1. ENVIRONMENTAL PATHOLOGY
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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 Aminobiphenyl,2-naphthylamine
Oral cavity (smoking) polycyclic aromatic hydrocarbon,
NNK, NNN
Oral cavity (snuff) NNK, NNN, polonium 210

16. 200x higher affinity for Hgb than O2
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. obstructive lung disease
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. 10 cigars per day can cause fetal hypoxia
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. 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

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. LIVER 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:
mitochondrial injury
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. - increase myocardial O2 demand, dec O2 supply lea-
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
- 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% 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. sources of indoor air pollutants: tobacco smoke,
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. CATEGORY & SOURCE EFFECTS & DISEASES
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. radiation is energy distributed across electromagne-
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. Clinical Manifestations of Exposure to Ionizing Radiation
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 < mild nausea & % 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. Radiation Therapy – to the chest or abdomen, can
Central nervous > 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
Thermal Burns
- 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; 3rd & 4th
degree burns; grossly, white or charred, dry & anes-
hetic (due to nerve ending destruction)

89. partial-thickness burns: deeper portions of dermal
appendages are spared; 1st degree burns (epithelial
involvement only) & 2nd 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

97. NUTRITION
and
DISEASE

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)
A child whose weight falls to <80% of normal is con-
sidered malnourished
- Marasmus: malnutrition caused primarily by severe
reduction in caloric intake

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

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 α1- 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)2D by α1-hydro-
xylase in the kidney; most active form of vit D

114. 3 mechanisms regulating production of 1,25(OH)2D
(1) feedback loop, ↑ 1,25(OH)2D down-regulate synthe-
sis 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 α1-
hydoxylase
(3) Hypophosphatemia activates α1-hydroxylase, in-
creasing 1,25(OH)2D
- 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)

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. Vitamin K 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 B1)
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:
A polyneuropathy (dry beriberi)
A cardiovascular syndrome (wet beriberi)
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 B2)
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. 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 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 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 B6 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. Folate : 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 B12; deficiency of either folate or vit B12
→ 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 B6 & B12
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 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 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

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