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