altered cells and tissues notes

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.html


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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


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



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Pathophysiology

Cellular adaptation of squamous and columnar

epithelial cells in transformation zone of the cervix



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No signs and symptoms

Risk factors

Early onset sexual activity

Multiple partners (>3)

Exposure to human papillomavirus (HPV)

Smoking



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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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A. Metaplasia A. 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

altered cells and tissues notes

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