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OLGA MUNAR BAUSA, M.D., DPSP. MECHANISMS OF TOXICITY toxicology - detection, effects & mecha- nisms of action of poisons & toxic chemicals toxicity –

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Presentation on theme: "OLGA MUNAR BAUSA, M.D., DPSP. MECHANISMS OF TOXICITY toxicology - detection, effects & mecha- nisms of action of poisons & toxic chemicals toxicity –"— Presentation transcript:

1 OLGA MUNAR BAUSA, M.D., DPSP

2 MECHANISMS OF TOXICITY toxicology - detection, effects & mecha- nisms of action of poisons & toxic chemicals toxicity – relative phenomenon that de- pends on structure & properties of chemical & on its dose

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5 BASIC PRINCIPLES OF XENOBIOTIC METABOLISM most xenobiotics are lipophilic lipophilic toxicants are metabolized to hydro- philic metabolites - phase I rx: hydrolysis : reduction : oxidation

6 -phase II rxn: glucuronidation : sulfation : methylation : conjugation genetic variations in level of activity of xenobiotic metabolizing enzymes - CYP1A1 : lung CA - GSTM1 deficiency : lung, bladder & colon CA

7 multiple pathways involved in metabolism of a chemical toxicant endogenous factors (nutritional & hormonal status) alter enzyme activities exogenous factors (chemicals,drugs,ethanol, stress) can induce/inhibit enzyme activities

8 PHASE 1 REACTIONS: Cytochrome P-450-dependent monooxyge- nase system – activity is highest in the liver - eg: metabolism of benzo[a]pyrene to a secondary metabolite that binds to DNA causing lung and skin tumors Flavin-containing monooxygenase system - located in the SER of the liver

9 - oxidizes nicotine in cigarette smoke Peroxidase-dependent cooxidation - high activity in seminal vesicles, kidneys & urinary bladder. -involved in metabolism of 2-naphthylamine found in synthetic dyes associated with in- creased risk of bladder cancer

10 PHASE II REACTIONS: Glucuronidation – secondary metabolite is excreted in urine resulting to formation of N- hydroxy-2-naphthylamine - increased incidence in can- cer of urinary bladder in workers exposed to synthetic dyes

11 Biomethylation – inorganic mercury (HgCl2), causes necrosis of proximal convoluted tubules of kidneys - exposure occurs in industries manufacturing germicides, fungicides, electro- nics and plastics Glutathione conjugation – vinyl chloride used in the manufacture of plastics, can cause angio- sarcoma of the liver in exposed workers

12 Common Environmental and Occupational Exposures PERSONAL EXPOSURES Tobacco Use includes cigarettes, cigars, pipes & snuff major risk factor for lung Ca interacts with other environmental and occupational exposures ( additive/synergistic effect)

13 eg: increase risk of lung CA in cigarette smokers exposed to asbestos mainstream cigarette smoke : - particulate phase: tar w/o H2O or nicotine - gas phase 43 known carcinogens in mainstream smoke carcinogenic metals – arsenic, nickel, cadmium & chromium potential promoters – acetaldehyde & phenol

14 irritants - nitrogen dioxide, formaldehyde cilia toxins – hydrogen cyanide

15 ORGAN CARCINOGEN Lung, larynx polycyclic aromatic hydrocarbons 4-methynitrosoamino-1-3-pyridyl -1-butanone (NNK) polonium 210 Esophagus N’-nitrosonornicotine (NNN) Pancreas NNK Bladder 4-Aminobiphenyl,2-naphthylamine Oral cavity (smoking) polycyclic aromatic hydrocarbon, NNK, NNN Oral cavity (snuff) NNK, NNN, polonium 210

16 carbon monoxide – colorless, odorless gas; 200x higher affinity for Hgb than O2 - impairs release of O2 from Hgb decreases delivery of oxygen to the peripheral tissues nicotine – important constituent of cigarette smoke - crosses blood brain barrier ;stimulates nicotine receptors in brain

17 - responsible for acute effects me- diated by catecholamines ( increased heart rate/BP, increased coronary blood flow, in- creased contractility & cardiac output and mobilization of FFA - also responsible for tobacco addiction

18 mortality – lung cancer, IHD and chronic obstructive lung disease risk factor with HPN & hypercholesterolemia for coronary artery ds and arteriosclerosis risk factor for acute MI and stroke in women taking oral contraceptives increases platelet adhesion & aggregation leading to arrhythmia; causes imbalance in the demand for O2 & supply to myocardium

19 effects of maternal smoking to the fetus – 10 cigars per day can cause fetal hypoxia resulting to low birth weight, prematurity & spontaneous abortion - serious complications are premature rupture of membranes, placenta previa & abruptio placenta sidestream smoke – also called passive smo- king or environmental tobacco smoke (ETS)

20 - in infants & young children, causes increased incidence of respiratory, ear infections and asthma attacks - increases risk of lung cancer, IHD & acute MI Alcohol Abuse - ethanol from alcoholic drinks like beer, wine & distilled spirits

21 - legal definition for drunk driving is blood alcohol concentration of 100 mg/dl - occasional drinkers, 200 mg/dl pro- duces inebriation; coma, death & respiratory arrest at mg/dl - habitual drinkers can tolerate levels up to 700 mg/dl; this is due to increased in- duction by cytochrome P-450 xenobiotic me- tabolizing enzyme, CYP2E1.

22 - ethanol is metabolized to acetaldehyde by alcohol dehydrogenase (gastric mucosa and liver) & by cytochrome P-450 & catalase (liver) - acute action is CNS depressant Mechanisms of Disease Caused by Ethanol Abuse Organ System Lesion Mechanism Liver fatty change toxicity acute hepatitis alcoholic cirrhosis

23 Nervous sys Wernicke syndrome thiamine def Korsakoff syndrome toxicity & thiamine def cerebellar degeneration nutritional def peripheral neuropathy thiamine def Cardiovascular cardiomyopathy toxicity system hypertension vasopressor GIT gastritis toxicity pancreatitis toxicity Skeletal muscle rhabdomyolysis toxicity

24 Reproductive testicular atrophy ? system spontaneous abortion ? Fetal alcohol growth retardation toxicity syndrome mental retardation birth defects LIVER - fatty change, acute alcoholic hepatitis & cirrhosis Fatty Change – acute, reversible - mechanisms:

25 - increase catabolism of fat by pe- ripheral tissues increase delivery of FFA - metabolism of ethanol & acetalde- hyde converts nicotinamide adenine dinucleo- tide (NAD+) to reduced form, NADH; excess NADH over NAD stimulates lipid synthesis - oxidation of fatty acids by mito- chondria is decreased - acetaldehyde forms adducts with tubulin, impairs function of microtubules decrease transport of lipoproteins from liver

26 Acute Alcoholic Hepatitis - reversible form of liver injury - fever, liver tenderness & jaundice - toxic effect of ethanol is mediated by: a. mitochondrial injury b. glutathione depletion c. altered metabolism of methionine & cyto- kine release from Kupffer cells

27 - histo: focal areas of hepatocyte necrosis & cell injury by fat accumulation & alcoholic hyalin or mallory bodies; neutrophils accu- mulate around foci of necrosis

28 Alcoholic Cirrhosis - irreversible liver damage; chronic ethanol use - gross: hard, shrunken liver - histo: formation of micronodules of regenera- ting hepatocytes surrounded by dense bands of collagen - fatal ds; weakness, muscle wasting, ascites, gastrointestinal hemorrhage & coma

29 - patients with cirrhosis have depleted liver stores of alpha-tocopherol, increases their vulnerability to oxidative injury

30 NERVOUS SYSTEM - acute depressive effects & addiction are rela- ted to fluidization of membrane phospholipids & altered signal transduction - chronic thiamine deficiency leads to degene- ration of nerve cells, reactive gliosis & atrophy of cerebellum & peripheral nerves - ataxia, disturbed cognition, ophthalmoplegia & nystagmus (Wernicke syndrome)

31 - alcoholics with poor nutrition develop severe memory loss (Korsakoff syndrome) Cardiovascular System - cardiomyopathy, degenerative ds of the heart muscle -hypertension, secondary to vasopressor effects of ethanol by increased release of catechol- amines - one to two drinks/day show protective effect; increased levels of HDL & decreased platelet aggregation

32 Gastrointestinal Tract - acute gastritis, acute & chronic pancreatitis Skeletal Muscle - muscle weakness, pain & myoglobin break- down Reproductive System -testicular atrophy; decreased fertility in men & women, spontaneous abortion Fetal Alcohol Syndrome - consequence of maternal ethanol consump- tion at levels of one drink/day

33 - growth & developmental defects; growth retardation, microcephaly, atrial septal de- fect etc. -pathogenesis: acetaldehyde crosses the pla- centa & damages fetal brain Ethanol and Cancer - increased incidence of cancer of the oral ca- vity, pharynx, esophagus, liver & breast

34 Drug Abuse Sedative-Hypnotics - ethanol:widely abused CNS depressant -barbiturates: illegal drugs ; downers; induce sedation & decrease anxiety; develops tolerance causing drug users to increase the dose : chronic use induces cytochrome P-450 activity, increasing metabolism of drugs (dicumarol, tetracycline, digoxin, OC)

35 - simultaneous use of ethanol & barbiturates is lethal, causing coma & CPA -Diazepam (valium): safer sedative, can cause drowsiness, dizziness & coma but do not in- duce cytochrome P-450 activity Psychomotor Stimulants a. cocaine (crack): produces rapid “high” of short duration (euphoria, increased energy and stimulation

36 : chronic use can cause insomnia, in- creased anxiety, paranoia & hallucinations : acute overdose causes seizures, car- diac arrhythmias & respiratory arrest : main mechanism of cocaine action is to block reuptake of dopamine, serotonin & catecholamines (E & NE) in the presynaptic terminals : prolongs dopaminergic effects in brain’s pleasure centers (limbic system) causing intense euphoria

37 - CVS effects of cocaine: accumulation of catechol- amines causes stimulation of alpha & beta-adrenergic receptors ( increased BP, heart rate with coronary spasms - increase myocardial O2 demand, dec O2 supply lea- ding to arrhythmias & ischemia causing MI - typical patient with cocaine-induced MI: male in early 30’s; cigarette smoking compounds the risk - chronic effects: atherosclerosis, cardiomyopathy & myocarditis

38 - causes fetal hypoxia b. Amphetamines – overdose causes sweating, tremors restlessness & confusion leading to delirium, convul- sions, cardiac arrhythmias, coma & death - molecular basis of addiction is unknown; underlying abnormality in dopamine D4 receptor Narcotics - relieve pain but can also cause sedation & altered mood - IV heroin abuse induces suppression of anxiety, seda- tion, mood changes, nausea & respiratory depression

39 - chronic abuse induces tolerance & psychologic de- pendence - IV users susceptible to infections: 4 sites most com- monly affected are skin/subcutaneous tissue, heart valves, liver & lungs - endocarditis, involving right sided heart valves (tri- cuspid); most common organism is S. aureus - viral hepatitis, acquired by casual sharing of dirty needles; incidence of AIDS also increasing

40 Hallucinogens - mescaline, psilocybin & marijuana - active ingredient in marijuana is tetrahydrocannabi- nol (THC) - chronic marijuana smoking has similar lung effects of tobacco smoking, however it is not carcinogenic Therapeutic Drugs - adverse drug reactions (ADRs) are untoward effects of drugs that are given in conventional therapeutic settings

41 Exogenous Estrogens and Oral Contraceptives - estrogens for postmenopausal syndrome may be given alone & are usually natural estrogens - oral contraceptives contain synthetic estrogens, always with progesterone Exogenous Estrogens - adverse effects of estrogen therapy:  endometrial carcinoma – estrogen therapy increases the risk threefold to sixfold after 5 years of use & more than tenfold after 10 years

42  breast carcinoma – the increased risk is small & not influenced by the addition of progestins  thromboembolism  cardiovascular disease – estrogens tend to elevate level of HDL & reduce level of LDL, which is protec- tive against development of atherosclerosis - progestins counters the es- trogen effect; 40% to 50% decrease in the risk of IHD in women who received postmenopausal estro- gen therapy

43 Oral Contraceptives - combined OCs contain a synthetic estradiol & variable amounts of progestins; few preparations contain only progestins - currently prescribed OCs contain smaller amounts of estrogens (<50 ug/day); associated with fewer side effects - adverse effects:  breast carcinoma – slight increase in breast CA risk when combined oral contraceptives are used by wo- men younger than 45 yrs, particularly nulliparous women younger than 25 yrs

44  endometrial cancer – no increased risk, OCs exert a protective effect  cervical cancer – increase risk correlated with dura- tion of use  ovarian cancer – OCs protect against ovarian CA; longer they are used, the greater the protection  thromboembolism – containing > 50 ug estrogens are associated with increase risk of venous throm- bosis & pulmonary thromboembolism due to increa- sed hepatic synthesis of coagulation factors & re- duced levels of antithrombin III

45 - <50 ug estrogens, less risk especially in women younger than 35 yrs who do not smoke - 3 rd generation OCs (combine low dose estrogens with synthetic progestins) reduces risk of MI but confer higher risk of venous thrombosis than 2 nd generation OCs  hypertension – slight increase in BP  cardiovascular disease – approximately 29% increa- sed risk of MI, especially during the first yr of com- bined HRT use.

46  cholecystitis – increased risk of gallbladder disease Acetaminophen - when taken in large doses will cause hepatic necro- sis; toxic dose is gm - nausea, vomiting, diarrhea, shock followed by jaun- dice - serious overdosage causes liver failure, with centri- lobular necrosis involving entire lobule - concurrent renal & myocardial damage seen in some patients

47 Aspirin (Acetylsalicylic Acid) - overdose in children result from accidental ingestion; in adults, suicidal - toxic dose in children is 2-4 gm; in adults, gm -chronic aspirin toxicity (salicylism) develop in persons who take 3 gm or more daily, dose required to treat chronic inflammatory conditions : headache, dizziness, ringing in the ears (tinnitus), difficulty in hearing, mental confusion, drowsiness, nausea, vomiting & diarrhea; CNS chan- ges may lead to convulsions & coma

48 : erosive gastritis causes GI bleeding leading to gastric ulceration : bleeding tendency is also associated because aspirin acetylates platelet cyclooxygenase & blocks thromboxane A2, an activator of platelet aggregation - mixtures of aspirin & phenacetin or acetaminophen when taken for years causes renal papillary necrosis, referred to as analgesic nephropathy

49 OUTDOOR AIR POLLUTION - major sources of ambient air pollutants are:  combustion of fossil fuels – motor vehicles (complex mixtue of carbon monoxide, oxides of nitrogen, hydro- carbons, diesel exhaust particles, lead oxide  photochemical reactions- oxides of nitrogen & vola- tile hydrocarbons interact in the atmosphere to pro- duce ozone  power plants – release sulfur dioxide

50 Health Effects of Outdoor Air Pollutants POLLUTANT POPULATIONS AT RISK EFFECTS Ozone healthy adults & children decreased lung function increased airway reactivity lung inflammation athletes, outdoor workers decreased exercise capacity asthmatics increased hospitalizations Nitrogen healthy adults increased airway reactivity dioxide asthmatics decreased lung function children increased respiratory infcxn Sulfur healthy adults increased respiratory sx dioxide px with chr lung ds increased mortality increased hospitalization asthmatics decreased lung function

51 Acid arosols healthy adults altered mucociliary clearance children increased respiratory infcxn asthmatics decreased lung function Particulates children increased respiratory infcxn decreased lung function px with chronic lung excess mortality & heart ds asthmatics increased attacks INDOOR AIR POLLUTION -sources of indoor air pollutants: tobacco smoke, gas cooking stoves & furnaces, wood stoves, cons- truction materials, furniture, radon, allergens ( pets, dust mites, fungal spores & bacteria

52 Health Effects of Indoor Air Pollutants POLLUTANT POPULATIONS AT RISK EFFECTS Carbon monoxide adults & children acute poisoning nitrogen dioxide children increased respiratory infecxns wood smoke children increased respiratory infecxns Formaldehyde adults & children eye & nose irritation, asthma Radon adults & children lung cancer Asbestos fibers maintenance & lung cancer, mesothelioma abatement workers Manufactured maintenance & skin & airway irritation mineral fibers construction workers Bioaerosols adults & children allergic rhinitis, asthma

53 INDUSTRIAL EXPOSURES  VOLATILE ORGANIC COMPOUNDS Aliphatic Hydrocarbons – industrial solvents & dry- cleaning agents - absorbed thru the lungs, skin & GIT - eg: chloroform & CCl4; both are carcino- genic in rodents - methylene chloride used in paint remo- vers & aerosols; metabolized by cytochrome P-450 to CO2 & CO; CO causes respiratory depression & death

54 - acute exposure of perchloroethylene causes CNS depression, confusion, dizziness, im- paired gait & nausea; repeated exposures causes dermatitis; human carcinogen Petroleum Products – gasoline, kerosene, mineral oil & turpentine - inhalation causes dizziness, incoor- dination & CNS depression Aromatic Hydrocarbons – benzene, toluene & xylene - toluene & xylene are not carcino- genic

55 - inhalation of benzene causes bone marrow toxicity, aplastic anemia & acute leukemia  POLYCYCLIC AROMATIC HYDROCARBONS - among the most potent chemical carcinogens - benzo(a)pyrene is the prototype of PAH; cigarette smoking is another important source of benzo(a) pyrene - occupational exposure to PAH is associated with an increased risk of lung & bladder cancers

56  PLASTICS, RUBBER AND POLYMERS - occupational exposure to vinyl chloride monomers used to produce polyvinyl chloride resins is associa- ted with angiosarcoma of the liver - VC is metabolized by the cytochrome P-450 system in the liver to chloroacetaldehyde which covalently binds to DNA & is mutagenic - exposure of rubber workers to 1,3-butadiene is asso- ciated with increased risk of leukemia

57  METALS Lead – inhalation is the most important route of occupational exposure; from urban air due to leaded gasoline, soil contaminated with exterior lead paint, water supply due to lead plumbing & house dust in homes with interior lead paint - also absorbed in the GIT from lead glazed ce- ramics, lead solder in food & softdrink cans - absorbed lead is 80 to 85% taken up by bone bone & developing teeth in children; blood accumu- lates 5 to 10 % ; remainder in soft tissues

58 - lead deposited in bones has a half-life of 30 yrs; lead clears rapidly in blood; presence of lead in blood indicates recent exposure - toxicity related to following biochemical effects: high affinity for sulfhydryl groups – inhibits enzy- mes in heme biosynthesis: -aminolevulinic acid dehydratase & ferroketolase leading to micro- cytic hypochromic anemia competition with calcium ions – also interferes with nerve transmission & brain development

59 inhibition of membrane-associated enzymes – inhi- bits 5’-nucleotidase activity Na-K pumps leading to hemolysis, renal damage & HPN impaired metabolism of 1,25-dihydroxyvitamin D - consequences of lead exposure: brain: adult – headache, memory loss; child- ence- phalopathy, mental deterioration gingiva: lead line blood: microcytic, hypochromic anemia; red cell basophilic stippling peripheral nerves: demyelination

60 kidney: chronic tubulointerstitial disease gastrointestinal tract: abdominal pain epiphyses of children’s bones: radiodense deposits TOXIC AND CARCINOGENIC METALS METAL DISEASE OCCUPATION Mercury renal toxicity chlorine-alkali industry muscle tremors, dementia cerebral palsy mental retardation Arsenic cancer of skin, lung, liver miners, smelters, oil re- finery & farm workers Beryllium acute lung irritant beryllium refining, aero-

61 chronic lung hypersxn space manufacturing, ? Lung cancer ceramics Cobalt & lung fibrosis toolmakers, grinders, Tungsten carbide asthma diamond polishers Cadmium renal toxicity battery workers, smel- ? Prostate cancer ters,welders, soldering Chromium lung & nasal CA pigment workers, smel- ters, steel workers Nickel lung & nasal sinuses CA smelters, steel workers, electroplating

62 AGRICULTURAL HAZARDS HEALTH EFFECTS OF AGRICULTURAL PESTICIDES CATEGORY EXAMPLE EFFECTS & DISEASE Insecticides Organochlorines neurotoxicity; hepatoxivity DDT Chlordane Lindane Methoxychlor Organophosphates neurotoxicity; delayed Parathion neuropathy Diazinon Malathion Carbamates neurotoxicty (reversible) Aldicarb Carbaryl

63 Botanical agents Paresthesia; lung irritant; Nicotine allergic dermatitis Pyrethrins Rotenone Herbicides Arsenic compds Hyperpigmentation;gang- rene; anemia, sensory neu- ropathy; cancer Dinitrophenols Hyperthermia; sweating Chlorophenoxy 2,4-D & 2,4,5-T ? Lymphoma; sarcoma TCDD fetotoxicity; immunotoxicity cancer Paraquat acute lung injury Atrazine ? Cancer Alachlor ? cancer

64 Fungicides Captan ? Reproductive toxicity Maneb Benomyl Rodenticides Fluoroacetate cardiac & resp failure Warfarin hemorrhage Strychnine respiratory failure Fumigants Carbon disulfide cardiac toxicity Ethylene dibromide neurotoxicity Phosphine lung edema; brain damage Chloropicrin eye irritation; lung edema; arrhythmias

65 NATURAL TOXINS CATEGORY & SOURCE EFFECTS & DISEASES EXAMPLE Mycotoxins ergot alkaloids Claviceps fungi gangrene, convulsions, abortion aflatoxins Aspergillus flavus liver cancer tricothecenes Fusarium, Trichoderma diarrhea, ataxia Phytotoxins cycasin Cycad flour amyotrophic lateral scle- rosis monocrotaline Senecio plants hepatitis safrole Black pepper cancer solanine Soanaceae plants neurotoxin (potato)

66 Animal toxins venoms snakes cardiotoxin, neurotoxin bees direct toxicity, cardiotoxin saxitoxin dinoflagellates neurotoxin, paralysis ciguatoxin dinoflagellates paresthesia, paresis, vomi- ting, diarrhea tetrodotoxin puffer fish neurotoxin, shock RADIATION INJURY - radiation is energy distributed across electromagne- tic spectrum as waves (long wavelengths, low fre- quency) or particles (short wavelengths, high frequen- cy)

67 -nonionizing radiation is characterized by long wave- lengths & low frequencies; eg are electric power, ra- dio waves & microwaves, infrared & ultraviolet light -ionizing radiation is characterized by short wavelen- gths & high frequency; eg are X-rays, gamma rays & cosmic rays -Particulate radiation is classified by the type of par- ticles emitted: alpha, beta, electrons, protons, neutron

68  Ionizing Radiation -Acute effects range from overt necrosis at high doses (>10Gy), killing of proliferating cells at intermediate doses (1-2Gy) & no histopathologic effect at doses less than 0.5Gy -Delayed effects are: mutations, chromosome aberra- tions, & genetic instability; genetically damaged cells may become malignant -Cancers induced by ionizing radiation occurred after doses > 0.5Gy -Delayed injury is caused by combination of atrophy of parenchymal cells, ischemia due to vascular damage and fibrosis

69 ACUTE INJURY AND DELAYED COMPLICATIONS CAUSED BY IONIZING RADIATION ORGAN ACUTE INJURY DELAYED COMPLICATIONS Bone marrow atrophy hypoplasia, leukemia Skin erythema epidermal atrophy; dermal fib- rosis; cancer Heart interstitial fibrosis Lung edema, endothelial interstitial & intra-alveolar & epithelial cell death fibrosis; cancer GIT edema, mucosal ulcers; fibrosis; strictures; ad- ulcers hesions; cancer

70 Liver veno-occlusive disease cirrhosis; liver tumors Kidney vasodilation cortical atrophy, interstitial fibrosis Urinary mucosal erosion submucosal fibrosis bladder Brain edema, necrosis necrosis of white matter, gliosis; brain cancer Testis necrosis tubular atrophy Ovary atresia of follicles stromal fibrosis Thyroid hypothyroidism; cancer

71 Breast fibrosis; cancer Thymus, LN atrophy lymphoma  Clinical Manifestations of Exposure to Ionizing Radiation Acute, Whole-Body Exposure -potentially lethal; acute radiation syndrome or radiation sickness -depending on the dose, four clinical syndromes are produced: subclinical or podromal syndrome, hematopoietic syndrome, GI syndrome, central nervous syndrome

72 Clinical Features of the Acute Radiation Syndrome CATEGORY WHOLE-BODY SYMPTOMS PROGNOSIS DOSE (rem) Subclinical <200 mild nausea & 100% survival vomiting; lympho- cytes <1500/ul Hematopoietic intermittent n & V infections petechiae, hge may require BM transplant max neutrophil & platelet dep in 2 wk lympho <1000/ul Gastrointestinal N,V, diarrhea shock & death in hge & infcxn in 1-3 wk days even severe n & p dep w/ replacement lympho <500/ul therapy

73 Central nervous >1000 intractable n&v death in hr system confusion, somno- lence, convulsions coma in 15min-3 hr lymphos absent  Radiation Therapy – to the chest or abdomen, can cause acute radiation sickness & neutrophil & plate- let depression - transient fatigue, vomiting & anorexia - shrink the tumor mass & relieve pain or compression of adjacent tissues - cancer patients treated with radiation therapy may develop sterility, a secondary malignant

74 neoplasm, or delayed radiation injury  Growth and Developmental Abnormalities Preimplantation embryo Critical stages of organogenesis – implantation up to 9 weeks of gestation, exposure of mother even to dxtic radiation can produce congenital malformations Fetal period – from 9 wks of gestation until birth - maternal irradiation will produce ab- normalities of the CNS & reproductive system; in- creased incidence of childhood leukemia & brain tumors

75 Postnatal period – retardation of bone growth & ma- turation in infants & young children  Induction of Mutations – chromosome aberrations & Mutations when exposed to ionizing radiation  Delayed Radiation Injury – delayed complications in- clude carcinogenesis, damage to the heart, lungs, CNS or kidneys; infertility, cataracts, fibrous strictures, chronic ulcers, impaired wound healing, infections - tissues most vulnerable sites of delayed radiation injury are:

76 Blood vessels – show subintimal fibrosis, fibrosis of muscle wall, degeneration of internal elastic lamina & severe narrowing of lumen

77 Skin- chronic changes in the skin & hair follicles in- clude desquamation replaced by atrophic epidermis with hyperkeratosis, hyperpigmentation & hypopig- mentation - dilated subcutaneous vessels surrounded by dense bands of collagen in the dermis; impaired healing, infection& ulceration; radiation dermatitis - skin cancer, especially basal cell & squamous cell CA may occur 20 yrs after exposure

78 Heart – fibrosis of the pericardium can cause cons- trictive pericarditis; injury to the capillaries & coro- ries can cause myocardial ischemia & fibrosis Lungs – acute lung injury & delayed radiation pneu- monitis; both internal & external irradiation increase the incidence of lung cancer which is synergistic with cigarette smoking Kidneys & urinary bladder – moderately susceptible; delayed peritubular fibrosis, vascular damage glome- rular hyalinization develop leading to hypertension & atrophy

79 - UB is sensitive with acute necrosis of epithelium followed by submucosal fibrosis, contrac- ture, bleeding & ulceration Gastrointestinal tract – esophagitis, gastritis, ente- ritis, colitis & proctitis associated with exfoliation of epithelial mucosa, susceptibility to infection & loss of electrolytes & fluid Breast – dxtic doses of ionizing radiation during adolescence increase the incidence of breast cancer after years

80 - radiotherapy for breast cancer causes dense fibrotic reaction with extreme pleomorphism of epithelial cells Ovary & testis – spermatogonia extremely sensitive to irradiation causing suppression of meiosis & infer- tility; blood vessels obliterated & seminiferous tubu- les become fibrotic Eyes & central nervous system – lens is sensitive causing cataracts; retinal & ciliary arteries may also be damaged; brain shows focal necrosis & demye- lination of white matter; spinal cord, small blood vessels are damaged leading to necrosis, demyeli-

81 nation & paraplegia (transverse myelitis) ULTRAVIOLET RADIATION -divided into UVA, UVB & UVC; ozone is a protective agent against UVR because it completely absorbs all UVC & partially absorbs UVB -two major health effects of UVR: premature aging of the skin & skin cancer -acute effects of UVA & UVB are short lived & rever- sible: erythema, pigmentation & injury to langerhans cells & keratinocytes in the epidermis

82 - repeated exposure to UVR give rise to pre- mature aging of skin; IR increases deposition of co- llagen in the dermis while UVR causes degenerative changes in elastin & collagen (wrinkling, increased laxity & leathery appearance); irreversible changes

83 PHYSICAL ENVIRONMENT  Mechanical Force Abrasion – scrape, superficial epidermis is torn off by friction or force

84 Laceration – irregular tear in the skin produced by overstretching; maybe linear or stellate depending on the tearing force - bridging strands of fibrous tissue or blood vessels across the wound - margins are hemorrhagic & traumatized Incision – made by a sharp cutting object (knife, scalpel or a piece of glass) - margins are relatively clean, no bridging strands of fibrous tissue; can be approximated by

85 sutures leaving little or no scar Contusion – injury caused by blunt force damaging small blood vessels & causes interstitial bleeding without disruption of the continuity of the tissue

86 Gunshot wounds – close range gunshot wound(with- in 1 foot): gray black discoloration about the wound entrance (fouling) from the heat, smoke & burned powder deposits exiting with the bullet from muzzle : discrete, large particles of unburned pow- der producing a halo of stippling about the point of entry - firearms held more than a foot away but within 3 feet, there may be only stippling without fouling - at greater distances, niether is pre- sent

87 - exit wounds are more irregular than en- trance wounds, margins may be everted, no fouling or stippling with little surrounding abrasion

88  Thermal Injuries - clinical significance depends on : depth of the burn; percentage of body surface involved; presence of in- ternal injuries from inhalation of hot & toxic fumes; promptness & efficacy of therapy - full-thickness burn: total destruction of the epidermis & dermis with loss of dermal appendages; 3 rd & 4 th degree burns; grossly, white or charred, dry & anes- hetic (due to nerve ending destruction) Thermal Burns

89 -partial-thickness burns: deeper portions of dermal appendages are spared; 1 st degree burns (epithelial involvement only) & 2 nd degree burns (both epider- mis & superficial dermis); grossly, pink or mottled with blisters & are painful - burn > 50% of the total body surface, superficial or deep is grave & fatal - inhalation injury: water-soluble gases (chlorine, sulfur oxides & ammonia) will produce inflammation & swe- lling leading to partial or complete airway obstruction

90 - secondary infection is an important complication in all burn patients who have lost epidermis; organ sys- tem failure resulting from sepsis is the leading cause of death in burn patients; most common organism is P. aeruginosa, followed by S. aureus and Candida - development of hypermetabolic state with excess heat loss & increased need for nutritional support; >40% of body surface is burned, the resting meta- bolic rate is twice normal rsulting to breakdown of tissue, loss of protein stores & starvation

91 Hyperthermia – prolonged exposure to elevated am- bient temperatures Heat cramps – result from loss of electrolytes thru excessive sweating; cramping of voluntary muscles usually in association with vigorous exercise Heat exhaustion – most common heat syndrome; su- dden onset with prostration & collapse; results from failure of CVS to compensate for hypovolemia secon- dary to water depletion Heat stroke – associated with high ambient tempe- tures & high humidity; marked generalized periphe- ral vasodilation with peripheral pooling of blood and

92 decreased effective circulating blood volume; necro- sis of muscles & myocardium causing arrhythmias, DIC & other systemic effects; common among elderly persons, young athletes, military recruits & persons with CV disease Hypothermia – prolonged exposure to low ambient temperature; at 90F, loss of conciousness occurs, followed by bradycardia & atrial fibrillation at lower core temperatures Electrical Injuries - cause sudden death by disruption of neural regula- tory impulses producing cardiac arrest or may cause

93 thermal injury to organs interposed in the pathway of the current - most important variables are resistance of the tissues to the conductance of the electric current & the inten- sity of the current - the greater the resistance of tissues, the greater the heat generated; dry skin is resistant while resistance is greatly decreased in wet skin - high intensity current (lightning) produces linear ar- borizing burns in the skin known as lightning marks

94 Injuries Related to Changes in Atmospheric Pressure High-Altitude Illness – mountain climbers with alti- tudes above 4000 m; lowered O2 tension produces progressive mental obtundation accompanied by in- creased capillary permeability & pulmonary edema Blast Injury – violent increase in pressure either in the atmosphere (air blast) or in water ( immersion blast) - in air blast, compression wave impinges on the side toward the explosion (collapse the thorax or compress the abdomen with rupture of internal organs)

95 - in immersion blast, the pressure is supplied to the body from all sides Decompression (Caisson) Disease – encountered in deep-sea divers & underwater workers who spend long periods in caissons or tunnels under increased atmos- pheric pressure - function of Henry’s law, states that the so- lubility of a gas in a liquid (blood) is proportional to the partial pressure of that gas in the environment - as the underwater depth & atmospheric pre- ssure increase, increasing amount of oxygen & gases

96 dissolve in the blood & tissue fluids; once ascent begins (decompression), dissolved gases come out of solution & form minute bubbles in the blood & tissues - coalescence of bubbles produces larger masses pro- ducing emboli in the bloodstream; periarticular bub- bles produce the bends; bubbles in the lungs causes respiratory difficulties with substernal pain (chokes) - involvement of the inner ear may produce vertigo & staggers; caisson ds of the bone in the form of asep- tic necrosis of the femoral & humeral heads & medu- llary foci of the lower femur & upper tibia

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98 NUTRITIONAL DEFICIENCIES  Protein-Energy Malnutrition - refers to a range of clinical syndromes characterized by inadequate dietary intake of protein & calories - two protein compartments: somatic protein compart- ment (skeletal muscles) & visceral compartment ( pro- tein stores in visceral organs, primarily the liver) - Marasmus: malnutrition caused primarily by severe reduction in caloric intake - A child whose weight falls to <80% of normal is con- sidered malnourished

99 : infections common -Kwashiorkor : occurs when protein deprivation is greater than the reduction in total calories : most common form; seen in children who have been weaned early due to arrival of another child & fed exclusively CHO diet : more severe than marasmus; marked protein deprivation associated with severe loss of vis- ceral protein compartment resulting to hypoalbumine- mia giving rise to generalized or dependent edema

100 : child with marasmus suffers growth re- tardation & loss of muscle; loss of muscle results from catabolism & depletion of the somatic protein compart- ment : visceral protein compartment is depleted only marginally, serum albumin levels are either normal or only slightly reduced : subcutaneous fat is also mobilized & used as a fuel : head appears too large for the body; ex- tremities are emaciated; presence of anemia & multivi- tamin deficiencies; immune deficiency (T cell mediated

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102 : relative sparing of subcutaneous fat & muscle mass; skin lesions with alternating zones of hy- perpigmentation, areas of desquamation & hypopig- mentation (“flaky paint” appearance) : hair changes include loss of color or al- ternating bands of pale & darker hair, straightening, line texture, & loss of firm attachment to the scalp : other features include enlarged, fatty liver (reduced synthesis of carrier proteins), early apa- thy, listlessness & loss of appetite -Secondary PEM : seen in chronically ill or hospita- lized patients; common complication in advanced can-

103 cer patients & in patients with AIDS; also called cache- xia : px with chronic GI disease & elderly px who are weak & bedridden will show physical signs of PEM (1) depletion of subcutaneous fat in the arms, chest wall, shoulders or metacarpal regions; (2) was- ting of the quadriceps femoris & deltoid muscles; (3) ankle or sacral edema

104 Comparison of Severe Marasmus-Like and Kwashiorkor Like Secondary Protein-Energy Malnutrition SYNDROME CLINICAL TIME CLINICAL LAB PROGNOSIS SETTING COURSE FEATURES FINDINGS Marasmus Chronic illness mos hx of wt N or mildly depends Like PEM (chr lung ds; CA) loss; muscle reduced on under wasting; ab- serum Pr lying ds sent subcu fat Kwashior- Acute, catabo- wks N fat & serum poor Kor like lic illness muscle; albumin PEM (severe trauma, edema; <2.8 gm/dl burns, sepsis) easily pluckable hair

105  Morphology -Central anatomic changes in PEM are (1) growth fai- lure (2) peripheral edema in kwashiorkor (3) loss of body fat & atrophy of muscle more severe in maras- mus kwashiorkor marasmus Liver enlarged & fatty normal Small bowel mucosal atrophy; loss rare of villi & microvilli; disa- ccharidase deficiency BM hypoplastic (↓red cell precursors); folate deficiency ( microcytic-macrocytic anemia) Brain cerebral atrophy cerebral atrophy

106  Anorexia Nervosa and Bulimia -Anorexia nervosa : self-induced starvation resulting in marked weight loss : similar clinical findings with severe PEM with prominent endocrine effects. a. Amenorrhea – dxtic feature; results from decreased secretion of gonadotropin-releasing hormone and decreased secretion of luteinizing and FSH. b. Cold intolerance, bradycardia, constipation c. Skin changes – dry, scaly & yellow due to ex- cess carotene in the blood

107 d. Decreased bone density due to low estro- gen level : major complication is increased susceptibi- lity to cardiac arrhythmia and sudden death resulting from hypokalemia - Bulimia: condition in which the patient binges on food and then induces vomiting; occur primarily in previous- ly healthy young women with obsession of attaining thinness. : amenorrhea occurs in < 50% of cases

108 : major medical complications is related to con – tinual induced vomiting and include: 1) electrolyte im- balances (hypokalemia); 2) pulmonary aspiration of gastric contents; 3) esophageal & cardiac rupture Vitamin Deficiencies  Fat soluble : A, D, E and K  Water soluble

109 Fat –Soluble Vitamins  Vitamin A - functions: a component of visual pigment (retinal) : maintains normal vision in reduce light : maintenance of specialized epithelia, mainly mucus-secreting cells : maintenance of resistance to infection, esp in children Visual process involves four forms of vit A containing pigments: rhodopsin (rods) – most light sensitive pig- ment; impt in reduced light

110 : 3 iodopsins (cone cells) – each responsive to specific colors in bright light - synthesis of rhodopsin from retinol involves: (1) oxi- dation to all-trans-retinal (2) isomerization to 11-cis- retinal during dark adaptation (3) interaction with op- sin to form rhodopsin retinoic acid regulates the expression of genes enco- ding a number of cell receptors & secreted proteins, including receptors for growth factors ability of vit A to stimulate the immune system through formation of 14-hydroxyretinol; bioavailability of vit A is reduced during infections

111 - Deficiency state: impaired vision in reduced light ( night blindness) xerophthalmia (dry eyes): lacrimal & mucus-secreting epithelium is replaced by keratinized epithelium causing dryness of conjunctivae (xerosis); build-up of keratin debris in small opaque plaques (Bitot spots); erosion of the roughened corneal surface with softening & destruction of the cornea (kera- tomalacia); total blindness epithelium lining the upper respiratory passages & urinary tract is replaced by keratinizing squamous cells ( squamous metaplasia) causing pulmonary

112 infections & renal & urinary bladder stones immune deficiency causing common infections such as measles, pneumonia & infectious diarrhea - Toxicity acute toxicity- headache, vomiting, stupor & papille- dema chronic toxicity- associated with weight loss, nausea & vomiting; dryness of the lip mucosa; bone & joint pain; hyperostosis; hepatomegaly with parenchymal damage & fibrosis; osteoclast forma- tion causing ↑ bone resorption & osteoporosis leading to fractures

113  Vitamin D - Metabolism two sources: endogenous synthesis in the skin & diet (1) absorption of vit D in the gut or synthesis from pre- cursors in the skin (2) Binding to a plasma α 1 - globulin (D binding protein) & transport to liver (3) Conversion to 25-hydroxyvitamin D by 25-hydroxy- lase in the liver (4) Conversion of 25(OH)D to 1,25(OH) 2 D by α 1 -hydro- xylase in the kidney; most active form of vit D

114 3 mechanisms regulating production of 1,25(OH) 2 D (1) feedback loop, ↑ 1,25(OH) 2 D down-regulate synthe- sis by inhibiting action of α 1 -hydroxylase, & ↓ levels have the opposite effect (2) Hypocalcemia stimulates secretion of PTH which converts 25(OH)D to 1,25(OH) 2 D by activating α 1 - hydoxylase (3) Hypophosphatemia activates α 1 -hydroxylase, in- creasing 1,25(OH) 2 D - Functions maintenance of normal plasma level of calcium & phosphorous

115 stimulates intestinal absorption of Ca & phosphorous with hypocalcemia, collaborates with PTH in the mo- bilization of Ca from the bone stimulates the PTH-dependent reabsorption of Ca in the distal renal tubules - Deficiency States rickets in growing children osteomalacia in adults - Morphology basic derangement in both rickets & osteomalacia is excess of unmineralized matrix

116 gross skeletal changes depends on the severity of ra- chitic process, its duration & the stresses to which in- dividual bones are subjected -Softened occipital bones are flattened, parietal bones buckled inward by pressure; release of pressure, elas- tic recoil snaps the bones back into their original po- sitions (craniotabes) -Excess of osteoid produces frontal bossing & squared appearance to the head -Rachitic rosary: overgrowth of cartilage or osteoid ti- ssue at the costochondral junction causing deforma- tion of the chest

117 -Pigeon breast deformity: anterior protrusion of the sternum due to inward bending of the respiratory mus- cles due to weakened metaphyseal areas of the ribs -Harrison’s groove: inward pull at the margin of the dia- phragm, girdling the thoracic cavity at the lower margin of the rib cage -Rickets in ambulating child, deformities affect the spine, pelvis & long bones (tibia) causing lumbar lordo- sis & bowing of the legs -Osteomalacia in adults: excess of persistent osteoid due to inadequate mineralization of newly formed osteoid matrix by osteoblasts; bone is weak & vulne- rable to fractures & microfx (vertebra & femoral neck)

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119 -histo: unmineralized osteoid appears a thickened la- yer of of matrix arranged about the more basophilic, normal mineralized trabeculae -Osteoporosis results from reduced production of os- teoid whish is the protein matrix of the bone  Vitamin E -Metabolism: related to 4 tocopherols & 4 tocotrienols which exhibit vit E biologic activity; α-tocopherol is the most active & most widely available Absorption of tocopherols requires normal biliary tract & pancreatic function

120 After absorption, Vit E is transported in the blood (chy- lomicrons); Vit E accumulates throughout the body, mostly in fat depots, liver & muscle - Functions antioxidant that scavenges free radicals formed in redox reactions throughout the body role in termination of free-radical-generated lipid pe- roxidation chain rxns (cellular & subcellular membra- nes rich in polyunsaturated lipids) together with selenium, they metabolize peroxides be- fore they can cause membrane damage

121 - Deficiency States nervous system is the target of vit E deficiency; neurons with long axons are vulnerable due to their large mem- brane surface area mature red cells also affected in Vit E def due to oxida- tive injury by generation of superoxide radicals during oxygenation of hemoglobin hypovitaminosis E occurs in: (1) fat malabsorption seen in cholestasis, cystic fibrosis & primary small intestinal disease; (2) infant low BW with immature liver & GIT; (3) abetalipoproteinemia; (4) rare autosomal recessive syndrome of impaired Vit E metabolism

122 - Morphology degeneration of axons in the posterior columns of the spinal cord, with accumulation of lipopigment & loss of nerve cells in the dorsal root ganglia ( due to dying- back type of axonopathy) myelin degeneration in sensory axons of peripheral nerves; degenerative changes in the spinocerebellar tracts denervation muscle disease in skeletal muscle -Neurologic manifestations of Vit E def are: depressed/ absent tendon reflexes; ataxia; dysarthria; loss of po- sition & vibration sense; loss of pain sensation

123 -Muscle weakness; impaired vision & eye movement disorders leading to total ophthalmoplegia -Protective effects of Vit E & other antioxidants against atherosclerosis & cancer; Vit E inhibits atheroma for- mation by reducing LDL oxidation; scavenge free ra- dicals→prevents DNA damage & mutagenesis→ ↓ CA  Vitamin K - Functions required cofactor in hepatic carboxylation of procoa- gulants – factors II (prothrombin), VII, IX & X; protein C & protein S

124 Carboxylation provides Ca dependent interaction of the clotting factors with a phospholipid surface in- volved in generation of thrombin Carboxylation of osteocalcin, a noncollagenous pro- tein sereted by osteoblasts, facilitates binding to calcium; vit K may favor calcification of bone proteins - Deficiency occurs (1) in fat malabsorption syndromes (biliary tract ds); (2) after destruction of the endogenous vit K synthesizing flora from ingestion of broad-spectrum antibiotics; (3) in neonatal period, when liver reserves are small, bacterial flora not yet developed & vit K in breast milk is low; (4) in diffuse liver ds

125 development of bleeding diathesis; hemorrhagic ds of the newborn; intracranial hemorrhage, bleeding in the skin, umbilicus & viscera in adults, bleeding diathesis characterized by hemato- mas, hematuria, melena, ecchymoses & bleeding from the gums  Thiamine (Vitamin B 1 ) gut absorption→phosphorylation→thiamine pyrophos- phate ( active form) -3 major functions: (1) regulates oxidative decarboxyla- tion of α-ketoacids → adenosine triphosphate; (2) acts as cofactor for transketolase in the pentose phosphate

126 pathway; & (3) maintains neural membranes & normal nerve conduction (peripheral nerves) - Deficiency seen in chronic alcoholics, precocious vomiting of pregnancy, from debilitating illnesses that impair the appetite, predispose to vomiting or cause diarrhea major targets are the peripheral nerves, the heart and brain; 3 distinctive syndromes: i. A polyneuropathy (dry beriberi) ii. A cardiovascular syndrome (wet beriberi) iii. Wernicke-Korsakoff syndrome

127 polyneuropathy is symmetric & takes the form of non- specific peripheral neuropathy with myelin degenera- tion; disruption of axons (motor, sensory & reflex arcs) first appears in the legs extend to the arms (toe drop, foot drop & wrist drop); sensory loss with muscle weakness, hyporeflexia or areflexia beriberi heart disease- associated with peripheral va- sodilation→AV shunting of blood→high output car- diac failure→peripheral edema - heart is markedly enlarged & globular (four-chamber dilation) with pale, flabby myocardium; mural thrombi present in the dilated atria

128 Wernicke-Korsakoff syndrome- in severe deficiency states; Wernicke encephalopathy is marked by oph- thalmoplegia, nystagmus, ataxia, mental derangement (confusion, apathy, listlessness & disorientation) Korsakoff psychosis – serious impairment of remote recall (retrograde amnesia), inability to acquire new information & confabulation; CNS lesions affect the mamillary bodies, periventricular regions of the tha- lamus, floor of the fourth ventricle & anterior region of the cerebellum

129  Riboflavin (Vitamin B 2 ) -Functions: converted to coenzymes flavin mononuc- leotide & flavin adenine dinucleotide, cofactors for many enzymes in intermediary metabolism -Distributed in meat, dairy products & vegetables as free riboflavin or riboflavin phosphate; absorbed in the upper gastrointestinal tract - Deficiency seen in alcoholics, chronic infections, advanced can- cer, debilitating diseases & anorexia nervosa

130 Cheilosis – first & most characteristic sign; begins as areas of pallor at the angles of the mouth; later, cracks or fissures appear from cor- ners of the mouth & become secondarily infected Glossitis – tongue becomes atrophic, colored magenta hue resembling red-blue color of cyanosis Eye change – superficial interstitial keratitis; early sta- ges, superficial layers of cornea are inva- ded by capillaries; interstitial inflammato- ry infiltration & exudation →opacities & ulcerations of the cornea

131 greasy, scaling dermatitis on the nasolabial folds → butterfly distribution involving the cheeks & ears; atrophy of the skin presence of erythroid hypoplasia in the bone marrow  Niacin generic designation for nicotinic acid & its active deri- vative, nicotinamide essential component of 2 coenzymes, NAD & NADP, important in cellular intermediary metabolism NAD – coenzyme involved in fat metabolism, CHO & amino acids

132 NADP – involved in dehydrogenation rxns, hexose- monophosphate shunt of glucose metabolism derived from diet or synthesized endogenously; grains legumes, seed oils & meat; synthesized endogenously from tryptophan Pellagra – result from either niacin or tryptophan def.; usually in combination with other vit deficiencies; seen among alcoholics, with chronic debilitating diseases, like HIV infection; seen with long term drug intake of isoniazid & 6-mercaptopurine Morphology - Pellagra refers to rough skin; “three Ds”

133 I. Dermatitis – bilaterally symmetric; found on ex- posed areas of the body; redness, thickening & roughening of the skin; extensive scaling & desquamation→fissures & chronic inflamma- tion; occur in mucous membranes of mouth & vagina ii Diarrhea – caused by atrophy of columnar epithe- lium of the GIT followed by submucosal infla- mmation & ulceration iii Dementia – results from degeneration of the neu- rons in brain with degeneration of correspon- ding tracts in the spinal cord

134  Pyridoxine (Vitamin B 6 ) -Consists of pyridoxine, pyridoxal & pyridoxamine with their phosphate forms converted in tissues to coenzyme form, pyridoxal 5-phosphate→participates as a cofactor of enzymes in- volved in transamination, carboxylations & deaminations in lipid & AA metabolism present in all foods; deficiency seen in patients under isoniazid tx; estrogens & penicillamine;in alcoholics be- cause of acetaldehyde (alcohol metabolite)→pyridoxine degradation

135 given to pregnant women vit B 6 deficiency is associated with high levels of plas- ma homocysteine→ risk factor for atherosclerosis clinical findings same with riboflavin & niacin deficien- cy → seborrheic dermatitis, cheilosis, glossitis, peri- pheral neuropathy & sometimes convulsions  Vitamin C (Ascorbic Acid) Source: diet; cannot be synthesized endogenously; pre- sent in milk, liver, fish, fruits & vegetables

136 Functions – activation of prolyl & lysyl hydroxylases from inactive precursors for procollagen hydroxylation; antioxidant → scavenge free radicals; Vits E & C act in synergistic fashion Deficiency -Scurvy: characterized by bone disease in growing children; hemorrhages & healing defects in both children & adults -morphology: (1) hemorrhages: defect in collagen syn- thesis → inadequate support of walls of capillaries & venules → purpura & ecchymoses in skin & gin- gival mucosa

137 : loose attachment of periosteum to bone with vascular wall defects →subperiosteal hematomas & bleeding into joint spaces with mild trauma : retrobulbar, subarachnoid & intracerebral he- morrhages are fatal (2) skeletal changes: insufficient production of osteoid matrix by osteoblasts →failure or slow resorprtion of cartilaginous matrix → cartilaginous overgrowth and widening of the epiphysis → stress on the scorbutic bone → bowing of long bones of lower legs & abnor- mal depression of the sternum with outward projec- tion of the ribs

138 : in severely scorbutic children & adults → gin- gival swelling, hemorrhages & scondary bacterial periodontal infection; perifollicular, hyperkeratotic, papular rash ringed by hemorrhages : defect in collagen synthesis → impaired wound healing & localization of focal infections; anemia is common due to bleeding & ↓ in iron absorption  Folate essential cofactors in nucleic acid synthesis; conver- sion of 5-methyltetrahydrofolate to tetrahydrofolate requires vit B 12 ; deficiency of either folate or vit B 12 → megaloblastic anemia

139 folate supplements have been shown to ↓ the risk of neural tube defects in the fetus during the first trimes- ter of pregnancy low plasma folate is associated with high levels of plas- ma homocysteine, same with vits B 6 & B 12 Sources: whole-wheat flour, beans, nuts, liver & green leafy vegetables Metabolism: oral contraceptives, anticonvulsants, etha- nol, & cigarette smoking interfere with folate absorption & metabolism

140 chronic diseases (intestinal malabsorption & metasta- tic cancer combined folate & vit B 12 deficiency contribute to the development of colon cancer; mechanisms: (1) altered DNA methylation; (2) accumulation of cells in S phase with ↑ susceptibility of DNA damage; (3) alterations of nucleotide pools → impair DNA synthesis & repair vit B12 deficiency is associated with myelin degenera- tion in both sensory & motor pathways of the spinal cord, in contrast to folate deficiency

141 Mineral Deficiencies  Iron – essential component of hemoglobin and of iron containing metalloenzymes - hypochromic microcytic anemia  Zinc – component of enzymes, principally oxidases - acrodermatitis enteropathica, anorexia with diarrhea, growth retardation, impaired wound healing, hypogonadism with diminished reproduc- tive capacity, altered immune function, impaired night vision, depressed mental function, increased incidence of congenital malformations in infants

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143  Iodine – component of thyroid hormone - goiter and hypothyroidism  Selenium – component of glutathione peroxidase - myopathy, rarely cardiomyopathy  Copper – component of cytochrome c oxidase, dopa- mine β-hyrdoxylase, tyrosinase, lysyl oxidase & unknown enzyme involved in cross-linking keratin - muscle weakness, neurologic defects, hy- popigmentation, abnormal collagen cross-linking

144  Manganese – component of metalloenzymes, inc- luding oxidoreductases, hydrolases and lipases  Fluoride – unknown mechanism - dental caries


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