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8/19/2019 Environmental Pathology & Nutrition - Dr. Padla
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Pathology 1.4
ENVIRONMENTAL PATHOLOGY & NUTRITIONDR. PADLAJULY 8, 2013
UTLINE
I. Global burden of disease
II. Climate change
III. Toxicity of chemicals
IV.
Environmental pollution
V.
Benzene
VI.
Tobacco smoke
VII.
Alcohol
III.
Drug therapyIX.
Physical agents of Injury
X.
Malnutrition / Nutrition Deficiency
XI.
Protein energy malnutrition
XII.
Vitamin deficiency
III. Diet
IV. Obesity
GLOBAL BURDEN OF DISEASE (GBD)
Has set the standard for reporting health information to compare how
diseases affect different parts of the world, different countries, or
different regions in the same country.
CLIMATE CHANGE
Global warming
- ↑ Greenhouse gases (carbon dioxide emission from
fossil fuels, nitrogen dioxide and sulfur dioxide from
industries)
- ↑ Temperature
TOXICITY OF CHEMICALS
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PATHOLOGY 1.4
ENVIRONMENTAL POLLUTION
CADMIUM (in batteries)Laptops and cellphones use cadmium.
Workers are exposed to cadmium through the skin; exists in vapour or
in excess water during the manufacture production.
o Ex: In Japan, cadmium contaminated the water.
Findings: post-menopausal women in the area suffered from
osteoporosis (“Itai-itai”, bone pain)
Bone resorption causes the bone to become fragile; easily
fractures - causes pain
MOA: Cadmium is absorbed; produces highly reactive ROS;
once absorbed, destroys the kidney, specifically the tubular
epithelial cells.
Results to calcium-losing nephropathy. Normally, the kidneyreabsorbs the calcium, then recycled with the help of Vit. D
for utilization of calcium.
With cadmium, a highly reactive radical, the kidney is unable
to reabsorb the calcium. Calcium is lost. Once calcium is lost,
calcium levels decrease in the blood.
The body senses low levels of calcium, compensates by
increasing the levels through secreting a parathyroid
hormone which acts on the osteoclasts of the bone.
Osteoclasts then resorb the bone for the bone to be able to
supply the needed calcium for utilization.
This resorption continues as a cycle and results to
osteoporosis.
As a result of this compensation, one can have
parathyroidism.
BENZENE
Individuals exposed to this chemical suffer from acute myelogenous
leukaemia. Investigations are still being made as incidence of this
leukemia is higher with the occupation.
MOA: Benzene and 1,3 butadeine disrupt the hematopoetic
differentiation in the bone marrow.
As these chemicals are absorbed, they are converted to highly reactive
metabolite oxygen species. These then go to the bone marrow and
disrupts the development of bone marrow stem cells that should
differentiate to myelocytes, granulocytes (neutrophils, eosinophils,
platelets and RBC)
As the maturation process is blocked, stem cells remain as
myelogenous promyeloctes, which are the leukemic cells. These cells
then accumulate in the blood circulation without maturation.
MUST DETERMINE levels safe for the individuals to work with.
Treatment: Vit. A to stimulate stem cell maturation
Chemotherapy
TOBACCO SMOKE
Predisposing factor to COPD (chronic bronchitis, emphysema) and
cancer; causes squamous metaplasia.
Toxicants:
o
cilia toxin hydrogen cyanide
o
nicotine
o
Benzo[a]pyrene
o
Polycyclic aromatic hydrocarbon
Metabolism of Benzo[a]pyrene
ALCOHOL
Ethanol is the most widely used and abused agent in the world sinis ingested in alcoholic beverages such as beer, wine and distilled
spirits.
It is absorbed unaltered in the stomach and small intestine then
distributed to all the tissues and fluids of the body in direct propo
to the blood level.
Remember!
Most important catalyst: CYTOCHROME P450 enzyme system located
primarily in the endoplasmic reticulum of the liver but is also present in
skin, lungs and GI mucosa. CYP450 is involved in the detoxification of
endogenous hormones and natural products as well as on the activation
of xenobiotics to reactivate intermediates or ultimate carcinogens.
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PATHOLOGY 1.4
Alcohol Metabolism in the Liver
Acetaldehype produced is converted to Acetate by Acetaldehyde
Dehydrogenase (ADH) which is then utilized in the mitochondrialrespiratory chain.
Acetate, which is water soluble, can readily be excreted
Hepatitis (accumulation of fat and neutrophils; presence of Mallory bo
(intracytoplasmic accumulation of hyaline)-pointed structure)
DRUG THERAPY
Can cause Adverse Drug Reactions (ADRs) –untoward effects
drugs given in conventional therapeautic settings.
Examples: oral contraceptives & HRT, Acetaminophen, Aspir
(acetylsalicylic acid) (see table for other examples)
Effects of Alcohol in the Liver
Acetaldehyde triggers inflammatory cascade in cells
Causes fatty changeo Alcohol oxidation by ADH causes the reduction of NAD to
NADH decreasing the NAD and increasing NADH. NAD is
required for fatty oxidation and conversion of lactate into
pyruvate. NAD deficiency is the main cause of fat
accumulation.
o
Destruction of Lipoprotein metabolism which mobilizes fat
o
Chronic Alcoholism: Hepatic Necrosis Scar formation
Liver Cirrhosis Hepatic failure or Hepatocellular Carcinoma
Asians are fast acetylators, which mean that there is rapid formation
of Acetaldehyde. However, they have low levels of Acetaldehyde
Dehydrogenase so there is less formation of the readily excreted
Acetate. Acetaldehyde remains in the circulation which causes the
“facial flushing syndrome.”
Metabolism of Ethanol
3 pathways composed of 3 enzyme systems with a common endpoint of
biotransformation into Acetaldehyde.
1. Alcohol Dehydrogenase (ADH)
o
Main enzyme system involved in alcohol metabolism
o
Located in the cytosol of hepatocytes
2. Microsomal Ethanol-Oxidizing System (MEOS)
o
Participates in metabolism at high blood alcohol levels
o Involves CYPs particularly CYP2E1
o
Located in the Smooth Endoplasmic Reticulum
3. Catalase
o
It is of minor importance since it metabolizes no more than 5%
ethanol in the liver
o Located in the peroxisome
o Uses hydrogen peroxide as substrate
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PATHOLOGY 1.4
Acetaminophen Metabolism
PHYSICAL AGENTS OF INJURY
Mechanical trauma
Heat/Temperature
Pressure
Electricity
Radiation
RADIATION
Energy that travels in the form of waves or high-speed particles
Can be divided into Non-ionizing and Ionizing radiation
NON-IONIZING RADIATION
o Can move atoms in a molecule or cause them to vibrate but it is
not sufficient to displace bound electrons from atoms.
o E.g. UV, infrared light, microwave and sound waves
IONIZING RADIATION
o Has sufficient energy to remove tightly bound electrons
o Disrupts outermost electron shell making it more active, cau
tissue damage and DNA destruction
o Electrons on the outer orbit of a chemical are very reactive be
of the charge imbalance of protons in the nucleus and electro
This leads to the interaction of electrons with other chemical
interaction is considered injurious.
TOTAL BODY IRRADIATION
Exposure of large areas to even very small doses of radiation may
devastating effects Higher levels of exposure causes acute radiation syndromes; at
progressively higher doses, it may involve the hematopoietic,
gastrointestinal and central nervous systems
Acute Radiation Syndrome Classification
Category
Whole-Body
Dose (rem) Symptoms Prognosis
Subclinical <200 Mild nausea and vomiting 100% survival
Lymphocytes <1500/μL
Hematopoieti
c
200-600 In term itt en t nausea and
vomiting
Infections
Petechiae, hemorrhage May require bone marrow t
Maximum neutrophil and
platelet depression in 2wk
Lymphocytes <1000/μL
Gastrointesti
nal
600-1000 Nausea, vomit ing, diarrhea
Hemorrhage and
infection in 1-3 wk
Shock and death in 10-14 d
with replacement thera
Severe neutrophil and
platelet depression
Lymphocytes <500/μL
Central
nervous
system
>1000 Intractable nausea and
vomiting
Death in 14-36 hr
Confusion, somnolence,
convulsions
Coma in 15 min-3 hr
Table 9-18. Clinical Features of the Acute Radiation Syndrome
*The unit for whole body dose is already changed from rem to Sievert (uniformity. “rem” is a unit of dose based on the amount of radiation co
from the source while sievert (Sv) depends on the biologic rather than t
physical effects of radiation.
* if the dose is used, biologic effects might be different depen
on the type of radiation
Susceptibility of tissues to radiation is dependent on the ability of ce
to divide
1. Labile cells (e.g. hematopoietic cells) are constantly dividin
making it more sensitive to radiation exposure
2. Stable cells are less mitotic making them less susceptible to
radiation
3.
Permanent cells (e.g. nerve and muscle cells) do notundergo mitosis so they are not likely to be damaged
ACETAMINOPHEN
Analgesic
At therapeutic doses, about 95% undergoes detoxification in the
liver by phase II enzymes and is excreted in the urine as glucoronate
or sulfate conjugates
About 5% or less is metabolized through the activity of CYPs
(particularly CYP2E1) to NAPQI (N-acetyl-p-benzoquinoneimine)
o A highly reactive metabolite which can cause Centrilobular
Necrosis of the liver and liver failure. The injury produced by
NAPQI involve two mechanisms
1.
Covalent binding to hepatic proteins which causes damageto cellular membranes and mitochondrial dysfunction
2. Depletion of GSH (glutathione) making hepatocytes more
susceptible to reactive oxygen species-induced injury.
o Toxicity begins with nausea, vomiting, diarrhea and sometimes
septic shock, followed in a few days by jaundice ( beginning of
liver failure)
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PATHOLOGY 1.4
Thymus (L: Normal; R: Radiation injury)
Lymphocytes are destroyed by radiation
Hasall’s corpuscles disappear
Thymic atrophy secondary to radiation
Blood vessel with Fibrinoid necrosis
Capillaries and venules exposed to radiation Fibrinoid necrosis of
endothelial walls
Endothelial cells release mediators inflammatory cascade
o Single layer of epithelial cells, ideal for exchange, thickens and
becomes fibrotic
o Exchange in blood vessels is compromised leading to:
Metabolites are not excreted causing tissue atrophy
Necrosis of tissues and organs Fibrosis
Narrowing and thrombosis of lumen
MALNUTRITION / NUTRITIONAL DEFICIENCIES
n appropriate diet should provide:
Carbohydrates, fats and proteins for sufficient energy of body’s
metabolic needs
Amino acids and fatty acids as building blocks for synthesis of
structural and functional proteins and lipids
Vitamins and minerals as coenzymes or hormones in vital
metabolic pathways
Malnutrition or Protein Energy Malnutrition (PEM) is a conseque
inadequate intake of proteins and calories, or deficiencies in the digest
absorption of proteins, resulting in the loss of fat, and muscle tissue, w
loss, lethargy and generalized weakness.
TWO KINDS OF MALNUTRITION
1. Primary Malnutrition: One or all of the components of prop
are missing (e.g starvation)
2. Secondary Malnutrition: Supply for nutrients is adequat
there is insufficient intake, malabsorption, impaired utilizatstorage, excess loss or increased need for nutrients. (e.g. An
nervosa and bulimia)
PROTEIN ENERGY MALNUTRITION
Malnutrition is determined according to BMI. A BMI less than 16kg
considered malnourished.
MARASMUS (Somatic Protein Component)
Skin, bones, muscle tissue are lost
o Weight falls to 60% of normal sex, height and age.
o Growth retardation and loss of muscle.
o Serum albumin levels are either normal or slightly re
because visceral compartment is only slightly depleted
o Losses of muscle and fat lead to emaciation of extremities.
appears too big for body.
o
Anemia and multiple vitamin deficiencies are present. o
Presence of immune deficiency particularly T-cell me
immunity
KWASHIORKOR (Visceral Protien Component)
o
Protein deprivation>Total calories reduction
o
Seen in children who have been subsequently fed,
exclusively of carbohydrate diet
o
Marked protein deprivation associated with severe loss of v
protein compartment
o Presence of hypoalbuminemia which gives rise to generali
dependent edema and ascites (globular stomach)
o Loss of weight masked by increased fluid retention
Dietary Insufficiency
Conditions that lead to dietary insufficiency:
o
Poverty
o
Infections
o
Chronic Alcoholism
o
Acute and chronic illness
o
Ignorance and failure of diet supplementation
o
Self-imposed dietary restriction
o
Others: Malabsorption syndrome, genetic diseases spe
drug therapies and total parenteral nutrition
a. Anorexia Nervosa
o Psychological, self-induced food deprivation
o Highest death rate of any psychiatric disorder
o Amenorrhea is a common disorder
o Increased susceptibility to cardiac arrythemia and su
death resulting from hypokalemia
b. Bulimia
o
Psychological, binges on food and induces vomiting
o
More common and has a better prognosis
o
Hypokalemia, pulmonary aspiration of gastric cont
esophgaheal and gastric cardiac rupture may be preset
o No specific signs or symptoms
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PATHOLOGY 1.4
o Characterized by skin lesions with alternating zones of
hyperpigmentation, hypopigmentation, areas of desquamation
o Hair changes: over-all loss of color and alteration bands of pale
and darker hair
o Enlarged fatty liver
o Development of apathy, listlessness and loss of appetite
o There is also presence of vitamin deficiencies, defects in immunity
and secondary infections.
omparison of Severe Marasmus-like and Kwashiorkor-like Secondary PEMClinical Features Laboratory findings
arasmus
History of weight loss
Muscle wasting
Absent subcutaneous
fat
Normal or mildly reduced
serum protein
washiorkor Normal fat and muscle
Edema
Easily pluckable hair
Serum albumin < 2.8gm/dl
VITAMIN DEFICIENCY
tamin A
Fat-soluble
More than 90% are stored in the liver Name given to a group of related compounds:
o Retinol (Vitamin A Alcohol)
o Retinal (Vitamin A aldehyde)
o Retinoic acid (Vitamin A acid)
Functions:
o
Maintenance of normal vision: the visual process involves four
forms of vitamin A- containing pigments namely rhodopsin (most
light-sensitive pigment, important in reduced light) and three
iodopsins in cone cells.
o
Cell growth and differentiation: maintains specialized epithelia
(when deficiency state exists, epithelium undergoes squamous
metaplasiakeratinizing epithelium)
o
Metabolic effects of retinoids o
Host resistance to infections: reduce morbidity and mortality of
diarrhea and measles.
o Treatment of skin disorders (severe acne and some forms of
psoriasis) and acute promyelocytic leukemia
Deficiencies may lead to:
o Night blindness
o Xerophthalmia (dry eye) Bitot spots (formation of keratin debris
in small opaque plaques)Keratomalacia (corneal destruction)
total blindness
o
Hyperplasia and hyperkeratinisation of the epidermis
o
Immune deficiency
Fat Soluble
VITAMIN FunctionsDeficiency Syndromes
Vitamin AA component of visual
pigment
Night blindness,
xerophthalmia,
blindness
Maintenance of
specialized epithelia
Squamous metaplasia
Maintenance of
resistance to infection
Vulnerability to
infection, particularly
measles
Vitamin D
Facilitates intestinal
absorption of calcium
and phosphorus and
mineralization of bone
Rickets in children,
osteomalacia in adults
Vitamin EMajor antioxidant,
scavenges free radicals
Spinocerebellar
degradation
Vitamin K
Cofactor in hepatic
carboxylation of
procoagulants – factors
II (prothrombin), VII, IX,
and X, and protein C
and S
Bleeding diathesis
Water Soluble
VITAMIN FunctionsDeficiency Syndromes
Vitamin B1
(Thiamine)
As pyrophosphate, is
coenzyme in
decarboxylation
reactions
Dry and wet beriberi,
Wernicke syndrome,Korsakoff syndrome
Vitamin B2
(Riboflavin)
Converted to
coenzymes flavin
mononucleotide and
flavin adenine
dinucleotide, cofactors
for many enzymes in
intermediary
metabolism
Ariboflavinosis,
chellosis, stomatitis,
glossitis, dermatitis,
corneal vascularization
Niacin
Incorporated into
nicotinamide adenine
dinucleotide (NAD) and
NAD phosphate,
involved in a variety of
redox reactions
Pellagra – “three D’s”:
dementia, dermatitis,
diarrhea
Vitamin B6
(Pyridoxine)
Derivatives serve as
coenzymes in many
intermediary reactions
Chellosis, glossitis,
dermatitis, peripheral
neuropathy
Vitamin B12
Required for normal
folate metabolism of
DNA synthesis
Maintenance ofmyelinization of spinal
cord tracts
Combined system
disease (megaloblastic
pernicious anemia and
degeneration of
posterolateral spinal
cord tracts)
Vitamin C
Serves in many
oxidation-reduction
(redox) reactions and
hydroxylation of
collagen
Scurvy
Folate
Essential for transfer
and use of 1-carbon
units in DNA synthesis
Megaloblastic anemia,
neural tube defects
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PATHOLOGY 1.4
Pantothenic
acid
Incorporated in
coenzyme A
No nonexperimental
syndrome recognized
BiotinCofactor in
carboxylation reactions
No clearly defined
clinical syndrome
DIET
ber
Colon cancer protective effect
Tends to move the elements in the GIT and colon forward through
a regulated /regular peristaltic movement
Absorbs harmful chemicals in the GIT, like fat, bile, and normal
flora for excretion
Less fiber, less GI movement, more prone to carcinogenesis
OBESITY
efinition: Accumulation of adipose tissue that is of sufficient magnitude to
pair health
GENERAL CONSEQUENCES OF OBESITY
Insulin Resistance and hyperinsulinemia
-it has been speculated that excess insulin may play a role in the retention
of sodium, expansion of blood volume, production of excess NE, and
smooth muscle proliferation that are the hallmarks of hypertension
Hypertriglyceridemia and low HDL
-increased risk of coronary artery disease in the very obese
Non-alcoholic fatty liver disease
-most often I diabetic patients and can progress to fibrosis and cirrhosisCholelithiasis (gallstones)
-an increase in total body cholesterol, increased cholesterol turnover, and
augmented biliary excretion of cholesterol all act to predispose to the
formation of cholesterol rich gallstones.
Hypoventilation and hypersomnolence
Degenerative joint disease (osteoarthritis)
-cumulative effects of increased load on weight bearing joints
-------------------------------------------------------------------------------------------
These were included in his slide presentation but were skipped/not
elaborated during his lecture:
Outdoor air pollution
o
fossil fuelso ozone
o nitrogen dioxide
o
sulfur dioxide
o acid aerosols
o particulates
Indoor air pollution
o carbon monoxide
o nitrogen dioxide
o wood smoke
o Formaldehyde
o Radon
o Asbestos
o Manufactured mineral fibers
o Bioaerosols
Industrial exposures
o Volatile organic compounds
o Polycyclic aromatic
o hydrocarbons
o Plastics, Rubbers, Polymers
o
Metals
Agricultural hazards
o
Insecticides
o Fungicides
o Rodenticides
o Fumigants
Natural Toxins
o Mycotoxins
o Phytotoxins
o Animal toxins
Physical environment
o
Mechanical force
o
Thermal injuries
-
burns
-
hyperthermia
- hypothermia local
- hypothermia
o Electrical injuries
o Changes in atmospheric pressure
- high-altitude illness
- blast injury
- decompression disease
(caisson’s disease)
Additives & Contaminants (Food safety)
o
Natural
o
Agricultural
o Industrial
Edited by: Sheila Ramo
With respect to carcinogenesis, 3 aspects of the diet are of major
concern:
1. Content of exogenous carcinogens
2. Endogenous synthesis of carcinogens from dietary
components
3.
Lack of protective factors
Recommended