histopathreport

Effects Of Tobacco

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 EffectsTar CarcinogenesisPolycyclic aromatic hydrocarbons Carcinogenesis

Nicotine Ganglionic stimulation and depression; tumor production

Phenol Tumor production; mucosal irritation

Benzopyrene CarcinogenesisCarbon monoxide Impaired oxygen transport and

utilization

Formaldehyde Toxicity to cilia; mucosal irritation

Oxides of nitrogen Toxicity to cilia; mucosal irritationNitrosamine 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

How smoking causes cancer

Heart Attack and Stroke

Smoking leads to heart attackand 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

Normal Alveoli Emphysema

LIVER• Fatty changes• Alcoholic hepatitis• Cirrhosis

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PANCREATITIS• Characterized by inflammation which may

ultimately lead to scarring

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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

EFFECTS OF ALCOHOL

Absorbed UNALTERED <10%

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.)

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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)

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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…LiverGITCNS

Cardiovascular systempancreas

CHRONIC ALCOHOLISMLIVER

LIVER• Fatty changes• Alcoholic hepatitis• Cirrhosis

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CHRONIC ALCOHOLISMGASTROINTESTINAL

TRACT

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

CHRONIC ALCOHOLISMTHYMINE

DEFICIENCY

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

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CHRONIC ALCOHOLISMCARDIOVASCULAR

SYSTEM

CARDIOVASCULAR SYSTEM• Injury to the myocardium may produce dilated

congestive cardiomyopathy (alcoholic cardiomyopathy)

• Chronic alcoholism is associated with ↑ incidence of hypertension

CARDIOVASCULAR SYSTEM• 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

CARDIOVASCULAR SYSTEM• Heavy alcohol consumption, with

attendant liver injury,– results in ↓ HDL levels• ↑ likelihood of CHD

CHRONIC ALCOHOLISMPANCREAS

PANCREAS• Excessive alcohol intake

↑ risk of acute and chronic pancreatitis

CHRONIC ALCOHOLISMUSE OF ETHANOL

DURING PREGNANCY

USE OF ETHANOL DURING PREGNANCY

• Fetal alcohol syndrome–Microcephaly–Growth retardation– Facial abnormalities in newborns–Reduction in mental functions as the child

grows older

USE OF ETHANOL DURING PREGNANCY

• Consumption during the 1st trimester is particularly harmful

CHRONIC ALCOHOLISMCANCER

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

infraredMicro-wave

Sound/radio wave

IONIZING RADIATIONMerits 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

Main Determinants of the Biologic Effects of Ionizing Radiation

• 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

Main Determinants of the Biologic Effects of Ionizing Radiation

• Cell proliferation–Because ionizing radiation damages

DNA, rapidly dividing cells are more vulnerable to injury than quiescent cells.

Main Determinants of the Biologic Effects of Ionizing Radiation

• Cell proliferation–Except at extremely high doses that

impair DNA transcription, DNA damage is compatible with survival in nondividing cells, such brain & myocardium.

Main Determinants of the Biologic Effects of Ionizing Radiation

• Cell proliferation–Dividing cells:•Mutations and chromosomal

abnormalities are recognized by cell cycle checkpoints, which initiate events that lead to growth arrest and apoptosis

Main Determinants of the Biologic Effects of Ionizing Radiation

• 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.

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Main Determinants of the Biologic Effects of Ionizing Radiation

• 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

Main Determinants of the Biologic Effects of Ionizing Radiation

• Vascular damage–May cause narrowing or occlusion of

the blood vessel leading to impaired healing, fibrosis, and chronic ischemic atrophy

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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

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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

Acute Effects on Hematopoietic and Lymphoid Systems

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

• APLASTIC ANEMIA• Transient aplasia

Acute Effects on Hematopoietic and 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

Acute Effects on Hematopoietic and 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

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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

Injury by physical Agents

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 Burnsclinical 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

• HyperthermiaProlonged exposure to elevated ambient temperatures can result in heat cramps, heat exhaustion, and heat stroke.

• HypothermiaProlonged 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.

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