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418 Cards in this Set

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increase in size of an organ or tissue due to an increase in the size of cells
hypertrophy
cause of hypertrophy
increased workload
increase sin size of an organ or tissue caused by an increase in the number of cells
hyperplasia
example of hyperplasia
glandular proliferation during pregnancy
failure of cell production
aplasia
absence of an organ due to aplasia
agenesis
decrease in cell production that is less extreme than aplasia
hypoplasia
decrease in the size of an organ or tissue from a decrease in the mass of preexisting cells
atrophy
causes of atrophy
disuse
nutrition/oxygen deprivation
diminished endocrine stimulation
denervation
aging
intracytoplasmic vacuoles containing debris from degraded organelles
autophagic granules

sign of atrophy
replacement of one differentiated tissue by another
metaplasia
replacement of epithelium with squamous cells, often in areas with chronic irritation
squamous metaplasia
formation of new bone at sites of tissue injury
osseous metaplasia
proliferation of hematopoietic tissue at sites other than bone marrow such as liver or spleen
myeloid metaplasia
causes of hypoxic cell injury
ischemia: obstruction of blood flow

anemia: reduced number of O2 carrying RBCs

CO poisoning: chemical alteration of Hemoglobin resulting in reduce O2 carrying capacity

decreased perfusion of tissues by O2 carrying blood

poor oxygenation of blood (pulmonary disease)
signs of early stage hypoxic cell injury aka decreased ATP availability
failure of cell membrane pump (NaKATPase pump) causing
cellular swelling (hydropic change),
swelling of ER,
swelling of mitochondria,
disaggregation of ribosomes- failure of protein synthesis
stimulation of phosphofructokinase activity: increased glycolysis, accumulation of lactate, decreased intracellular pH
signs of late stage hypoxic cell injury
plasma, lysosome,and organelle membrane damage (loss of phospholipids)
formation of myelin figures
cell blebs- disordered cytoskeleton
cell death
irreversible damage to cell membranes leading to massive Ca influx and extensive calcification of mitochondria
enzymes used in the diagnosis of MI
aspartate aminotransferase (AST or SGOT)
Lactate dehydrogenase
Creatine kinase
troponins
myoglobin
necrotic cells release _______ into circulation due to loss of cell membrane integrity
intracellular enzymes and other proteins
enzymes released due to liver damage
alanine aminotransferase (ALT)
alkaline phosphatase
gamma-glutamyltransferase (GGT)
cell tolerance to hypoxia:
neuron
cardiac/liver cells
muscle
neuron: 3-5 minutes
heart/liver: 1-2 hours
skeletal muscle: many hours
molecules with single unpaired electrons in the outer orbital
free radicals
examples of free radicals
superoxide, hydroxyl radical
how are free radicals generated?
metabolism
oxygen toxicity
ionizing radiation
UV light
drugs and chemicals: use P450 system
reperfusion after ischemic injury
mechanisms that degrade free radicals
intracellular enzymes like glutathione peroxidase, catalase, superoxide dismutase
spontaneous decay
exogenous and endogenous antioxidants (vit. A, C, E, cysteine, glutathione, selenium, ceruloplasmin, transferin)
sum of degradative and inflammatory reactions occurring after tissue death caused by injury within a living organism
necrosis
degradative reactions in cells caused by intracellular enzymes indigenous to cell
autolysis
cellular degradation by enzymes derived from sources extrinsic to cell
heterolysis
degradative reaction in cells by intracellular enzymes AFTER DEATH of entire organism
postmortem autolysis (not necrosis)
type of necrosis caused by a sudden cutoff of blood supply to an organ supplied by end arteries with limited collateral circulation.
esp. heart and kidney
coagulative necrosis
tissue changes in coagulative necrosis
-preservation of tissue architecture
-increased cytoplasmic eosinophilia (protein denaturation, loss of cytoplasmic RNA)
-nuclear changes:
morphological hallmark of irreversible cell injury
nuclear changes
chromatin clumping and shrinking with increased basophilia
pyknosis
fragmentation of chromatin
karyorrhexis
fading of chromatin material
karyolysis
necrosis caused by ischemic injury to central nervous system including suppurative infection
liquefactive necrosis
necrosis caused by vascular occlusion and most often affects lower extremities
gangrenous necrosis
when gangrenous necrosis is complicated by infective heterolysis and consequent liquefactive necrosis
wet gangrene
necrosis that occurs as part of granulomatous inflammation
caseous necrosis
infection characterized by the formation of pus (liquefied tissue debris and neutrophils)
suppurative infection
leading cause of caseous necrosis
TB
necrosis with cheese like consistency

histologically: amorphic eosinophilic apearance
caseous necrosis
when gangrenous necrosis occurs without liquefaction
dry gangrene
deposition of fibrin like proteinaceous material in arterial walls
fibrinoid necrosis
necrosis caused by severe injury to tissue with high fat content
traumatic fat necrosis
complication of acute hemorrhagic pancreatitis, causes a release of proteolytic and lipolytic pancreatic enzymes that digest the parenchyma, fatty acids are released forming calcium salts (saponification)
enzymatic fat necrosis
programmed cell death
apoptosis
extrinsic pathway of apoptotic initiation of apoptosis
death receptors are members of TNF receptor family that contain a cytoplasmic domain involved in protein interactions

mediated by FAS receptor activating procaspase
intrinsic or mitochondrial pathway of apoptosis
increased mitochondrial permeability and release of pro-apoptotic molecules into cytoplasm (no role for death receptors)

Growth factors and other signals stimulate production of anti-apototic members of BCL-2 family of proteins
apoptosis by direct activation of caspases by granzyme B (T-cell protease that activates the caspase cascade)
cytotoxic T-cell activation
anti-apoptotic signals
GF, BCL-2, BCL-x family of proteins
the final phase of apoptosis is mediated by a proteolytic cascade of which enzymes?
caspase
caspase
c: cysteine protease

aspase: ability to cleave aspartic acid residues

proteolytic cascade of apoptosis
importance of caspases
prompt clearance of apoptotic cells before they undergo secondary necrosis and release cellular contents resulting in inflammation
tumor suppressor gene, accumulates when DNA is damaged and arrests cell cycle in G1 phase to allow time for repair.

If no repair occurs, triggers apoptosis
p53
apoptosis due to growth factor deprivation
growth factor deprivation: (hormone sensitive cells, lymphocytes not stimulated by antigens/cytokines, neurons deprived of growth factors)

triggered by intrinsic (mitochondrial) pathway

too many pro-apoptotic members related to anti-apoptotic Bcl family
DNA damage mediated apoptosis
DNA damage (genotoxic stress)

p53 acculumates when DNA is damaged and arrests cell cycle in G1 phase

if DNA repair fails, p53 triggers apoptosis
apoptosis induced by tumor necrosis factor family of receptors
cell surface receptor FAS induces apoptosis when it is engaged by Fas ligand which is produced by cells of immune system

important in recognizing self antigens
Cytotoxic T-lymphocyte mediated apoptosis
kill target cell by directly inducing the effector phase of apoptosis

CTLs secrete perforin (transmembrane pore forming molecule) which allows entry of CTL granule granzyme B

GRANZYME B CLEAVES ASPARTATE residues and ACTIVATES cellular CASPASES
dysregulated apoptosis
defective apoptosis and increased cell survival

increased apoptosis and excessive cell death
subcellular responses to injury
lysosomal catabolism: heterophagy (endocytosis, phagocytosis, pinocytosis); autophagy (autophagic vacuole, autophagolysome)

induction of smooth ER

mitochondrial alterations (change in membrane permeability)

cytoskelal abnormalities
examples of induction or hypertrophy of smooth ER
drug tolerance

detoxification
examples of cytoskeletal abnormalities
thin filaments (movement)

microtubules

intermediate filaments (maintain cell shape)
intracellular accumulations
normal cellular constituents: water, lipids, proteins, carbs

abnormal substance (exogenous: mineral, infectious agent products or endogenous: abnormal synthesis or metabolism)

pigment
reasons for abnormal intracellular accumulations
1. endogenous substance is produced at a normal rate but rate of metabolism is inadequate to remove it.
2. accumulates due to genetic or acquired defects in metabolism, transport, packaging, or secretion.
3. exogenous substance accumulates because cell is unable to degrade it or transport it to other sites
cholesterol deposit examples
atherosclerosis

xanthomas

Niemann pick disease
lipid accumulation
fatty liver- most often due to alcohol abuse
protein accumulation examples
amyloidosis

due to defects in protein folding
hyaline accumulation
collagenous fibrous tissue in old scars may appear hyalinous

in HTN and DM the walls of arterioles esp. in kidney become hyalinized
glycogen accumulation
in DM: found in kidney tubules

glycogen storage disease
pigment accumulation
exogenous pigments: tatoos, coal dust

endogenous: lipofusin, melanin, hemosiderin/rust
dystrophic calcification
necrosis and damaged tissues
metastatic calcification causes
increase PTH

destruction of bone

vitamin D related disorders

renal failure
structural and biochemical changes with aging
decreased repair

decreased synthesis

less efficient organelles
what is replicative senescence?
cells become arrested after a fixed number of cell divisions
prolonged life span due to _____ receptor in response to __________
IGF-1

decreased caloric intake
general pathology
reactions of cells and tissues to abnormal stimuli that underly all diseases
special pathology
specific responses of specialized organs and tissues to more or less well defined stimuli
4 aspects of disease that form the core of pathology
etiology
pathogenesis
morphologic changes
clinical manifestations
etiology
cause:
intrinsic or genetic
acquired: environment
pathogenesis
sequence of events from initial stimulus to expression
morphologic changes
structural alteration in cells or tissues that are either characteristic of the disease or diagnostic
father of modern pathology
Rudolf Virchow
pathologic hyperplasia
excessive hormonal stimulation or growth factors acting on target cells
cause of hyperplasia
increased production of growth factors and hormones and transcription factors
increase in size of cells
hypertrophy
increase in number of cells
hyperplasia
shrinkage in size of cell by loss of cell substance
atrophy
causes of pathologic atrophy
decreased workload (disuse)

loss of innervation (denervation)

diminished blood supply (ischemia)
what is replicative senescence?
cells become arrested after a fixed number of cell divisions
prolonged life span due to _____ receptor in response to __________
IGF-1

decreased caloric intake
general pathology
reactions of cells and tissues to abnormal stimuli that underly all diseases
special pathology
specific responses of specialized organs and tissues to more or less well defined stimuli
4 aspects of disease that form the core of pathology
etiology
pathogenesis
morphologic changes
clinical manifestations
etiology
cause:
intrinsic or genetic
acquired: environment
pathogenesis
sequence of events from initial stimulus to expression
morphologic changes
structural alteration in cells or tissues that are either characteristic of the disease or diagnostic
father of modern pathology
Rudolf Virchow
pathologic hyperplasia
excessive hormonal stimulation or growth factors acting on target cells
cause of hyperplasia
increased production of growth factors and hormones and transcription factors
increase in size of cells
hypertrophy
increase in number of cells
hyperplasia
shrinkage in size of cell by loss of cell substance
atrophy
causes of pathologic atrophy
decreased workload (disuse)

loss of innervation (denervation)

diminished blood supply (ischemia)

inadequate nutrition (marasamus, cachexia)

loss of endocrine stimulation

aging (senile)

pressure
example of physiologic atrophy
during development
mechanism of atrophy
increased protein degradation

acid hydrolases from lysosomes released to degrade endocytosed proteins

ubiquitin proteasome pathway

hormones (glucocorticoids, thyroid hormones) stimulate proteasome mediated protein degradation (insulin opposes)

cytokines like TNF increase proteolysis
histological change in atrophy
increased number of autophagic vacuoles
reversible change from one cell type to another

reaction due to chronic irritation
metaplasia
most common example of metaplasia
change in respiratory tract from columnar to squamous epithelium
Barrett esophagus
change from squamous to columnar cells due to gastric acid reflux
3 ways free radicals can damage cells
1. lipid peroxidation of membranes (oxygen damages double bonds in polyunsaturated membrane lipids)
2. DNA fragmentation (react with thymine in nuclear and mitochondrial DNA)
3. protein cross linking (promote sulfhydryl mediated protein cross-linking resuling in increased degradation)
mitochondrial dysfunction
increase cytosolic Ca associated with ATP depletion results in increased CA uptake into mitochondria activating phospholipase and leading to phospholipid breakdown
reversible cell injury
plasma membrane alterations

mitochondrial changes

dilation of ER

nuclear alterations
morphological changes following cell death in a living tissue
necrosis
What happens in acetaminophen poisoning
acetaminophen is detoxified into a highly toxic metabolite by cytochrome p-450

the metabolites are detoxified by interaction with GSH

When GSH is depleted the toxic metabolites accumulate and destroy nucleophilic macromolecules

causing massive liver cell necrosis 3-5 days after ingestion

treatment:
N-acetylcysteine
activated charcoal
loss of membrane integrity, enzymatic digestion of cells, and frequently a host reaction
necrosis
cell plasma membrane remains intact but structure is altered so it becomes a target for phagocytosis
apoptosis
morphological features of apoptosis
cell shrinkage

chromatin condensation

cytoplasmic blebs

phagocytosis
human genome
approximately 20,000-25,000 human genes
study of chromosomes
karyotyping
karyotype staining
use Giemsa staining- G banding

metaphase spread

arranged long to short
karyotype notation
total number of chromosome, sex chromosome complement, description of abnormalities in ascending numerical order

p: petit arm
q: long arm

banded regions are numbered from the centromere outward
major categories of genetic disorders
1. chromosome abnormalities (ex. trisomy)
2. single-gene disorders (ex. cystic fibrosis, marfan, sickle cell anemia, huntingtons) (inheritied in recognizable patterns)
3. multifactorial disorders (combo of mutations and environment)
4. mitochondrial disorders (really multifactorial) (mutations in the nonchromosomal DNA of mitochondria)
most common of the chromosomal disorders and major cause of metal retardation
Trisomy 21- Down syndrome
increased risk of trisomy 21:
advanced maternal age (meiotic nondisjunction of chromosome 21)
clinical features of Down syndrome
flat facial profile
oblique palpebral fissures
epicanthic folds
congenital heart disease
leukemia risk
abnormal immune response
reduced life span (now median age of death- 47)
mental retardation
intestinal stenosis
gap between 1st and 2nd toe
umbilical hernia
abundant neck skin
XXY
Klinefelter syndrome: male hypogonadism with 2 or more X chromosomes and 1 or more Y chromosomes
most common cause of hypogonadism in the male
Klinefelter's syndrome
signs of Klinefelter syndrome
eunuchoid body habitus
abnormally long legs
small atrophic testes
lack secondary male sex characteristics
gynecomastia
IQ slightly lower
rarely diagnosed before puberty
elevated FSH levels
low testosterone
high estradiol
monosomy of X chromosome
Turner syndrome
most common sex chromosome abnormality in females:
Turner syndrome
Signs of Turner syndrome
hypogonadism in females
edema of dorsum of hand and foot
swelling of nape of neck- distened lymphatic channels- cystic hygroma
-bilateral neck webbing and persistent looseness of skin on back of neck
-Congenital heart disease
-preductal coarctation of aorta and bicuspid aortic valve
-failure to develop normal secondary sex characteristics at puberty
-normal mental status
-shortness of stature
-most important cause of primary amenorrhea
-hypothyroidism
-glucose intolerance
-insulin resistance
-obesity
-treatment: GH- worsens insulin resistance
-broad chest
-wide spaced nipples
-pigmented nevi
-streak ovaries
-cubitus valgus
determinant of genetic sex
Y chromosome
sex based on histologic characteristics of gonads
gonadal sex
gender depending on presence of mullerian or wolffian ducts
ductal sex
sex based on appearance of external genitalia
phenotypic or genital sex
disagreement between criteria for determining sex
sexual ambiguity
true hermaphrodite
presence of both ovarian and testicular tissue

very rare

may have ovaries on one side and testes on other

or ovotestes- mix of tissue
pseudohermaphrodite
disagreement between phenotypic and gonadal sex
female pseudohermaphroditism
XX

development of ovaries and internal genitalia is normal

external genitalia- ambiguous or virilized- exposure to androgenic steroids during gestation

Congenital adrenal hyperplasia
male pseudohermaphroditism
possess a Y chromosome

Gonads are testes

genital duct or external genitalia are incompletely differentiated- ambiguous or female ext. genitalia

defective virilization of male embryo due to genetically determined defects in androgen synthesis or action
molecular basis of disorder
enzyme defects

defects in receptors or transport systems

alteration in nonenzyme proteins

adverse reactions to drugs
enzyme defect diseases
phenylketonuria

tay-sachs

SCID

Lesch-Nyhan syndrome

alpha-1 antitrypsin deficiency
phenylketonuria
inability to convert phenylalanine to tyrosine

most often in caucasians (scandinavian)

severe mental retardation by 6 months

treated with diet

90% of children born to such women are mentally compromised with congenital defects
Tay-Sachs disease
gangliosidosis

sphingolipidoses- group of lysosomal storage diseases

Ashkenazi jews

mental deteriorization at 6 months of age

cherry red spot on macula

muscle flaccity, blindness, pathetic vegetative state
severe combined immunodeficiency
defects in both cell mediated and humoral immune responses

infants with thrush, rash, failure to thrive

defects in T cell with secondary effects on humor immunity

X linked recessive (more common in boys)

or caused by an autosomal recessive deficiency of adenosine deaminase- toxic to T cells
Lesch-Nyhan syndrome
x-linked

lack of hypoxanthine guanine phosphoribosyl transferase (HGPRT) in males with an increase in uric acid

HGPRT- used in salvage pathway of purine synthesis resulting in an increase in de novo synthesis

hyperuricemia, neurologic deficits, mental retardation, self-mutilation, gouty arthritis
alpha-1 antitrypsin deficiency
failure to inactivate neutrophil elastase in lungs-> destruction of elastin in walls of lung alveoli

pulmonary emphysema
single gene disorder
familial hypercholesterolemia

vitamin D resistance

Cystic Fibrosis

Sickle Cell anemia

Thalassemias
familial hypercholesterolemia
mutation in the gene encoding the receptor for LDL which is involved in the transport and metabolism of cholesterol

loss of feedback control

premature atherosclerosis

increased risk of MI

tendinous xanthomas
most frequent mendelian disorder
familial hypercholesterolemia
genetic inheritance of familial hypercholesterolemia
heterozygotes: 50% of normal LDL receptors

homozygotes: virtually no normal LDL receptors (MI before age 20)

both have decreased clearance and increases synthesis of LDL

also have impaired IDL transport to liver (same receptors)- IDL becomes more LDL
vitamin D resistance
single gene disorder

decreased synthesis of 1,25OH2D- advanced renal disease, inherited deficiency in renal alpha-1-hydroxylase (Vit. D dependant rickets type 1)

end organ resistance to 1,25OH2D- inherited absence or defective receptor for acute metabolite of vit. D (vit D dependant rickets type 2)
cystic fibrosis
-defective Cl ion transport in exocrine glands, sweat glands, lungs, pancreas
-most lethal genetic disease that affects caucasians
-autosomal recessive (heterozygotes asymptomatic)
-abnormally viscous mucous secretions
-many different possible mutations, grouped into 6 classes based on effects on CFTR protein
-sweat test: measure ionic component to determine severity
Thalassemia
-single gene/transport system
-due to decreased synthesis of either the alpha or beta globin chain of HbA (a2B2)
-B thalassemia: decreased B synthesis, a-thalassemia- decreased A synthesis
-free chains aggregate into insoluble inclusions and hemolysis in the spleen
-b-thalassemis is most common in mediterannean or africa and southeast asia
-anemia manifests 6-9 months after birth (HbF changes to HbA)
peripheral blood smear abnormalities in thalassemia
anisocytosis: variation in size
poikilocytosis: variation in shape
microcytosis: small size
hypochromia: poor hemoglobinization
severity of a-thalassemia
-depends on number of a-globin genes affected (4 possible)
-silent carrier: 1 a-globin chain deleted
-a-thalassemia trait: deletion of 2 a-globin
-hemoglobin H disease: deletion of 3 a-globin genes
-hydrops fetalis- deletion of all 4 a-globin genes
sickle cell anemia
-single gene, transport system
-produce defective hemoglobin
-normal adult hemoglobin a2B2, small amounts of HbA2 (a2delta2) and fetal (a2gamma2)
-abnormality in B-globin gene
-POINT MUTATION CAUSING SUBSTITUTION OF VALINE FOR GLUTAMIC ACID RESIDUE IN BETA CHAIN
prevalence of sickle cell anemia
-8% of black americans are heterozygous
-in homozygotes: almost all hemoglobin is HbS
-in heterozygotes: 40% of hemoglobin is HbS- sickle cell trait
what is the benefit of sickle cell trait
protection against falciparum malaria

where malaria is endemic in Africa: 30% are heterozygotes
single gene disorders that have alterations in non-enzyme proteins
osteogenesis imperfecta
ehlers-danlos syndrome
marfan syndrome
duchenne muscular dystrophy
spherocytosis
neurofibromatosis
Osteogenesis imperfecta
-deficiency of TYPE 1 COLLAGEN
-brittle bone disease
-joints, eyes, ears, skin, teeth affected
-autosomal dominant inheritance
-less severe: make normal collagen, just in decreased amounts
-more severe or lethal: make abnormal chains that cannot form triple helix configuration
signs of OI
-blue sclerae
-increased number of fractures
-hearing loss (bones conduction)
-dental imperfections
-deficiency of dentin
type 1 form of OI
mutations aquired not inherited
type 2 form of OI
-fatal in utero
-multiple fractures before birth
Ehlers-Danlos syndrome
DEFECT IN SYNTHESIS OR STRUCTURE OF FIBRILLAR COLLAGEN
inheritance of ehlers-danlos syndrome
-variable inheritance: autosomal dominant or autosomal recessive
-6 types
signs of Ehlers-Danlos syndrome
-skin and joint hypermobility
-dislocations
-skin, arterial, uterine rupture
-congenital scoliosis
-ocular fragility
-bruising
-cutis laxa
Marfan syndrome
defect in extracellular glycoprotein FIBRILLIN-1

fibrillin- major component of microfibrils in ECM, scaffolding for elastic fibers

disorder of connective tissue

especially: skeleton, eyes, cardiovascular system

diagnosis based on major involvement of 2 of the 4 major organ systems
inheritance of Marfan syndrome
autosomal dominant (70-85%)
remainder caused by new mutations
Duchenne muscular dystrophy
-X linked
-most common and severe form of muscular dystrophy
-becomes evident at age 5
-wheelchair bound at age 10
spherocytosis
intrinsic defect in red cell membrane making cell spheroid, less deformable, and vulnerable to splenic squestration and destruction

red cells must undergo extreme deformation to leave the cords of billroth and enter sinusoids of the spleen- spherocytes trapped, lactic acid accumulates, pH falls, glycolysis limited, macrophages phagocytose spherocytes
inheritance of spherocytosis
autosomal dominant (75%)

remainder autosomal recessive inheritance- more severe
treatment of spherocytosis
splenectomy
neurofibromatosis Type 1
-autosomal dominant
-most common type
-neurofibromas
-gliomas of optic nerve
-pigmented nodule of iris (Lisch nodule)
-cutaneous hyperpigmented macules (cafe au lait spots)
-highly variable effects
-may have no symptoms
-or spinal deformities, disfiguring lesions, compression of vital structures including spinal cord
neurofibromatosis type 2
-autosomal dominant
-range of tumors esp. bilateral 9 nerve schwannomas and multiple meningiomas
-ependymomas of SC
-non-neoplastic lesions: schwannosis, meningioangiomatosis, glial hamartia
-non-sense mutations cause a more severe phenotype than missense
glial hamartia
microscopic nodular collections of glial cells at abnormal locations, often in superficial and deep layers of cerebral cortex
multifactorial disease
congenital malformations

adult diseases

mitochondrial diseases
congenital malformations
-cleft lip
-club foot
-congenital heart defects
-pyloric stenosis
-neural tube defect
multifactorial diseases
coronary heart disease
HTN
Alzheimers
cancer
diabetes
gout
bipolar affective disorder
schizophrenia
alcoholism
type of disorder that result from the combined actions of environmental influences and mutant genes

dosage like effect- range of severity
multifactorial disease
5 features that characterize multifactorial inheritance
1. risk is conditioned by number of mutant genes inherited
2. the rate of recurrence of the disorder (2-7%) is the same for all first degree relatives
3. the likelihood that both twins will be affected is less than 100% but much greater than non-identical twins
4. risk of recurrence of phenotypic abnormality in subsequent pregnancies depends on outcome of previous pregnancies (if 1 child affected- 7% chance next affected, after 2 affected, risk rises to 9%)
5. expression of trait may be continous or discontinuous (might have to cross a threshold before apparent)
transmission of certain single gene disorders does not follow mendelian principles
nonclassical inheritance
examples of disorders with nonclassical inheritance
fragile X syndrome
Fragile X syndrome
-non-classical inheritance
-2nd most common cause of mental retardation after down syndrome
-much more common in males
-constriction in long arm of x chromsome
-long face, large mandible
-large everted ears
-large testicles (macro-orchidism)
-hyperextensible joints
-high arched palate
-mitral valve prolapse
-can mimic CT disorder
pharmacology interested in genetic factors related to drug sensitivity and adverse reactions
pharmacogenetics
3 requirements to be an autoimmune reaction
1. presence of autoimmune reaction
2. evidence that reaction is not due to tissue damage
3. absence of other well-defined cause of disease
immunologic tolerance
state in which the individual is incapable of developing an immune response to a specific antigen
self tolerance
lack of responsiveness to individual's own antigens

2 types central and peripheral tolerance
central tolerance
deletion of self reactive T and B lymphocyte clones during maturation in (thymus (t cells) and bone marrow (b cells)
peripheral tolerance
back up mechanisms to kill self reactive T cells:
-anergy
-supression by regulatory T cells
-clonal deletion by activation induced cell death
potential causes of autoimmunity
1. inheritance of susceptible genes
2. environmental triggers, particularly infections, which promote the activation of self-reactive lymphocytes
organ specific autoimmunity examples
type 1 DM

MS
systemic autoimmune disease
SLE: antibodies against DNA, platelets, red cells, protein-phospholipid complexes
systemic lupus erythematosus
-antinuclear antibodies (ANAs)
-antibodies against cell surface antigens of blood cells
-antibodies against cytoplasmic components
-injury to skin, joints, kidney, and serosal membranes
-usually in women
-more severe in african-american women
-usually arises in 20-30s
lupus ANAs against 4 targets
1. DNA
2. Histones
3. nonhistone proteins bound to RNA
4. to nucleolar antigens
Technique to detect ANAs
immunofluorescence
-most common test
-sensitive test- but not specific to lupus
-DIAGNOSTIC TEST FOR LUPUS: ANTIBODIES TO DOUBLE STRANDED DNA- SMITH ANTIGEN
4 patterns of nuclear fluorescence that suggest the type of antibody in the patient's serum
1. homogenous or diffuse nuclear staining
2. rim or peripheral staining patterns
3. speckled pattern
4. nucleolar pattern
risk factors for developing lupus
-genetic makeup regulates the formation of autoantibodies (HLA)
-but expression of the disease is influenced by non-genetic factors
-some have inherited deficiencies of early complement components (might favor tissue deposits)
-drugs like hydralazine, procainamide, d-penicillamine can induce a SLE response
-exposure to UV light exacerbates disease
-sex hormones
-immunologic factors: T and B cells activated against self
main manifestations of lupus
hematologic
arthritis
skin
fever
fatigue
weight loss
renal
most common causes of death in lupus
renal failure

intercurrent infections

coronary artery disease
Chronic Discoid Lupus Erythematosus
-skin manifestations that mimic SLE
-skin plaques with edema, erythma, scaliness, FOLLICULAR PLUGGING, skin atrophy, surrounded by elevated erythematous border
-check for antibodies to double stranded DNA
subacute cutaneous lupus erythematosus
-widespread rash, superficial, non-scarring rash
-mild systemic symptoms
drug induced lupus erythematosus
-SLE like syndrome due to:
hydralazine
procainamide
isoniazid
d-penicillamine
develop ANAs, but many don't have clinical symptoms
Sjogren syndrome
-dry eyes (keratoconjunctivitis sicca)
-dry mouth (xerostomia)

immunologically mediated destruction of lacrimal and salivary glands

most often occurs in women: 50-60 y.o.

isolated form: sicca syndrome

secondary form: with another autoimmune disease (60%)
disorders associated with secondary sjogren syndrome
RA (most commmon)
SLE
polymyositis
scleroderma
vasculitis
mixed CT disease
thyroiditis
Tests to diagnose Sjogren syndrome
antibodies against SS-A (Ro)
antibodies against SS-B (La)

SS-A early onset, longer duration of disease, extraglandular manifestations

BIOPSY OF LIP- MICROSCOPIC EXOCRINE GLANDS
Mikulicz syndrome
lacrimal and salivary gland enlargement

can be caused by sarcoidosis, leukemia, lymphoma, tumors
lymph node abnormalities in sjogren syndrome
enlargement with pleomorphic infiltrate of cells with frequent mitoses

increased risk of non-hodgkin lympohomas (b cell type) in salivary glands and lymph nodes

increased risk of lymphoid malignacies
scleroderma
-abnormal accumulation of fibrous tissue in skin and multiple organs (GI, kidneys, heart, muscles, lungs)
-aka systemic sclerosis
-occurs more often in women age 50-60
2 types of scleroderma
diffuse: widespread skin involvement at onset progressing to early visceral involvement

limited: skin involvement is confined to fingers, forearms, face
CREST syndrome of scleroderma
C: calcinosis
R: raynaud phenomenon
E: esophageal dysmotility
S: sclerodactyly
T: telangiectasia

antibodies to centromeres
causes of scleroderma
combination of abnormal immune response and vascular damage leading to accumulation of growth factors that act on fibroblasts and stimulate collagen production
vascular changes with scleroderma
:microvascular disease
:intimal proliferation
:capillary dilation with leaking and destruction
:nailfold capillary loops
(early in couse)
distinctive features of scleroderma
-raynaud phenomenon
-dysphagia
-distal esophagus dilation and atony
-abdominal pain, intestinal obstruction, malabsorption syndrome, weight loss, anemia
-respiratory difficulties due to pulmonary fibrosis
-R sided cardiac dysfunction
-myocardial fibrosis-> arrhythmias or cardiac failure
-mild proteinuria
-most ominous manifestation: malignant HTN
- fatal renal failure
-more severe in blacks
inflammatory myopathies
-injury and inflammation of mainly skeletal muscles

3 disorders:
1. dermatomyositis
2. polymyositis
3. inclusion body myositis
mixed connective tissue disease
coexistence of features of SLE, polymyositis, RA, systemic sclerosis, high titers of antibodies to RNP particle containing U1 RNP

little renal disease

extremely good response to corticosteroids

possibly just a heterogeneous mixture of subsets of SLE, systemic sclerosis, and polymyositis
polyarteritis nodosa and other vasculitides
-necrotizing inflammation of blood vessel walls
immunodeficiencies

primary:

secondary
primary: genetically determined

secondary: due to environment, infection, age, malnutrition, iatrogenic
x-linked agammaglobulinemia of bruton
-failure of B cell precursors to mature
-light chains are not produced
-more susceptible to bacteria
-more common in males
-usually manifests in infancy or childhood
signs of immunodeficency in x-linked agammaglobulinemia of bruton
recurrent bacterial infections
-acute and chronic pharyngitis
-sinusitis (need abx)
-otitis media
-bronchitis
-pneumonia

commonly caused by H. influenzae, S. pneumoniae, s. aureus

persistant infection by giardia lamblia (normally resisted by secreted IgA)

most viral, fungal, protozoal infections are handled by T cell mediated immunity

arthritis may be due to mycoplasma infection
X linked agammaglobulinemia of bruton
-B cells absent or decreased in circulation
-depressed levels of all classes of immunoglobulins
-underdeveloped germinal centers of lymph nodes, peyers patches, appendix, tonsils
-plasma cells absent
-normal T cell mediated reactions
-treatment: replacement therapy of immunoglobulins
common variable immunodeficiency
-hypogammaglobulinemia
-usually affects all antibody classes
-usually normal or near normal numbers of B cells in blood and lymphoid tissues
-T cells cannot differentiate into plasma cells
-affects both sexes equally
-onset later in childhood or adolescence
common variable immunodeficiency

vs.

x linked agammaglobulineamia
common variable immunodeficiency:
normal numbers of B cells in blood and lymphoid tissue
B cells cannot differentiate into plasma cells
affects both sexes equally
enlargement of B cell areas
feedback inhibition is stopped due to lack of IgG
risk of lymphoid malignancy
high frequency of autoimmune disease

X-linked agammaglobulinemia:
mostly in males
germinal centers of lymph nodes, peyer's patches, appendix, tonsils underdeveloped
plasma cells absent
T cell reactions are normal
B cells absent or decreased
isolated IgA deficiency
mucosal defenses are weakened

more susceptible to infections in respiratory, GI, UG tracts

recurrent sinopulmonary infections and diarrhea

do not give IgA unless they have not antibodies to IgA- can cause severe or fatal anaphylactic reactions
hyper IgM syndrome
functionally abnormal T cells fail to induce B cells make antibodies that undergo isotype switching

recurrent pyogenic infections due to low IgG antibodies

IgM antibodies react with blood giving rise to autoimmune hemolytic anemia, thrombocytopenia, and neutropenia
Di george syndrome
failure of development of the 3rd and 4th pharnygeal pouches (become thymus, parathyroids, thyroid)

-variable loss of T cell mediated immunity
-tetany (lack of parathyroids)
-congenital defects of heart and great vessels
-abnormal appearance of mouth, ears, face
-absence of cell mediated immunity (low T lymphcytes)
-normal number of plasma cells
-poor defense against fungal and viral infections
-T cell zones of lymphoid organs are depleted (paracortical areas of lymph nodes, periarteriolar sheaths of spleen)
-T cell function improves with age, by 5 years no noticeable deficit
-if thymus is completely absent- transplant
severe combined immunodeficiency
defects in both humoral and cell-mediated immune response

thrush, diaper rash, failure to thrive

Tx: bone marrow transplant

2 most common forms:
-ADA deficiency-remnants of Hassall's corpuscles present
-X linked SCID: thymus contains lobules of undifferentiated epithelial cells resembling fetal thymus
-Both have hypoplastic lymphoid tissue, marked depletion of T cell areas and sometimes both T and B cell zone depletion
immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome)
X linked recessive

thrombocytopenia, eczema, vulnerable to recurrent infection

normal thymus

progressive secondary depletion of T lymphocytes in peripheral blood and T cell zones of lymph nodes

patients do not make antibodies to polysaccharide antigens

WASP- protein family that link membrane receptors like antigen receptors to cytoskeletal elements, maintain cytoskeleton integrity, signal transduction
amyloidosis
amyloid: pathologic proteinaceous substance deposited between tissues and organs

cross-B-pleated sheet conformation made of mostly fibril proteins
accumulation causes pressure atrophy
3 most common forms of amyloid proteins
1. AL (amyloid light chain)- derived from plasma cells and contains immunoglobulin light chains

2. AA (amyloid associated)- made by liver

3. A beta: found in cerebral lesion of alzheimer diease
how are amyloidosis classified
based on constituent chemical fibrils

primary amyloidosis: systemic or generalized pattern associated with IMMUNOCYTE DYSCRASIA

secondary amyloidosis: when a complication of underlying CHRONIC INFLAMMATORY or tissue destructive pattern
primary amyloidosis
systemic or generalized pattern of amyloidosis associated with immunocyte dyscrasia

usually plasma cell dyscrasia, multiple myeloma,
plasma-cell tumor,
osteolytic lesions
reactive systemic amyloidosis
amyloidosis secondary to an associated inflammatory condition

protracted breakdown of cells due to inflammatory conditions

associated with:
-RA
-ankylosing spndylitis
-inflammatory bowel disease (chrohn and ulcerative collitis)

heroine users who inject subcutaneously have a high occurence rate of generalized AA amyloidosis

chronic skin infections associated with skin popping of narcotic
hemodialysis associated amyloidosis
amyloid deposits of B2-microglobulin due to long term hemodialysis

may deposit in joints, synovium, or tendon sheaths
heredofamily amyloidosis

familial Mediterranean fever
autosomal recessive

fever with inflammation of serosal surfaces (including peritoneum, pleura, synovial membrane)

mainly in armenian, sephardic jewish, and arabic origins

associated with widespread involvement of AA proteins indistinguishable from reactive systemic amyloidosis
localized amyloidosis
-limited to a single organ or tissue
-nodular deposits most often in lung, larynx, skin, urinary bladder, tongue, eye
-frequently infiltrates of lymphocytes and plasma cells are present in periphery of amyloid masses
endocrine amyloid
amyloid deposits in endocrine tumors

ex. medullary carcinoma of thyroid gland, islet tumors of pancreas, pheochromocytomas
amyloid of aging
systemic amloidosis in elderly

senile cardiac amyloidosis

can cause restrictive cardiomyopathy and arrhythmias (in both homo and heterozygotes)

amyloid composed of TTR (transthyretin) molecule

4% of black population in US have mutant allele
pathogenesis of amyloidosis
-abnormal protein foldings deposited in tissue
1. normal proteins that have a tendency to fold improperly, associate and form fibrils, do so when produced in increased amounts
2. mutant proteins: structurally unstable and prone to misfoldings and subsequent aggregation

normally misfolded proteins are degraded intracellularly in proteasomes or by macrophages

if quality control mechanisms fail- misfolded proteins accumulate
clinical manifestations of amyloidosis
weakness
weight loss
light-headedness
syncope

non-specific until organ more affected
normal fluid homeostasis
1. maintenance of vessel wall integrity
2. maintenance of intravascular pressure and osmolarity

3. maintenance of blood as a liquid until injury necessitates clot formation
shock
temperature <96.8 or >101.3
resp >20
HR >90
WBC >12000 or <4000 (immunocompromised)
>10% band forms
<90 mmHg MAP
<65mmHg with fluid resuscitation
3 most important causes of pathology in western society that are disturbances in normal blood flow
MI
PE
CVA
thrombosis
clotting at inappropriate sites
embolism
migration of clots
obstruction of blood flow to tissue causing cell death
infarction
inability to clot after vascular injury leads to
hemorrhage
edema
increased fluid in interstitial tissue spaces: hydrothorax, hydropericardium, hydroperitoneum
anasarca
severe generalized edema with profound subcutaneous tissue swelling
Edema due to increased hydrostatic pressure
impaired venous return
-CHF
-constrictive pericarditis
-ascites (liver cirrhosis)
-venous obstruction or compression
-thrombosis
-external pressure
-lower extremity inactivity with dependency

Arteriolar dilation
-heat
-neurohumoral dysregulation
Edema due to reduced plasma osmotic pressure (hypoproteinemia)
protein losing glomerulopathies
liver cirrhosis (ascites)
malnutrition
protein-losing gastroenteropathy
Edema due to lymphatic obstruction
inflammatory
neoplastic
post surgical
post irradiation
causes of edema due to sodium retention
excessive salt intake with renal insufficiency
increased tubular reabsorption of sodium
renal hypoperfusion
increased renin-angiotensin-aldosterone secretion
edema due to inflammation
acute or chronic inflammation
angiogenesis
dependent edema
edema due to gravity

prominent feature of congestive heart failure

R ventricle failure
non-dependent edema
edema due to nephrotic syndrome

affects all parts of the body equally

periorbital edema characteristic finding in severe renal disease (edema often in loose CT area like eyelids first)

pitting edema
hyperemia
INCREASED INFLOW leads to engorgement with oxygenated blood resulting in ERYTHEMA
congestion
DIMINISHED OUTFLOW leads to capillary beds swollen with deoxygenated blood resulting in CYANOSIS
hemorrhage
extravasation of blood due to vessel rupture

capillaries- bleed in chronic congestion

artery/vein rupture: trauma, atherosclerosis, inflammatory or neoplastic erosion of vessel wall
hematoma
accumulation of blood within a tissue
petechiae
minute 1-2mm hemorrhages into skin, mucous membranes, or serosal surfaces

associated with increased intravascular pressure, low platelet counts (thrombocytopenia), defective platelet function (as in uremia), or clotting factor deficits
purpura
slightly larger than 3 mm hemorrhages

associated with
increased intravascular pressure,
low platelet counts (thrombocytopenia),
defective platelet function (as in uremia),
or clotting factor deficits or trauma,
vasculitis,
or increased vascular fragility (amyloiditis)
ecchymoses
1-2cm subcutaneous hematomas

usually after trauma
causes of subcutaneous hematomas
associated with
increased intravascular pressure,
low platelet counts (thrombocytopenia),
defective platelet function (as in uremia),
or clotting factor deficits or trauma,
vasculitis,
or increased vascular fragility (amyloiditis)
color change in hematomas
1. erythrocytes are degraded and phagocytosed by macrophage
2. hemoglobin (red-blue) is then converted to bilirubin (blue-green)
3. converted to hemosiderin (gold-brown)
large accumulations of blood in a body cavity
hemothorax, hemopericardium, hemoperitoneum, hemoarthrosis
Risk with extensive hemorrhage
jaundice from massive breakdown of Red cells and release of bilirubin
2 functions of hemostasis
1. maintain blood in a fluid, clot-free state
2. ready to induce a rapid and localized hemostatic plug at site of vascular injury
thrombosis
formation of a blood clot in uninjured vasculature or thrombotic injury of a vessel after minor injury

pathological opposite of hemostasis
3 components that regulate hemostasis and thrombosis
1. vascular wall
2. platelets
3. coagulation cascade
intrinsic pathway of clotting cascade
factor 12- hageman factor
kallikrein
factor 11
factor 9
factor 8- thrombin
extrinsic pathway of clotting
factor 7 activates
tissue factor (thromboplastin)
intrinsic and extrinsic pathways of clotting meet at
factor 10
common pathway
factor 10
factor 5
Factor 2 (prothrombin is activated to 2a thrombin)
thrombin cleaves fibrinogen to fibrin
virchow triad
3 risk factors for thrombus formation
1. endothelial injury (most important)
2. blood hypercoagulability
3. stasis or turbulent blood flow
endothelial injury
does not require physical disruption

dysfunctional endothelium may release too many procoagulant factors or too few anticoagulant effectors

may occur due to hemodynamic stresses of
1. HTN,
2. turbulent flow over scarred valves,
3. bacterial endotoxins
4. hypercholesterolemia
5. homocystinuria,
6. cigarette smoke
factors that favor thrombus formation
exposure of membrane bound tissue factor-> extrinsic coagulation sequence
factors that inhibit thrombosis
antithrombin 3- inactivates thrombin and factors 10 and 9

tissue factor pathway inhibitor: inactivates tissue factors 7, 10

PGI2, NO, adenosine diphosphate inhibit platelet aggregation

t-PA stimulates fibrinolytic cascate
turbulence
contributes to thrombosis

form countercurrents, pockets of stasis instead of normal laminar flow with platelets flowing centrally
how does stasis and turbulence alter blood flow?
1. bring platelets in contact wtih endothelium
2. prevent dilution of activated clotting factors with fresh blood

most common cause of thrombosis
3. retard the inflow of clotting factor inhibitors
4. promote endothelial cell activation
hypercoagulability: definition and causes
definition:
any alteration of the coagulation pathway that predisposes to thrombosis

causes:
primary-genetic
secondary- acquired
Secondary (acquired) hypercoaguability states due to:
cardiomyopathy
nephrotic syndrome
hyperestrogenic state
OC use
sickle cell anemia
smoking
thrombosis
area of attachment to underlying vessel or heart wall
arterial thrombi
grow in retrograde direction from point of attachment
venous thrombi
extend in the direction of blood flow
grossly apparent lamination of a thrombosis called
lines of zahn
lines of Zahn are formed from
layers of platelets mixed with fibrin and darker layers containing more red cells
thrombi that adhere to wall of heart chamber or aortic lumen

due to abnormal myocardial contraction
mural thrombi
the most common sites of arterial thrombi
coronary arteries

cerebral arteries

femoral arteries
arterial thrombi
injured arterial wall

on atherosclerotic plaque

usually occlusive
venous thrombosis or phlebothrombosis
usually occlusive
usually form in static environment
tend to contain enmeshed erythrocytes- why aka red or stasis thrombi
How can you tell the difference between a postmortem clot and a venous thrombi
Postmortem clots
-gelatinous
-dark red dependent portion where cells have settled
-yellow chicken fat supernatant
-usually not attached to underlying wall

venous thrombi
-firmer
-point of attachment
-reveal strands of pale gray fibrin on transection
fates of a thrombus
1. propagation (toward heart)
2. embolization
3. dissolution
4. organization and recanalization (form new channels through vessel)
disseminated intravascular coagulation (DIC)
widespread fibrin thrombi in microcirculation

can cause diffuse circulatory insufficency (esp. to brain, heart, kidneys)

rapid consumption of platelets and coagulation proteins at the same time that fibrinolytic mechanisms are activated- can become a serious bleeding disorder

not a primary disease
but a
widespread activation of thrombin
embolism
detached intravascular solid, liquid, or gasseous mass that is carried in blood to a new site

aka thromboembolism (usually contain part of thrombus)
rare forms of emboli
droplets of fat
bubbles of air/Nitrogen
atherosclerotic debris (cholesterol)
tumor fragments
bits of bone marrow
foreign bodies
pulmonary embolism
200,000 deaths/year

95% originate from deep leg vein thrombi above the level of the knee

usually pass through the R side of heart to the pulmonary vasculature (may be multiple emboli)

60-80% are clinically silent

can cause right heart failure (cor pulmonale) when 60% or more of the pulmonary circulation is obstructed with emboli

obstruction of medium size arteries may result in pulmonary hemorrhage but usually not pulmonary infarction due to dual blood flow
systemic thromboembolism
emboli traveling in arterial circulation

most from intracardiac mural thrombi

most from L ventricle walls infarcts (then L atria, then aortic aneurysms, ulcerated atherosclerotic plaques)

can lodge anywhere but mainly the Lower extremities and 2ndly the brain

outcome depends on collateral vascular supply to the tissue, tissue vulnerability to ischemia, and the caliber of the vessel occluded
amniotic fluid embolism
1 in 50000 deliveries
mortality rate of 20-40%

caused by infusion of fluid or tissue into the maternal circulation by a tear in the placental membranes or rupture of uterine veins

sudden severe dyspnea, cyanosis, hypotensive shock, seizures, coma

pulmonary edema and DIC develop
infarction
area of ischemic necrosis caused by occlusion of the arterial supply or venous drainage
classification of infarcts
based on color and the presence or absence of microbial infection

red- hemorrhagic
white- anemic

septic or bland
red hemorrhagic infarcts occur
1. venous occlusion
2. loose tissues (lung), blood collects
3. tissues with dual circulation
4. tissues with sluggish venous outflow
5. when flow is re-established to a previous site of occlusion and necrosis
white (anemic) infarcts occur
1. arterial occlusions in solid organs with end arterial circulation (solidity limits hemorrhage)
dominant histological characteristic of infarction
ischemic coagulative necrosis

(if occulusion occurs minutes to hours before death there might be no histologic changes, if the patient survives 12-18hours the only change might be hemorrhage)
How does the body deal with infarction
inflammatory response begins in a few hours and is well defined in 1-2 days

gradual degradation of dead tissue with phagocytosis

most are replaced with scar tissue

the brain is the exception- ischemic injury-> liquefactive necrosis
septic infarction
when embolism occurs by fragmentation of bacterial vegetation from a heart valve when microbes seed an area of necrotic tissue

infarct is converted to an abscess
factors that influence development of an infarct
1. nature of the vascular supply
2. rate of development of the occlusion
3. vulnerability of a given tissue to hypoxia
4. blood oxygen content
organs with single blood supply
kidney
spleen

obstruction causes infarction
areas with dual blood supply
lungs
liver
hand
forearm

insensitive to infarction
rate of development of occlusion
slow developing occlusions allow for time to develop alternative perfusion pathways

collateral circulation
vulnerability to hypoxia
neurons- irreversible damage after 3-4 minutes
myocardial cells- damage after 20-30 minutes
fibroblasts- viable after hours of ischemia
oxygen content of blood
partial flow obstruction in an anemic or cyanotic patient might lead to infarction
shock
cardiovascular collapse

final common pathway for many potentially lethal events

systemic hypoperfusion due to reduction in CO or low circulating blood flow

hypotension, impaired tissue perfusion, cellular hypoxia
5 categories of shock
cardiogenic: myocardial pump failure
hypovolemic: loss of blood/plasma volume
septic: systemic microbial infection
neurogenic: spinal cord injury, loss of vascular tone and peripheral pooling of blood
anaphylactic shock: IgE mediated hypersensitivity, associated with systemic vasodilation and increased vascular permeability
1st cause of mortality in intensive care units
shock
classification of infarcts
based on color and the presence or absence of microbial infection

red- hemorrhagic
white- anemic

septic or bland
red hemorrhagic infarcts occur
1. venous occlusion
2. loose tissues (lung), blood collects
3. tissues with dual circulation
4. tissues with sluggish venous outflow
5. when flow is re-established to a previous site of occlusion and necrosis
white (anemic) infarcts occur
1. arterial occlusions in solid organs with end arterial circulation (solidity limits hemorrhage)
dominant histological characteristic of infarction
ischemic coagulative necrosis

(if occulusion occurs minutes to hours before death there might be no histologic changes, if the patient survives 12-18hours the only change might be hemorrhage)
How does the body deal with infarction
inflammatory response begins in a few hours and is well defined in 1-2 days

gradual degradation of dead tissue with phagocytosis

most are replaced with scar tissue

the brain is the exception- ischemic injury-> liquefactive necrosis
septic infarction
when embolism occurs by fragmentation of bacterial vegetation from a heart valve when microbes seed an area of necrotic tissue

infarct is converted to an abscess
factors that influence the severity of an infarct
1. nature of the vascular supply
2. rate of development of the occlusion
3. vulnerability of a given tissue to hypoxia
4. blood oxygen content
organs with single blood supply
kidney
spleen

obstruction causes infarction
areas with dual blood supply
lungs
liver
hand
forearm

insensitive to infarction
rate of development of occlusion
slow developing occlusions allow for time to develop alternative perfusion pathways

collateral circulation
vulnerability to hypoxia
neurons- irreversible damage after 3-4 minutes
myocardial cells- damage after 20-30 minutes
fibroblasts- viable after hours of ischemia
oxygen content of blood
partial flow obstruction in an anemic or cyanotic patient might lead to infarction
shock
cardiovascular collapse

final common pathway for many potentially lethal events

systemic hypoperfusion due to reduction in CO or low circulating blood flow

hypotension, impaired tissue perfusion, cellular hypoxia
5 categories of shock
cardiogenic: myocardial pump failure
hypovolemic: loss of blood/plasma volume
septic: systemic microbial infection
neurogenic: spinal cord injury, loss of vascular tone and peripheral pooling of blood
anaphylactic shock: IgE mediated hypersensitivity, associated with systemic vasodilation and increased vascular permeability
Main cause of mortality in intensive care units
shock
septic shock
results from spread and expansion of an initially localized infection into the bloodstream

most caused by endotoxin, gram negative bacilli- endotoxic shock
what is an endotoxin
bacterial wall lipopolysaccharides that are released when the cell walls are degraded

from gram negative bacilli
How does septic shock occur after LPS exposure?
1. LPS attaches to LPS binding protein

2. LPS-LPS binding protein complex binds to cell surface receptor (CD14) and then binds a signaling transducing protein (mammalian toll like receptor protein 4)
3. signals from TLR4 activate vascular wall cells and leukocytes and initiate a cascade of cytokine mediators
4. TLR-4 down regulates anticoagulation mechanisms including tissue factor pathway inhibitor and thrombomodulin
5. TLR4 engagement on monocytes and macrophages causes mononuclear cell activation with production of cytokines IL-1 and TNF
LPS
at low doses: activate monocytes and macrophages, enhance ability to eliminate bacteria

activate complement
produce cytokines: TNF, IL-1, Il-6, chemokines

TNF and IL-1 act on endothelial cells to stimulate the expression of cytokines and chemokines
endotoxic shock
higher levels of LPS and augmentation of cycokine cascade cause cytokine induced secondary effectors (NO) to become significant

cytokines TNF and Il-1 cause fever and increased synthesis of acute phase reactants

diminished cell production of thrombomodulin and tissue factor pathway inhibitor
results of cytokines and secondary mediators in endotoxic shock
systemic vasodilation (hypotension)

diminished myocardial contractility

widespread endothelial injury and activation causing systemic leukocyte adhesion and pulmonary alveolar capillary damage

activation of coagulation system- culminating in DIC
low quantities of lipopolysaccharide
monocyte/macrophage neutrophil activation

endothelial cell activation

complement activation (C3a, C5a)

local inflammation
moderate quantities of lipopolysaccharides
fever

liver releases acute phase reactants

bone release leukocytes
high quantities of lipopolysaccharides
low cardiac output
low peripheral resistance
blood vessel injury
thrombosis
DIC (disseminated intravascular coagulation)
ARDS (adult respiratory distress syndrome)
endotoxic shock
hypoperfusion from widespread vasodilation, vasodilation, myocardial pump failure, DIC
superantigens
bacterial proteins that can cause syndromes similar to septic shock

toxic shock syndrome toxin 1 made by staphlococci

polyclonal T-lymphocyte activators that induce systemic inflammatory cytokine cascades

effects: diffuse rash, vasodilation, hypotension, death
3 stages of shock
1. initial nonprogressive
2. progressive stage
3. irreversible stage
initial nonprogressive stage of shock
reflex compensatory mechanisms are activated and maintain perfusion to vital organs

baroreceptor reflexes, catecholamine release, activation of renin-angiotensin axis, ADH release, sympathetic stimulation

tachycardia, peripheral vasoconstriction (cool skin), renal conservation of fluid
progressive stage of shock
hypoperfusion and onset of worsening circulation and metabolic imbalances including acidosis

widespread tissue hypoxia
glycolysis- lactic acid
low tissue pH-> blunts vasomotor response, arterioles dilate, blood pools in microcirculation (risk for DIC)

confusion, urine output declines
irreversible stage of shock
body has incurred cellular and tissue injury so severe that survival is not possible

lysosomal enzyme leakage
myocardial contractile function worsens (NO synthesis)
if ischemic bowel flora enters circulation endotoxic shock may be superimposed

complete renal shutdown, acute tubular necrosis
manifestations of shock depend on precipitating insult
hypovolemic and cardiogenic: hypotension, weak, rapid pulse, tachypnea, cool, clammy, cyanotic skin

septic shock: warm, flushed skin due to peripheral vasocilation
exacerbate shock
electrolyte disturbances
metabolic acidosis
cardiac, cerebral, pulmonary changes
renal insuffiency
cardiogenic shock associated with extensive MI and gram - shock
75% mortality rate even with the best care possible
Most common cancer diagnoses
prostate

breast
most cancer deaths
lung
neoplasm means
new growth
neoplasm
abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change
oncology
study of tumors or neoplasms
cancer
term for all malignant tumors
2 basic components of tumors
1. proliferating neoplastic cells that constitute their parenchyma

2. supportive stroma made of CT and blood vessels
desmoplasia
parenchymal cells can stimulate the formation of abundant collagenous stroma
classification of benign epithelial tumors
based on cells of origin
microscopic architecture
macroscopic patterns
adenoma
benign epithelial neoplasm that forms glandular patterns

and

tumors derived from glands
benign epithelial neoplasm producing visible finger-like projections
papillomas
macroscopically visible projection above mucosal surface that projects into gastric or colonic lumen
polyp
malignant tumors arising from mesenchymal tissue and contain little CT
sarcoma

fibrosarcoma
liposarcoma
leiomyosarcoma
rhabdomyosarcoma
malignant neoplasms of epithelial cell origin derived from any of the 3 germ layers
carcinoma
carcinoma with a glandular growth pattern
adenocarcinoma
carcinoma producing squamous cells
squamous cell carcinoma
cancer composed of undifferentiated cells
undifferentiated malignant tumor
pleomorphic adenoma tumors
mixed tumors with epithelial components scattered in a myxoid stroma with more than one neoplastic cell type, derived from 1 germ layer
teratoma or dermoid cysts
from totipotential cells in gonads, usually more than one neoplastic cell type derived from more than one germ layer
melanocarcinoma
carcinoma of melanocytes
seminoma
carcinoma of testicular origin
hepatoma
hepatocellular carcinoma
hamartoma
benign tumor indigenous to the particular site
anaplasia
lack of differentiation
malignant tumors
usually poorly differentiated
primitive, unspecialized cells
anaplasia: to form backward, revert to a lower level of differentiation
benign tumors
usually well differentiated
leiomyoma
neoplastic cell in a benign smooth muscle tumor
dysplasia
disordered growth
loss in uniformity
pleomorphism
more mitotic figures
changes involve entire thickness of the epithelium
4 phases of tumor growth
1. malignant change in the target cell- transformation
2. growth of transformed cells
3. local invasion
4. distant metastases
pleomorphism
variation in size and shape
changes in anaplasia
hyperchomatic nuclei- abundant DNA
nuclei are disproportionately large
nuclear shape is very variable
chromatin- coarsely clumped
large nucleoli
mitoses: higher proliferative activity
loss of polarity: orientation is disturbed
formation of tumor giant cells: single huge polymorphic nucleus and other with 2 or more nuclei
time for a tumor to become detectable
30 population doublings with a cell cycle time of 3 days- 90 days
10^9
weighs 1 gram

really the period before a tumor becomes detectable is unpredictable due to latent phase
maximal tumor size compatible with life
1 kg,
10^12 cells
3 factors that determine the rate of tumor growth
1. doubling time of tumor cells
2. fraction of tumor cells in the replication pool
3. rate at which cells are shed and lost in the growing lesion
growth fraction
the proportion of cells within the tumor population that are in the proliferative pool
as tumors grow: cells leave the proliferative pool due to
shedding
lack of nutrients
apoptosis
by differentiating
by reversion to G0
tumor facts
derived from single cell

by the time it is detectable, most cells are not in the replicative pool

often diagnosed when fairly advanced in life cycle
rates of tumor growth
is faster with less differentiated tissues
depends on blood supply
hormonal stimulation
depends on doubling time
benign tumors
cohesive expansile masses
remain localized at site of origin
do not have the capacity to infiltrate, invade or metastasize
malignant tumors
poorly demarcated from the surrounding tissue
lack well-defined cleavage plane
slowly expanding malignant tumors may develop an enclosing capsule that may push into normal structures
2 main features that differentiate malignant from benign tumors
development of metastases

invasiveness
carcinoma in situ
preinvasive stage

cytologic features of malignancy without invasion of the basement membrane
metastases
tumor implants discontinuous with the primary tumor

marks tumor as malignant
all cancers can metastasize except
malignant neoplasms of glial cells in CNS- gliomas

basal cell carcinomas of the skin
3 pathways that disseminate cancer
1. direct seeding of body cavities or surfaces

2. lymphatic spread

3. hematogenous spread
3 categories of genetic predisposition to cancer
1. autosomal dominant inherited syndromes
2. defective DNA repair syndromes
3. familial cancers
nonhereditary predisposing conditions to cancer
chronic inflammation

precancerous conditions
molecular basis of cancer
nonlethal genetic damage lies at the heart of carcinogenesis

mutation due to environmental agents (any acquired defect caused by exogenous agents) or inherited in germ line

some mutations are spontaneous and stochastic

a tumor is formed by the clonal expansion of a single precursor cell that has incurred the genetic damage
most common method to determine tumor clonality
analysis of methylating patterns adjacent to the polymorphic locus of the human androgen receptor gene (HUMARA)
4 classes of normal regulatory genes that are the principle targets of genetic damage
1. growth promoting oncogenes (mutants are considered dominant because they transform cells despite normal counterpart)
2. growth inhibiting tumor suppressor genes (both alleles must be damaged)
3.genes that regulate programmed cell death (apoptosis)
4. genes involved in DNA repair
phenotypic attributes of a malignant neoplasm
excessive growth
local invasiveness
ability to form distant metastases

characteristics are acquired- tumor progression
p53
guardian of the genome

most common target for genetic alteration in human tumors

homozygous loss of p53 gene activity can occur in virtually every kind of cancer

in most cases the inactivating mutations affect both p53 alleles and are acquired in somatic cells

sometimes people inherit one mutant p53 gene
7 fundamental changes in cell physiology that determine malignant phenotype
1. self sufficiency in growth signals
2. insensitivity to growth-inhibitory signals
3. evasion of apoptosis
4. defects in DNA repair
5. limitless replicative potential
6. sustained angiogenesis
7. ability to invade and metastasize
steps involved in cell proliferation
1. binding of growth factor to its receptor on the cell membrane
2. transient and limited activation of the growth factor receptor which activates signal transducing proteins
3. transmission of the transduced signal across the cytosol to the nucleus by second messengers or that directly activate transcription
4. induction and activation of nuclear regulatory factors that initiate
DNA transcription
5. entry and progression of the cell into the cell cycle resulting in cell division
tumor suppressor genes
proteins that apply brakes to cell proliferation

regulate cell growth (not prevent tumor formation)

discovered in retinoblasoma
Knudson's "two hit hypothesis"
in hereditary cases:
1 genetic change (1st hit) is inherited from parent and present in all somatic cells

2nd mutation (second hit) occurs in one of retinal cells

sometimes both mutations hit a single retinal cell whose progeny form the tumor
retinoblastoma
60% Sporadic
40% inherited

predisposition autosomal dominant trait
evasion of apoptosis
characteristic of neoplastic cells

BCL2

reduced cell death
3 types of DNA repair
1. mismatch repair
2. nucleotide excision repair
3. recombinant repair

defects in these result in neoplasia
a clock that counts cell divisions
telomere shortening

tumor cells have unrestricted proliferative capacity, maintain telomere length and function

may have defects in cell-cycle checkpoints
sustained angiogenesis
tumors secrete vascular endothelial growth factor (VEGF)

tumors cannot enlarge beyond 1-2mm in diameter unless vascularized
tumor blood vessels
tortuous
irregular shaped
leaky probably due to vascular endothelial growth factor
tumor cells may line structures that resemble capillaries: vasculogenic mimicry
ability to invade and metastasize
metatastic cascade
1. invasion of extracellular matrix

2. vascular dissemination and homing of tumor cells
invasion of extracellular matrix
a. breach basement membrane
b. traverse interstitial CT
c. gain access to circulation
vascular dissemination and homing of tumor cells
vulnerable to destruction by innate and adaptive immune defenses in circulation
b. must adhese to endothelium and pass through BM
c. need adhesion molecules (integrins, laminin receptors, fibronectin) and proteolytic enzymes
organ tropism
1. tumor cells may have adhesion molecules whose ligands are expressed preferentially on endothelial cells of the target organ
2. target organs may liberate chemoattractants that recruit tumor cells to the site
3. the target tissue may be an unpermissive environment for the tumor to grow
type 4 collagen
component of basement membranes
cadherins
cell-cell adhesion