Histopathreport

Effects of Tobacco
It is the most common exogenous cause of
human cancers, being responsible for 90% of
lung cancers
The main culprit is the cigarette smoking but
smokeless tobacco (snuff, chewing tobacco,
etc.) is also harmful to health and an
important cause of oral cancer

When you inhale smoke, these chemicals
enter your lungs and spread around the rest of
your body
 Tar, not nicotine, is the cancer-causing
agent in cigarette smoke
 The use of tobacco products not only creates
personal risks but passive tobacco inhalation
from the environment (Secondhand smoker)
can cause lung cancer in non-smokers

EFFECTS OF SELECTED TOBACCO SMOKE CONSTITUENTS
Substance Effects
Tar Carcinogenesis
Polycyclic aromatic hydrocarbons Carcinogenesis
Nicotine Ganglionic stimulation and
depression; tumor production
Phenol Tumor production; mucosal irritation
Benzopyrene Carcinogenesis
Carbon monoxide Impaired oxygen transport and
utilization
Formaldehyde Toxicity to cilia; mucosal irritation
Oxides of nitrogen Toxicity to cilia; mucosal irritation
Nitrosamine Carcinogenesis

Adverse effects
of smoking:
those that are
more common
are in boldface

Lung Cancer
Genetic and epigenetic changes lead to cancer
through alteration of critical cellular pathways
that foster uncontrolled cell growth and
defeat of normal mechanisms to restrain their
growth and spread
Exposure to cigarette smoke carcinogens
leads to DNA damage and subsequent
mutations in P53 and K-RAS in lung cancer.

Lung Cancer
Normal Lung Lung with cancer

How smoking damages your lungs

Smoking leads to heart attack
and stroke
Smoking is one cause of dangerous plaque
buildup inside your arteries
 Plaque is made of cholesterol and scar tissue.
It clogs and narrows your arteries. This can
trigger chest pain, weakness, heart attack, or
stroke. Plaque can rupture and cause clots that
block arteries
 Completely blocked arteries can cause sudden
death

Emphysema
The lung is made up of numerous minute
air sacs called alveoli, each surrounded
by very thin walls. Networks of capillaries
run through these walls and exchange of
carbon dioxide with oxygen takes place
between the blood in those capillaries
and the air in the alveoli

Emphysema
The alveolar walls are vested
with elastic fibers so that they
can stretch with inhalation and
recoil with exhalation

Emphysema
Emphysema is a pathological
condition of the lung that results
from breakdown of the elastic fibers.
This ultimately leads to disruption of
the alveolar walls themselves, due to
rupture of the alveoli from over
inflation

LIVER
• Fatty changes
• Alcoholic hepatitis
• Cirrhosis

Downloaded from: StudentConsult (on 23 June 2013 05:17 AM)
© 2005 Elsevier

PANCREATITIS
• Characterized by inflammation which may
ultimately lead to scarring

USE OF ETHANOL DURING
PREGNANCY
• Fetal alcohol syndrome
–Microcephaly
–Growth retardation
–Facial abnormalities in newborns
–Reduction in mental functions as the child
grows older

Injury by Therapeutic Drugs &
Drugs of Abuse

Injury by Therapeutic Drugs
Adverse drug reactions (ADRs) refer to untoward
effects of drugs that are given in conventional
therapeutic settings. These reactions are
extremely common in the practice of medicine
and affect almost 10% of patients admitted to a
hospital.

Oral Contraceptives (Ocs)
• Always contain a synthetic estradiol and a
variable amount of a progestin. They act by
inhibiting ovulation or preventing
implantation.
• There is evidence that the use of OCs is
associated with
thromboembolism, cardiovascular
disease, and hepatic adenoma.

Anabolic Steroids
• Anabolic steroids are synthetic versions of
testosterone, and for performance
enhancement they are used at doses that are
about 10 to 100 times higher than therapeutic
indications.

• Anabolic steroids have multiple adverse
effects including stunted growth in
adolescents, acne, gynecomastia and
testicular atrophy in males, and growth of
facial hair and menstrual changes in women.
Other effects include psychiatric problems and
premature heart attacks.

Acetaminophen
• Acetaminophen is the most commonly used
analgesic in the United States.
• Toxicity begins with nausea, vomiting,
diarrhea, and sometimes shock, followed in a
few days by evidence of jaundice.

Aspirin (Acetylsalicylic Acid)
• A source of salicylate poisoning is the
excessive use of ointments containing oil of
wintergreen (methyl salicylate).
• Proprietary analgesic mixtures of aspirin and
phenacetin or its active metabolite,
acetaminophen, when taken over several
years, can cause analgesic nephropathy.

INJURY BY NONTHERAPEUTIC AGENTS
(DRUG ABUSE)
• Drug abuse generally involves the use of mind-
altering substances, beyond therapeutic or
social norms.

Cocaine
• Cocaine is extracted from the leaves of the
coca plant, and is usually prepared as a water-
soluble powder, cocaine hydrochloride.
• Sold on the street, it is liberally diluted with
talcum powder, lactose, or other look-alikes.

Heroin
• Heroin is an addictive opioid derived from the
poppy plant that is closely related to
morphine. Its use is even more harmful than
that of cocaine.
• Effects are varied and include
euphoria, hallucinations, somnolence, and
sedation.

Methamphetamine
• Also known as speed or meth.
• It acts by releasing dopamine in the brain,
which inhibits presynaptic neurotransmission
at corticostriatal synapses, slowing glutamate
release.
• Long-term use leads to violent behaviors,
confusion, and psychotic features that include
paranoia and hallucinations.

MDMA
• MDMA (3,4
methylenedioxymethamphetamine) is
popularly known as ecstasy.
• It is generally taken orally. Its effects, which
include euphoria and hallucinogen-like
feelings that last for 4 to 6 hours, are mainly
due to an increase in serotonin release in the
CNS.

Marijuana
• Marijuana, or pot, is made from the leaves of
the Cannabis sativa plant, which contain the
psychoactive substance 9-
tetrahydrocannabinol (THC).
• Its use distorts sensory perception and impairs
motor coordination. With continued use these
changes may progress to cognitive and
psychomotor impairments

80 mg/dL3
bottles 15 oz 4-5 oz

Figure 9-12 Metabolism of ethanol: oxidation of ethanol to acetaldehyde by three different routes, and the generation of acetic acid. Note that oxidation by ADH (alcohol
dehydrogenase) takes place in the cytosol; the cytochrome P-450 system and its CYP2E1 isoform are located in the endoplasmic reticulum (microsomes), and catalase is located in
peroxisomes. Oxidation of acetaldehyde by ALDH (aldehyde dehydrogenase) oc-curs in mitochondria. ADH oxidation is the most important route; catalase is involved in only 5% of
ethanol metabolism. Oxidation through CYPs may also generate reactive oxygen species (not shown). (From Parkinson A: Biotransformation of xenobiotics. In Klassen CD [ed]: Casarett
and Doull's Toxicology: The Basic Science of Poisons, 6th ed. New York, McGraw-Hill, 2001, p 133.)
© 2005 Elsevier

ACETALDEHYDE
• Responsible for some of the
acute affects of alcohol and;
• Development of oral cancers

ACETALDEHYDE
• Efficiency of alcohol metabolism varies
between populations, depending on:
–Expression levels of ADH and ALDH
isoenzymes
–Presence of genetic variants that alter
enzyme activity

ACETALDEHYDE
• ALDH2*1
– Normal allele
• ALDH2*2
– Inactive variant
– Dominant-negative activity
• One copy of ALDH2*2 reduces ALDH activity
significantly

ALCOHOL OXIDATION BY ADH
• Causes reduction of NAD to NADH
– Consequent ↓ in NAD and ↑ in NADH
• NAD deficiency is a main cause of fat
accumulation in the liver of alcoholics
• ↑ NADH/NAD ratio in alcoholics causes lactic
acidosis

METABOLISM OF ETHANOL IN THE
LIVER BY CYP2E1
• Produces ROS
• Causes lipid peroxidation of cell membranes
• Alcohol also causes release of endotoxin (lps)
from gm— bacteria in the intestinal flora
– Stimulates production of TNF and other cytokines
from macrophages and Kupffer cells, leading to
hepatic injury

ACUTE ALCOHOLISM
• Exerts its effects mainly on the CNS
– But may induce hepatic and gastric changes
• Reversible if alcohol consumption is discontinued
• Multiple fat droplets accumulate in the
cytoplasm of heptocytes (fatty change or
steatosis)

ACUTE ALCOHOLISM
• Gastric changes:
–Acute gastritis
–ulceration

ACUTE ALCOHOLISM
• CNS:
–Depressant
–Consequently, there is stimulation &
disordered cortical, motor & intellectual
behavior

ACUTE ALCOHOLISM
• CNS:
–At progressively higher blood levels, cortical
neurons & lower medullary centers are
depressed
• including those that regulate respiration
RESPIRATORY ARREST

CHRONIC ALCOHOLISM
• Affects:
–Liver
–Stomach
–All other tissues and organs

CHRONIC ALCOHOLISM
• Chronic alcoholics suffer significant morbidity
and have a shortened life span, related
principally to damaged…
Liver
GIT
CNS
Cardiovascular system
pancreas

CHRONIC ALCOHOLISM
GASTROINTESTINAL
TRACT

GASTROINTESTINAL TRACT
• Massive bleeding from:
– Gastritis
– Gastric ulcer
– Esophageal varices (associated with cirrhosis)

CHRONIC ALCOHOLISM
THYMINE
DEFICIENCY

THYMINE DEFICIENCY
• Principal lesions:
– Peripheral neuropathies
– Wernicke-Korsakoff syndrome
– Cerebral atrophy
– Cerebellar degeneration
– Optic neuropathy

CHRONIC ALCOHOLISM
CARDIOVASCULAR
SYSTEM

CARDIOVASCULAR SYSTEM
• Injury to the myocardium may produce dilated
congestive cardiomyopathy (alcoholic
cardiomyopathy)
• Chronic alcoholism is associated with ↑
incidence of hypertension

• Moderate amounts of alcohol (20-30 g of
daily intake=250 mL of wine)
–↑ HDL levels
–Inhibit platelet aggregation
• Thus protecting against coronary heart dse

• Heavy alcohol consumption, with
attendant liver injury,
–results in ↓ HDL levels
• ↑ likelihood of CHD

PANCREAS
• Excessive alcohol intake
↑ risk of acute and chronic
pancreatitis

CHRONIC ALCOHOLISM
USE OF ETHANOL
DURING
PREGNANCY

USE OF ETHANOL DURING
PREGNANCY
• Consumption during the 1st trimester
is particularly harmful

CANCER
• Chronic alcohol consumption is associated
with ↑ incidence of cancer of the:
– Oral cavity
– Esophagus
– Liver
– Breast

CANCER
• Acetaldehyde is considered to be the
main agent associated with
alcohol-induced laryngeal and
esophageal cancer

RESVERATOL in Red Wine
• Contributes to the protective effect
against CVD in moderate wine
drinkers and possibly provides the
clue to the “French paradox”

INJURY PRODUCED BY
IONIZING RADIATION

RADIATION
• Non-ionizing radiation
–Can move atoms in a molecule or cause
them to vibrate, but is NOT sufficient to
displace bound electrons from atoms
• Ionizing radiation
–Has sufficient energy to remove tightly
bound electrons

NON-IONIZING RADIATION IONIZING RADIATION
•Alpha particle
•Beta particle
•High-energy neurons
•Gamma rays
X-ray
UV Micro-
wave
infrared
Micro-
wave
Sound/radio
wave

IONIZING RADIATION
Merits Demerits
•Treatment of cancer
•Diagnostic imaging
•Therapeutic or
diagnostic
radioisotopes
•Fibrosis
•Mutagenesis
•Carcinogenesis
•Teratogenesis

Main Determinants of the Biologic
Effects of Ionizing Radiation
• Rate of Delivery
–Although the effect of radiant energy is
cumulative, divided doses may allow cells to
repair some of the damage between
exposures
–In fractionated doses of radiant
energy, repair during “recovery” intervals is
incomplete
• Radiation therapy of tumors exploits
the general capability of normal cells
to repair themselves and recover
more rapidly than tumor cells, and
thus not sustain as much cumulative
radiation damage

• Field size
–The body can sustain relatively high
doses of radiation when delivered to
small, carefully shielded fields,
whereas smaller doses delivered to
large fields may be lethal

• Cell proliferation
–Because ionizing radiation damages
DNA, rapidly dividing cells are more
vulnerable to injury than quiescent
cells.

–Except at extremely high doses that
impair DNA transcription, DNA damage
is compatible with survival in
nondividing cells, such brain &
myocardium.

–Dividing cells:
• Mutations and chromosomal
abnormalities are recognized by cell cycle
checkpoints, which initiate events that
lead to growth arrest and apoptosis

• Oxygen effects and hypoxia
–The production of ROS from the
radiolysis of water is the most
important mechanism of DNA damage
by ionizing radiation

Figure 9-17 Effects of ionizing radiation on DNA and its consequences. The effects on DNA can be direct, or most importantly, indirect, through free radical formation.
© 2005 Elsevier

• Oxygen effects and hypoxia
–Poorly vascularized tissues with low
oxygenation, such as the center of
rapidly growing tumors, are generally
less sensitive to radiation therapy than
nonhypoxic tissues

• Vascular damage
–May cause narrowing or occlusion of
the blood vessel leading to impaired
healing, fibrosis, and chronic ischemic
atrophy

MORPHOLOGY
• NUCLEUS:
– Swelling
– Membrane breakdown
• CHROMOSOMES:
– Structural changes: deletion, break, translocation
& fragmentation
– Condensation & clumping of chromatin
– Polyploidy & aneuploidy

MORPHOLOGY
• MITOTIC SPINDLE:
–Becomes disorderly
• CYTOPLASMIC CHANGES:
–Swelling
–Mitochondrial distortion
–Degeneration of ER

MORPHOLOGY
• Giant cells with pleomorphic or more
than one nucleus may appear and persist
for years after exposure.
• At extremely high doses, markers of cell
death—pyknosis and lysis, appear quickly

MORPHOLOGY
• Similarity between radiation injured cells
and cancer cells:
–Cellular pleomorphism
–Giant-cell formation
–Conformational changes in nuclei
–Abnormal mitotic figures

MORPHOLOGY
• LM:
–Vascular change and interstitial fibrosis
are prominent in irradiated tissue
–Intermediate post-irradiation period:
• Vessels may only show dilation

MORPHOLOGY
• LM:
–With higher doses / with time, a variety of
degenerative changes may appear:
• Endothelial cell swelling & vacuolation
• Dissolution with total necrosis of the walls of
the small vessels

MORPHOLOGY
–Endothelial cell proliferation and
collagenous hyalinization with thickening of
the media
• Resulting in narrowing or even obliteration of
the vascular lumens
• At this time an ↑ in interstitial collagen in the
irradiated field usually becomes evident
 Scarring and contractions

Total Body Irradiation
• Exposure of large areas of the body to even
very small doses of radiation may have
devastating effects
• <1 Sv
– Minimal or no symptoms
• Higher levels
–Acute radiation symptoms

Acute Effects on Hematopoietic and
Lymphoid Systems
• High dose levels & large exposure fields:
– Severe lymphopenia may appear w/in hours
– Shrinkage of lymph nodes & spleen
• Radiation directly destroys lymphocytes
• Sublethal doses:
– Regeneration from viable precursors is prompt,
leading to restoration of normal lymphocyte ct
w/in weeks to months

Lymphoid Systems
• Hematopoietic precursors in BM are also
quite sensitive to radiant energy, which
produces a dose-dependent marrow
aplasia
• APLASTIC ANEMIA
• Transient aplasia

Lymphoid Systems
• Granulocyte ct:
– may first rise but begin to fall toward the end of
the first week
– Near zero levels during the second week
– Recovery of normal granulocyte ct may require 2-
3 months

Lymphoid Systems
• Platelet ct
– Similar w/ granulocytes but somewhat delayed
• Red cell ct
– Falls
– Anemia appears after 2-3 weeks and may persist
for months

Fibrosis
• Occur weeks or months after irradiation
as a consequence of the replacement of
dead parenchymal cells by connective
tissue, leading to the formation of scars
and adhesions

DNA Damage & Carcinogenesis
• Single-base damage
• Single- & double-stranded breaks
• DNA protein crosslinks
• Double-stranded breaks
– Repaired by:
• Homologous recombination
• Nonhomologous end joining (NHEJ)

DNA Damage & Carcinogenesis
• Repair by NHEJ
– Short deletions or duplications
– Gross chromosomal aberrations
• Translocations
• Inversions
• If replication of cells containing DSBs is not
stopped, this may initiate carcinogenesis

Cancer Risks from Exposures to
Low-level Radiation
• Any cell capable of division that has
sustained a mutation has the potential to
become cancerous

Divided into the following:
• Mechanical injury
• Thermal injury
• Electrical injury
• Ionizing radiation

MECHANICAL TRAUMA
The type of injury depends on the shape of
the colliding object, the amount of energy
discharged at impact, and the tissues or
organs that bear the impact.

Patterns of injury can be divided:
• Abrasions
• contusions
• lacerations
• incised wounds
• puncture wounds

THERMAL INJURY
Causes of thermal injury:
• Thermal Burns
• Hyperthermia
• Hypothermia

Thermal Burns
clinical significance:
• Depth of the burns
• Percentage of body surface involved
• Internal injuries caused by the inhalation of hot and
toxic fumes
• Promptness and efficacy of therapy, especially fluid
and electrolyte management and prevention or
control of wound infections

Classification of burns:
• Superficial burns
• Partial thickness burns
• Full-thickness burns
• Full-thickness burns with damage to muscle
tissue

• Hyperthermia
Prolonged exposure to
elevated ambient
temperatures can result in
heat cramps, heat
exhaustion, and heat
stroke.
• Hypothermia
Prolonged exposure to low
ambient temperature leads

• ELECTRICAL INJURY
Electrical injuries, which are
often fatal, can arise from
contact with low-voltage
currents (i.e., in the home
and workplace) or high-
voltage currents carried by
high-power lines or
lightning.

Injuries are of mechanical injury are two types:
• burns
• ventricular fibrillation or cardiac and
respiratory center failure, resulting from
disruption of normal electrical impulses.

Updates:
EHSI: ‘Skin Gun’ For Burns is Latest Stem
Cell Treatment
The skin gun looks and works similar to an artist’s
airbrush, and sprays a solution of the patient's
adult stem cells in water. The clinical trials prove
that skin gun could represent an incredible
breakthrough in burn treatment, helping to
shape the future of stem cell therapy and
regenerative medicine
February 03, 2011 09:01 AM Eastern
Daylight
Time http://www.businesswire.com/news/
home/20110203005414/en/EHSI-
%E2%80%98Skin-Gun%E2%80%99-Burns-
Latest-Potential-Stem

Histopathreport

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