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8/13/2019 Altered Cells and Tissues Notes
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Altered Cells and Tissues
Chapter 2, Pathophysiology: A Clinical
ApproachBraun and Anderson
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Module 1
Review of Cellular Structure and
Function
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Which statement is accurate regarding the intra- and extra-
cellular concentrations of sodium and potassium?
A. [Na+]i= 145mM, [Na+]e= 12mM, [K+]i=3.5mM, [K+]e= 160 mM
B. [Na+]i= 12mM, [Na+]e= 145mM, [K+]i =160mM, [K+]e= 3.5 mM
C. [Na+]i= 140mM, [Na+]e= 145mM, [K+]i=16mM, [K+]e= 14 mM
D. [Na+]i= 12mM, [Na+]e= 15mM, [K+]i =160mM, [K+]e= 135 mM
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Which organelle is involved in cellular respiration and
linked to the development of oxidative stress?
A. Endoplasmic reticulum
B. Golgi apparatus
C. LysosomeD. Mitochondria
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What is a peroxisome?
A. Involved in proteolysis of abnormally folded
proteins
B. Membrane-enclosed sac containing oxidases
C. The organelle responsible for producing ATP
D. Prepares cellular products for secretion
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What is the most important
determinant of cell shape?
A. Cytoskeleton
B. Extracellular matrix
C. NucleusD. Plasmalemma
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What process does the image show?
A. Active transport
B. Diffusion
C. Osmosis
D. Facilitated diffusion
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What process does the image show?
A. Primary active
transport
B. Secondary active
transportC. Osmosis
D. Facilitated diffusion
Extracellular space
Na+ Glutamate
Intracellular space
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What else could this be called?
A. Carrier transport
B. Antiport
C. Facilitated diffusion
D. Symport
Extracellular space
Na+ Glutamate
Intracellular space
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What is the ATP-dependent process that results in the
ingestion of small vesicles?
A. Phagocytosis
B. Exocytosis
C. PinocytosisD. Endocytosis
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Give an example of a negative feedback
pathway
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Module 2
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Cellular Stress
Positive stressors
Adaptation
Negative stressors
Death
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Cellular Adaptations
Occur in response to signals Chemical
Hormones
Cytokines
Mechanical Stretch
Pressure
Shear
Humoral
Temperature Or to a lack of signaling
Apoptosis
Atrophy
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Atrophy
Decreased cell size
-trophy
Relating to maintenance
of function
Related to loss of
signaling
Neural, endocrine,
mechanical, etc.
Cellular atrophy can lead
to tissue involution
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Why does muscle atrophy occur
following spinal cord injury?
Muscular disuse
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Hypertrophy
Greater functioning
Cell enlargement
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The -plasias -plasia from the same rootas plastic
To change
Hyperplasia
To change more
Increase in cell number
Mitosis
Metaplasia
To change into somethingdifferent
Change in cell subtype (e.g.simple to stratified)
same type (e.g. epithelium)
Dysplasia
To change into somethingdysfunctional
Change in shape, size,number, function
Often due to geneticmutation
May be precancerous cells
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Dysplasia
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Module 3
Cellular Injury and Death
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Mechanisms of Cell Death
Apoptosis
Pronounced -pa-tosis
The pt is like
pterodactyl
Programmed cell death
Crucial for proper fetal
development
Neat and tidy
No cellular debris
*No inflammation
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Process of Apoptosis
Cell begins to shrink following cleavage of cytoskeleton
Breakdown of nuclear chromatin often leads to nuclearcondensation Nuclei may take on horseshoe shape
Cells continue to shrink, packaging themselves into a form
that allows removal by macrophages Phagocytes clear apoptotic cells in a clean and tidy fashion
Avoids inflammation
Plasma membrane changes trigger macrophage response Translocation of phosphatidylserine from inner side of membrane to
outer side End stages of apoptosis are often characterized by
appearance of membrane blebs Small vesicles called apoptotic bodies are also sometimes
observed
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Mechanisms of Apoptosis
Intracellular signals
Extracellular death activatorsbinding to
receptors at the cell surface
Apoptosis-Inducing Factor (AIF)
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Caspase Pathways Intrinsic pathwaymitochondria mediated;
caspase 9 Extrinsic pathwayinvolves death receptors
(TNFR, Fas); caspase 8
Converge to active executioner caspases 3 and 7
Hail et al. Apoptosis (2006)
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Apoptosis Triggered by Internal Signals
Cytochrome c leaks out
Cytochrome c binds to Apaf-1
apoptotic protease activating
factor-1
Complexes aggregate to form
apoptosomes
Bind to and activate caspase-9
Intrinsic or mitochondrial pathway
Outer mitochondrial membranes
display anti-apoptotic Bcl-2 proteins
Cellular stress causes pro-apoptotic
Bcl-2 proteins in cytosol to bind
mitochondrial Bcl-2s
Activation of Bax
Bax creates holes in outer
mitochondrial membrane
Permeability Transition (PT) pore
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Caspases
Over a dozen
Proteases Cleave proteins at aspartic acid residues
Other caspases most common targets
Caspase cascade
Caspase-9 Caspase-3 and -7 targets
Executioner" caspases
cascade of proteolytic activity digestion of cytoplasmic proteins
degradation of chromosomal DNA
phagocytosis of the cell
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p53
Product of tumor suppressor gene p53
Prevents cell from completing cell cycle if cell is damaged
Dose response Minor damage, p53 halts cell cycle until damage is repaired
Major damage, p53 triggers apoptosis
Key in protection against cancer Tumor suppressor
More than half of human cancers harbor p53 mutations
Mice cured of cancer by production of p53 in tumor cells
Excess production of p53 protein leads to accelerated aging
Mice expressing high levels of the anti-aging protein Sirt1 have productionof p53 depressed and are more susceptible to cancer
Under physiological conditions, p53 seems to protect against both cancerand aging protection from oxidative damage?
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Apoptosis Triggered by External Signals
Extrinsic or death receptor pathway
Fas and TNFR integral membrane proteins
Binding of ligand transmits signal to cytoplasm that
activates caspase 8
Caspase 8 initiates cascade of caspase activation Initiator caspase
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Apoptosis triggered by external
signals Cytotoxic T cells
bind target
produce moreFasL
binds with Fas on
target cell leading
to apoptosis
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Apoptosis-Inducing Factor (AIF)
Neurons
Caspase-independent mechanism
AIF normally located in intermembrane space of
mitochondria When cell receives death signal
AIF released from mitochondria
Migrates into nucleus
Binds to DNA Triggers destruction of DNA
Initiated by oxidative damage?
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IAP = inhibitor of apoptosis proteins
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Apoptosis and Cancer
Some viruses prevent apoptosis of cells they
have transformed
Several HPV have been implicated in cervical cancer
One produces protein (E6) that binds and inactivates p53
Epstein-Barr Virus (EBV)
Mononucleosis and some lymphomas
Produces protein similar to anti-apoptotic Bcl-2
Produces another protein that causes cell to increaseproduction of anti-apoptotic Bcl-2
Both make cells more resistant to apoptosis
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Apoptosis and CancerB-cell leukemias and lymphomas express high levels of Bcl-2s
Block apoptotic signals
Translocation of BCL-2 gene into enhancer region for antibodyproduction
Melanoma cells inhibit expression of Apaf-1 gene
Some cancer cells secrete elevated levels of "decoy" molecule that bindsFasL
Bound FasL cannot bind Fas
Cytotoxic T cells (CTL) cannot kill these cancerous cells
Especially lung and colon cancer cells
Other cancer cells express high levels of FasL
Kill CTL
CTL also express Fas protected from their own FasL
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Apoptosis and the Immune System
The immune response to a foreign invaderinvolves the proliferation of lymphocytes
T and/or B cells
When job is done, must die off leaving a smallpopulation of memory cells
Apoptosis
Genetic defects in apoptosis
Rare
Most common are mutations in Fas gene
FasL gene or caspases
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Apoptosis and the Immune System
Autoimmune lymphoproliferative syndrome (ALPS) Accumulation of lymphocytes in lymph nodes and spleen
Appearance of clones that are autoreactive Autoimmune disorders
Hemolytic anemia
Thrombocytopenia
Lymphoma
Cancerous clone of lymphocytes.
In most patients, mutation is present in germline every cell carries it
In a few cases mutation is somatic In a precursor cell in bone marrow
Genetic mosaics some lymphocytes undergo apoptosis normally, others that do not
The latter tend to out-compete and become major population inlymph nodes and blood
A t i d AIDS
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Allergies.htmlhttp://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Allergies.html8/13/2019 Altered Cells and Tissues Notes
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Apoptosis and AIDS
Acquired immunodeficiency syndrome
Decline in number of CD4+ T cells Responsible, directly or indirectly, for all immune responses.
HIV (human immunodeficiency virus)
Invades CD4+ T cells Fewer than 1 in 100,000 CD4+ T cells in blood actually
infected
What kills so many uninfected CD4+ cells?
Apoptosis
Mechanism unclear
All T cells, both infected and uninfected, express Fas
Expression of a HIV gene, Nef
Cell expresses high levels of FasL at its surface
When infected T cell encounters uninfected one the interaction
of FasL with Fas on the uninfected cell
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Apoptosis and Organ Transplants
Certain parts of body are "immunologically privileged Anterior chamber of eye
Testes
Antigens fail to elicit immune response
Cells express high levels of FasL at all times Antigen-reactive T cells killed when they enter
Graft-Versus-Host Disease
If transplanted organ cells could be made to express highlevels of FasL, might protect graft from attack by host Tcells
Animal results mixed Allografts engineered to express FasL have shown increased
survival for kidneys but not for hearts or islets of Langerhans
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Mechanisms of Cell Death
Necrosis
Disorderly and messy
Cellular debris initiate
inflammation
Lack of metabolism
means loss of ATP
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What is most ATP used for in
cells?Na/K Pump
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If ions move, what else moves?
Current / HO
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If a cell cannot manage water
hydropic degeneration occurs.
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Causes of Cellular Damage
TIPS
Toxins
Infections
Physical injury Serum deficits
Oxidative stress
Free radicals of oxygen Reactive oxygen species
(ROS)
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Reactive Oxygen Species
Reaction between O2 andwater
Mitochondria
Then reactions with
molecules containing largeamounts of hydrogen
Lipids and proteins
Superoxide (O2-)
Hydrogen peroxide (H2O2)
Hydroxyl radical (OH)
Peroxynitrite (ONOO-)
ROS removed by enzymes Catalase
H2O2H2O + O2
Superoxide dismutase(SOD)
Removes extra electron anddonates it to a metal ion
Peroxidase
Antioxidants
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Module 4
Clinical Models
li i f h f
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Application of the Concepts of
Alterations in Cells and Tissues
Cerebral Atrophy
Cardiac Hypertrophy
Acromegaly
Cervical Metaplasia and Dysplasia
Air Pollution and Cardiovascular Disease
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Cerebral Atrophy Pathophysiology
Reduction in size of
the cells in the
cerebrum of the brain
Progressive reductionin the size of the
neurons
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Atrophy
Cerebral atrophy
Neuronal death resulting in loss of cerebral volume
Alzheimers, TBI, Cerebral infarction (stroke), Multiplesclerosis, Parkinsonism, Huntingtons
Global or focal
Symptoms depend
on location
Recovery often limited bylow mitotic activity of
adult neurons
AD Typical aging
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Atrophy
Muscular atrophy
Disuse
Co-morbidity of several diseases
cancer, AIDS, congestive heart failure, COPD, renalfailure, and severe burns
Cachexia
Body-wasting associated with cancer, AIDS and
other diseases Starvation
Denervation or loss of neural stimulation
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Cardiac Hypertrophy Pathophysiology
Increased myocardial
mass
Etiology
Excessive cardiacworkload
Increased functional
demand
Inherited genetic trait
C di H t h P th h i l
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Cardiac Hypertrophy Pathophysiology
Categories Primary
Inherited non-sex-linked genetic trait
Secondary Response to increased LV workload
Myocyte hypertrophy
C di H t h
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Cardiac Hypertrophy
Clinical Manifestations
Variable
Mild to severe
Shortness of breath
Syncope
Impaired cardiac function
C di H t h
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Cardiac Hypertrophy
Diagnostic Criteria
Genetic testing
Hypertension
Reduced exercise tolerance
Ventricular arrhythmia
Altered conduction or conduction cell activity
Heart murmur
C di H t h
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Cardiac Hypertrophy
Treatment
Surgical
Pharmacologic
drugs that relax ventricles
Drugs that reduce cardiac work
Decrease pressure that the heart must pump against
Afterload
Non-pharmacologic activity restriction
A l
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Acromegaly
Pathophysiology
Acro-, tip or extremity
-megaly, great or large
Condition of cellular
hyperplasia Results from excessive
hormonal stimulation
Pituitary
Growth hormone Liver
Insulin-like growth
factor-1 (IGF-1)
A l
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Acromegaly
Pathophysiology
Leads to excessive growth
Bones, cartilage, soft tissues, organs
Occurs after epiphyseal plate closure
Acromegaly
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Acromegaly
Clinical Manifestations
Mostly related to CTgrowth
Soft tissue swelling
Altered facial features
Pain and numbness inhands
Voice deepening
Snoring
Skin changes
Altered reproductivefunction
Acromegaly
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Acromegaly
Diagnostic Criteria
History and physical examination
Laboratory analysis
Glucose tolerance test
Growth hormone
IGF-1
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Acromegaly Treatment
Pharmacologic
Drugs to reduced growth hormone secretion
Nonpharmacologic
Radiation therapy to promote death in growth
hormone hyper-secreting cells
Surgical
Removal of tumor (adenoma) causing
hypersecretion of growth hormone
Cervical Metaplasia and Dysplasia
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Cervical Metaplasia and Dysplasia
Pathophysiology
Cellular adaptation of squamous and columnar
epithelial cells in transformation zone of the cervix
Cervical Metaplasia and Dysplasia
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Cervical Metaplasia and Dysplasia
Clinical Manifestations
No signs and symptoms
Risk factors
Early onset sexual activity
Multiple partners (>3)
Exposure to human papillomavirus (HPV)
Smoking
Cervical Metaplasia and Dysplasia
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Cervical Metaplasia and Dysplasia
Diagnostic Criteria
History and physical examination
Screening tests
Microscopic examination of transformation zone
cells
HPV screening
Diagnostic tests
Biopsy of cervical tissue for microscopic
examination
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Cervical Metaplasia and Dysplasia
A. Metaplasia A. Dysplasia
Cervical Metaplasia and Dysplasia
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p y p
Treatment
Risk reduction
Elimination of damaged cells
Cold therapy
Surgical excision
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Environmental Toxins
Mercury Poisoning
Mercury Poisoning
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Mercury Poisoning
Mercury Three forms
Elemental metallic
Liquid at room temp.
Inorganic Ionic
Hg2+
Organic
Bound to an organic
compund
E.g. Methyl
groupmethyl
mercury
Chemistry determineseffect
Mercury Poisoning
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Mercury Poisoning Elemental mercury (Hg)
Easily vaporizes
well absorbed (80%)through inhalation
Lipid-soluble
easy passage into RBCs
Mercury Poisoning
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Mercury Poisoning Elemental mercury (Hg)
Mostly converted to an
inorganic divalent or mercuricform by catalase
Inorganic mercury
poor lipid solubility, limited
permeability to the blood
brain barrier, and excretion
in feces
Small amounts of nonoxidized
elemental mercury persist
Central nervous system
toxicity.
Elemental mercury as a vapor
can penetrate CNS
Ionized and trapped
Significant toxic effects
Not well absorbed by GI tract
only mildly toxic when
ingested
Mercury Poisoning
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y g
Inorganic mercury
Highly toxic and corrosive
Found mostly as mercuric salt
batteries
Orally or dermal sources
~10% absorption
Nonuniform mode of distribution
Poor lipid solubility Renal accumulates
Limited acute CNS penetration
However, slow elimination and chronic
exposure allow for significant CNS
accumulation of mercuric ions and
subsequent toxicity
Long-term dermal exposure to inorganicmercury may also lead to toxicity
Excretion mostly fecal
Renal excretion insufficient
Chronic exposure and accumulation
within brain
Mercury Poisoning
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y g
Organic mercury
3 forms
Aryl-
Short chain alkyl compounds
Long chain alkyl compounds
Absorbed more completely in GI than
inorganic salts
Higher lipid solubility and mild corrosiveness
Once absorbed
Aryl and long chain alkyl compounds
Converted to inorganic forms
Similar toxic properties to inorganic
mercury
Short chain alkyl mercurials
Methyl-mercury (CH3-Hg)
Stable and readily absorbed in GI (90-95%)
high lipid solubility
Distributed uniformly
Accumulates in brain, kidney, liver,
hair, skin
Mercury Poisoning
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Once absorbed
Short chain alkyl mercurials
Methyl-mercury (CH3-Hg)
Stable and readily absorbed in GI(90-95%)
high lipid solubility
Distributed uniformly
Accumulates in brain, kidney, liver,hair, skin
Cross blood brain barrier, placentaand erythrocytes
Neurological symptoms
Teratogenic
High blood to plasma ratio
Mercury Poisoning
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y g
Methyl-mercury
High affinity for sulfhydryl groups
Enzyme dysfunction
Choline acetyl transferase
Acetylcholine production
Acetylcholine deficiency
Motor dysfunction
Fecal excretion dominant (~90%)
Biological half-life of methyl-mercury ~ 65 days
Organic mercury is found most commonly inantiseptics, fungicides, and industrial run-off
Mercury Poisoning - Effects
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Depend on nature, intensity,
and chemical form.
Acute exposure to inhaled
elemental mercury
Pulmonary symptoms
fever, chills, shortness of breath,
metallic taste, and pleuritic chest
pain
Maybe stomatitis (oral
inflammation/ulceration)
Complications
interstitial emphysema,
pneumatocele, pneumothorax,
pneumomediastinum, and
interstitial fibrosis.
Chronic and intense acuteexposure
Cutaneous and neurologicalsymptoms.
Classic triad
Tremors, gingivitis, and erethism
Insomnia, shyness, memory loss,
emotional instability, depression,anorexia, vasomotor disturbance,uncontrolled perspiration, andblushing)
In elderly
Mercury toxicity can bemisdiagnosed
Parkinsons, senile dementia,metabolic encephalopathy,depression, or Alzheimer disease
Mercury Poisoning-Effects
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Mercury Poisoning Effects Inorganic mercury or mercuric
salt exposure mainly occurs
through GI Renal failure, dementia,
acrodynia Pink disease, mercury allergy
Organic mercury poisoning
Ingestion of contaminated food Delayed onset - enzyme
depletion
Neurological symptoms Accumulates in
Cerebral cortex
especially visual cortex Motor and sensory centers
cerebellum, precentral
and postcentral cortex
Auditory center
temporal cortex
All forms of mercury are
toxic to the fetus Methyl-mercury most
readily passes through
placenta.
Maternal exposure canlead to spontaneous
abortion or retardation
Even with asymptomatic
patient