Ch9-EnvNut

7/28/2019 Ch9-EnvNut

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ENVIRONMENTAL

&

NUTRITIONAL

PATHOLOGY


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Environmental and

Nutritional Pathology Environment and Disease

Common Exposures Environmental

Occupational

Nutritionand Disease


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Reported Occupational Diseases

Disease Number Percentage

Repeated trauma 276,600 64

Skin disorders 57,900 13

Lung conditions due to

toxic exposures

20,300 5

Physical injury 16,600 4

Poisoning 5,100 1

Lung disease due todusts 2,900 1

All other illnesses 50,600 12

Total 430,000 100


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Mechanisms of ToxicityThreshold effect

Absorption at portals of entry

ingestion inhalation

skin contact

Distribution within the body Metabolism and Excretion

Toxic effects


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Xenobiotic Mechanisms Phase I Reactions (Smooth ER), makes them

less lipophilic by adding a direct polar group Cytochrome P-450-dependent monooxygenase

system

Flavin-containing monooxygenase system

Peroxidase-dependent cooxidation

Phase II Reactions, combines them with other

polar substances

Glucuronidation

Biomethylation

Glutathione conjugation


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Contents of Toxic Waste Dumps

Acetone DDT, DDE, DDD

Aldrin/Dieldrin 1,1 and 1,2-Dichloroethane

Arsenic Lead

Barium Mercury

Benzene Methylene chloride

2-Butanone Nickel

Cadmium Pentachlorophenol

Carbon tetrachloride Polychlorinated biphenyls

Chlordane Tri- and TetrachloroethyleneChloroform Toluene

Chromium Vinyl Chloride

Cyanide Zinc


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Dose-response Curve


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CommonExposures Personal

Medications

Outdoor Air Pollution

Indoor Air Pollution Industrial Exposures

Agricultural Hazards

Natural Toxins

Radiation Injury

Physical Injury


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Tobacco

440,000 premature deaths/year in USA

cancer

cardiovascular disease

respiratory diseasecerebrovascular disease

$150 billion in health related costsBy far the most preventable cause

of death in the United States


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Tobacco and Cancer

70% of all lung cancers

30% of all cancers


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Organ-Specific Carcinogens in Tobacco Smoke

Organ Carcinogen

Lung, larynx Polycyclic aromatic hydrocarbons

4-(Methylnitrosoamino)-1-(3-pyridyl)-1-buta-none

(NNK)

Polonium 210

Esophagus N'-Nitrosonornicotine (NNN)

Pancreas NNK (?)

Bladder 4-Aminobiphenyl, 2-naphthylamine

Oral cavity (smoking) Polycyclic aromatic hydrocarbons, NNK, NNN

Oral cavity (snuff) NNK, NNN, polonium 210

Data fr om Szczesny LB, H olbrook JH : Cigarette smoking. In Rom WH (ed): Envir onmental

and Occupational Medicine, 2nd ed. Boston, L ittle, Br own, 1992, p. 1211.


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Relative Risks for Current Smokers of Cigarettes

Disease or Condition Males Females

Coronary heart disease

Age 3564 2.8 3.1

Age 65 1.5 1.6

Cerebrovascular lesions

Age 3564 3.3 4

Age 65 1.6 1.5

Aortic aneurysm 6.2 7.1

Chronic airways obstruction 10.6 13.1Cancer

Lip, oral cavity, pharynx 10.9 5.1

Esophagus 6.8 7.8

Stomach 2 1.4

Pancreas 2.3 2.3

Larynx 14.6 13

Lung 23.3 12.7

Cervix 1.6

Kidney 2.7 1.3Bladder, other urinary organs 3.3 2.2


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Cigarettes And The Workplace

Similar to asbestos exposure, cigarette smoke issynergistic with radon decay products in causinglung cancer

Cigarette smoke exacerbates bronchitis, asthma,and pneumoconiosis associated with exposureto silica, coal dust, grain dust, cotton dust, and

welding fumes


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Alcohol 15 to 20 million alcoholics in the USA

100,000 deaths/year due to alcohol

abuse

Economic losses of $100 to $130billion/year

One to two drinks/day reduces

incidence of coronary artery disease** What kind of person would put this kind of bullet on a

powerpoint?

A) Drinker? B) Non-Drinker? C) Alcoholic in Denial?


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Definition of Alcoholism


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Effects of Blood Alcohol Levels in the Absence of Tolerance

Blood Level, mg/dL Usual Effect

20 Decreased inhibitions, a slight

feeling of intoxication

80 Decrease in complex cognitive

functions and motor performance

200 Obvious slurred speech, motor

incoordination, irritability, and

poor judgment

300 Light coma and depressed vital

signs

400 Death

Harrison Internal Med, 16th Ed


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Metabolism Of Ethanol

ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase

20%

80%


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LEGAL INTOXICATION

0 08%


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Widmark Equation C = A / (W * r)

C = concentration of EtOH in mg/dl

A = mass of alcohol ingested in grams density of ethanol = 0.8

W = body weight in grams

r = Widmark distribution for ethanol 0.55 mL/ g body weight for females

0.68 mL / g body weight for males

Elimination of ethanol = 0.015%/h (15mg/dl/h) zero order kinetics

Medical measurements use mg/dl in plasma, whereaslegal definitions use percentage (mass/volume) in wholeblood to estimate the alcohol level in whole blood using the alcohol

level in blood plasma, divide by 1.16


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Alcohol and the Liver Fatty Change

present in over 90% of binge and chronic drinkers liver is enlarged but patient is asymptomatic

changes are reversible with cessation of drinking

macrosteatosis w/o inflammation or necrosis

Alcohol hepatitis only between 10 - 15% of alcoholics will developalcoholic hepatitis

may have systemic symptoms and jaundice

hepatocellular necrosis with Mallory bodies and PMNs

(central hyaline sclerosis) thought to be a precursor of cirrhosis

Alcoholic cirrhosis shrunken nodular liver with uniform small nodules

(micronodular cirrhosis)


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Fatty Change Biochemistry

Catabolism of fat by peripheral tissues isincreased, and there is increased delivery offree fatty acids to the liver

An excess of NADH over NAD stimulates

lipid biosynthesis Oxidation of fatty acids by mitochondria is

decreased

Acetaldehyde forms adducts with tubulin andimpairs function of microtubules, resulting indecreased transport of lipoproteins from theliver


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Neurologic Manifestations of Alcoholism

Wernicke syndrome

confusion, ataxia, and diplopia from

ophthalmoplegia

damage to mammillary bodies, cerebellum and

periaqueductal gray matter of the midbrain due to thiamine deficiency

may respond to prompt thiamine replacement

Korsakov syndrome memory loss and confabulation

results from thiamine deficiency and direct

toxicity


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Mechanisms of Disease Caused by Ethanol Abuse

Organ System Lesion Mechanism

Liver Fatty change Toxicity

Acute hepatitis

Alcoholic cirrhosis

Nervous system Wernicke syndrome Thiamine deficiency

Korsakoff syndrome Toxicity and thiamine

deficiency

Cerebellar degeneration Nutritional deficiency

Peripheral neuropathy Thiamine deficiency

Cardiovascular

system

Cardiomyopathy Toxicity

Hypertension Vasopressor


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Mechanisms of Disease Caused by Ethanol Abuse

Organ System Lesion Mechanism

Gastrointestinal

tract

Gastritis Toxicity

Pancreatitis Toxicity

Skeletal muscle Rhabdomyolysis Toxicity

Reproductive

system

Testicular atrophy ?

Spontaneous

abortion

?

Fetal alcohol

syndrome

Growth retardation Toxicity

Mental retardation

Birth defects

Th ti D


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Therapeutic Drugs

(Medications)Oral Contraceptives (BCPs)

Hormone Replacement Therapy (HRT)Acetaminophen

Aspirin

O l C t ti (BCP )


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Oral Contraceptives (BCPs) Breast cancer and other cancers

no increase in breast cancer

decrease endometrial and ovarian cancers increase in cervical cancer (?lifestyle induced)

Thromboembolic events DVT and Pulmonary Embolism increased

adds to other risk factors (e.g. Factor V Leiden)

Cardiovascular disease with current low estrogen pills, risk of MI and

atherosclerosis not increased in non-smoking women < 45 y

ischemic stroke increased regardless of age or smoking Liver tumors

benign hepatic adenomas

older women with prolonged use

may rupture and cause intra-abdominal bleeding

Hormone Replacement Therapy (HRT)


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Hormone Replacement Therapy (HRT)

Cancer in women with a uterus combined estrogen and

progestin Rx necessary to reduce endometrial cancer

WHI showed increased risk of breast cancer in women

who used HRT combined therapy for 5 years

Thromboembolic events elevated approximated twofold in HRT users, especially

within the first 2 years

Cardiovascular disease WHI reported 29% increased risk of myocardial

infarction, especially during the first year of combined

HRT use


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Acetaminophen (Tylenol)

Does not affect cyclooxygenase so bleeding

associated with aspirin does not occur

Has analgesic and antipyretic actions but no

anti-inflammatory action

Large doses may produce hepatic necrosis

patients should not exceed recommended dose

(4 grams/day)

toxic dose in adults is 15 to 25 gm dose should be reduced in children with fever or

dehydration

Aspirin


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Aspirin

Overdose

respiratory alkalosis followed by metabolic acidosis that

may be fatal

Chronic aspirin toxicity (salicylism)

headache, dizziness, ringing in the ears (tinnitus),

mental confusion, drowsiness, nausea, vomiting, anddiarrhea

Inhibits cyclooxygenase (COX 1 & 2)

Erosive gastritis is a major cause of GI bleeding

May be implicated in Reye syndrome (fatty liver

with encephalopathy) in children < 15 years old,

especially with influenza and chicken pox


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Cox-1 and Cox-2 Inhibitors

Cyclooxygenase 1

constitutively expressed and active in the

normal platelet (thromboxane A2)

involved in synthesis of gastro-protective

prostaglandins

Cyclooxygenase 2

induced, especially in inflamed tissue

in vessel wall produces prostacyclin (PGI2)

Aspirin and other nonselective NSAIDS

inhibit both COX-1 and COX-2


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Figure 2-16 Generation of arachidonic acid metabolites and their roles in inflammation. The molecular

targets of action of some anti-inflammatory drugs are indicated by a red X. COX, cyclooxygenase; HETE,

hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid.

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 August 2005 06:35 PM)

2005 Elsevier

I d Ai P ll ti


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Indoor Air Pollution

Carbon Monoxide CONitrogen Dioxide NO2

Wood SmokeFormaldehyde

RadonManufactured Mineral Fibers

Bioaerosols R d


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Radon

Radon is a radioactive gas and a decay

product of uranium It is widely distributed in the soil and is

prevalent in homes (especially in basements)

Radon decay products are alpha emitters

10% of US homes have levels associated with

an increased risk of lung cancer and an

estimated 10,000 lung cancers per year in theUnited States are due to radon. Smoking

elevates risk.

Proper venting reduces the exposure

L d


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Lead Lead is classified as a heavy metal (others

include mercury, arsenic, and cadmium)

Source of exposure

lead paint

lead solder in plumbing (older houses)

lead-glazed ceramics

industrial exposure

Route of exposure

inhalation with industrial exposure

ingestion with household exposure

L d Di t ib ti d E ti


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Lead Distribution and Excretion

Lead is a divalent cation that is taken up by

bone and developing teeth in children (80%to 85%) Half-life of lead in bone is 30 years

Blood accumulates 5% to 10% of lead, butlead is rapidly cleared from the blood

lead in blood indicates recent exposure

blood level does not allow the determination of

total body burden Remainder is distributed in the soft tissues

Excretion is via the kidneys

Eff t f L d


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Effects of Lead High affinity for sulfhydryl groups

inhibition of heme biosynthesis with hypochromicanemia and basophillic stippling of erythrocytes

Competition with calcium ions

As a divalent cation, lead competes with calcium and is

stored in bone. It also interferes with nerve transmission and brain

development.

Inhibition of membrane-associated enzymes

Lead inhibits 5'-nucleotidase activity and sodium-

potassium ion pumps, leading to decreased survival of

red blood cells (hemolysis), renal damage, and

hypertension.


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Consequences

of lead

exposure


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RADIATION

T Curie vs. Becqerel

IONIZING vs. NON-IONIZING

PARTICULATE vs. NON-PARTICULATE(Photons)

ENERGY: Kev, Mev (~Wavelength)

Linear EnergyTransfer (LET), RelativeBiologic Effect (RBE)

LD50@60d


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This is the single most

RADIOSENSITIVE CELL

In your body

R di ti D i t


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Radiation Dosimetry Roentgen:unit of charge produced by x-rays or gamma

rays that ionize a specific volume of air

RAD(radiation absorbed dose):the dose of radiationthat will produce absorption of 100 ergs of energy per gramof tissue; 1 gm of tissue exposed to 1 roentgen of gammarays is equal to 93 ergs

Gray(Gy): the dose of radiation that will produceabsorption of 1 joule of energy per kilogram of tissue; 1 Gycorresponds to 100 rad (SI unit for absorbed dose)

REM(radiation equivalent man):the dose of radiation thatcauses a biologic effect equivalent to 1 rad of x-rays orgamma rays

Sievert(Sv): the dose of radiation that causes a biologiceffect equivalent to 1 Gy of x-rays or gamma rays; 1 Svcorresponds to 100 rem (SI unit)

A t Eff t f I i i R di ti


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Acute Effects of Ionizing Radiation

Free radical generation Ionizing radiation + H20 H30

+ + OH

DNA Damage double-stranded DNA breaks needed to kill cell

(mammalian cells can repair single strandedbreaks)

cross-linking of DNA strands, cleavage ofsugar-phosphate bonds

Tumor-suppressor genep53activation cell cycle arrest in presence of damaged DNA

repair of DNA damage or apoptosis

Acute Whole Body Radiation


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Acute Whole Body Radiation LD50 @ 6 wks 2.5 to 4.0 Gy (250 to 400 rad)

Hematopoietic 200600 REM

Maximum neutrophil and platelet depression in 2 wk

Gastrointestinal 6001000 REM

Nausea, vomiting, diarrhea

Hemorrhage and infection in 13 wk

Central nervous system >1000 REM

Intractable nausea and vomiting

Confusion, somnolence, convulsions

death in 1436 hr

Th ti R di ti


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Therapeutic Radiation

External radiation is delivered to malignant

neoplasms at fractionated doses up to 40 to70 Gy (4000 to 7000 rad), with shielding of

adjacent normal tissues

Therapeutic radiation alone seems to addlittle risk of AML but can increase the risk in

people exposed to alkylating agents

Fatigue, nausea and vomiting frequent Bone marrow suppression may occur

especially with chest or abdominal radiation

D l d R di ti I j


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Delayed Radiation Injury

Carcinogenesis (atom bomb survivors)

myeloid leukemias peak 5 to 7 years after exposure

breast and thyroid cancers may show greater latency

no germline mutations noted in progeny of survivors

Vascular effects endothelial necrosis followed by intimal and medial

fibrosis

capillaries may become thrombosed and obliterated or

ectatic Parenchymal atrophy and fibrosis


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Radiation effects on TISSUE

ACUTE (vasculitis, possibly fibrinoid necrosis)

CHRONIC (fibrosis)

Physical Injury


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Physical InjuryAbrasion

basically a scrape

superficial epidermis is torn off by friction or force

regeneration without scarring usually occurs

Laceration vs. Incision

a laceration is an irregular tear in the skin produced byoverstretching. The wound margins are frequently hemorrhagicand traumatized

an incision is made by a sharp cutting object. The margins ofthe incision are usually relatively clean

Contusion an injury caused by a blunt force that damages small blood

vessels and causes interstitial bleeding, usually withoutdisruption of the continuity of the tissue (cfecchymosis)


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Adult Mortality Rates in the United States, Ages 2544, in 1998

Rate per 100,000 population

Cause Hispanic Black White

Unintentional injuries 33.4 40.1 31.6

Cancer 16.8 38.0 25.3

Homicide 13.1 36.2 4.7

Human immunodeficiency virus 12.1 43.3 4.8

Heart disease 10.3 43.5 18.3

Suicide 7.8 17.0

Total 130.2 303.7 139.4Data from CDC Fact Book, 2000/2001, Department of Health and Human Services, Centers

for Disease Control and Preventi on.


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GUNSHOT WOUND

Entrance Vs. ExitFar range Vs. Close range

BURNS


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BURNS 1st, 2nd, 3rd, 4th Degree

FULL vs. PARTIAL Thickness

Survival

PERCENT of body using the rule of NINES

DEGREE (i.e., Depth) Respiratory Tract Involvement

AGE

Speed of access to Burn Unit Immune System (Pseudomonas, S. aureus,

Candida)

HYPER


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HYPER-THERMIA HEATCRAMPS: Electrolyte loss via sweat

EXHAUSTION: Water depletion and lack

of cardiovascular compensation

STROKE: Extensive peripheral

vasodilatation, i.e., shocky, very serious,

T>106, over 110 have been reported, high

mortality.

HYPO


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HYPO-THERMIAOften in setting of

homelessness or alcoholism

or both< 90 often fatal, assoc. w.

BRADYCARDIA ATRIAL FIBRILLATION

LIGHTNING/ELECTRICAL


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LIGHTNING/ELECTRICAL ELECTRIC DISTURBANCES

NEURAL EKG

THERMAL INJURY, depends upon a particular

tissues RESISTANCE to electrical flow LIGHTNING MARKS


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ATMOSPHERICPRESSURE

Altitude Illness

Blast Injuries

Decompression Injuries


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ALTITUDE ILLNESS

Caused by LOW Oxygen Tension HIGH ALTITUDES (>4000 m)

OBTUNDATION INCREASED CAPILLARY PERMEABILITYACUTE PULMONARY EDEMA (HAPE)

Q: What is the name of the base camp at Mt. Everest

A: Pulmonary Edema


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BLAST INJURIES

RELATED TO RAPID ATMOSPHERIC

PRESSURE CHANGES

LUNGS

VISCERA, especially GAS filled viscera

Rupture, Hemorrhage, etc.

IMMERSION BLAST also possible,

causing more of a total body compressionsyndrome


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DECOMPRESSION

Related to GAS SOLUBILITY in diversascending rapidly, especially the moreNON-SOLUBLE gasses, like NITROGEN,and, to a lesser extent, XENON

AIR EMBOLISM is the common pathologyACUTE:

BENDS (peri-articular), acute

CHOKES (lungs), acute STAGGERS (inner ear), acute

CHRONIC:ASEPTIC NECROSIS: humeri, femurs

NUTRITION & DISEASE


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NUTRITION& DISEASE Food Safety

Additives

Contaminants

Nutritional DeficienciesVitamins

Minerals

Obesity

Diet and Disease

Chemoprevention of Cancer

Vitamin Deficiency and Excess


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Vitamin Deficiency and Excess Fat soluble vitamins

A, D, E, K readily stored in body fat

poorly absorbed in digestive disorders involvingmalabsorbtion of fat

Water soluble vitamins remaining vitamins

readily excreted in urine

Vitamin storesvitamins B-12 and A: stores sufficient for 1 year

folate and thiamine may become depletedwithin weeks when eating a deficient diet

Vitamin D Metabolism


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Vitamin D Metabolism Absorption of vitamin D in the gut or

synthesis from precursors in the skin Binding to a plasma 1 -globulin (D-

binding protein) and transport to liver

Conversion to 25-hydroxyvitamin D,25(OH)D (calcidol) by 25-hydroxylase in

the liver

Conversion of 25(OH)D to 1,25(OH)2 D(calcitrol, Vitamin D3) by 1-hydroxylase

in the kidney; biologically this is the most

active form of vitamin D.

Functions of Vitamin D


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Functions of Vitamin D

Stimulates intestinal absorption of calcium

and phosphorus

Collaborates with PTH in the mobilization

of calcium from bone

Stimulates the PTH-dependent reabsorption

of calcium in the distal renal tubules

1,25(OH)2 D, the biologically active form ofvitamin D, is best regarded as a steroid

hormone which acts by binding to a high-

affinity receptor


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Vitamin D Deficiency

Holick et al (2005) reported the results of alarge North American study that assessed

the vitamin D status of postmenopausal

women receiving therapy to treat or preventosteoporosis

52% of 1536 women had inadequate

[25(OH)D] levels (


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Vit i D D fi i


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Vitamin D Deficiency

Childhood: Rickets epiphyses are open

cartilage overgrowth

Adults: osteomalacia bone matrix is not calcified

vs osteoporosis (matrix reduced)

ADULTSCHILDREN

(RICKETS)

OSTEOMALACIA1) Bone fractures that happenwith very little injury2) Muscle weakness

3) Widespread bone pain,es eciall in the hi s

Vitamin K


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Vitamin K

Clotting factors VII, IX, and X and

prothrombin (II) all require carboxylation of

glutamate residues for functional activity

anticoagulant coumadin is a Vitamin K

antagonist

Activation of anticoagulant proteins C and S

also requires glutamate carboxylation

Sources

endogenous intestinal bacterial flora

diet

Vitamin K Deficiency


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Vitamin K Deficiency Causes

fat malabsorption reduced gut bacterial flora

administration of wide specturm antibiotics

neonatal period before gut is colonized

liver disease with reduced recycling of vitamin K

Effects of vitamin K deficiency

bleeding diathesis

estimated 3% prevalence of vitamin K-

dependent bleeding diathesis among neonates

warrants routine prophylactic vitamin K therapy

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