly
• Pale, gray, waxy cut surface
§ Amyloid in the heart – feels like candle wax
• Diffuse deposition between myofibers
o Amyloid Proteins
§ ***AL protein (from amyloid light chain) – called primary but clearly
secondary!
• Produced / made by plasma cells
• Composed of Ig chains (complete or partial)
• Associated with B-cell proliferations (mult. myeloma** - plasma cell
cancer) – misfolded protein is part of light chain of antibody*
§ ****AA Fibril (amyloid-associated)
• Derived from serum amyloid associated (SAA) protein
o Made in liver as part of “acute phase reaction”

• Associated with long-standing chronic inflammatory diseases
o Inflammatory response – liver pumps out proteins = acute
phase reactants = SAA which misfolds as AA = amyloid **
§ A-beta-amyloid
• Derived from glycoprotein amyloid precursor protein (APP)
• Found in cerebral lesions of Alzheimer’s disease*
§ ATTR
• Abnormal form of transthyretin (TRR)*
• Results from gene mutation
• Typical of familial amyloid polyneuropathies
§ A-beta-2 microglobulin
• Part of MHC I molecule*
• Normally excreted through kidney
• Associated with dialysis-related amyloidosis – dialysis machine
cannot get rid of it well*
§ A Cal
• Precursor protein is calcitonin
• Associated with medullary thyroid cancer
§ AIAPP
• Precursor protein is islet amyloid peptide
• Associated with pancreas amyloid in diabetes mellitus
§ AANF
• Precursor protein is atrial natriuretic factor
• Found in isolated cardiac atrial amyloidosis
o Classification of Amyloidosis
§ By organ involvement
• Systemic (generalized)
• Local
o Single organ deposition of amyloid
o Often associated with chronic inflammatory infiltrate
o Typically, AL amyloid
o Endocrine Amyloid
§ Associated with endocrine neoplasms
• Medullary carcinoma of the thyroid – 10s?
• Islet cell tumor of pancreas
• Pheochromocytoma
• Undifferentiated carcinoma of stomach
§ Associated with diabetes mellitus type 2
• Amyloid deposition in the islets of
Langerhans
o Amyloid of Aging
§ Senile systemic amyloidosis

• Heart disease is main clinical problem,
therefore, senile cardiac amyloidosis*
• ATTR
§ By clinical setting
• Primary amyloidosis
o Associated with immunocyte abnormality (mult. myeloma =
plasma cell cancer)
o Typically, systemic deposition of AL amyloid*
o Associated with Bence Jones Proteins (Ig light chains) in
urine
• Secondary amyloidosis
o Reactive amyloidosis
o Typically systemic deposition of AA protein*
o Associated with prolonged chronic inflammation
§ Autoimmune diseases (RA)
§ Skin popping = form of drug abuse* IV drug abuse –
small amount in subcutaneous = more sustained
but less intense*
§ Infectious Disease
• Tuberculosis, bronchiectasis, osteomyelitis
• Hereditary
o Familial amyloidosis
o More than 1 form, typically rare and geographically limited
§ *Familial Mediterranean fever (autosomal
recessive)
• Mutation in gene for pyrin à increased
inflammation following minor trauma* à
AA amyloidosis
• AA protein (same as reactive amyloidosis)**
§ Amyloid polyneuropathies (autosomal dominant)
• ATTR
o Amyloidosis Clinical Features
§ Can be unsuspected finding at autopsy
§ Renal involvement à proteinuria
§ Liver involvement à hepatomegaly = usually no clinical dysfunction
§ Spleen involvement à splenomegaly = usually no clinical dysfunction
§ Cardiac involvement à cardiomegaly
• Conductive disturbance à arrhythmia
• Restrictive cardiomyopathy
o Amyloidosis Diagnosis and Prognosis
§ Diagnosis requires biopsy (tissue is the issue) *** LM and EM
§ Diagnosis à additional workup
• To determine subtype of amyloidosis
• To diagnoses underlying cause

§ Mean survival (general amyloidosis) = 1-3 years usually AL
Environment and Nutritional Pathology
- Environmental Diseases
o Lesions and diseases caused by chemical or physical injuries or nutritional origin
o Voluntary or Involuntary
o Major Public Health Concern
- Tobacco
o Cigarettes, cigars, pipes & snuff
o Most preventable cause of death
o More morbidity/mortality
§ 390,000 premature deaths/year in the US
§ 10 million cases of chronic diseases
o Dose-dependent survival in pack years
o PACK YEARS = # packs x # of years = how to quantify smoking habit
o Noxious chemicals, >2000, >60 carcinogens
o Nicotine – addictive and acute effects of smoking
§ Smoking is a gateway to other cancers
o 70 carcinogens and polyaromatic hydrocarbon = main carcinogen in many cancers*
o Smoking consists of two chronic diseases
o Lung disease à COPD – chronic bronchitis and emphysema
§ Pure chronic bronchitis
• Large airways (trachea and bronchi) – chronic bronchitis
o Mucous hypersecretion
§ Mucous blocks airways
o Inflammation
• Small airways (bronchioles) – chronic bronchioles
o Peribronchiolar fibrosis
o Airway obstruction
§ Pure emphysema
• Acinus (respiratory bronchiole, alveolar ducts and alveoli)
o Loss of elastic recoil
o Emphysema
o Air exchange is difficult due to damaged alveoli
§ à emphysema on top à
• Neutrophil Elastase
o Increased due to smoking à tissue damage and increased
neutrophils and macrophages that break down tissues
o Atherosclerosis and Heart Disease
§ Increased platelet aggregation – clots
§ Decreased myocardial oxygen supply
§ Myocardial infarction
§ Multiplicative effect with hypertension and hypercholesterolemia
o Lung Cancer

§ Related to "pack history"
§ Carcinogens in cigarettes - polycyclic aromatic hydrocarbons
§ Causes 80-90% of all lung cancer – NSCL (non-small cell lung carcinoma)/SC
(small cell lung carcinoma)
• Different treatments but smoking usually gives you both
§ Synergistic affect with other environmental exposures
o Smoking and Cancer
§ Oral cavity
§ Larynx
§ Esophagus
§ Bladder
§ Pancreas
• Can also cause other cancers
o Second-Hand Smoke
§ Relative risk of lung cancer in nonsmokers exposed to smoke is 1.3 X
unexposed
§ Increased risk of ischemic heart disease, MI, respiratory infections and
asthma
o Fetal Tobacco Syndrome
§ Increases the risk of spontaneous abortions and preterm birth
§ Placental abruption
§ Intrauterine growth restriction (SGA)
§ SIDS
- Lead Toxicity / Poisoning
o Lead sources: air and food
o Absorption: Lungs and GI tract*
o Occupational Exposure
§ Mines, foundries, batteries, and spray paints
o Non-occupational Exposure
§ Flaking lead paint – houses before 1978
o 80% absorbed in bones, developing teeth
o 5-10% remains in blood
o Excreted in kidneys
o Major anatomic targets:
§ Bone marrow and blood
§ Nervous System
§ GI and Kidneys
o Skeleton and Lead Toxicity
§ Competes with calcium and binds phosphates
• Lead is absorbed as a dysfunctional calcium depositions = called
lead lines
§ Half-life of 20-30 years
§ Radiographic lead lines
§ Growth

o Hematopoietic System
§ High affinity for sulfhydryl groups
§ Interferes with 2 heme synthesis enzymes
• Lead interferes with heme synthesis à develop anemia with
basophilic stippling*** - have low RBCs due to crappy hemes
§ Increased free protoporphyin
• Lesions on RBCs = basophilic stippling = clumps of ribosomes
• Measure increased protoporphyin = lead poisioning
§ ß Anemia with basophilic stippling
o GI and Kidney – Lead Toxicity
§ GI: Lead "Colic" (stomach pain) by extremely severe, poorly localized
abdominal pain
§ Kidneys: proximal tubular damage with intranuclear inclusions.
§ Chronic damage - interstitial fibrosis and renal failure
o Nervous System
§ Young children - sensory, motor and psychological impairments
§ Severe changes in CNS: brain edema, demyelination of white matter and
necrosis
§ Adults: peripheral demyelinating neuropathy. Extensor muscles of the
wrist and fingers, wrist drop and foot drop
• Children are affected more acutely* due to 50% absorption of
eating lead paint – IQ problems or encephala = brain swelling /
inflammation
• Adults = usually more at work, myelin is screwed up and messes
with nerves
• Brain, digestive, kidneys and cardio
o Lead Paint Laws
§ Congress passed the Residential Lead-Based Paint
§ Hazard Reduction Act of 1992, also known as Title X
§ 5ug/ml = LEAD POISIONING
§ 1 cm^2 lead paint chip = 175,000 ug
- Carbon Monoxide
o Systemic asphyxiate (suffocation) that is an important cause of accidental and
suicidal death.
o Colorless, odorless gas made during incomplete combustion of fossil fuel, tobacco.
o Carbon-based gas
§ Hemoglobin – 4 spots for O2, CO2 binds to hemoglobin with a 200X more
affinity, impairs release of O2
o CO has 200 fold higher affinity for Hgb than O2, increases heme affinity for O2,
impairs release of O2 from Hgb
o Chronic exposure in tunnel and underground garage workers, highway toll booths
o In a small, closed garage, the average running car can produce sufficient CO to
induce coma or death within 5 minutes
§ More CO = more symptoms

o Acute and chronic symptoms
o Cherry red lividity – post-mortem finding = blood pooling
o Necrosis of globus pallidus = CO has a high affinity for this part of the brain
o
- Alcohol Abuse
o Half of Western adults drink alcohol
o 5-10% are chronic alcoholics.
§ >10,000,000 chronic alcoholics in US
o Causes > 100,000 deaths/year in US.
§ 50% are accidents, homicides, suicides.
§ 25% are due to cirrhosis of the liver
o 1.8 million deaths/year worldwide are due to alcohol use.
o Chronic alcoholics shortened life due to damage to liver, G.I., CNS, cardiovascular
system and pancreas.
o Alcohol Metabolism
§ Absorbed unaltered in the stomach and small intestine
• Amount exhaled = amount in bloodstream because it is absorbed
unaltered
§ Distributed to all tissues in direct proportion to the blood level
§ Less then 10% is excreted unchanged in urine, sweat or breath
§ Amount exhaled is proportional to the blood level
o Blood Alcohol Levels
§ Effects vary by age, sex, body fat.
§ 80 mg/dL is legally drunk driving:
§ 8 beers, 12 oz wine, 6 oz whiskey
§ 200 mg/dL drowsiness
§ 300 mg/dL stupor.
§ >300 mg/dl can cause coma, respiratory arrest.
§ Chronic alcoholics tolerate 700 mg/dL because induction the metabolism by
cytochrome P450 system.
§ The effects of alcohol also vary by age, sex, and body fat.
• Can be due to fat distribution and metabolism
o Alcohol Metabolism (cont)
§ Alcohol oxidized to acetaldehyde by 3 enzyme systems in the liver.
§ Acetaldehyde metabolized by acetaldehyde dehydrogenase to acetate.
• All occurs in the liver
• ADH and ALDH
o Variations in Metabolism
§ Half of Asians have mutation in gene that encodes for acetaldehyde
dehydrogenase
§ Results in low enzyme levels
§ Homozygous state causes flushing, tachycardia, hyperventilation after
drinking alcohol due to accumulation of acetaldehyde
• Accumulation of acetaldehyde = ASIAN FLUSH!

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