Transcript Slide 1

OLGA MUNAR BAUSA, M.D., DPSP
MECHANISMS OF TOXICITY
• toxicology - detection, effects & mechanisms of action of poisons & toxic chemicals
•toxicity – relative phenomenon that depends on structure & properties of chemical
& on its dose
BASIC PRINCIPLES OF
XENOBIOTIC METABOLISM
• most xenobiotics are lipophilic
• lipophilic toxicants are metabolized to hydrophilic metabolites
- phase I rx: hydrolysis
: reduction
: oxidation
-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
• 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
PHASE 1 REACTIONS:
• Cytochrome P-450-dependent monooxygenase 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
- 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 increased risk of bladder cancer
PHASE II REACTIONS:
• Glucuronidation – secondary metabolite is
excreted in urine resulting to formation of Nhydroxy-2-naphthylamine
- increased incidence in cancer of urinary bladder in workers exposed to
synthetic dyes
• Biomethylation – inorganic mercury (HgCl2),
causes necrosis of proximal convoluted tubules
of kidneys
- exposure occurs in industries
manufacturing germicides, fungicides, electronics and plastics
• Glutathione conjugation – vinyl chloride used
in the manufacture of plastics, can cause angiosarcoma of the liver in exposed workers
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)
• 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
• irritants - nitrogen dioxide, formaldehyde
• cilia toxins – hydrogen cyanide
ORGAN
Lung, larynx
Esophagus
CARCINOGEN
polycyclic aromatic hydrocarbons
4-methynitrosoamino-1-3-pyridyl
-1-butanone (NNK)
polonium 210
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
• 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
- responsible for acute effects mediated by catecholamines ( increased heart
rate/BP, increased coronary blood flow, increased contractility & cardiac output and
mobilization of FFA
- also responsible for tobacco
addiction
• 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
• 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 smoking or environmental tobacco smoke (ETS)
- increases risk of lung cancer, IHD & acute
MI
- in infants & young children, causes increased
incidence of respiratory, ear infections
and asthma attacks
Alcohol Abuse
- ethanol from alcoholic drinks like beer,
wine & distilled spirits
- legal definition for drunk driving is
blood alcohol concentration of 100 mg/dl
- occasional drinkers, 200 mg/dl produces inebriation; coma, death & respiratory
arrest at 300-400 mg/dl
- habitual drinkers can tolerate levels
up to 700 mg/dl; this is due to increased induction by cytochrome P-450 xenobiotic metabolizing enzyme, CYP2E1.
- 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
Liver
Lesion
fatty change
acute hepatitis
alcoholic cirrhosis
Mechanism
toxicity
Nervous sys
Wernicke syndrome
Korsakoff syndrome
thiamine def
toxicity &
thiamine def
cerebellar degeneration nutritional def
peripheral neuropathy thiamine def
Cardiovascular cardiomyopathy
system
hypertension
toxicity
vasopressor
GIT
toxicity
toxicity
gastritis
pancreatitis
Skeletal muscle rhabdomyolysis
toxicity
Reproductive
system
testicular atrophy
spontaneous abortion
?
?
Fetal alcohol
syndrome
growth retardation
mental retardation
birth defects
toxicity
LIVER
- fatty change, acute alcoholic hepatitis & cirrhosis
• Fatty Change – acute, reversible
- mechanisms:
- increase catabolism of fat by peripheral tissues
increase delivery of FFA
- metabolism of ethanol & acetaldehyde converts nicotinamide adenine dinucleotide (NAD+) to reduced form, NADH; excess
NADH over NAD stimulates lipid synthesis
- oxidation of fatty acids by mitochondria is decreased
- acetaldehyde forms adducts with
tubulin, impairs function of microtubules
decrease transport of lipoproteins from liver
• 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 & cytokine release from Kupffer cells
- histo: focal areas of hepatocyte necrosis &
cell injury by fat accumulation & alcoholic
hyalin or mallory bodies; neutrophils accumulate around foci of necrosis
• Alcoholic Cirrhosis
- irreversible liver damage; chronic ethanol use
- gross: hard, shrunken liver
- histo: formation of micronodules of regenerating hepatocytes surrounded by dense bands
of collagen
- fatal ds; weakness, muscle wasting, ascites,
gastrointestinal hemorrhage & coma
- patients with cirrhosis have depleted liver
stores of alpha-tocopherol, increases their
vulnerability to oxidative injury
NERVOUS SYSTEM
- acute depressive effects & addiction are related to fluidization of membrane phospholipids
& altered signal transduction
- chronic thiamine deficiency leads to degeneration of nerve cells, reactive gliosis & atrophy
of cerebellum & peripheral nerves
- ataxia, disturbed cognition, ophthalmoplegia
& nystagmus (Wernicke syndrome)
- 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 catecholamines
- one to two drinks/day show protective effect;
increased levels of HDL & decreased platelet
aggregation
Gastrointestinal Tract
- acute gastritis, acute & chronic pancreatitis
Skeletal Muscle
- muscle weakness, pain & myoglobin breakdown
Reproductive System
-testicular atrophy; decreased fertility in men &
women, spontaneous abortion
Fetal Alcohol Syndrome
- consequence of maternal ethanol consumption at levels of one drink/day
- growth & developmental defects; growth
retardation, microcephaly, atrial septal defect etc.
-pathogenesis: acetaldehyde crosses the placenta & damages fetal brain
Ethanol and Cancer
- increased incidence of cancer of the oral cavity, pharynx, esophagus, liver & breast
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)
- simultaneous use of ethanol & barbiturates
is lethal, causing coma & CPA
-Diazepam (valium): safer sedative, can cause
drowsiness, dizziness & coma but do not induce cytochrome P-450 activity
• Psychomotor Stimulants
a. cocaine (crack): produces rapid “high” of
short duration (euphoria, increased energy and
stimulation
: chronic use can cause insomnia, increased anxiety, paranoia & hallucinations
: acute overdose causes seizures, cardiac 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
- CVS effects of cocaine: accumulation of catecholamines causes stimulation of alpha & beta-adrenergic
receptors ( increased BP, heart rate with coronary
spasms
- increase myocardial O2 demand, dec O2 supply leading 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
- causes fetal hypoxia
b. Amphetamines – overdose causes sweating, tremors
restlessness & confusion leading to delirium, convulsions, 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, sedation, mood changes, nausea & respiratory depression
- chronic abuse induces tolerance & psychologic dependence
- IV users susceptible to infections: 4 sites most commonly affected are skin/subcutaneous tissue, heart
valves, liver & lungs
- endocarditis, involving right sided heart valves (tricuspid); most common organism is S. aureus
- viral hepatitis, acquired by casual sharing of dirty
needles; incidence of AIDS also increasing
• Hallucinogens
- mescaline, psilocybin & marijuana
- active ingredient in marijuana is tetrahydrocannabinol (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
• 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
 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 protective against development of atherosclerosis
- progestins counters the estrogen effect; 40% to 50% decrease in the risk of
IHD in women who received postmenopausal estrogen therapy
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 women younger than 45 yrs, particularly nulliparous
women younger than 25 yrs
 endometrial cancer – no increased risk, OCs exert a
protective effect
 cervical cancer – increase risk correlated with duration 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 thrombosis & pulmonary thromboembolism due to increased hepatic synthesis of coagulation factors & reduced levels of antithrombin III
- <50 ug estrogens, less risk especially
in women younger than 35 yrs who do not smoke
- 3rd generation OCs (combine low dose
estrogens with synthetic progestins) reduces risk of
MI but confer higher risk of venous thrombosis than
2nd generation OCs
 hypertension – slight increase in BP
 cardiovascular disease – approximately 29% increased risk of MI, especially during the first yr of combined HRT use.
 cholecystitis – increased risk of gallbladder disease
Acetaminophen
- when taken in large doses will cause hepatic necrosis; toxic dose is 15-25 gm
- nausea, vomiting, diarrhea, shock followed by jaundice
- serious overdosage causes liver failure, with centrilobular necrosis involving entire lobule
- concurrent renal & myocardial damage seen in some
patients
Aspirin (Acetylsalicylic Acid)
- overdose in children result from accidental ingestion;
in adults, suicidal
- toxic dose in children is 2-4 gm; in adults, 10-30 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 changes may lead to convulsions & coma
: 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
OUTDOOR AIR POLLUTION
- major sources of ambient air pollutants are:
 combustion of fossil fuels – motor vehicles (complex
mixtue of carbon monoxide, oxides of nitrogen, hydrocarbons, diesel exhaust particles, lead oxide
 photochemical reactions- oxides of nitrogen & volatile hydrocarbons interact in the atmosphere to produce ozone
 power plants – release sulfur dioxide
Health Effects of Outdoor Air Pollutants
POLLUTANT
Ozone
POPULATIONS AT RISK
healthy adults & children
EFFECTS
athletes, outdoor workers
asthmatics
decreased lung function
increased airway reactivity
lung inflammation
decreased exercise capacity
increased hospitalizations
Nitrogen
dioxide
healthy adults
asthmatics
children
increased airway reactivity
decreased lung function
increased respiratory infcxn
Sulfur
dioxide
healthy adults
px with chr lung ds
increased respiratory sx
increased mortality
increased hospitalization
decreased lung function
asthmatics
Acid arosols
healthy adults
children
asthmatics
altered mucociliary clearance
increased respiratory infcxn
decreased lung function
Particulates
children
increased respiratory infcxn
decreased lung function
excess mortality
px with chronic lung
& heart ds
asthmatics
increased attacks
INDOOR AIR POLLUTION
-sources of indoor air pollutants: tobacco smoke,
gas cooking stoves & furnaces, wood stoves, construction materials, furniture, radon, allergens ( pets,
dust mites, fungal spores & bacteria
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 &
abatement workers
lung cancer, mesothelioma
Manufactured
mineral fibers
maintenance &
construction workers
skin & airway irritation
Bioaerosols
adults & children
allergic rhinitis, asthma
INDUSTRIAL EXPOSURES
 VOLATILE ORGANIC COMPOUNDS
Aliphatic Hydrocarbons – industrial solvents & drycleaning agents
- absorbed thru the lungs, skin & GIT
- eg: chloroform & CCl4; both are carcinogenic in rodents
- methylene chloride used in paint removers & aerosols; metabolized by cytochrome P-450
to CO2 & CO; CO causes respiratory depression &
death
- acute exposure of perchloroethylene
causes CNS depression, confusion, dizziness, impaired gait & nausea; repeated exposures causes
dermatitis; human carcinogen
Petroleum Products – gasoline, kerosene, mineral oil
& turpentine
- inhalation causes dizziness, incoordination & CNS depression
Aromatic Hydrocarbons – benzene, toluene & xylene
genic
- toluene & xylene are not carcino-
- 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
 PLASTICS, RUBBER AND POLYMERS
- occupational exposure to vinyl chloride monomers
used to produce polyvinyl chloride resins is associated 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 associated with increased risk of leukemia
 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 ceramics, lead solder in food & softdrink cans
- absorbed lead is 80 to 85% taken up by bone
bone & developing teeth in children; blood accumulates 5 to 10 % ; remainder in soft tissues
- 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 enzymes in heme biosynthesis:
-aminolevulinic
acid dehydratase & ferroketolase leading to microcytic hypochromic anemia
• competition with calcium ions – also interferes with
nerve transmission & brain development
• inhibition of membrane-associated enzymes – inhibits 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- encephalopathy, mental deterioration
• gingiva: lead line
• blood: microcytic, hypochromic anemia; red cell
basophilic stippling
• peripheral nerves: demyelination
• 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 refinery & farm workers
Beryllium
acute lung irritant
beryllium refining, aero-
chronic lung hypersxn
? Lung cancer
space manufacturing,
ceramics
Cobalt &
lung fibrosis
Tungsten carbide asthma
toolmakers, grinders,
diamond polishers
Cadmium
renal toxicity
? Prostate cancer
battery workers, smelters,welders, soldering
Chromium
lung & nasal CA
pigment workers, smelters, steel workers
Nickel
lung & nasal sinuses CA
smelters, steel workers,
electroplating
AGRICULTURAL HAZARDS
HEALTH EFFECTS OF AGRICULTURAL PESTICIDES
CATEGORY
EXAMPLE
EFFECTS & DISEASE
Insecticides
Organochlorines
DDT
Chlordane
Lindane
Methoxychlor
Organophosphates
Parathion
Diazinon
Malathion
Carbamates
Aldicarb
Carbaryl
neurotoxicity; hepatoxivity
neurotoxicity; delayed
neuropathy
neurotoxicty (reversible)
Botanical agents
Nicotine
Pyrethrins
Rotenone
Herbicides
Arsenic compds
Dinitrophenols
Chlorophenoxy
2,4-D & 2,4,5-T
TCDD
Paraquat
Atrazine
Alachlor
Paresthesia; lung irritant;
allergic dermatitis
Hyperpigmentation;gangrene; anemia, sensory neuropathy; cancer
Hyperthermia; sweating
? Lymphoma; sarcoma
fetotoxicity; immunotoxicity
cancer
acute lung injury
? Cancer
? cancer
Fungicides
Captan
Maneb
Benomyl
? Reproductive toxicity
Rodenticides
Fluoroacetate
Warfarin
Strychnine
cardiac & resp failure
hemorrhage
respiratory failure
Fumigants
Carbon disulfide
Ethylene dibromide
Phosphine
Chloropicrin
cardiac toxicity
neurotoxicity
lung edema; brain damage
eye irritation; lung edema;
arrhythmias
NATURAL TOXINS
CATEGORY &
EXAMPLE
Mycotoxins
ergot alkaloids
aflatoxins
tricothecenes
Phytotoxins
cycasin
monocrotaline
safrole
solanine
SOURCE
EFFECTS & DISEASES
Claviceps fungi
gangrene, convulsions,
abortion
Aspergillus flavus
liver cancer
Fusarium, Trichoderma diarrhea, ataxia
Cycad flour
Senecio plants
Black pepper
Soanaceae plants
(potato)
amyotrophic lateral sclerosis
hepatitis
cancer
neurotoxin
Animal toxins
venoms
saxitoxin
ciguatoxin
snakes
bees
dinoflagellates
dinoflagellates
tetrodotoxin
puffer fish
cardiotoxin, neurotoxin
direct toxicity, cardiotoxin
neurotoxin, paralysis
paresthesia, paresis, vomiting, diarrhea
neurotoxin, shock
RADIATION INJURY
- radiation is energy distributed across electromagnetic spectrum as waves (long wavelengths, low frequency) or particles (short wavelengths, high frequency)
-nonionizing radiation is characterized by long wavelengths & low frequencies; eg are electric power, radio waves & microwaves, infrared & ultraviolet light
-ionizing radiation is characterized by short wavelengths & high frequency; eg are X-rays, gamma rays &
cosmic rays
-Particulate radiation is classified by the type of particles emitted: alpha, beta, electrons, protons, neutron
 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 aberrations, & 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
ACUTE INJURY AND DELAYED COMPLICATIONS
CAUSED BY IONIZING RADIATION
ORGAN
ACUTE INJURY
DELAYED COMPLICATIONS
Bone marrow
atrophy
hypoplasia, leukemia
Skin
erythema
epidermal atrophy; dermal fibrosis; cancer
Heart
------
interstitial fibrosis
Lung
edema, endothelial
& epithelial cell death
interstitial & intra-alveolar
fibrosis; cancer
GIT
edema, mucosal
ulcers
ulcers; fibrosis; strictures; adhesions; cancer
Liver
veno-occlusive disease
cirrhosis; liver tumors
Kidney
vasodilation
cortical atrophy, interstitial
fibrosis
Urinary
bladder
mucosal erosion
submucosal fibrosis
Brain
edema, necrosis
necrosis of white matter,
gliosis; brain cancer
Testis
necrosis
tubular atrophy
Ovary
atresia of follicles
stromal fibrosis
Thyroid
------
hypothyroidism; cancer
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
Clinical Features of the Acute Radiation Syndrome
CATEGORY
Subclinical
Hematopoietic
WHOLE-BODY
DOSE (rem)
<200
200-600
SYMPTOMS
PROGNOSIS
mild nausea &
vomiting; lymphocytes <1500/ul
100% survival
intermittent n & V
petechiae, hge
infections
may require BM
transplant
max neutrophil &
platelet dep in 2 wk
lympho <1000/ul
Gastrointestinal 600-1000
N,V, diarrhea
shock & death in
hge & infcxn in 1-3 wk 10-14 days even
severe n & p dep
w/ replacement
lympho <500/ul
therapy
Central nervous
system
>1000
intractable n&v
death in 14-36 hr
confusion, somnolence, convulsions
coma in 15min-3 hr
lymphos absent
 Radiation Therapy – to the chest or abdomen, can
cause acute radiation sickness & neutrophil & platelet 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
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 abnormalities of the CNS & reproductive system; increased incidence of childhood leukemia & brain
tumors
• Postnatal period – retardation of bone growth & maturation in infants & young children
 Induction of Mutations – chromosome aberrations &
Mutations when exposed to ionizing radiation
 Delayed Radiation Injury – delayed complications include 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:
• Blood vessels – show subintimal fibrosis, fibrosis of
muscle wall, degeneration of internal elastic lamina &
severe narrowing of lumen
• Skin- chronic changes in the skin & hair follicles include desquamation replaced by atrophic epidermis
with hyperkeratosis, hyperpigmentation & hypopigmentation
- 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
• Heart – fibrosis of the pericardium can cause constrictive pericarditis; injury to the capillaries & corories can cause myocardial ischemia & fibrosis
• Lungs – acute lung injury & delayed radiation pneumonitis; 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 glomerular hyalinization develop leading to hypertension &
atrophy
- UB is sensitive with acute necrosis of
epithelium followed by submucosal fibrosis, contracture, bleeding & ulceration
• Gastrointestinal tract – esophagitis, gastritis, enteritis, 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 15-20 years
- 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 & infertility; blood vessels obliterated & seminiferous tubules become fibrotic
• Eyes & central nervous system – lens is sensitive
causing cataracts; retinal & ciliary arteries may also
be damaged; brain shows focal necrosis & demyelination of white matter; spinal cord, small blood
vessels are damaged leading to necrosis, demyeli-
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 & reversible: erythema, pigmentation & injury to langerhans
cells & keratinocytes in the epidermis
- repeated exposure to UVR give rise to premature aging of skin; IR increases deposition of collagen in the dermis while UVR causes degenerative
changes in elastin & collagen (wrinkling, increased
laxity & leathery appearance); irreversible changes
PHYSICAL ENVIRONMENT
 Mechanical Force
• Abrasion – scrape, superficial epidermis is torn off by
friction or force
• 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
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
• Gunshot wounds – close range gunshot wound(within 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 powder 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 present
- exit wounds are more irregular than entrance wounds, margins may be everted, no fouling
or stippling with little surrounding abrasion
 Thermal Injuries
Thermal Burns
- clinical significance depends on : depth of the burn;
percentage of body surface involved; presence of internal 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; 3rd & 4th
degree burns; grossly, white or charred, dry & aneshetic (due to nerve ending destruction)
-partial-thickness burns: deeper portions of dermal
appendages are spared; 1st degree burns (epithelial
involvement only) & 2nd degree burns (both epidermis & 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 & swelling leading to partial or complete airway obstruction
- secondary infection is an important complication in
all burn patients who have lost epidermis; organ system 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 metabolic rate is twice normal rsulting to breakdown of
tissue, loss of protein stores & starvation
Hyperthermia – prolonged exposure to elevated ambient 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; sudden onset with prostration & collapse; results from
failure of CVS to compensate for hypovolemia secondary to water depletion
• Heat stroke – associated with high ambient tempetures & high humidity; marked generalized peripheral vasodilation with peripheral pooling of blood and
decreased effective circulating blood volume; necrosis 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 regulatory impulses producing cardiac arrest or may cause
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 intensity 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 arborizing burns in the skin known as lightning marks
Injuries Related to Changes
in Atmospheric Pressure
• High-Altitude Illness – mountain climbers with altitudes above 4000 m; lowered O2 tension produces
progressive mental obtundation accompanied by increased 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)
- 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 atmospheric pressure
- function of Henry’s law, states that the solubility of a gas in a liquid (blood) is proportional to
the partial pressure of that gas in the environment
- as the underwater depth & atmospheric pressure increase, increasing amount of oxygen & gases
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 producing emboli in the bloodstream; periarticular bubbles 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 aseptic necrosis of the femoral & humeral heads & medullary foci of the lower femur & upper tibia
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 compartment (skeletal muscles) & visceral compartment ( protein stores in visceral organs, primarily the liver)
- A child whose weight falls to <80% of normal is considered malnourished
- Marasmus: malnutrition caused primarily by severe
reduction in caloric intake
: 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 visceral protein compartment resulting to hypoalbuminemia giving rise to generalized or dependent edema
: child with marasmus suffers growth retardation & loss of muscle; loss of muscle results from
catabolism & depletion of the somatic protein compartment
: 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; extremities are emaciated; presence of anemia & multivitamin deficiencies; immune deficiency (T cell mediated
: relative sparing of subcutaneous fat &
muscle mass; skin lesions with alternating zones of hyperpigmentation, areas of desquamation & hypopigmentation (“flaky paint” appearance)
: hair changes include loss of color or alternating 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 apathy, listlessness & loss of appetite
-Secondary PEM : seen in chronically ill or hospitalized patients; common complication in advanced can-
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) wasting of the quadriceps femoris & deltoid muscles; (3)
ankle or sacral edema
Comparison of Severe Marasmus-Like and Kwashiorkor
Like Secondary Protein-Energy Malnutrition
SYNDROME
Marasmus
Like PEM
CLINICAL
SETTING
TIME CLINICAL LAB
PROGNOSIS
COURSE FEATURES FINDINGS
Chronic illness mos
hx of wt N or mildly depends
(chr lung ds; CA)
loss; muscle reduced
on under
wasting; ab- serum Pr lying ds
sent subcu fat
Kwashior- Acute, cataboKor like
lic illness
PEM
(severe trauma,
burns, sepsis)
wks
N fat &
serum
muscle;
albumin
edema;
<2.8 gm/dl
easily
pluckable hair
poor
 Morphology
-Central anatomic changes in PEM are (1) growth failure (2) peripheral edema in kwashiorkor (3) loss of
body fat & atrophy of muscle more severe in marasmus
Liver
Small bowel
BM
Brain
kwashiorkor
marasmus
enlarged & fatty
normal
mucosal atrophy; loss
rare
of villi & microvilli; disaccharidase deficiency
hypoplastic (↓red cell precursors); folate
deficiency ( microcytic-macrocytic anemia)
cerebral atrophy
cerebral atrophy
 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 excess carotene in the blood
d. Decreased bone density due to low estrogen level
: major complication is increased susceptibility 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 previously healthy young women with obsession of attaining
thinness.
: amenorrhea occurs in < 50% of cases
: major medical complications is related to con –
tinual induced vomiting and include: 1) electrolyte imbalances (hypokalemia); 2) pulmonary aspiration of
gastric contents; 3) esophageal & cardiac rupture
Vitamin Deficiencies
 Fat soluble : A, D, E and K
 Water soluble
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 pigment; impt in reduced light
: 3 iodopsins (cone cells) – each responsive
to specific colors in bright light
- synthesis of rhodopsin from retinol involves: (1) oxidation to all-trans-retinal (2) isomerization to 11-cisretinal during dark adaptation (3) interaction with opsin to form rhodopsin
• retinoic acid regulates the expression of genes encoding 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
- 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 (keratomalacia); total blindness
• epithelium lining the upper respiratory passages &
urinary tract is replaced by keratinizing squamous
cells ( squamous metaplasia) causing pulmonary
infections & renal & urinary bladder stones
• immune deficiency causing common infections such
as measles, pneumonia & infectious diarrhea
- Toxicity
• acute toxicity- headache, vomiting, stupor & papilledema
• chronic toxicity- associated with weight loss, nausea
& vomiting; dryness of the lip mucosa; bone &
joint pain; hyperostosis; hepatomegaly with
parenchymal damage & fibrosis; osteoclast formation causing ↑ bone resorption & osteoporosis
leading to fractures
 Vitamin D
- Metabolism
• two sources: endogenous synthesis in the skin & diet
• (1) absorption of vit D in the gut or synthesis from precursors in the skin
(2) Binding to a plasma α1- globulin (D binding protein)
& transport to liver
(3) Conversion to 25-hydroxyvitamin D by 25-hydroxylase in the liver
(4) Conversion of 25(OH)D to 1,25(OH)2D by α1-hydroxylase in the kidney; most active form of vit D
• 3 mechanisms regulating production of 1,25(OH)2D
(1) feedback loop, ↑ 1,25(OH)2D down-regulate synthesis by inhibiting action of α1-hydroxylase, & ↓ levels
have the opposite effect
(2) Hypocalcemia stimulates secretion of PTH which
converts 25(OH)D to 1,25(OH)2D by activating α1hydoxylase
(3) Hypophosphatemia activates α1-hydroxylase, increasing 1,25(OH)2D
- Functions
• maintenance of normal plasma level of calcium &
phosphorous
• stimulates intestinal absorption of Ca & phosphorous
• with hypocalcemia , collaborates with PTH in the mobilization 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
• gross skeletal changes depends on the severity of rachitic process, its duration & the stresses to which individual bones are subjected
-Softened occipital bones are flattened, parietal bones
buckled inward by pressure; release of pressure, elastic recoil snaps the bones back into their original positions (craniotabes)
-Excess of osteoid produces frontal bossing & squared
appearance to the head
-Rachitic rosary: overgrowth of cartilage or osteoid tissue at the costochondral junction causing deformation of the chest
-Pigeon breast deformity: anterior protrusion of the
sternum due to inward bending of the respiratory muscles due to weakened metaphyseal areas of the ribs
-Harrison’s groove: inward pull at the margin of the diaphragm, 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 lordosis & 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 & vulnerable to fractures & microfx (vertebra & femoral neck)
-histo: unmineralized osteoid appears a thickened layer of of matrix arranged about the more basophilic,
normal mineralized trabeculae
-Osteoporosis results from reduced production of osteoid 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
• After absorption, Vit E is transported in the blood (chylomicrons); 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 peroxidation chain rxns (cellular & subcellular membranes rich in polyunsaturated lipids)
• together with selenium, they metabolize peroxides before they can cause membrane damage
- Deficiency States
• nervous system is the target of vit E deficiency; neurons
with long axons are vulnerable due to their large membrane surface area
• mature red cells also affected in Vit E def due to oxidative 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
- 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 dyingback 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 position & vibration sense; loss of pain sensation
-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 formation by reducing LDL oxidation; scavenge free radicals→prevents DNA damage & mutagenesis→ ↓ CA
 Vitamin K
- Functions
• required cofactor in hepatic carboxylation of procoagulants – factors II (prothrombin), VII, IX & X; protein
C & protein S
• Carboxylation provides Ca dependent interaction of
the clotting factors with a phospholipid surface involved in generation of thrombin
• Carboxylation of osteocalcin, a noncollagenous protein 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
• development of bleeding diathesis; hemorrhagic ds
of the newborn; intracranial hemorrhage, bleeding
in the skin, umbilicus & viscera
• in adults, bleeding diathesis characterized by hematomas, hematuria, melena, ecchymoses & bleeding from
the gums
 Thiamine (Vitamin B1)
• gut absorption→phosphorylation→thiamine pyrophosphate ( active form)
-3 major functions: (1) regulates oxidative decarboxylation of α-ketoacids → adenosine triphosphate; (2) acts
as cofactor for transketolase in the pentose phosphate
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;
•
i.
ii.
iii.
3 distinctive syndromes:
A polyneuropathy (dry beriberi)
A cardiovascular syndrome (wet beriberi)
Wernicke-Korsakoff syndrome
• polyneuropathy is symmetric & takes the form of nonspecific peripheral neuropathy with myelin degeneration; 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 vasodilation→AV shunting of blood→high output cardiac failure→peripheral edema
- heart is markedly enlarged & globular
(four-chamber dilation) with pale, flabby myocardium;
mural thrombi present in the dilated atria
• Wernicke-Korsakoff syndrome- in severe deficiency
states; Wernicke encephalopathy is marked by ophthalmoplegia, 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 thalamus, floor of the fourth ventricle & anterior region
of the cerebellum
 Riboflavin (Vitamin B2)
-Functions: converted to coenzymes flavin mononucleotide & 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 cancer, debilitating diseases & anorexia nervosa
• Cheilosis – first & most characteristic sign; begins as
areas of pallor at the angles of the mouth;
later, cracks or fissures appear from corners 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 stages, superficial layers of cornea are invaded by capillaries; interstitial inflammatory infiltration & exudation →opacities &
ulcerations of the cornea
• 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 derivative, nicotinamide
• essential component of 2 coenzymes, NAD & NADP,
important in cellular intermediary metabolism
• NAD – coenzyme involved in fat metabolism, CHO &
amino acids
• NADP – involved in dehydrogenation rxns, hexosemonophosphate 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”
I.
Dermatitis – bilaterally symmetric; found on exposed areas of the body; redness, thickening
& roughening of the skin; extensive scaling &
desquamation→fissures & chronic inflammation; occur in mucous membranes of mouth
& vagina
ii Diarrhea – caused by atrophy of columnar epithelium of the GIT followed by submucosal inflammation & ulceration
iii Dementia – results from degeneration of the neurons in brain with degeneration of corresponding tracts in the spinal cord
 Pyridoxine (Vitamin B6)
-Consists of pyridoxine, pyridoxal & pyridoxamine with
their phosphate forms
• converted in tissues to coenzyme form, pyridoxal
5-phosphate→participates as a cofactor of enzymes involved in transamination, carboxylations & deaminations
in lipid & AA metabolism
• present in all foods; deficiency seen in patients under
isoniazid tx; estrogens & penicillamine;in alcoholics because of acetaldehyde (alcohol metabolite)→pyridoxine
degradation
• given to pregnant women
• vit B6 deficiency is associated with high levels of plasma homocysteine→ risk factor for atherosclerosis
• clinical findings same with riboflavin & niacin deficiency → seborrheic dermatitis, cheilosis, glossitis, peripheral neuropathy & sometimes convulsions
 Vitamin C (Ascorbic Acid)
• Source: diet; cannot be synthesized endogenously; present in milk, liver, fish, fruits & vegetables
• 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 synthesis → inadequate support of walls of capillaries
& venules → purpura & ecchymoses in skin & gingival mucosa
: loose attachment of periosteum to bone with
vascular wall defects →subperiosteal hematomas &
bleeding into joint spaces with mild trauma
: retrobulbar, subarachnoid & intracerebral hemorrhages 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 & abnormal depression of the sternum with outward projection of the ribs
: in severely scorbutic children & adults → gingival 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; conversion of 5-methyltetrahydrofolate to tetrahydrofolate
requires vit B12; deficiency of either folate or vit B12
→ megaloblastic anemia
• folate supplements have been shown to ↓ the risk of
neural tube defects in the fetus during the first trimester of pregnancy
• low plasma folate is associated with high levels of plasma homocysteine, same with vits B6 & B12
• Sources: whole-wheat flour, beans, nuts, liver & green
leafy vegetables
• Metabolism: oral contraceptives, anticonvulsants, ethanol, & cigarette smoking interfere with folate absorption
& metabolism
• chronic diseases (intestinal malabsorption & metastatic cancer
• combined folate & vit B12 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 degeneration in both sensory & motor pathways of the spinal
cord, in contrast to folate deficiency
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 reproductive capacity, altered immune function, impaired
night vision, depressed mental function, increased
incidence of congenital malformations in infants
 Iodine – component of thyroid hormone
- goiter and hypothyroidism
 Selenium – component of glutathione peroxidase
- myopathy, rarely cardiomyopathy
 Copper – component of cytochrome c oxidase, dopamine β-hyrdoxylase, tyrosinase, lysyl oxidase &
unknown enzyme involved in cross-linking keratin
- muscle weakness, neurologic defects, hypopigmentation, abnormal collagen cross-linking
 Manganese – component of metalloenzymes, including oxidoreductases, hydrolases and
lipases
 Fluoride – unknown mechanism
- dental caries