Ch. 9 - environmental diseases Flashcards
climate change
- CV, cerebrovascular and respiratory diseases caused by heat waves and air pollution
- gastroenteritis and infectious disease epidemics caused by water and food contamination as a result of floods
- vector borne infectious disease: dengue fever, malaria, west nile virus
- malnutrition through disruption of crops
xenobiotics
exogenous chemicals in the environment – air, water, food, soil- that may be absorbed into the body through inhalation, ingestion and skin contact
(most are metabolized through the liver via CYP process)
detoxification process?
- most solvents are lipophilic, facilitating their transport in blood by lipoproteins and their penetration through the PM of cells
- some agents are modified after entry in the body, but most solvents, drugs and xenobiotics are metabolized to form inactive water soluble products (detoxification) or are activated to form toxic metabolites
- Phase 1 reactions: chemicals undergo hydrolysis, oxidation or reduction into primary metabolites
- Phase 2 rxns: products are often metabolized into water soluble secondary metabolites through glucuronidation, sulfation, methylation and conjunction with glutathione
- water soluble compounds then excreted in urine, bile, or feces
Drug-Metabolizing enzymes: catalyze biotransformation of xenobiotics and drugs
CYP
Cytochrome P450 enzyme System (CYP):
• most important catalyst of phase 1 reactions
• a large family of enzymes with preferential affinity toward different substrates
• system catalyzes reactions that either detoxify xenobiotics or activate xenobiotics into active compounds that cause cellular injury
• may produce reactive oxygen species (ROS) as a byproduct
o ex: production of toxic trichloromethyl free radical from carbon tetrachloride in the liver
o generation of DNA binding metabolite from benzo[a]pyrene – carcinogen in smoke
what induces CYP activity?
o chemicals, drugs, smoking, alcohol, hormones
o fasting decreases CYP activity
o Inducers of CYP bind to nuclear receptors, which then heterodimerize with the retinoic X receptor (RXR) to form a transcriptional activation complex that associates with promoter elements: nuclear receptors participating in CYP induction: aryl hydrocarbon receptor, PPAR, CAR and PXR
what do you see in radiation?
leukemias and lyphomas (and some thyroid cancers)
ozone
- Ozone: results from the interaction of UV radiation and O2 → ozone (O3)
- ozone that accumulates in the lower atmosphere is problematic- and is formed by reaction of Nitrogen oxides and volatile organic compounds in the presence of sunlight→ production of free radicals
- Free radicals injure epithelial cells along resp. tract and type I alveolar cells, causing release of inflamm. mediators
particulate matter
emitted by coal and oil-fired power plants – results in fine or ultrafine particles (less than 10um) that are most harmful
o they are readily inhaled into the alveoli, phagocytosed by mac. and neut. and inflamm. mediators such as macrophage inaflamm. protein and endothelin are released.
• causes irritation to eyes, throats and lungs and asthma attacks
o exposure to particles greater than 10 um in diameter is not as harmful b/c they are trapped in mucociliary epithelium of airways
CO poisoning?
- CO is a systemic asphyxiant that kills by inducing CNS depression
- Hgb has a 200x affinity for CO than O2, resulting in carboxyhemoglobin that does not carry O2
- Systemic hypoxia develops when Hgb is 20-30% saturated with CO
- Unconsciousness = 60-70% saturated
symptoms of CO poisoning
o widespread ischemic changes in CNS – esp. basal ganglia and lenticular nuclei
o often permanent damage results – impairment in memory, vision, hearing, speech
o Acute CO poisoning: cherry red color of skin and mucus membranes
o with longer survival the brain may be slightly edematous with punctate hemorrhages and hypoxia-induced neuronal changes
o 30% saturation: see headaches, SOB on exertion
o 50% saturation: see loss of consciousness, convulsions, coma
o 60% saturation: death
formaldehyde
used to manufacture cabinetry, furniture, adhesives
o causes difficulty breathing, burning in eyes and throat, can trigger asthma attacks
plumbism
Lead poisoning (plumbism):
• most common type of chronic metal poisoning in US, primarily affects children
• subclinical poisoning: children exposed to below 10ug/dL
o low intellectual capacity, behavioral problems, hyperactivity, poor organization skills
• high levels of lead cause disturbances in CNS in adults and children, peripheral neuropathies in adults
• children absorb 35% more of lead, and have more permeable brain blood barriers thus they are at higher susceptibility to brain damages than adults
what do you see besides neural problems in lead poisoning?
- peripheral neuropathies in adults, CNS disturbances in children
- “Lead Lines”: Lead interferes with normal remodeling of cartilage and primary bone trabeculae in epiphyses in children – thus in children can see increased bone density detected as radiodense lines
- Inhibition of healing: Pb inhibits the healing of fractures by increasing chondrogenesis and delaying cartilage mineralization - Microcytic Hypochromic anemia: steming from suppression of Hgb synthesis
- (basophilic stippling)
blood changes seen in lead poisoning?
- decreased Hgb synth
- basophilic stipling of RBCs
3, microcytic, hypochromic anemia
Blood/Marrow changes: inhibition of ferrochelatase results in appearance of scattered ringed sideroblasts (red cell precursors with iron-laden mitrochondria detected with Prussian blue stain), microcytic and hypochromic anemia with mild hemolysis and basophilic stipling of RBCs
where do you see macrocytic anemia?
folate deficiency
brain damage seen in lead poisonining?
o Children: CNS is greatly affected (reduced IQ, learning disabilities, delayed motor development, blindness, seizures, coma) – see brain edema, demylenination of cerebral cerebellar white matter, necrosis of cortical neurons, encephalopathy
o Adults: CNS is less affected – see peripheral demyelinating neuropathy involving commonly used muscles. See extensor muscles of wrist/fingers causing wrist-drop, followed by paralysis of peroneal mm. causing foot-drop
other effects of pb poisoning?
- GI tract: abdominal pain, “colic”
- Gingiva: lead line
- Bones: radiodense deposits in children
- Kidneys: chronic tubulointerstitial disease
glutathione reductase
scavenger of free radicals
- protecting mechanism for mercury
mercury poisoning
Mad Hatter” syndrome
• contaminated fish (methyl mercury): swordfish, shark, bluefish
o ex. Minimata bay in Japan → “Minmata disease” = cerebral palsy, deafness, blindness, mental retardation
• mercury vapors released from metallic mercury in dental amalgams
Symptoms:
- neurotoxicity, dementia, delirium, tremor, gingivitis, bizarre behavior
- nephrotoxicity: acute tubular necrosis
Treatment:
administer antichelating drugs (glutathione reductase)
- developing brain is very sensitive to methyl mercury (thus women are advised not to eat sushi)
arsenic poisoning
“poison of kings and king of poisons”
• found naturally in soils an waters, may be released during mining and smelting industries
Symptoms: ** thickening, lichenification, hyperpigmentation of skin***
• Severe disturbances of GI, CV and CNS that are often fatal (due to interference with mitochondrial oxidation phosphorylation )
• Neurologic effects: occur 2-8 weeks after exposure: sensorimotor neuropathy, causing pareshtesias, numbness and pain
• Increased risk for development of cancers
• Skin changes: hyperpigmentation and hyperkeratosis which may be followed by development of basal and squamous cell carcinomas
• arsenic induced skin tumors – differ from those from sunlight b/c they are in multiples and appear on palms and soles of feet
CN- poisoning
Symptoms:
• toxicity due to CN- blocking cellular respiration by binding to mitochondrial cytochrome oxidase (Cyt a3)
• acts as an asphyxiant
• “bitter almond-scented” breath
cadmium poisoning
• modern problem generated by mining, electroplating, production of nickel-cadmium batteries
Symptoms:
- obstructive lung disease caused by necrosis of alveolar macrophages: chronic bronchitis and emphezema
- kidney damage – tubular damage that may progress to end stage renal disease
- elevated risk of lung cancer
Itai-Itai
form of cadmium poisoning
“Itai-Itai” (bony defects with kidney disease)
o cadmium containing water used to irrigate rice fields in japan caused this disease in postmenopausal women
o combination of osteoporosis and osteomalacia along with renal disease
carbon tetrachloride
• Chloroform and carbon tetrachloride:
o found in degreasing and dry cleaning agents, paint removers
o results in dizziness, confusion , leading to CNS depression and coma
*** see hepatocellular carcinomas
benzene
o occupational exposure of rubber workers
o increases risk of leukemia and lymphomas (similar to radiation)
o Benzene is oxidized by hepatic CYP2E1 to toxic metabolites that disrupt the differentiation of hemopoetic cells in bone marrow → acute myeloid leukemia
polycyclic hydrocarbons
- released during combustion of fossil fuels, coal and gas at high temps.
- cause of scrotal cancer in chimney sweeps
- implicated in lung and bladder cancer
DDT
Organochlorines:
• DDT (dichlorodi-phenyltrichloroethane)
o used as pesticide, and banned in US
o anti-estrogenic or anti-androgenic activity
Dioxins/PCBs
PCB - used in coolant fluid
pneumoconiosis
from Coal/Mining Dust: coal dust, silica, asbestos, beryllium
pneumoconiosis = chronic, non-neoplastic lung disease
Vinyl Chloride
used in synth of polyvinyl resins
• angiosarcoma of liver (typically affects children under 5 y/o)
asbestos
bronchogenic carcinomas and mesotheliomas
pthalates
flexible plastics, such as medical containers (ill infants using IV bag admin.)
• endocrine disruption and testicular dysgenesis syndrome
• hypospadias, cryptorchidism, testicular cell abnormalities
tobacco facts
- stats show smokers die 8 years earlier
- strongly linked with develop. of atherosclerosis
- most common exogenous cause of human cancers: cigarette smoking!
- Cessation of smoking reduces, within 5 years, the overall mortality and risk of death from CV disease. Lung cancer mortality decreases by 21% within 5 years, but the risk lasts for 30 years
most common diseases of smoking?
• Cigarette smoking → emphysema, chronic bronchitis, COPD, lung cancer, atherosclerosis, MI’s, cancers of lips, mouth, pharynx, esophagus, pancreas, bladder, kidney and cervix
how does smoking cause lung cancer?
- polycyclic hydrocarbons and nitrosamines are potent carciongens → lung cancer
- CYPs and phase II enzymes increase the water solubitiliy of carcinogens, facilitating their excretion, however some intermediates are electrophilic and form DNA adducts. If adducts persist they can cause mutation in oncogenes such as K-Ras and p53 → lung cancer
smoking and atherosclerosis?
• increased platelet aggregation → decreased myocardial O2 supply (b/c of significant lung disease coupled with hypoxia related to the CO content of cig. smoke), increased O2 demand → decreased threshold for MI → combined with HTN and hypercholesterolemia → atherosclerosis, myocardial infarctions
smoking and emphysema/bronchitis?
- agents in smoke irritate the tracheobronchial mucosa → inflammation and increased mucus production→ (bronchitis)
- recruitment of leukocytes to the lung with increased local elastase production and subsequent injury to lung tissue → emphysema
what other cancers are related with tobacco?
tobacco → oral cavity, esophageal, pancreas and bladder cancers
alcohol stats
- 5-10% of the population are alcoholics (10 million)
- 100,000 alcohol consumption deaths annually (50% caused by drunk driving)
- after consumption alcohol is absorbed unaltered in the stomach and SI, it is then distrubted to ALL the tissues and fluids of the body in direct proportion to the blood level
- 80 mg/dL in blood = legal definition of drunk driving
- chronic alcoholics can tolerate a very large amount of ethanol in blood due to accelerated ethanol metabolism through CYP’s
metabolism of ethanol
done almost exclusively in liver:
- ADH: turns ethanol –> acetaldehyde in cytosol.
- ALDH turns acetabldehyde to acetic acid (used in mito resp chain) in mitochondria
Alternative pathway:
- MEOS: microsomal ehtanol-ox system participates when there are high alcohol levles through CYP2E1
- Peroxisomes: use catalase to convert 5% of ethanol into acetaldehyde
alcohol and drug catabolism
• When alcohol is present in blood at high concentrations, it competes with other CYP2W1 substrates and delays drug catabolism, potentiating the depressant effects of narcotic, sedative and other CNS systems
ALDH2*2:
• ALDH2*2: individuals homozygous for this allele are completely unable to oxidize acetaldehyde and inability to tolerate alcohol
o results in nausea, flushing, tachycardia, hyperventilation
why do you see fatty liver in alcoholics?
- Fatty liver: NAD+ is needed for FA oxidation in liver and for conversion of lactate to pyruvate, thus in alcoholics this is all used up and they have fatty livers (due to ADH)
- Increase in NADH/NAD ratio → lactic acidosis
- metabolism of ethanol by CYP2E1 cause ROS and lipid peroxidation of cell membranes
acute alcoholism
effects in CNS, hepatic and gastric changes that are reversible, fatty change/hepatic steatosis, acute gastritis and ulceration, alcohol is a depressant that causes disordered cortical, motor and intellectual behavior.
chronic alcoholism
- liver see cirrhosis, steatosis, fatty changes, portal HTN and increased risk of hepatocellular carcinoma.
- GI see gastritis, gastric ulcer, esophageal varices.
- thiamine, Vit B deficiency resulting in peripheral neuropathies and Wernick-Korsakoff syndrome.
- Heart: dilated congestive cardiomyopathy (alcoholic cardiomyopathy), HTN
- acute and chronic pancreatitis and adenocarcinomas
- fetal alcohol syndrome (microcephaly, growth retardation, facial abnormalities)
- increased risk of oral, esophageal, liver and breast cancer
HRT
Hormone Replacement Therapy (HRT):
** increases risk of endometrial, ovarian and breast cancers**
- administration of estrogens together with progesterone – prescribed for hot flashes, has been showed to slow progression of osteoporosis and reduce likelihood of MI
- estrogen alone is used only in hysterectomized women due to risk of uterine cancer
- while it does reduce number of fractures it increases risk of breast cancer after 5-8 years of use
- has a protective effect on development of atherosclerosis and CAD under 60 but has a specific therapeutic window
- increases the risk of venous thromboembolism, DVT and pulmonary embolism and stroke
OC’s
Oral contraceptives: (OC’s)
• thromboembolism: esp. a problem in women with Leiden mutations. Increased risk due to generation of acute phase response with increases in CRP and coagulation factors and reduction of anticoagulants
• cardiovascular disease
• Cancers: endometrial and ovarian cancers
• Hepatic adenoma - benign, but can rupture
anabolic steroids
• use of synthetic versions of testosterone
• results in stunted growth in adolescents, acne, gynecomastia (enlarged breast tissue), testicular atrophy, growth of facial hair and menstrual changes in women
• psychiatric problems, premature heart attacks, hepatic cholestasis
- also see hair loss, arrhythmias, cardiac arrest
acetaminophen
“tylenol”
• it is the cause of 50% of acute liver failure in US
• at therapeutic doses 95% undergoes detoxification in liver by phase II enzymes and is excreted in urine as glucuronate or sulfate conjugates
• 5% is metabolized through CYPs (CYP2E) to NAPQI (a highly reactive metabolite)
• NAPQI is normally conjugated with glutathione, but when taken in large doses unconjugated NAPQI accumulates and causes hepatocellular injury leading to centrilobular necrosis and liver failure.
• The injury produced by NAPQI involves two mechanisms:
o (1) covalent binding to hepatic proteins, which causes damage to cellular membranes and mitochondrial dysfunction
o (2) depletion of GSH, making hepatocytes more susceptible to reactive oxygen species–induced injury.
• Note: because alcohol induces CYP2E in the liver, toxicity can occur at lower doses in chronic alcoholics.
sx of tyelonol poisoning?
acetaminophen toxicity: nausea, vomiting, diarrhea, shock → followed by jaundice in a few days → liver failure (centrilobular necrosis)
• tx: N-acetylcysteine, which restores GSH (if given in 12 hours)
aspirin overdose (acute)
Aspirin (Acetylsalicylic Acid): see gastric ulceration and bleeding: most commonly see cardiopulmonary arrest due to pulm. edema. See hyperthermia, tachypnia, resp. alkalosis, met. acidosis, hypokalemia and hypoglycemia
• Acute salicylate overdose: alkalosis as a consequence of the stimulation of the respiratory center in the medulla. This is followed by paradoxical metabolic acidosis/ aciduria. This is followed by accumulation of pyruvate and lactate, caused by uncoupling of oxidative phosphorylation and inhibition of the Krebs cycle. Metabolic acidosis enhances the formation of non-ionized forms of salicylates, which diffuse into the brain and produce effects from nausea to coma.
chronic salicylism
- too much aspirin
headaches, dizziness, ringing in the ears (tinnitus), hearing impairment, mental confusion, drowsiness, nausea, vomiting, and diarrhea. The CNS changes may progress to convulsions and coma. → acute erosive gastritis and GI bleeding - can also cause allergies and bonchospasm
opiod narcotics
ex. heroin
targets Mu opioid receptor (agonist)
psychomotor stimulants
ex. cocaine - antagonist of dopamine transporter
ex. amphetmines/MDMA - toxicity via serotonin receptors
cocaine
1/2 life around 40 mins - thus there is no “safe dose”
- crystallization = crack
- produces intense euphoria and stimulation – physcological withdrawal is extreme
*Acute overdose: seizures, cardiac arrhythmias, and respiratory arrest
***Cardiovascular: behaves as a sympathomimetic
o blocks the reuptake of dopamine in CNS
o blocks the reuptake of both epinephrine and norepinephrine at adrenergic nerve endings, while stimulating the presynaptic release of norepinephrine.
o Results in accumulation of neurotransmitters in synapses→ excess stimulation= tachycardia, hypertension, and peripheral vasoconstriction.
o Induces myocardial ischemia, by causing coronary artery vasoconstriction, and enhancing platelet aggregation and thrombus formation.
o dual effect of cocaine and cigarette smoking = increased myocardial oxygen demand by its sympathomimetic action, and, at the same time, decreasing coronary blood flow → myocardial ischemia → myocardial infarction.
o lethal arrhythmias: enhanced sympathetic activity by disrupting normal ion (K +, Ca 2 +, Na +) transport in the myocardium.
• CNS: hyperpyrexia and seizures
• Pregnancy: fetal hypoxia and spontaneous abortion
• Other Effects: perforation of nasal septum, decreased lung diffusing capacity of those that inhale, dilated cardiomyopathy
heroin
note: morphine is synthetic of heroin
more harmful than cocaine
• euphoria, hallucinations, somnolence, sedation
Sudden Death:
o usually related to overdose/drug purity.
o due to resp. depression, arrhythmia, cardiac arrest, severe pulmonary edema
Pulmonary Injury:
o edema
o septic embolism from endocartditis lung abscess
o opportunistic infections
o foreign-body granulomas (also found in spleen, liver and nodes)
o see polarized light off of trapped talc crystals
Infections: via viral hepatitis and AIDS o skin/subcutaneous tissue o heart valves: right side tricuspid – S. aureus o liver o lungs
Skin:
o see cutaneous lesions, cellulitis, ulcerations and injections
o scarring and hyperpigmentation over commonly used vv.
Renal problems:
o amyloidosis, secondary to skin infections and focal glomerulosclerosis → proteinuria and nephrotic syndrome
Tx: use Methadone as a means to treat addiction
