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Pathology 1st LE > Environmental Pathology and Nutrition (trans7) > Flashcards

Environmental Pathology and Nutrition (trans7) Flashcards

1
Q

GLOBAL BURDEN OF DISEASE (GBD)
1990 WHO project that estimates the burden imposed by environmental disease including communicable and nutritional diseases

A

Uses disability adjusted life years (DALY)

o Years of life lost due to premature mortality + years of life lost to disability in a population

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2
Q

GLOBAL BURDEN OF DISEASE (GBD)

Trends:

A

o Increase in mortality due to HIV/AIDS and associated infections
o Dec. 11.2% in deaths due to infectious disease, maternal, neonatal, nutritional disorders
o Inc. 39.2% in deaths due to noncommunicable diseases (cancer, cardiovascular, DM)
o Inc 9.2% in deaths due to injuries
o Mean age of world’s population from 26.1 => 29.5 years
o Life expectancy increased for both males (54.4 => 58.3 years) and females (57.8 => 61.8 years)
o Undernutrtion as the single leading global cause of health loss

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3
Q

GLOBAL BURDEN OF DISEASE (GBD)

Trends:

A

o Ischemic heart disease and cerebrovascular disease remain the leading causes of death in developed countries
- Risk factors: smoking, hypertension, obesity, hypercholesterolemia, alcohol abuse
o In developing countries, 5 out of 10 leading causes of death are infectious diseases
- Respiratory, respiratory infections, HIV/AIDS, diarrheal diseases, TB, malaria

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4
Q

o 70% of mortality in children is due to pneumonia, diarrheal disease, malaria, measles, perinatal/neonatal problems
o Decline in deaths of children less than 5 years from 1990 to 2010 (11.5 million → 7 million)
o Emerging infectious diseases also play a role in GBD

A

o 70% of mortality in children is due to pneumonia, diarrheal disease, malaria, measles, perinatal/neonatal problems
o Decline in deaths of children less than 5 years from 1990 to 2010 (11.5 million => 7 million)
o Emerging infectious diseases also play a role in GBD
- Infectious disorders whose incidence has recently increased or expected to increase in the future
**Categories:
 Newly evolved strains (multidrug-resistant TB, malaria, S. aureus)
 Pathogens endemic in other species that “jumped” to humans (HIV)
 Recent increased incidence (Dengue fever)

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5
Q

CLIMATE CHANGE

 Preeminent global cause of environmental disease in 21st century and beyond if there is no immediate action taken

A

Climate change is partly man-made
o Inc. atmospheric levels of greenhouse gases: CO2, ozone, methane + water vapor producing the greenhouse effect
o Inc. CO2 atmospheric level is also due to deforestation

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6
Q

MECHANISM OF TOXICITY

Toxicology

A

o Science of poisons. It studies the distribution, effects, and mechanisms of action of toxic agents.
o Also includes study of effects of physical agents such as radiation and heat

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7
Q

MECHANISM OF TOXICITY

Poison

A

o Basically a quantitative concept strictly dependent on dosage.
o “All substances are poisons; the right dosage differentiates a poison from a remedy.” – Paracelcus

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8
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Xenobiotic Metabolism

A

Xenobiotics

  • exogenous chemicals in the environment in air, water, food, and soil that affect humans when entered in the body through inhalation, ingestion, and skin contact
  • These chemicals enter through the first entry points (which are the skin, lungs, and the gastrointestinal tract), absorbed into the blood stream, circulate and distributed to the tissues before they are metabolized.
  • These chemicals may also act directly to the cells at the site of entry itself
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9
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Xenobiotic Metabolism

A
  • Metabolism of xenobiotics occurs in two phases and the enzymes that catalyze their biotransformation are known as drug-metabolizing enzymes
  • *Both types of reactions may produce reactive oxygen species (ROS)
  • *Some metabolites may be converted to metabolites that may affect the DNA and lead to short or long term toxicity
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10
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Xenobiotic Metabolism - Phase I

A

Chemicals undergo hydrolysis, oxidation, or reduction

  • *Cytochrome P-450 enzyme system (CYP)
  • The most important catalyst, found primarily in the ER of the liver but is also present in the first entry points, and other organs
  • his system catalyzes reactions that either
    (1) detoxify xenobiotics or
    (2) less commonly convert xenobiotics into active compounds that cause cellular injury
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11
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Xenobiotic Metabolism - Phase II

A

 Includes glucuronidation, sulfation, methylation, and conjugation with glutathione.
 Products of phase I are converted to water-soluble substances and then excreted into the urine, bile, or feces.
 The enzyme that participates in this phase include cytochrome P-450 as well

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12
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Outdoor Air Pollution - Ozone

A

 From the interaction of ultraviolet radiation and oxygen in the stratosphere and naturally accumulating in the ozone layer (10-30miles above earth’s surface).
 Cloroflourocarbon, which are refrigerants, and aerosols drift to the stratosphere, reacts and participate in destroying the ozone.

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13
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS Outdoor Air Pollution - Particulate

A

Particulate
 Particularly important cause of morbidity and mortality related to pulmonary inflammation and secondary cardiovascular effects
 Emitted by coal- and oil-fired power plants, by industrial processes burning these fuels, and by diesel exhausts
 Those particles that are less than 10 μm in diameter are readily inhaled into the alveoli, phagocytosed by macrophages and neutrophils. These respond by releasing a number of inflammatory mediators.
 In contrast, those that are larger than 10μm are trapped by mucociliary epithelium in the airways or removed in the nose

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14
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS Outdoor Air Pollution - Carbon Monoxide (CO)

A

 Gas produced from any process results in the incomplete oxidation of hydrocarbons.
 Most important source is the burning of carbonaceous materials, as occurs in cigarettes, furnaces, and automotive engines.
 In acute toxicity, high levels of carboxyhemoglobin
results to having a characteristic generalized cherryred color of the skin and mucous membrane.
 Brain may appear slightly edematous, with punctate hemorrhages and hypoxia-induced neural changes.

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15
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Indoor Pollutants - Wood Smoke

A

Causes: Oxides of Nitrogen Carbon, Particulates, Polycyclic Hydrocarbons
Disease/Conditions: Lung Irritant/
Infections, Cancer

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16
Q 
TOXICITY OF CHEMICAL AND PHYSICAL AGENTS 
Indoor Pollutants - Bioaerosols
-Microbiologic agents
-Pet dander
-Dust mites
-Fungi
-Mold
A 
Causes: Infections Allergens
Disease/Conditions:  
- Legionnaires disease
- VIRAL
- pneumonia
- Common COLD
- Rhinitis
- Eye irritation
- ASTHMA
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17
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Indoor Pollutants - Radon (from uranium)
- Soil, Homes, Mines

A

Causes: Hiigh dose, long duration

Disease/Conditions: Lung cancer

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18
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Indoor Pollutants - Formaldehyde:
Concentrations > 0.1 ppm
- BUILDINGMATERIALS: cabinets, furnitures, adhesives

A 
Causes: POOR VENTILATION
Disease/Conditions: 
- Irritant (breathing difficulties, burning sensation in the eyes)
- Asthma attack
- Cancer
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19
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Heavy Metals

A

o Lead, Mercury, Arsenic and Cadmium are the heavy metals most commonly associated with harmful effects in humans

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20
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Heavy Metals - Lead
 Can be found in Mining, Foundry work, House Paints, Spray Paints, Water supply, Gasoline, Battery, Soil, Lead Pipe

A

Effects:

  • Hematologic
  • Skeletal
  • Neurologic
  • Gastrointestinal/Renal (Proximal Tubular Damage with Intranuclear Inclusions (Protein Aggregates)
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21
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Heavy Metals - Lead
Action:
- Binds sulfhydryl groups that inhibits Calcium metabolism
- Inhibit Hemesynthesis by inhibiting:
1. a - Aminolevulinic Acid Dehydratase
2. Ferrochelatase (Protorporphyrin to Iron)
- Compete w/ Calcium:
1. dec healing Fracture Chondrogenesis vs Mineralization,
2. (X) Vit. D Metabolism and Ca+ Homeostasis
- dec Neurotransmitters
- dec Ca+ Homeostasis
- dec Uric Acid Excretion

A

Condition:

  • Microcytic, Hypochromic Anemia, Mild Hemolysis, Basopilic stippling
  • Ring sideroblasts (Red cell precursors), Mild hemolysis, inc Protoporphyrin levels
  • Growth Leadlines:
    1. Bones
    2. Gums (dark pigmentation)
  • Headache, Memory loss, Demyelination, Encephalopathy, Behavioral Changes, Psychoses, Mental Deterioration, dec I.Q. Level, dec Hearing, Foot Drop, Wrist Drop, Impaired Peripheral Nerve, Blindness, Seizures, Coma, Learning Disability, Psychomotor Development
  • Renal Failure, Saturnine Gout, Interstitial Fibrosis
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22
Q 
TOXICITY OF CHEMICAL AND PHYSICAL AGENTS 
Heavy Metals - Mercury
Can be classified as:
- Metallic
- Inorganic
- Organic (from bacterial- Methyl)
A

Mercury: Swordfish, Shark, BlueFish
 Can be found in Cave Painting, Cosmetic, Treatment for Syphilis, Diuretics, Production of Gold,
Inhalation, Contaminated Fish, Dental Amalgams, Mining contaminating rivers, Mercury Base, Fungicide,
Power Plants

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23
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Heavy Metals - Mercury
Action:
- Binds to Sulfhydryl Groups
- Lipid Soluble
- Glutathione (suflhydryl donor-protective mechanism)

A 
Condition: 
Mad Hatter Disease
Tremor
Gingivitis
Bizarre Behavior
Minamata Disease (Cerebral Palsy, deafness,
blindness, mental retardation, CNS defects)
Neuromotor
Cognitive
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24
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Heavy Metals - Arsenic
“poison of kings and king of poisons”

A

 Can be found in soil, water, wood preservers, herbicides, mines, smelting industries, herbal medicines (Treatment for ACUTE PROMYELOCYTIC LEUKEMIA)

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25
Q 
TOXICITY OF CHEMICAL AND PHYSICAL AGENTS 
Heavy Metals - Arsenic
Action:
- Cellular Metabolism
- Mitochondrial oxidative phosphorylation
- Enzymes
- Ion Channels
- may involve NUCLEOTIDE EXCISION REPAIR
A

Condition:

  • Sensorimotor Neuropathy (2-8 wks after exposure)
  • Hyperpigmentation
  • Hyperkeratosis
  • CANCER (Skin, bladder, Lung)
  • NON-MALIGNANT RESPIRATORY DISEASE
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26
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Heavy Metals - Cadmium

A

 Can be found in mining, Electroplating, Ni-Cd battery, Soil and Plants Food (Fertilizers/ Irrigation), Zinc Smelters

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27
Q 
TOXICITY OF CHEMICAL AND PHYSICAL AGENTS 
Heavy Metals - Cadmium
Action:
- Reactive O2 Species
- Uptake by ZIP8 (Zinc Transporter)
- Alveolar Cells (Lungs)
- Tubular Cells (Kidney)
- Calcium Loss
A

Condition

  • Obstructive Lung Disease (alveolar epith cell necrosis)
  • Renal Tubular damage = End Stage Renal Disease
  • Skeletal Abnormalities
  • “ITAI-ITAI”
  • Osteoporosis
  • Osteomalacia
  • Lung Cancer
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28
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Occupational Health Risk

A
  1. Organic solvents
  2. Polycyclic Hydrocarbons
  3. Organochlorines (PESTICIDES)
  4. Pneumoconioses
  5. Vinyl Chloride
  6. Bisphenol A (BPA) Polycarbonate
  7. Tobacco smoking
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29
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Occupational Health Risk - 1-3 Butadiene and benzene

A

 Found in rubber factories
 Oxidized by hepatic CYP2E1 to toxic metabolites
 Leads to disruption of hematopoetic cell multiplication that causes ACUTE MYELOGENOUS LEUKEMIA
 When hematopoetic cells are destroyed, this leads now to a condition known as APLASTIC ANEMIA

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30
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Occupational Health Risk - Pneumoconioses

A

 Also known as Chronic non-neoplastic lung disease
 It is usually due to inhalation of coal dust, silica, asbestos and beryllium
 Dangerous substances are usually 10 millimicrons because they are not filtered or cilitated out
 These substances are phagocytized by macrophages in the lung but is not killed. Macrophages still release inflammatory mediators that recruit more cells to the area leading to fibrosis.
 Fibrosing reactions of the lungs inhibit respiration. Patients die of respiratory failure eventually.

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31
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Agricultural Hazards

A

o General population exposed get into food, air, water, etc.
o Insecticides: can pollute and contaminate agricultural products that will later be consumed by the population
o Fungicides
o Rodenticides: very potent and can kill humans
o Fumigants: used for mosquitoes, affect the population and ecosystem

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32
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Natural Toxins
Mycotoxins: Toxic metabolite produced by fungi that is commonly known as molds

A

Phytotoxins
 Toxins that are poisonous to plants
 Eg. Aflatoxin: Aflatoxin is a naturally occurring mycotoxin produced by some molds. These molds grow on plants, which they contaminate with the aflatoxin they produce. Such plants include peanuts and other legumes. Aflatoxin is carcinogenic in the liver if consumed.

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33
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Tobacco
 Most common exogenous cause of human cancers (responsible for 90% of lung cancers).
 The main culprit for tobacco exposure is cigarette smoking; but smokeless tobacco (snuff, chewing tobacco, etc.) is also harmful to health and an important cause of oral cancer.
 Passive tobacco inhalation from the environment (“secondhand smoke”) can cause lung cancer in non-smokers.
 Smoking is the most preventable cause of human death. It reduces overall survival through dosedependent effects

A 
Most common diseases caused by cigarette smoking involve the lung and includes:
 Emphysema
 Chronic bronchitis
 Chronic obstructive pulmonary disease
 Lung cancer
Smokers who have inherited alleles of the CYP1A1 gene that confer higher activity and increased inducibility of this enzyme may be at higher risk of developing lung cancer
1. Smokers: Squamous cell carcinoma
2. Non-smokers:Adenocarcinoma
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34
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Tobacco
Different xenobiotics in tobacco/cigarette smoke:
 Nicotine - an alkaloid present in tobacco leaves, is not a direct cause of tobacco-related diseases, but is rather the cause of addiction. Without it, it would be easy for smokers to stop the habit.
 Nicotine binds to receptors in the brain resulting to the release of catecholamines.
 This release is responsible for the acute effects of smoking, such as the increase in heart rate and blood pressure and the elevation in cardiac contractility and output
 Components of cigarette smoke, particularlypolycyclic hydrocarbons and nitrosamines, are potent carcinogens in animals and likely to be directly involved in the development of lung cancer in humans.

A

CYPs (cytochrome P-450 phase I enzymes) and phase II enzymes increase the water solubility of the carcinogens, facilitating their excretion.
 Some intermediates produced by CYPs are electrophilic and form DNA adducts.
 If such adducts persist, they can cause mutations in oncogenes and tumor suppressors such as K-Ras and p53, respectively.
 The risk of developing lung cancer is related to the intensity of exposure, frequently expressed in terms of “pack years” (e.g., one pack smoked daily for 20 years equals 20 pack years) or in cigarettes

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35
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Tobacco
Different xenobiotics in tobacco/cigarette smoke:
Benzopyrene – Carcinogenic chemical absorbed in the bloodstream and undergoes phase I metabolism by CYP450 in the liver
 Becomes a more toxic and highly reactive metabolite (may also be metabolized in lungs and acted upon by enzymes)
 Malignant Transformation

A

Cilia Toxin Hydrogen Cyanide: Chemical in tobacco that paralyzes cilia in the lungs that is needed for movement and protection
 If cilia do not move, they are not able to remove pollutants from the environment that may lead to infections.

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36
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Tobacco
Organ-Specific Carcinogens in Tobacco Smoke

A

Lung, larynx: Polycyclic aromatic hydrocarbons 4-(Methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) Polonium 210
Esophagus: N’-Nitrosonornicotine (NNN)
Pancreas: NNK
Bladder: 4-Aminobiphenyl, 2-naphthylamine
Oral cavity (smoking): Polycyclic aromatic hydrocarbons, NNK, NNN
Oral cavity (snuff): NNK, NNN, polonium 210

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37
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Alcohol Consumption
 Ethanol is the xenobiotic substance
Alcohol Metabolism and Products

A

Alcohol Metabolism and Products
- Most of the alcohol in the blood is oxidized to acetaldehyde in the liver by three enzyme systems: alcohol dehydrogenase, microsomal ethanol-oxidizing system and catalase

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38
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Alcohol Consumption
Alcohol dehydrogenase
 Main enzyme system involved in alcohol metabolism
 Located in the cytosol of hepatocytes
 Acetaldehyde produced by alcohol metabolism is converted to acetate by acetaldehyde dehydrogenase (and microsomal ethanol-oxidizig system), which is then utilized in the mitochondrial respiratory chain
 About 50% of Asians have very low alcohol dehydrogenase activity, due to the substitution of lysine for glutamine at residue 487
 They are completely unable to oxidize acetaldehyde and cannot tolerate alcohol
 Nausea, flushing, tachycardia, and hyperventilation are manifested after alcohol ingestion

A

Microsomal ethanol-oxidizing system
 Participates in metabolism at high blood alcohol levels
 Involves CYPs, particularly CYP2E1, located in the smooth endoplasmic reticulum
 Induction of CYPs by alcohol explains the increased susceptibility of alcoholics to other compounds metabolized by the same enzyme system, which include drugs, anesthetics, carcinogens, and industrial solvents
 When alcohol is present in the blood at high concentrations, it competes with other CYP2E1 substrates and delays drug catabolism.
- This enhances the depressant effects of narcotic, sedative, and psychoactive drugs in the CNS
Catalase
 Uses hydrogen peroxide as its substrate
 Of minor importance as this system metabolizes no more than 5% of ethanol in the liver

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39
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Alcohol Consumption
Toxic Metabolites of Ethanol Oxidation: Acetaldehyde

A

 Direct product of alcohol oxidation

 Many toxic effects and is responsible for some of the acute effects of alcohol and for the development of oral cancers

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40
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Alcohol Consumption
Toxic Metabolites of Ethanol Oxidation: Nicotinamide Adenine Dinucleotide (NAD) Deficiency

A

 Alcohol oxidation by alcohol dehydrogenase causes the reduction of NAD to NADH, with a decrease in NAD and increase in NADH as a result
 NAD is required for fatty acid oxidation in the liver and for the conversion of lactate into pyruvate
 NAD deficiency is the main cause of accumulation of fat in the liver of alcoholics.
 The increase in the NADH/NAD ratio in alcoholics also causes lactic acidosis.

41
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Alcohol Consumption
Toxic Metabolites of Ethanol Oxidation: Reactive Oxygen Species (ROS)

A

 Produced from CYP2E1 ethanol metabolism in the liver

 Causes lipid peroxidation of hepatocyte cell membranes

42
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Alcohol Consumption
Toxic Metabolites of Ethanol Oxidation: Endotoxin

A

 Alcohol also causes the release of endotoxin (lipopolysaccharide) from gram-negative bacteria in the intestinal flora
 This endotoxin release stimulates the production of TNF (tumor necrosis factor), and other cytokines from macrophages and Kupffer cells that leads to hepatic injury

43
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Alcohol Consumption
Effects of Alcohol Consumption: Acute Alcoholism
 Exerts effects mainly on the CNS, but may induce hepatic and gastric changes that are reversible if alcohol consumption is discontinued.
 Liver: Fatty change or hepatic steatosis (occur even with moderate intake of alcohol)
 GIT: Acute gastritis and ulceration

A

CNS: Depressant that first affects subcortical structures that modulate cerebral cortical activity (probably the high brain stem reticular formation)
 Stimulation and disordered cortical, motor, and intellectual behavior happen as a result
 At progressively higher blood alcohol levels, cortical neurons followed by lower medullary centers are depressed, including those that regulate respiration
 Respiratory arrest may follow.

44
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Alcohol Consumption
Effects of Alcohol Consumption: Chronic Alcoholism

A

 Affects not only the liver and stomach, but virtually all other organs and tissues as well.
 Cause of significant morbidity and shortened life span related principally to damage to the liver, GI tract, CNS, cardiovascular system, and pancreas
 Alcohol induces CYP450 enzymes => increased metabolism => increased alcohol tolerance => individual does not get drunk, but body undergoes deleterious effects anyway

45
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Alcohol Consumption
Effects of Alcohol Consumption: Chronic Alcoholism

A

Liver: the main site of chronic injury
 In addition to fatty change manifested in acute alcoholism, alcoholic hepatitis and cirrhosis may also occur
 Cirrhosis is associated with portal hypertension and an increased risk for the development of hepatocellular carcinoma

46
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Alcohol Consumption
Effects of Alcohol Consumption: Chronic Alcoholism

A

GI tract: Massive bleeding from gastritis, gastric ulcer, or esophageal varices (associated with cirrhosis), which may be fatal
Nutrient deficiencies:
 Ethanol (empty calories) – results in malnutrition
 Thiamine (vitamin B1) deficiency - common in chronic alcoholics
**Primary lesions resulting from this deficiency:
o peripheral neuropathies and the Wernicke- Korsakoff syndrome; cerebral atrophy, cerebellar degeneration, and optic neuropathy may also occur

47
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Alcohol Consumption
Effects of Alcohol Consumption: Chronic Alcoholism

A

Cardiovascular system: Injury to the myocardium may produce dilated congestive cardiomyopathy
 Chronic alcoholism is also associated with an increased incidence of hypertension
 Heavy alcohol consumption with accompanying liver injury results in decreased levels of HDL and increasing the likelihood of coronary heart disease

48
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Personal Exposure - Alcohol Consumption
Effects of Alcohol Consumption: Chronic Alcoholism
Pancreas: Excessive alcohol intake increases risk of
acute and chronic pancreatitis

A

Pregnancy: The use of ethanol during pregnancy can cause fetal alcohol syndrome
 Microcephaly, growth retardation, and facial abnormalities in the newborn, and reduction in mental functions as the child grows older
 Difficult to ascertain the minimal causative alcohol amount but consumption during the first trimester of pregnancy is particularly harmful

49
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Therapeutic Drugs – Adverse Drug Reaction (ADR)

A

Oral Contraceptives:
Associated with thromboembolism, cardiovascular disease, cancers, and hepatic adenoma
Hormone Replacement Therapy
 Increases the risk of breast cancer after a median time of 5 to 8 years
 Has a protective effect of the development of atherosclerosis and coronary disease in women under 60, but no protection in women who started HRT at an older age
 Increases the risk of venous thromboembolism

50
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Therapeutic Drugs – Adverse Drug Reaction (ADR)
Acetaminophen

A

 Non-prescription analgesic and antipyretic
 95% undergo detoxification in the liver by phase II enzymes and excreted in the urine as glucoronate or sulphate conjugates
 Around 5% is metabolized to NAPQI (N-acetyl pbenzoquinoneimine), a highly reactive metabolite, by CYP2E
- Large doses lead to accumulation of unconjugated NAPQI (since there isn’t enough CYP2E to metabolize) causes hepatocellular injury leading to centrilobular necrosis and liver failure

51
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Therapeutic Drugs – Adverse Drug Reaction (ADR)
Aspirin (Acetylsalicylic Acid)

A

 Overdose in children may result from accidental ingestion and suicidal attempts in adults
 Salicylism (chronic aspirin toxicity)
 Persons which take 3g or more daily (dose used to treat chronic pain or inflammatory conditions)
 Manifested by headache, dizziness, tinnitus, hearing impairment, mental confusion, drowsiness, nausea, vomiting and diarrhea
 CNS changes may progress to convulsions and coma
Morphologic consequences:
(a) Acute erosive gastritis – produce overt or covert GI bleeding leading to gastric ulceration
(b) Bleeding tendency - due to acetylation of platelet cyclooxygenase leading to inhibition of production of TXA2
(c) Petechial haemorrhages
**Acetaminophen + Aspirin intake over several years leads to analgesic nephropathy

52
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Physical Environment

A

o Physical Trauma
o Mechanical force – vehicular accident, fractures
o Thermal Injury

53
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Physical Environment - Thermal Injury
Hyperthermia
Heat cramps
1. Electrolyte loss via sweating; Electrolyte imbalance
2. Cramping of voluntary muscles because of vigorous exercise
3. Increase core body temperature
Heat exhaustion
 Prostration + collapse from hypovolemia due to dehydration
 (Rehydration will restore equilibrium)
Heat stroke
 Associated with increased ambient temp, high humidity and exertion
 General vasodilatation with peripheral pooling of blood and a decreased effective circulating blood volume
 Failure of the thermoregulatory mechanisms
 Sweating ceases and core body temperature may rise to as high as >40 degrees celsius, leading to multi-organ dysfunction

A

Hyperthermia
Hyporthermia
 Low ambient temperature (

54
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Radiation
 Ionizing radiation, Ultraviolet radiation
 Electromagnetic fields, Waves and particles
 Radiation destroys the cells

A

Acute: Direct radiation that affects the labile cells (cells that are rapidly dividing, where genes undergo division.) ie. Gastrointestinal cells.

  • *If amount of radiation is high, it does not matter what type of cell was irradiated because even nervous cells that are not susceptible to radiation can be affected, ie. CNS damage (CNS syndrome).
  • *If less amount of radiation, damage will happen only after a few weeks.
55
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Radiation

A

Other damages caused by radiation:
 Uranium, radon, polonium – have alpha, beta particles, neutrons that are released from radioactive materials
 Rapidly dividing cells undergoing mitosis are targeted. When mitotic spindles are spread out, they are more susceptible to radiation
 Conversion to ROS that produce injury take time that’s why there radiations have delayed complications.
 Radiations are used in x-ray, diagnosis purposes, treatment of cancers

56
Q

Effects Of Ionizing Radiation To Body Organs
Organ: Acute Injury: Delayed Complications
1. Bone Marrow: Atrophy: Hypoplasia, leukemia
2. Skin: Erythema: Atrophy of epidermis and fibrosis of dermis, cancer
3. Heart: none: Interstitial fibrosis
4. Lung: Edema, endothelial and epithelial cell death:
Interstitial and intraalveolar fibrosis; cancer
5. Gastrointestinal Tract: Edema, mucosal
ulcers: Ulcers, fibrosis, structures, adhesions, cancer6. Liver: Veno-occlusive disease: Cirrhosis, liver tumors
7. Kidney: Vasodilation: Cortical atrophy, interstitial fibrosis

A

Organ: Acute Injury: Delayed Complications

  1. Urinary bladder: Mucosal erosion: Submucosal fibrosis, cancer
  2. Brain: Edema, necrosis: Necrosis of white matter, gliosis, brain cancer
  3. Testis: Necrosis: Tubular atrophy
  4. Ovary: Atresia of follicles: Stromal fibrosis
  5. Thryoid: none: Hypothyroidism, cancer
  6. Breast: none: Fibrosis, cancer
  7. Thymus, lymph nodes: Atrophy Lymphoma
57
Q

TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Radiation - Clinical Features of the Acute Radiation Syndrome (ARS)
**measure radiation dosage in civerts. Note that in spite of recovery from more severe forms of acute radiation syndrome, symptoms of less severe exposure may remain in the patient (e.g. manifest signs of hematopoietic ARS after recovering from GI ARS.)

A
  1. subclinical
  2. hematopoietic
  3. gastrointestinal
  4. cental nervous system
    * *Subclinical
58
Q 
TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Clinical Features of the Acute Radiation Syndrome (ARS)
Hematopoietic
Whole body dose (rem):
Symptoms:
Prognosis:
A

Hematopoietic
Whole body dose (rem): 200-600
Symptoms: Intermittent nausea and vomiting, Petechiae, hemorrahge, Lymphocytes

59
Q 
TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Clinical Features of the Acute Radiation Syndrome (ARS)
Gastrointestinal
Whole body dose (rem):
Symptoms:
Prognosis:
A

Gastrointestinal
Whole body dose (rem): 600-1000
Symptoms: Nausea, vomiting, diarrhea, Hemorrhage and infection in 1-3 wk, Lymphocytes

60
Q 
TOXICITY OF CHEMICAL AND PHYSICAL AGENTS
Clinical Features of the Acute Radiation Syndrome (ARS)
Central Nervous System
Whole body dose (rem):
Symptoms:
Prognosis:
A

Central Nervous System
Whole body dose (rem): >1000
Symptoms: Intractable nausea and vomiting, Confusion, somnolence, convulsions, Coma in 15 min- 3hr, Lymphocytes absent
Prognosis: Death in 14-36 hrs

61
Q

SPECIFIC ENVIRONMENT DISORDERS

A
  1. Nutritional Diseases - Anorexia Nervosa, Bulimi
    a, Protein Malnutrion
  2. Vitamin Deficiencies (Vitamin A, D and C)
  3. Obesity
62
Q 
SPECIFIC ENVIRONMENT DISORDERS: Nutritional Diseases 
Anorexia Nervosa
-Self-induced starvation
-Psychiatric disorder
-Poorer prognosis like PEM
-Endocrine Effects:
dec GRH resulting to Amenorrhea
dec LH and FSH
dec Thyroxine release
-Wt. loss
-Cold intolerance
-Bradycardia
-Constipation
-Skin and hair changes
-Dehydration and electrolyte abnormality
-dec bone density due to dec estrogen
-Anemia
-Lymphopenia
-Hypoalbuminemia
-Hypokalemia leads to cardiac arrhythmia (major complication)
A

Bulimia

  • Binge eating – induced vomiting
  • Obsession w/ thinness and body image
  • Better prognosis
  • Chronic use of laxatives and diuretics
  • Amenorrhea less common due to normal weight and gonadotrophin levels
  • Hypokalemia: Cardiac arrhythmia
  • Pulmonary aspiration
  • Esophageal and gastric rupture
  • More common than AN
  • Altered serotonin metabolism has been suggested to be an important component of both diseases.
63
Q

SPECIFIC ENVIRONMENT DISORDERS: Protein Malnutrition
- Consequence of inadequate intake of proteins and calories or deficiencies in the digestion or absorption of proteins
- Results in the loss of fat and muscle tissue, weight loss, lethargy, and generalized weakness.
- Parameters for assessment:
 Body Mass Index (Normal: 18.5-25)
 Thickness of skin-fold
 Muscle (Mid-arm circumference)
 Serum proteins

A

Marasmus, Kwarshiorkor, Cachexia

64
Q

SPECIFIC ENVIRONMENT DISORDERS: Protein Malnutrition - Marasmus
 A child is considered to have marasmus when weight falls to 60% of normal for sex, height, and age
 Caused by: famine and disasters
 Manifested by growth retardation and loss of muscle; the latter resulting from catabolism and depletion of the somatic protein compartment, which are probable adaptive responses that provides the body with amino acids for energy.
 The visceral protein compartment, presumably more precious and critical for survival, is only marginally depleted.
 Serum albumin levels are either normal or only slightly reduced as a result

A

 Subcutaneous fat is also mobilized and used as fuel
 Low leptin production may stimulate the hypothalamic-pituitary-adrenal axis to produce high levels of cortisol that contribute to lipolysis
 Extremities are emaciated and the head appears too large for the body
 Anemia (hypoplastic bone marrow) and manifestations of multiple vitamin deficiencies present
 Cerebral atrophy present
 There is evidence of immune deficiency, particularly T cell–mediated immunity. As a result, concurrent infections are usually present, which impose additional nutritional demands

65
Q

SPECIFIC ENVIRONMENT DISORDERS: Protein Malnutrition - Kwashiorkor
 Occurs when protein deprivation is relatively more severe than the total caloric deficit
 The loss of weight in patients is masked by the increased fluid retention
 Relative sparing of subcutaneous fat and muscle mass
 Characteristic skin lesions, with alternating zones of hyperpigmentation, areas of desquamation, and hypopigmentation, giving a “flaky paint” appearance
 Hair changes include overall loss of color or alternating bands of pale and darker hair.
 Enlarged fatty liver (resulting from reduced synthesis of the carrier protein component of lipoproteins), and the development of apathy, listlessness, and loss of appetite
 Small bowel atrophy
 Vitamin deficiencies are likely to be present along with defects in immunity and secondary infections
 Hypoplastic bone marrow anemia present.
 Low iron, folate, protein, and iodine levels are contributory factors
 Parasitism and cerebral atrophy present as well

A

 Marked protein deprivation is associated with severe depletion of the visceral protein compartment resulting to hypoalbuminemia that gives rise to generalized or dependent edema
Caused by:
(a) Deficient protein absorption
(b) Protein-losing enteropathy
(c) Nephrotic syndrome
(d) Severe burns
(e) Fad diet – idiosyncratic diets that provide short term weight loss
(f) Rice-based milk formula replacing breast milk

66
Q

Kwashiorkor vs Marasmus
> Lack of proteins, but there may still be enough calories
> Severe depletion of visceral protein compartment
> Hypoalbuminemia results to EDEMA
> Relative sparing of subcutaneous fat and muscle mass
> “Flaky paint” skin lesions
> Hair changes (alternating color shades)
> Enlarged fatty live

A 
Marasmus
> Lack of proteins AND
calories
> Severe depletion of
somatic protein
compartment
> Normal or reduced serum
albumin levels
> Depletion of
subcutaneous fat and
muscle mass
> Depletion of
subcutaneous fat and
muscle mass
> Emaciated extremities
67
Q

SPECIFIC ENVIRONMENT DISORDERS: Protein Malnutrition - Cachexia
 A form of protein malnutrition that is a common complication in patients with AIDS or advanced cancers
 Cachexia occurs in about 50% of cancer patients, most commonly in individuals with gastrointestinal, pancreatic, and lung cancers, and is responsible for about 30% of cancer deaths
 A highly debilitating condition characterized by extreme weight loss, fatigue, muscle atrophy, anemia, anorexia, and edema
 Mortality generally the consequence of atrophy of the diaphragm and other respiratory muscles

A

Precise causes not known, but it is clear that
mediators secreted by tumors and during chronic
inflammatory reactions contribute to its
development:
(a) Proteolysis-inducing factor
 glycosylated polypeptide excreted in the urine of weight-losing patients with pancreatic, breast, colon, and other cancers
 Along with proinflammatory cytokines, it causes skeletal muscle breakdown through the NF-κB-induced activation of the ubiquitin proteasome pathway. There is promotion of the degradation of skeletal muscle structural proteins such as myosin heavy chain by upregulation of the expression of several muscle-specific ubiquitin ligases
(b) Lipid-mobilizing factor: increases fatty acid oxidation, and proinflammatory cytokines, such as TNF (originally known as cachectin), and IL-6.
(c) Other data implicate acquired abnormalities of the myofibril dystrophin-glycoprotein complex, the same membrane complex that is defective in several forms of muscular dystrophy

68
Q

SPECIFIC ENVIRONMENT DISORDERS: Vitamin Deficiencies - Vitamin A
Fat soluble vitamin with various forms:
 Retinol: transport and storage form
 Retinal: aldehyde form
 Retinoic acid: acid form
 Retinoids: generic term for various vit A forms, natural and synthetic chemicals structurally related to vit A

A

 Sources of preformed vit A: Liver, fish, eggs, milk, butter
 Carotenoid: provitamins that can be metabolized to active vit A in the body
 Sources of carotenoid: yellow and green leafy vegetables, carrots, squash, spinach
 Absorption requires bile and pancreatic enzymes
 Uptake in the liver cells takes place through apolipoprotein E receptor
 Stored in the ITO cells of liver (or Hepatic stellate cells)

69
Q

SPECIFIC ENVIRONMENT DISORDERS: Vitamin Deficiencies - Vitamin A
Functions:

A

(a) Maintenance of normal vision
(b) Cell growth and differentiation
(c) Regulation of lipid metabolism
(d) Host resistance to infections
(e) Photoprotective
(f) Antioxidants

70
Q

SPECIFIC ENVIRONMENT DISORDERS: Vitamin Deficiencies - Vitamin A
Deficiency leads to:

A

(a) Squamous metaplasia
(b) Night blindness
(c) Xerophthalmia
(d) Pneumonia, diarrhea, measles, severe acne, psoriasis
(e) Acute promyelocytic leukemia, neuroblastoma
(f) Coeliac disease, Crohn’s disease, colitis

71
Q

SPECIFIC ENVIRONMENT DISORDERS: Vitamin Deficiencies - Vitamin A
Toxicity leads to:

A

(a) Headache, dizziness, vomiting nausea, stupor, blurred vision, wt loss,
(b) Bone and joint pain
(c) Teratogenic

72
Q

SPECIFIC ENVIRONMENT DISORDERS: Vitamin Deficiencies - Vitamin D
 Major source is its endogenous synthesis from 7-dehydrocholesterol
 Dietary sources: deep sea fish, plants (ergosterol), grains
 1,25-dihydroxyvitamin D acts by binding to vit D receptor which associates w/ Retinoid X Receptor
 Cod liver oil: w/ antirachitic (anti-Rickets) property
 Macrophages, keratinocytes, breast, prostate and colon can produce 1,25-dihydroxyvitamin D, the synthesis of which occurs through activity of CYP27B in the mitochondria

A

Functions:

(a) Maintains plasma calcium and phosphorus homeostasis
(b) Supports metabolism
(c) Bone mineralization
(d) Neuromuscular transmission
(e) Stimulates calcium intestinal absorption and kidney reabsorption
(f) Immunomodulatory
(g) Antiproliferative effects
(h) Interacts w/ PTH in the regulation of blood calcium: PTH induces wasting of phosphorus in the urine and calcium retention
(i) Activates transcription of TRPV6 (encodes a calcium transport channel)

73
Q

SPECIFIC ENVIRONMENT DISORDERS: Vitamin Deficiencies - Vitamin D
Disorders related:

A

(a) Renal disorders
(b) Malabsorption
(c) Vitamin D receptor defect

74
Q 
SPECIFIC ENVIRONMENT DISORDERS: Vitamin Deficiencies - Vitamin D
Deficiencies lead to:
(a) Rickets (children)
(b) Osteomalacia (adults)
(c) Hypocalcemic tetany
A

Toxicities lead to: Metastatic calcification, bone pain

and hypercalcemia

75
Q

SPECIFIC ENVIRONMENT DISORDERS: Vitamin Deficiencies - Vitamin C (Ascorbic acid)
 Not synthesized endogenously
 Sources: milk, liver, fish, fruits, vegetables
 Functions:
(a) Accelerates hydroxylation and amidation reactions
(b) Activation of prolyl and lysyl hydroxylases (procollagen hydroxylation)
(c) Antioxidant (scavenge free radicals)
(d) Regenerate vitamin E

A

Deficiencies are observed in elderly, those who live alone, chronic alcoholics, patient undergoing peritoneal dialysis, hemodialysis, food faddist and infants maintained on formulas of evaporated milk
Deficiencies lead to:
(a) Impaired collagen formation
(b) Poor vessel support -> bleeding/ hemorrhages
(c) Inadequate synthesis of osteoid
(d) Impaired wound healing
(e) Scurvy

76
Q

SPECIFIC ENVIRONMENT DISORDERS: Vitamin Deficiencies - Vitamin C (Ascorbic acid)
Physiologic excess of vit C is limited due to: inherent instability, poor intestinal absorption and rapid urinary
excretion.

A

Toxicities lead to: possible iron overload, hemolytic anemia in those with G6PD deficiency and calcium oxalate kidney stones.

77
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity
 Obesity is a disease of caloric imbalance w/ intake greater than expenditure.
 An obese is an indivudual with BMI >30kg/m2.
 Central/Visceral Obesity: fat accumulates in the trunk and abdominal cavity
 Humoral and neural mechanisms control appetite, satiety and energy balance

A

Associated with
o inc caloric intake, refined sugar, sweetened beverages, vegetable oils
o inc incidence of type 2 diabetes, dyslipidemias , CVD, hypertension, cancer

78
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity

**3 Components Of Neurohumoral Mechanisms Regulating Energy Balance:

A

Peripheral or Afferent System, Arcuate Nucleus, Efferent System

79
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity

Components Of Neurohumoral Mechanisms Regulating Energy Balance - Peripheral or afferent system

A
  • Generates signals from various sites
  • Components:
    > Leptin and adiponectin from fat cells
    > Ghrelin from stomach
    > Peptide YY (PYY) from ileum and colon
    > Insulin from pancreas
80
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity

Components Of Neurohumoral Mechanisms Regulating Energy Balance - Arcuate nucleus in the hypothalamus

A
  • Processes and integrates neurohumoral peripheral signals and generates efferent signals
  • Contains 2 subsets of 1st order neurons which communicate w/ 2nd order neurons in the hypothalamus
    > POMC (pro-opiomelanocortin) neurons and CART (cocaine and amphetamine-regulated transcripts) neurons
    > Neurons containing NPY (neuropeptide Y) and AgRP (agouti-related peptide)
81
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity

Components Of Neurohumoral Mechanisms Regulating Energy Balance - Efferent system

A
  • Anabolic and catabolic pathways that carries the signals generated in the second order neurons of the hypothalamus to control food intake and energy
    expenditure, respectively
82
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity
Components Of Neurohumoral Mechanisms Regulating Energy Balance - Arcuate nucleus in the hypothalamus
**POMC/ CART neurons [Catabolic]
 Enhance energy expenditure and weight loss through production of Melanocyte-Stimulating Hormone (MSH) (anorexigenic)
 Activation of melanocortin receptors 3 and 4 (MC3/4R) in 2nd order neurons
 The 2nd order neurons are responsible for producing Thyroid-Stimulating Hormone (TSH) and Corticotropin-Releasing Hormone (CRH) that inc BMR and anabolic metabolism leading to weight loss

A

NPY/AgRP neurons [Anabolic]
 Promote food intake (orexigenic) and weight gain
 Via activation of Y1/5 receptors in secondary neurons which release melanin-concentrating hormone (MCH) and orexinleading to appetite stimulation

83
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity
Components Of Neurohumoral Mechanisms Regulating Energy Balance - Peripheral or afferent system
**Components of Afferent System - Leptin

A

Leptin
 Signals energy sufficiency; synthesized by adipose tissue when fat stores are abundant
 Product of the ob gene
 Insulin-stimulated glucose metabolism regulate leptin levels
 (+) POMC/CART neurons, (-) NYP/AgRP
 High leptin stimulates physical activity, heat production and energy expenditure
 Mediates thermogenesis (important catabolic effect)
 increase Norepinephrine (NE) release
 Proinflammatory cytokine
 Regulates hematopoiesis and lymphopoises
 OB-R (leptin receptor) (+) JAK/STAT pathway

84
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity
Components Of Neurohumoral Mechanisms Regulating Energy Balance - Peripheral or afferent system
**Components of Afferent System - Adiponectin

A

 “Fat-burning molecule” or “guardian angel vs. obesity”
 Produced by adipocytes
 High in obese; Low in lean individuals
 (+) FA oxidation in muscle
 dec FA influx, total hepatic triglyceride content and glucose production in the liver
 innc insulin sensitivity and protecting against metabolic syndrome
 Binds to AdipoR1 and AdipoR2 receptors in the brain, skeletal muscle and liver
 Binding to receptors (+) signals to activate cAMPdependent PKA => phosphorylates and inactivates aCoA carboxylase (FA synthesis key enzyme)

85
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity
Components Of Neurohumoral Mechanisms Regulating Energy Balance - Peripheral or afferent system
**Components of Afferent System - Gut hormones: Ghrelin, PYY, Amylin

A

(a) Ghrelin
- Only gut hormone that inc food intake => wt gain, inc caloric intake, inc energy utilization
- (+) NPY/AgRP
(b) PYY
- Decreases energy intake
- dec during fasting and inc after food intake
- inc after gastric bypass surgery
- PYY levels dec in Prader-Willi syndrome (disorder with hyperphagia and obesity)
(c) Amylin
- Decreases food intake and weight gain
- Secreted by pancreatic B-cells
- Like PYY, it (+) POMC/CART leading to decrease in food intake

86
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity
Actions of Adipocytes
o Produce leptin, adiponectin, cytokines (TNF, IL-6, IL-1 and IL- 18), chemokines and steroid hormones
o Increased production of cytokines and chemokines => chronic proinflammatory state => inc levels of C-reactive protein
o Control energy balance and energy metabolism
o Function as a link between lipid metabolism, nutrition and inflammation responses

A

Regulation of Adipocyte number
o Total number is established during childhood and adolescence
o inc in obese; dec lean individuals
o In adults, 10% is renewed annually but no. remains constant
**Role of the gut microbiome
o Diet affects the bacterial make-up of the colon
o Bacteria affect digestion and absorption of nutrients, epithelial integrity and inflammation
o Gut factors (PYY) may also be altered

87
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity

General Consequences of Obesity

A

Type 2 Diabetes, CAD, Nonalcoholic Fatty Liver, Cholelithiais, Hypoventilation and Hypersomnolence, Osteoarthritis

88
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity

General Consequences of Obesity - Type 2 Diabetes

A

> Insulin resistance and hyperinsulinemia => retention of Na, inc blood volume, production of excess NE and smooth muscle proliferation (hallmarks of hypertension)

89
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity

General Consequences of Obesity - Coronary Artery Disease (CAD)

A

> Hypertriglyceridemia and dec HDL => inc CAD risk

90
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity

General Consequences of Obesity - Cholelithiasis (gallstones)

A

> 6x more common in obese than lean individuals

> total body cholesterol, cholesterol turnover and augmented biliary excretion of cholesterol => formation of gallstones

91
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity

General Consequences of Obesity - Hypoventilation and Hypersomnolence

A

> Obesity Hypoventilation Syndrome/ Pickwickian
Syndrome => respiratory abnormality in very obese persons
Hypersomnolence: associated w/ apneic pauses during sleep, polycythemia and right-sided heart failure (cor pulmonale)

92
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity

General Consequences of Obesity - Ostheoarthritis

A

> A degenerative joint disease
Marked adiposity is a predisposing factor
In older person: cumulative effects of inc load on weightbearing joints

93
Q

Obesity and Cancer
o Obesity may lead to cancer (esophagus, pancreas, colon, rectum, breast, endometrium, kidney, thyroid,
gallbladder)

A

> Insulin resistance => hyperinsulinemia => (-) production of IGFBP-1 and IGFBP-2 (IGF binding protein-1 and -2) => inc levels of IGF-1 (insulin-like growth factor-1)
IGF-1 is a mitogen w/ receptor IGFR-1 (highly expressed in human cancers)
It binds w/ inc affinity to IGFR-1 and dec affinity w/ insulin receptor (also expressed in cancer)
Upon stimualtion, IGFR-1 activates RAS and PI3K/AKT pathways => growth of normal and neoplastic cells

94
Q

SPECIFIC ENVIRONMENT DISORDERS: Obesity
**Obesity has effects on steroid hormones used in the development of breast, uterus, etc
> inc synthesis of estrogen from androgen
precursors through aromatases
> inc androgen synthesis in ovaries and adrenals
> inc estrogen availability by (-) sex-hormonebinding globulin (SHBG) production

A

o Adiponectin is inversely related with obesity and acts as an insulin-sensitizing agent: decrease of adiponectin levels in obese persons => hyperinsulinemia
o Proinflammatory state associated w/ obesity can be carcinogenic

95
Q

Diet, Cancer and Atherosclerosis

Major Diet Concerns:

A

Exogenous carcinogens, Endogenous synthesis of carcinogens, Lack of protective factors, High-fiber intake, Antioxidants

96
Q

Diet, Cancer and Atherosclerosis: Major Diet Concerns:
Exogenous carcinogens
 Aflatoxin: involved in hepatocellular carcinoma.
 It causes mutation in codon 249 of tp53 gene.
 Food additives, artificial sweeteners, contaminating pesticides

A

Endogenous synthesis of carcinogens

- Nitrosamines and nitrosamides

97
Q

Diet, Cancer and Atherosclerosis: Major Diet Concerns:
Lack of protective factors
 inc fat intake and dec fiber intake => colon cancer
 inc fat intake => inc bile acids in gut => modification of intestinal flora => favour growth of microaerophilic bacteria => bile metabolites may function as carcinogen

A

High-fiber intake
 inc bulk of stool and dec transit time
 dec exposure of mucosa to putative offenders
 capacity of some fibers to bind carcinogens
Antioxidants
 Vit C, E, B-carotene, selenium: anticarcinogenic
 Retinoids: for therapy of acute promyelocytic leukemia
 Low levels of vit D => colon, prostate and breast cancer

98
Q

Diet and Atherosclerosis
 Strong association of hypercholesterolemia =>
atherosclerosis
 dec in the consumption of cholesterol and saturated animal fats (eggs, butter, beef) may dec serum cholesterol levels and retard atherosclerosis development
 Supplementation of fish oil fatty acid (omega-3 FA) might be protective vs atherosclerosis
 Caloric restrictions = Lowering levels of IGF-1 and insulin and activation of sirtuins => dec diseases, age-related immune decline, oxidative damage and inc resistance to carcinogenesis

A

Recommendations in consumptions of meals:
 Low carbohydrate diet
 Diet rich in fish, vegetables, whole grains, fruits, olive and penaut oils vs. saturated and trans fats
 Complex instead of simple carbohydrates
 Low salt: control hypertension

Pathology 1st LE (12 decks)

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