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.




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




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


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


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)




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




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




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

Environmental Pathology & Nutrition - Dr. Padla

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