Pathology 1.

4

ENVIRONMENTAL PATHOLOGY & NUTRITION

OUTLINE
I.
II.
III.
IV.
V.
VI.
VII.
VIII.
IX.
X.
XI.
XII.
XIII.
XIV.

Global burden of disease
Climate change
Toxicity of chemicals
Environmental pollution
Benzene
Tobacco smoke
Alcohol
Drug therapy
Physical agents of Injury
Malnutrition / Nutrition Deficiency
Protein energy malnutrition
Vitamin deficiency
Diet
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.

DR. PADLA
JULY 8, 2013

TOXICITY OF CHEMICALS

CLIMATE CHANGE
Global warming
↑ Greenhouse gases (carbon dioxide emission from
fossil fuels, nitrogen dioxide and sulfur dioxide from
industries)
↑ Temperature

34 | Velasco, Velasquez, Verdejo, Victorino, Villacarlos

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causes pain  MOA: Cadmium is absorbed.  As a result of this compensation. Findings: post-menopausal women in the area suffered from osteoporosis (“Itai-itai”. cadmium contaminated the water. the kidney reabsorbs the calcium. produces highly reactive ROS. the kidney is unable to reabsorb the calcium. MUST DETERMINE levels safe for the individuals to work with. one can have parathyroidism. stem cells remain as myelogenous promyeloctes. wine and distilled spirits.3 butadeine disrupt the hematopoetic differentiation in the bone marrow. exists in vapour or in excess water during the manufacture production. Normally. then recycled with the help of Vit. Villacarlos TOBACCO SMOKE Predisposing factor to COPD (chronic bronchitis. BENZENE Individuals exposed to this chemical suffer from acute myelogenous leukaemia. Verdejo. D for utilization of calcium. Workers are exposed to cadmium through the skin. lungs and GI mucosa. It is absorbed unaltered in the stomach and small intestine then distributed to all the tissues and fluids of the body in direct proportion to the blood level. specifically the tubular epithelial cells. bone pain)  Bone resorption causes the bone to become fragile. Calcium is lost. Victorino.PATHOLOGY 1. causes squamous metaplasia. Velasquez. MOA: Benzene and 1. 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.            ENVIRONMENTAL POLLUTION CADMIUM (in batteries) Laptops and cellphones use cadmium.  Results to calcium-losing nephropathy. 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 since it is ingested in alcoholic beverages such as beer. easily fractures . Once calcium is lost. These cells then accumulate in the blood circulation without maturation. destroys the kidney. calcium levels decrease in the blood.  The body senses low levels of calcium. emphysema) and cancer.  This resorption continues as a cycle and results to osteoporosis. These then go to the bone marrow and disrupts the development of bone marrow stem cells that should differentiate to myelocytes. o Ex: In Japan. compensates by increasing the levels through secreting a parathyroid hormone which acts on the osteoclasts of the bone. which are the leukemic cells. a highly reactive radical. once absorbed.  With cadmium. Investigations are still being made as incidence of this leukemia is higher with the occupation. eosinophils.4 Remember! Most important catalyst: CYTOCHROME P450 enzyme system located primarily in the endoplasmic reticulum of the liver but is also present in skin. they are converted to highly reactive metabolite oxygen species. platelets and RBC) As the maturation process is blocked. granulocytes (neutrophils. Treatment: Vit. As these chemicals are absorbed. Page 2 of 7 .  Osteoclasts then resorb the bone for the bone to be able to supply the needed calcium for utilization. A to stimulate stem cell maturation Chemotherapy 34 | Velasco.

o Destruction of Lipoprotein metabolism which mobilizes fat o Chronic Alcoholism: Hepatic Necrosis  Scar formation  Liver Cirrhosis  Hepatic failure or Hepatocellular Carcinoma 34 | Velasco. Acetaminophen. Aspirin (acetylsalicylic acid) (see table for other examples) Alcohol Metabolism in the Liver   Acetaldehype produced is converted to Acetate by Acetaldehyde Dehydrogenase (ADH) which is then utilized in the mitochondrial respiratory chain. NAD is required for fatty oxidation and conversion of lactate into pyruvate.” Effects of Alcohol in the Liver  Acetaldehyde triggers inflammatory cascade in cells  Causes fatty change o Alcohol oxidation by ADH causes the reduction of NAD to NADH decreasing the NAD and increasing NADH. which is water soluble.4 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. can readily be excreted Asians are fast acetylators. Examples: oral contraceptives & HRT. 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. However. Acetaldehyde remains in the circulation which causes the “facial flushing syndrome. they have low levels of Acetaldehyde Dehydrogenase so there is less formation of the readily excreted Acetate. NAD deficiency is the main cause of fat accumulation. Velasquez.PATHOLOGY 1. Acetate. presence of Mallory bodies (intracytoplasmic accumulation of hyaline)-pointed structure)   DRUG THERAPY Can cause Adverse Drug Reactions (ADRs) –untoward effects of drugs given in conventional therapeautic settings. Victorino. which mean that there is rapid formation of Acetaldehyde. Verdejo. 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 Hepatitis (accumulation of fat and neutrophils. Villacarlos Page 3 of 7 .

Villacarlos Gastrointesti nal 600-1000 Nausea. hemorrhage May require bone marrow transplant Maximum neutrophil and platelet depression in 2 wk Acetaminophen Metabolism Lymphocytes <1000/μL 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. Velasquez. this interaction is considered injurious. Permanent cells (e.PATHOLOGY 1. hematopoietic cells) are constantly dividing making it more sensitive to radiation exposure 2. convulsions Coma in 15 min-3 hr Lymphocytes absent *The unit for whole body dose is already changed from rem to Sievert (Sv) for uniformity. causing tissue damage and DNA destruction Electrons on the outer orbit of a chemical are very reactive because of the charge imbalance of protons in the nucleus and electrons. E. Clinical Features of the Acute Radiation Syndrome Category Subclinical Whole-Body Dose (rem) <200 Symptoms Mild nausea and vomiting Prognosis 100% survival Lymphocytes <1500/μL Hematopoieti c 200-600 Intermittent nausea and vomiting Infections Petechiae. o Toxicity begins with nausea. Victorino. infrared light. microwave and sound waves o IONIZING RADIATION Has sufficient energy to remove tightly bound electrons o 34 | Velasco. Stable cells are less mitotic making them less susceptible to radiation 3. it may involve the hematopoietic. * if the dose is used. UV. biologic effects might be different depending on the type of radiation Susceptibility of tissues to radiation is dependent on the ability of cells to divide 1. Covalent binding to hepatic proteins which causes damage to cellular membranes and mitochondrial dysfunction 2. vomiting. vomiting. “rem” is a unit of dose based on the amount of radiation coming from the source while sievert (Sv) depends on the biologic rather than the physical effects of radiation. TOTAL BODY IRRADIATION Exposure of large areas to even very small doses of radiation may have devastating effects Higher levels of exposure causes acute radiation syndromes. somnolence.g. followed in a few days by jaundice (beginning of liver failure)      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 o NON-IONIZING RADIATION Can move atoms in a molecule or cause them to vibrate but it is not sufficient to displace bound electrons from atoms. Depletion of GSH (glutathione) making hepatocytes more susceptible to reactive oxygen species-induced injury. Verdejo. at progressively higher doses. diarrhea Hemorrhage and infection in 1-3 wk Shock and death in 10-14 days even with replacement therapy Severe neutrophil and platelet depression Lymphocytes <500/μL Central nervous system >1000 Intractable nausea and vomiting Death in 14-36 hr Confusion.4 o o   Disrupts outermost electron shell making it more active.g. Labile cells (e. The injury produced by NAPQI involve two mechanisms 1.g. diarrhea and sometimes septic shock. This leads to the interaction of electrons with other chemicals. gastrointestinal and central nervous systems Acute Radiation Syndrome Classification Table 9-18. nerve and muscle cells) do not undergo mitosis so they are not likely to be damaged Page 4 of 7 .

g starvation) Secondary Malnutrition: Supply for nutrients is adequate but there is insufficient intake. ideal for exchange. excess loss or increased need for nutrients. o Anemia and multiple vitamin deficiencies are present. 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 34 | Velasco. esophgaheal and gastric cardiac rupture may be preset o No specific signs or symptoms Thymus (L: Normal. resulting in the loss of fat. Anorexia nervosa and bulimia) a. o Growth retardation and loss of muscle. binges on food and induces vomiting o More common and has a better prognosis o Hypokalemia. 1.g. (e. almost exclusively of carbohydrate diet Marked protein deprivation associated with severe loss of visceral protein compartment Presence of hypoalbuminemia which gives rise to generalized or dependent edema and ascites (globular stomach) Loss of weight masked by increased fluid retention Page 5 of 7 . and muscle tissue. Head appears too big for body. Velasquez.PATHOLOGY 1. Bulimia o Psychological. pulmonary aspiration of gastric contents. A BMI less than 16kg/m Is considered malnourished. o Serum albumin levels are either normal or slightly reduced because visceral compartment is only slightly depleted o Losses of muscle and fat lead to emaciation of extremities. Victorino. weight loss. lethargy and generalized weakness. Verdejo. - TWO KINDS OF MALNUTRITION Primary Malnutrition: One or all of the components of proper diet are missing (e. 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 An appropriate diet should provide:  Carbohydrates. muscle tissue are lost o Weight falls to 60% of normal sex. R: Radiation injury) Lymphocytes are destroyed by radiation Hasall’s corpuscles disappear Thymic atrophy secondary to radiation 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. malabsorption. height and age. 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 sudden death resulting from hypokalemia b. or deficiencies in the digestion or absorption of proteins. - - 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. Villacarlos  MARASMUS (Somatic Protein Component) Skin.4 Malnutrition or Protein Energy Malnutrition (PEM) is a consequence of inadequate intake of proteins and calories. bones. genetic diseases specific drug therapies and total parenteral nutrition PROTEIN ENERGY MALNUTRITION 2 Malnutrition is determined according to BMI. impaired utilization or storage. Anorexia Nervosa o Psychological. 2. o Presence of immune deficiency particularly T-cell mediates immunity o o o o o KWASHIORKOR (Visceral Protien Component) Protein deprivation>Total calories reduction Seen in children who have been subsequently fed.

PATHOLOGY 1. stomatitis.4 o o o o o Characterized by skin lesions with alternating zones of hyperpigmentation. Villacarlos As pyrophosphate. epithelium undergoes squamous metaplasiakeratinizing epithelium) o Metabolic effects of retinoids o Host resistance to infections: reduce morbidity and mortality of diarrhea and measles. cofactors for many enzymes in intermediary metabolism Incorporated into nicotinamide adenine dinucleotide (NAD) and NAD phosphate. hypopigmentation. Victorino. Comparison of Severe Marasmus-like and Kwashiorkor-like Secondary PEM Clinical Features Laboratory findings Marasmus Normal or mildly reduced  History of weight loss serum protein  Muscle wasting  Absent subcutaneous fat Kwashiorkor Normal fat and muscle Serum albumin < 2. glossitis. diarrhea Chellosis.containing pigments namely rhodopsin (most light-sensitive pigment. listlessness and loss of appetite There is also presence of vitamin deficiencies. Wernicke syndrome. neural tube defects Page 6 of 7 . o Cell growth and differentiation: maintains specialized epithelia (when deficiency state exists.8gm/dl Edema Easily pluckable hair VITAMIN DEFICIENCY Functions: o Maintenance of normal vision: the visual process involves four forms of vitamin A. glossitis. dermatitis. is coenzyme in decarboxylation reactions Converted to coenzymes flavin mononucleotide and flavin adenine dinucleotide. chellosis. xerophthalmia. and X. and protein C and S Water Soluble Folate Serves in many oxidation-reduction (redox) reactions and hydroxylation of collagen Essential for transfer and use of 1-carbon units in DNA synthesis Rickets in children. 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 Functions Vitamin A A component of visual pigment Maintenance of specialized epithelia Maintenance of resistance to infection Vitamin D Facilitates intestinal absorption of calcium and phosphorus and mineralization of bone Vitamin E Major antioxidant. Verdejo. Velasquez. dermatitis. peripheral neuropathy Combined system disease (megaloblastic pernicious anemia and degeneration of posterolateral spinal cord tracts) Scurvy Megaloblastic anemia. important in reduced light) and three iodopsins in cone cells. areas of desquamation Hair changes: over-all loss of color and alteration bands of pale and darker hair Enlarged fatty liver Development of apathy. scavenges free radicals Vitamin K VITAMIN Vitamin 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) VITAMIN measles Vitamin B1 (Thiamine) Vitamin B2 (Riboflavin) Niacin 34 | Velasco. involved in a variety of redox reactions Derivatives serve as coenzymes in many intermediary reactions Vitamin B12 Required for normal folate metabolism of DNA synthesis Maintenance of myelinization of spinal cord tracts Vitamin C Squamous metaplasia Vulnerability to infection. IX. blindness Cofactor in hepatic carboxylation of procoagulants – factors II (prothrombin). corneal vascularization Pellagra – “three D’s”: dementia. dermatitis. osteomalacia in adults Spinocerebellar degradation Bleeding diathesis Deficiency Syndromes Dry and wet beriberi. Korsakoff syndrome Ariboflavinosis. particularly Functions Vitamin B6 (Pyridoxine) Deficiency Syndromes Night blindness. defects in immunity and secondary infections. VII.

more prone to carcinogenesis With respect to carcinogenesis. 3 aspects of the diet are of major concern: 1. expansion of blood volume. e. bile. Lack of protective factors ` OBESITY Definition: Accumulation of adipose tissue that is of sufficient magnitude to impair health GENERAL CONSEQUENCES OF OBESITY a. and smooth muscle proliferation that are the hallmarks of hypertension b. production of excess NE. increased cholesterol turnover.burns . Hypertriglyceridemia and low HDL -increased risk of coronary artery disease in the very obese c. Velasquez. Degenerative joint disease (osteoarthritis) -cumulative effects of increased load on weight bearing joints Asbestos Manufactured mineral fibers Bioaerosols Edited by: Sheila Ramos ------------------------------------------------------------------------------------------These were included in his slide presentation but were skipped/not elaborated during his lecture:  Outdoor air pollution o fossil fuels o 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 34 | Velasco. Victorino.PATHOLOGY 1. Endogenous synthesis of carcinogens from dietary components 3.blast injury . and normal flora for excretion Less fiber.hyperthermia . and augmented biliary excretion of cholesterol all act to predispose to the formation of cholesterol rich gallstones. 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 . Hypoventilation and hypersomnolence f. Rubbers. less GI movement.4 Pantothenic acid Incorporated in coenzyme A Biotin Cofactor in carboxylation reactions o o o No nonexperimental syndrome recognized No clearly defined clinical syndrome  Industrial exposures o Volatile organic compounds o Polycyclic aromatic o hydrocarbons o Plastics. Villacarlos Page 7 of 7 . like fat.decompression disease (caisson’s disease)  Additives & Contaminants (Food safety) o Natural o Agricultural o Industrial DIET Fiber     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. Content of exogenous carcinogens 2.hypothermia o Electrical injuries o Changes in atmospheric pressure . Non-alcoholic fatty liver disease -most often I diabetic patients and can progress to fibrosis and cirrhosis d.hypothermia local . Insulin Resistance and hyperinsulinemia -it has been speculated that excess insulin may play a role in the retention of sodium. Cholelithiasis (gallstones) -an increase in total body cholesterol. Verdejo.high-altitude illness .