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ENVIRONMENTENVIRONMENTALAL
&&
NUTRITIONAL NUTRITIONAL
PATHOLOGYPATHOLOGY
Environmental andEnvironmental andNutritional PathologyNutritional Pathology
Environment and DiseaseEnvironment and Disease
Common Common ExposuresExposures EnvironmentalEnvironmental OccupationalOccupational
NutritionNutrition and Diseaseand Disease
Reported Occupational Diseases Reported Occupational Diseases
DiseaseDisease NumbeNumberr
PercentagePercentage
Repeated traumaRepeated trauma 276,60276,6000
6464
Skin disordersSkin disorders 57,90057,900 1313
Lung conditions Lung conditions due to toxic due to toxic exposuresexposures
20,30020,300 55
Physical injuryPhysical injury 16,60016,600 44
PoisoningPoisoning 5,1005,100 11
Lung disease due Lung disease due to duststo dusts
2,9002,900 11
All other illnessesAll other illnesses 50,60050,600 1212
TotalTotal 430,00430,0000
100100
Mechanisms of ToxicityMechanisms of Toxicity ThresholdThreshold effect effect AbsorptionAbsorption at portals of entry at portals of entry
ingestioningestion inhalationinhalation skin contactskin contact
DistributionDistribution within the body within the body MetabolismMetabolism and and ExcretionExcretion ToxicToxic effects effects
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
Dose-response Curve Dose-response Curve
CommonCommon ExposuresExposures PersonalPersonal MedicationsMedications Outdoor Air PollutionOutdoor Air Pollution Indoor Air PollutionIndoor Air Pollution Industrial ExposuresIndustrial Exposures Agricultural HazardsAgricultural Hazards Natural ToxinsNatural Toxins Radiation InjuryRadiation Injury Physical InjuryPhysical Injury
TobaccoTobacco 440,000 premature deaths/year in 440,000 premature deaths/year in
USAUSAcancercancercardiovascular disease cardiovascular disease respiratory diseaserespiratory diseasecerebrovascular diseasecerebrovascular disease
$150 billion in health related costs$150 billion in health related costs
By far By far the most preventable the most preventable cause of death in the United Statescause of death in the United States
Tobacco and Cancer70% of all lung cancers (sc,Nsc)
30% of all cancers
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 from Szczesny LB, Holbrook JH: Cigarette smoking. In Rom WH (ed): Environmental and Occupational Medicine, 2nd ed. Boston, Little, Brown, 1992, p. 1211.
Relative Risks for Current Smokers of CigarettesRelative Risks for Current Smokers of Cigarettes
Disease or Condition Males Males Females Females
Coronary heart disease Coronary heart disease
Age 35–64Age 35–64 2.82.8 3.13.1
Age ≥ 65Age ≥ 65 1.51.5 1.61.6
Cerebrovascular lesions Cerebrovascular lesions
Age 35–64Age 35–64 3.33.3 44Age ≥ 65Age ≥ 65 1.61.6 1.51.5
Aortic aneurysmAortic aneurysm 6.26.2 7.17.1
Chronic airways obstructionChronic airways obstruction 10.610.6 13.113.1Cancer Cancer
Lip, oral cavity, pharynxLip, oral cavity, pharynx 10.910.9 5.15.1
EsophagusEsophagus 6.86.8 7.87.8
StomachStomach 22 1.41.4
PancreasPancreas 2.32.3 2.32.3
LarynxLarynx 14.614.6 1313
LungLung 23.323.3 12.712.7
Cervix Cervix 1.6 1.6
KidneyKidney 2.72.7 1.31.3
Bladder, other urinary Bladder, other urinary organsorgans
3.33.3 2.22.2
Cigarettes And The WorkplaceCigarettes And The Workplace
Cigarette smoke exacerbates Cigarette smoke exacerbates bronchitis, asthma, and bronchitis, asthma, and pneumoconiosis associated with pneumoconiosis associated with exposure to silica, coal dust, grain exposure to silica, coal dust, grain dust, cotton dust, and welding dust, cotton dust, and welding fumesfumes
AlcoholAlcohol 15 to 20 million alcoholics in 15 to 20 million alcoholics in
the USAthe USA 100,000 deaths/year due to 100,000 deaths/year due to
alcohol abusealcohol abuse Economic losses of $100 to Economic losses of $100 to
$130 billion/year$130 billion/year
Definition of Alcoholism
?
Effects of Blood Alcohol Levels in the Absence of ToleranceEffects of Blood Alcohol Levels in the Absence of Tolerance Blood Level, mg/dLBlood Level, mg/dL Usual EffectUsual Effect
2020 Decreased inhibitions, a Decreased inhibitions, a slight feeling of slight feeling of intoxication intoxication
8080 Decrease in complex Decrease in complex cognitive functions and cognitive functions and motor performance motor performance
200200 Obvious slurred speech, Obvious slurred speech, motor incoordination, motor incoordination, irritability, and poor irritability, and poor judgment judgment
300300 Light coma and depressed Light coma and depressed vital signs vital signs
400400 Death Death Harrison Internal Med, 16th Ed
LEGAL INTOXICATION
0.08%
Alcohol and the LiverAlcohol and the Liver Fatty ChangeFatty Change
present in over 90% of binge and chronic present in over 90% of binge and chronic drinkersdrinkers
liver is enlarged but patient is asymptomaticliver is enlarged but patient is asymptomatic changes are reversible with cessation of changes are reversible with cessation of
drinkingdrinking macrosteatosis w/o inflammation or necrosismacrosteatosis w/o inflammation or necrosis
Alcohol hepatitisAlcohol hepatitis only between 10 - 15% of alcoholics will develop only between 10 - 15% of alcoholics will develop
alcoholic hepatitisalcoholic hepatitis may have systemic symptoms and jaundicemay have systemic symptoms and jaundice hepatocellular necrosis with Mallory bodies and hepatocellular necrosis with Mallory bodies and
PMNs (central hyaline sclerosis)PMNs (central hyaline sclerosis) thought to be a precursor of cirrhosis, 10-25% thought to be a precursor of cirrhosis, 10-25%
of A.H. will go to cirrhosis of A.H. will go to cirrhosis Alcoholic cirrhosisAlcoholic cirrhosis
shrunken nodular liver with uniform small shrunken nodular liver with uniform small nodules (micronodular cirrhosis)nodules (micronodular cirrhosis)
Fatty Change BiochemistryFatty Change Biochemistry Catabolism of fat by peripheral tissues Catabolism of fat by peripheral tissues
is increased, and there is increased is increased, and there is increased delivery of free fatty acids to the liverdelivery of free fatty acids to the liver
An excess of NADH over NAD An excess of NADH over NAD stimulates lipid biosynthesisstimulates lipid biosynthesis
Oxidation of fatty acids by Oxidation of fatty acids by mitochondria is decreasedmitochondria is decreased
Acetaldehyde forms adducts with Acetaldehyde forms adducts with tubulin and impairs function of tubulin and impairs function of microtubules, resulting in decreased microtubules, resulting in decreased transport of lipoproteins from the transport of lipoproteins from the liverliver
Neurologic Manifestations of AlcoholismNeurologic Manifestations of Alcoholism Wernicke syndromeWernicke syndrome
confusion, ataxia, and diplopia from confusion, ataxia, and diplopia from ophthalmoplegiaophthalmoplegia
damage to damage to mammillary bodiesmammillary bodies, , cerebellumcerebellum and and periaqueductal gray periaqueductal gray matter matter of the midbrainof the midbrain
due to thiamine deficiencydue to thiamine deficiency may respond to prompt thiamine may respond to prompt thiamine
replacementreplacement
Korsakov syndromeKorsakov syndrome memory loss and confabulationmemory loss and confabulation results from thiamine deficiency and results from thiamine deficiency and
direct toxicitydirect toxicity
Mechanisms of Disease Caused by Ethanol AbuseOrgan 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
Mechanisms of Disease Caused by Ethanol AbuseOrgan 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
Therapeutic DrugsTherapeutic Drugs(Medications)(Medications)
Oral Contraceptives (BCPs)Oral Contraceptives (BCPs)Hormone Replacement Hormone Replacement
Therapy (HRT)Therapy (HRT)AcetaminophenAcetaminophenAspirinAspirin
Oral Contraceptives (BCPs)Oral Contraceptives (BCPs)
Increased risk of cervical cancer. Decreased ovarian Increased risk of cervical cancer. Decreased ovarian and endometrial cancer.and endometrial cancer.
Thromboembolic events Thromboembolic events DVT and Pulmonary Embolism increasedDVT and Pulmonary Embolism increased adds to other risk factors (e.g. Factor V Leiden)adds to other risk factors (e.g. Factor V Leiden)
Cardiovascular diseaseCardiovascular disease with current low estrogen pills, risk of MI and with current low estrogen pills, risk of MI and
atherosclerosis not increased in non-smoking atherosclerosis not increased in non-smoking women < 45 ywomen < 45 y
ischemic stroke increased regardless of age or ischemic stroke increased regardless of age or smokingsmoking
Liver tumorsLiver tumors benign hepatic adenomas benign hepatic adenomas older women with prolonged useolder women with prolonged use may rupture and cause intra-abdominal bleeding may rupture and cause intra-abdominal bleeding
Hormone Replacement Therapy (HRT)Hormone Replacement Therapy (HRT)
Cancer Cancer in women with a uterus combined estrogen in women with a uterus combined estrogen
and progestin Rx necessary to reduce and progestin Rx necessary to reduce endometrial cancerendometrial cancer
WHI showed WHI showed increased risk of breast cancer increased risk of breast cancer in women who used HRT combined therapy in women who used HRT combined therapy for 5 years for 5 years
Thromboembolic eventsThromboembolic events elevated approximated twofold elevated approximated twofold in HRT in HRT
users, especially within the first 2 years users, especially within the first 2 years
Cardiovascular diseaseCardiovascular disease WHI reported WHI reported 29% increased risk of 29% increased risk of
myocardial infarctionmyocardial infarction, especially during the , especially during the first year of combined HRT use first year of combined HRT use
Acetaminophen (Tylenol)Acetaminophen (Tylenol) Does not affect cyclooxygenase so Does not affect cyclooxygenase so
bleeding associated with aspirin does bleeding associated with aspirin does not occurnot occur
Has Has analgesic and antipyretic actions analgesic and antipyretic actions but no anti-inflammatory actionbut no anti-inflammatory action
Large doses may produce Large doses may produce hepatic hepatic necrosisnecrosis patients should not exceed patients should not exceed
recommended dose (4 grams/day)recommended dose (4 grams/day) toxic dose in adults is 15 to 25 gmtoxic dose in adults is 15 to 25 gm dose should be reduced in children with dose should be reduced in children with
fever or dehydration fever or dehydration
AspirinAspirin
Chronic aspirin toxicity (salicylism) Chronic aspirin toxicity (salicylism) headache, dizziness, ringing in the ears headache, dizziness, ringing in the ears
((tinnitustinnitus), mental confusion, drowsiness, ), mental confusion, drowsiness, nausea, vomiting, and diarrheanausea, vomiting, and diarrhea
Inhibits cyclooxygenases (COX 1 & 2)Inhibits cyclooxygenases (COX 1 & 2) Erosive gastritis is a major cause of Erosive gastritis is a major cause of
GI bleedingGI bleeding May be implicated in Reye syndrome May be implicated in Reye syndrome
(fatty liver with encephalopathy) in (fatty liver with encephalopathy) in children < 15 years old, especially children < 15 years old, especially with influenza and chicken poxwith influenza and chicken pox
Cox-1 and Cox-2 InhibitorsCox-1 and Cox-2 Inhibitors Cyclooxygenase 1 (inhib of COX-1 is Cyclooxygenase 1 (inhib of COX-1 is
BADBAD)) constitutively expressed and active in the constitutively expressed and active in the
normal platelet (thromboxane A2)normal platelet (thromboxane A2) involved in synthesis of gastro-protective involved in synthesis of gastro-protective
prostaglandins prostaglandins Cyclooxygenase 2 (inhib of COX-2 is Cyclooxygenase 2 (inhib of COX-2 is
GOODGOOD)) induced, especially in inflamed tissueinduced, especially in inflamed tissue in vessel wall produces prostacyclin (PGIin vessel wall produces prostacyclin (PGI22))
Aspirin and other nonselective NSAIDS Aspirin and other nonselective NSAIDS inhibit both COX-1 and COX-2 inhibit both COX-1 and COX-2
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
Indoor Air PollutionIndoor Air PollutionCarbon Monoxide COCarbon Monoxide CONitrogen Dioxide NONitrogen Dioxide NO22 ( (from acid from acid
rainrain))Wood SmokeWood SmokeFormaldehydeFormaldehydeRadonRadonManufactured Mineral FibersManufactured Mineral FibersBioaerosolsBioaerosols
LeadLead Lead is classified as a heavy metal Lead is classified as a heavy metal
(others include mercury, arsenic, (others include mercury, arsenic, and cadmium)and cadmium)
Source of exposureSource of exposure lead paintlead paint lead solder in plumbing (older houses)lead solder in plumbing (older houses) lead-glazed ceramicslead-glazed ceramics industrial exposureindustrial exposure
Route of exposureRoute of exposure inhalation with industrial exposureinhalation with industrial exposure ingestion with household exposureingestion with household exposure
Lead Distribution and ExcretionLead Distribution and Excretion Lead is taken up by bone and Lead is taken up by bone and
developing teeth in children (80% to developing teeth in children (80% to 85%)85%) Half-life of lead in bone is 30 yearsHalf-life of lead in bone is 30 years
Blood accumulates 5% to 10% of lead, Blood accumulates 5% to 10% of lead, but lead is rapidly cleared from the but lead is rapidly cleared from the bloodblood lead in blood indicates recent exposurelead in blood indicates recent exposure blood level does not allow the blood level does not allow the
determination of total body burden determination of total body burden Remainder is distributed in the soft Remainder is distributed in the soft
tissuestissues Excretion is via the kidneysExcretion is via the kidneys
Effects of LeadEffects of Lead High affinity for sulfhydryl groupsHigh affinity for sulfhydryl groups
inhibition of heme biosynthesis with hypochromic inhibition of heme biosynthesis with hypochromic anemia and basophillic stippling of erythrocytesanemia and basophillic stippling of erythrocytes
Competition with calcium ionsCompetition with calcium ions As a divalent cation, lead competes with calcium As a divalent cation, lead competes with calcium
and is stored in bone. and is stored in bone. It also interferes with nerve transmission and It also interferes with nerve transmission and
brain development. brain development.
Inhibition of membrane-associated Inhibition of membrane-associated enzymesenzymes Lead inhibits 5'-nucleotidase activity and sodium-Lead inhibits 5'-nucleotidase activity and sodium-
potassium ion pumps, leading to decreased potassium ion pumps, leading to decreased survival of red blood cells (hemolysis), renal survival of red blood cells (hemolysis), renal damage, and hypertension. damage, and hypertension.
Consequences of lead exposure
Acute Effects of Ionizing RadiationAcute Effects of Ionizing Radiation Free radical generationFree radical generation
Ionizing radiation + HIonizing radiation + H220 → H0 → H3300++ + OH· + OH· DNA DamageDNA Damage
double-stranded DNA breaks needed to double-stranded DNA breaks needed to kill cell (mammalian cells can repair kill cell (mammalian cells can repair single stranded breaks)single stranded breaks)
cross-linking of DNA strands, cleavage cross-linking of DNA strands, cleavage of sugar-phosphate bondsof sugar-phosphate bonds
Tumor-suppressor gene Tumor-suppressor gene p53p53 activationactivation cell cycle arrest in presence of cell cycle arrest in presence of
damaged DNAdamaged DNA repair of DNA damage or apoptosisrepair of DNA damage or apoptosis
Acute Whole Body RadiationAcute Whole Body Radiation LD50 @ 6 wks 2.5 to 4.0 Gy (250 to 400 LD50 @ 6 wks 2.5 to 4.0 Gy (250 to 400
rad)rad) HematopoieticHematopoietic
200–600 REM200–600 REM Maximum neutrophil and platelet depression Maximum neutrophil and platelet depression
in 2 wk in 2 wk GastrointestinalGastrointestinal
600–1000 REM600–1000 REM Nausea, vomiting, diarrhea Nausea, vomiting, diarrhea Hemorrhage and infection in 1–3 wkHemorrhage and infection in 1–3 wk
Central nervous systemCentral nervous system >1000 REM>1000 REM Intractable nausea and vomitingIntractable nausea and vomiting Confusion, somnolence, convulsions Confusion, somnolence, convulsions death in 14–36 hrdeath in 14–36 hr
Therapeutic RadiationTherapeutic Radiation External radiation is delivered to External radiation is delivered to
malignant neoplasms at malignant neoplasms at fractionated doses up to 40 to 70 fractionated doses up to 40 to 70 Gy (4000 to 7000 rad), with Gy (4000 to 7000 rad), with shielding of adjacent normal shielding of adjacent normal tissues tissues
Fatigue, nausea and vomiting Fatigue, nausea and vomiting frequentfrequent
Bone marrow suppression may Bone marrow suppression may occur especially with chest or occur especially with chest or abdominal radiationabdominal radiation
Delayed Radiation InjuryDelayed Radiation Injury Carcinogenesis (atom bomb survivors)Carcinogenesis (atom bomb survivors)
myeloid leukemias peak 5 to 7 years myeloid leukemias peak 5 to 7 years after exposureafter exposure
breast and thyroid cancers may show breast and thyroid cancers may show greater latency greater latency
Vascular effectsVascular effects endothelial necrosis followed by endothelial necrosis followed by
intimal and medial fibrosis, often the intimal and medial fibrosis, often the endothelial cells look quite plump and endothelial cells look quite plump and atypical, as do the fibroblasts!atypical, as do the fibroblasts!
capillaries may become thrombosed capillaries may become thrombosed and obliterated or ectaticand obliterated or ectatic
Parenchymal atrophy and fibrosisParenchymal atrophy and fibrosis
Radiation effects on TISSUE
ACUTE (vasculitis, possibly “fibrinoid” necrosis)
CHRONIC (fibrosis)
Physical InjuryPhysical Injury AbrasionAbrasion
basically a scrapebasically a scrape superficial epidermis is torn off by friction or superficial epidermis is torn off by friction or
forceforce regeneration without scarring usually occursregeneration without scarring usually occurs
Laceration vs. IncisionLaceration vs. Incision a laceration is an irregular tear in the skin a laceration is an irregular tear in the skin
produced by overstretching. The wound margins produced by overstretching. The wound margins are frequently hemorrhagic and traumatizedare frequently hemorrhagic and traumatized
an incision is made by a sharp cutting object. The an incision is made by a sharp cutting object. The margins of the incision are usually relatively margins of the incision are usually relatively clean clean
ContusionContusion an injury caused by a blunt force that damages an injury caused by a blunt force that damages
small blood vessels and causes interstitial small blood vessels and causes interstitial bleeding, usually without disruption of the bleeding, usually without disruption of the continuity of the tissue (continuity of the tissue (cfcf ecchymosis) ecchymosis)
GUNSHOT WOUNDEntrance Vs. ExitFar range Vs. Close range
NOT CLOSE RANGE
CLOSE RANGE(POWDER BURNS)
EXIT WOUNDS are generally SLOPPIER
than ENTRANCE WOUNDS
HYPER-THERMIA HEAT
CRAMPS: Electrolyte loss via sweat (Na+, K+)
EXHAUSTION: Water depletion and lack of cardiovascular compensation
“STROKE”: Extensive peripheral vasodilatation, i.e., “shocky”, very serious, T>106º, over 110º have been reported, high mortality. In this case true “SHOCK” would be a better term than “STROKE”
HYPO-THERMIAOften in setting of homelessness or alcoholism or both< 90º often fatal, assoc. w. BRADYCARDIA ATRIAL FIBRILLATION
LIGHTNING/ELECTRICAL ELECTRIC DISTURBANCES
NEURAL (because nerve is such an EXCELLENT conductor of electricity)
EKG (like reverse cardioversion) THERMAL INJURY, depends upon a
particular tissue’s RESISTANCE to electrical flow
“LIGHTNING” MARKS
ATMOSPHERIC PRESSURE
Altitude IllnessBlast InjuriesDecompression Injuries
ALTITUDE ILLNESS Caused by LOW Oxygen Tension
HIGH ALTITUDES (>4000 m [12,000 feet]) OBTUNDATION INCREASED CAPILLARY PERMEABILITY ACUTE PULMONARY EDEMA (HAPE)
Q: What is the name of the base camp at Mt. Everest
A: Pulmonary Edema
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 compression syndrome
DECOMPRESSION Related to GAS SOLUBILITY in divers
ascending rapidly, especially the more NON-SOLUBLE gasses, like NITROGEN, and, to a lesser extent, XENON
AIR EMBOLISM is the common pathology ACUTE:
“BENDS” (peri-articular), acute “CHOKES” (lungs), acute “STAGGERS” (inner ear), acute
CHRONIC: ASEPTIC NECROSIS: humeri, femurs
NUTRITIONNUTRITION & DISEASE& DISEASE Food SafetyFood Safety
AdditivesAdditives ContaminantsContaminants
Nutritional DeficienciesNutritional Deficiencies VitaminsVitamins MineralsMinerals
ObesityObesity Diet and DiseaseDiet and Disease Chemoprevention of CancerChemoprevention of Cancer
Vitamin Deficiency and ExcessVitamin Deficiency and Excess Fat soluble vitaminsFat soluble vitamins
A, A, DD, E, , E, KK readily stored in body fatreadily stored in body fat poorly absorbed in digestive disorders poorly absorbed in digestive disorders
involving malabsorbtion of fatinvolving malabsorbtion of fat Water soluble vitaminsWater soluble vitamins
remaining vitaminsremaining vitamins readily excreted in urinereadily excreted in urine
Vitamin stores (fat stores longer than Vitamin stores (fat stores longer than water)water) vitamins B-12 and A: stores sufficient for vitamins B-12 and A: stores sufficient for
1 year1 year folate and thiamine may become depleted folate and thiamine may become depleted
within weeks when eating a deficient diet within weeks when eating a deficient diet
Vitamin D MetabolismVitamin D Metabolism Absorption of vitamin D in the gut or Absorption of vitamin D in the gut or
synthesis from precursors in the skin synthesis from precursors in the skin Binding to a plasma α1-globulin (D-Binding to a plasma α1-globulin (D-
binding protein) and transport to binding protein) and transport to liver liver
Conversion to 25-hydroxyvitamin D, Conversion to 25-hydroxyvitamin D, 25(OH)D (calcidol) by 25-hydroxylase 25(OH)D (calcidol) by 25-hydroxylase in the liver in the liver
Conversion of 25(OH)D to 1,25(OH)Conversion of 25(OH)D to 1,25(OH)22 D (calcitrol, Vitamin D3) by α1-D (calcitrol, Vitamin D3) by α1-hydroxylase in the kidney; hydroxylase in the kidney; biologically this is the most active biologically this is the most active form of vitamin Dform of vitamin D. .
Functions of Vitamin DFunctions of Vitamin D
Stimulates intestinal absorption of Stimulates intestinal absorption of calcium and phosphorus calcium and phosphorus
Collaborates with PTH in the Collaborates with PTH in the mobilization of calcium from bone mobilization of calcium from bone
Stimulates the PTH-dependent Stimulates the PTH-dependent reabsorption of calcium in the distal reabsorption of calcium in the distal renal tubulesrenal tubules
1,25(OH)1,25(OH)2 2 D, the biologically active D, the biologically active form of vitamin D, is best regarded form of vitamin D, is best regarded as a steroid hormone which acts by as a steroid hormone which acts by binding to a high-affinity receptor binding to a high-affinity receptor
Vitamin D DeficiencyVitamin D Deficiency Holick et al (2005) reported the Holick et al (2005) reported the
results of a large North American results of a large North American study that assessed the vitamin D study that assessed the vitamin D status of postmenopausal women status of postmenopausal women receiving therapy to treat or prevent receiving therapy to treat or prevent osteoporosisosteoporosis
52% of 1536 women had inadequate 52% of 1536 women had inadequate [25(OH)D] levels (<30 ng/mL)[25(OH)D] levels (<30 ng/mL)
36% and 18% had levels less than 25 36% and 18% had levels less than 25 and 20 ng/mL, respectively. and 20 ng/mL, respectively.
Holick MF et al: J Clin Endocrinol Metab 90:3215, 2005
Vitamin D DeficiencyVitamin D Deficiency Childhood: RicketsChildhood: Rickets
epiphyses are openepiphyses are open cartilage overgrowthcartilage overgrowth
Adults: Adults: osteomalaciaosteomalacia bone matrix is not calcifiedbone matrix is not calcified vs osteoporosis (matrix reduced)vs osteoporosis (matrix reduced)
ADULTS
CHILDREN (RICKETS)
OSTEOMALACIA1) Bone fractures that happen with very little injury2) Muscle weakness3) Widespread bone pain, especially in the hips
Vitamin KVitamin K
Clotting factors VII, IX, and X and Clotting factors VII, IX, and X and prothrombin (II) all require prothrombin (II) all require carboxylation of glutamate residues carboxylation of glutamate residues for functional activityfor functional activity anticoagulant coumadin is a Vitamin K anticoagulant coumadin is a Vitamin K
antagonistantagonist Activation of anticoagulant proteins Activation of anticoagulant proteins
C and S also requires glutamate C and S also requires glutamate carboxylationcarboxylation
SourcesSources endogenous intestinal bacterial floraendogenous intestinal bacterial flora dietdiet
Vitamin K DeficiencyVitamin K Deficiency CausesCauses
fat malabsorptionfat malabsorption reduced gut bacterial florareduced gut bacterial flora
administration of wide specturm antibioticsadministration of wide specturm antibiotics neonatal period before gut is colonizedneonatal period before gut is colonized
liver disease with reduced recycling of liver disease with reduced recycling of vitamin Kvitamin K
Effects of vitamin K deficiencyEffects of vitamin K deficiency bleeding diathesisbleeding diathesis estimated 3% prevalence of vitamin K-estimated 3% prevalence of vitamin K-
dependent bleeding diathesis among dependent bleeding diathesis among neonates warrants routine prophylactic neonates warrants routine prophylactic vitamin K therapy for all newborns vitamin K therapy for all newborns
ROCK
LAB
ROCK LAB