Pathology (environmental 2)
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What is the epidemiology of occupational diseases?
- Work-related accidents are the biggest problem in developing countries, while work-related diseases are more frequent in industrialized countries.
- The fraction of global disease attributed to occupational exposures includes 13% of all cases of chronic obstructive pulmonary disease, 9% of lung cancers, and 2 % of leukemias.
What are the health importance of organic solvents?
- Some, such as chloroform and carbon tetrachloride, are found in degreasing and dry cleaning agents and paint removers.
- Acute exposure to high levels of vapors from these agents can cause dizziness and confusion, leading to CNS depression and even coma.
- Lower levels are toxic for the liver and kidneys.
- Occupational exposure of rubber workers to benzene and 1,3-butadiene increases the risk of leukemia. Benzene is oxidized by hepatic CYP2E1 to toxic metabolites that disrupt the differentiation of hematopoietic cells in the bone marrow, leading to dose-dependent marrow aplasia and an increased risk of acute myeloid leukemia
How can Benzene cause leukemia?
Benzene is oxidized by hepatic CYP2E1 to toxic metabolites that disrupt the differentiation of hematopoietic cells in the bone marrow, leading to dose-dependent marrow aplasia and an increased risk of AML
What is the health importance of polycyclic hydrocarbons?
- Polycyclic hydrocarbons may be released during the combustion of fossil fuels, particularly when coal and gas are burned at high temperatures (such as in steel foundries), and are also present in tar and soot.
- Polycyclic hydrocarbons are among the most potent carcinogens, and industrial exposures have been implicated in the development of lung and bladder cancer
What is the health effect of organochlorines?
- Organochlorines (and halogenated organic compounds in general) are synthetic lipophilic products that resist degradation.
- Important organochlorines used as pesticides include DDT (dichlorodiphenyltrichloroethane), Lindane, Aldrin, and Dieldrin. Nonpesticide organochlorines include polychlorinated biphenyls (PCBs) and dioxin (TCDD; 2,3,7,8-tetrachlorodibenzo-p-dioxin).
- DDT was banned in the United States in 1973, but more than half of the U.S. population has detectable levels ofp, p′-DDE, a long-lasting DDT metabolite.
- PCB (another banned substance), dioxin, and PBDEs (polybrominated diphenyl ethers used as flame retardants) are also detectable in a large proportion of the U.S. population. Most organochlorines are endocrine disruptors with anti-estrogenic or anti-androgenic activity
................accounts for about 50% of the total amount of air pollutants
What are the health effects of dioxin and PCB?
- Very very stable
- Dioxins and PCBs can cause skin disorders such as folliculitis and a dermatosis known as chloracne (mainly dioxin) that is characterized by acne, cyst formation, hyperpigmentation, and hyperkeratosis, generally around the face and behind the ears.
- These toxins can also cause abnormalities in the liver and central nervous system.
- Because PCBs induce CYPs, workers exposed to these substances may show abnormal drug metabolism.
What are the major effects of aliphatic hydrocarbons?
- halogenated solvents such as carbon tetrachloride, chloroform, and trichloroethylene
- Acute--> CNS
- Chronic--> hepatic dysfunction and nephrotoxicity
What are the major effects of Aromatic Hydrocarbons?
- Benzene, toluene, and xylene are important aromatic hydrocarbons
- Acute-->CNS depression
- Long-term exposure to benzene is associated with hematotoxicity (thrombocytopenia, aplastic anemia, pancytopenia) and leukemia
What are the three major classes of pesticide?
chlorinated hydrocarbons (DDT and its analogs), acetylcholinesterase inhibitors (carbamates, organophosphates), and botanical agents (nicotine, rotenone, pyrethrum alkaloids).
What are the health effects of chlorinated hydrocarbons (DDT and analogs)?
- Persistent, poorly metabolized, lipophilic chemicals that exhibit significant bioaccumulation.
- Chlorinated hydrocarbons block physiologic inactivation in the sodium channels of nerve membranes and cause uncontrolled firing of action potentials.
- Tremor is usually the first sign of acute toxicity and may progress to seizures. Recent evidence suggests an association with brain and testicular cancer
What are the cholinesterase inhibitors used as pesticide?
The carbamates (eg, aldicarb, carbaryl) and organophosphates (eg, dichlorvos, malathion, parathion) are effective pesticides with short environmental half-lives used in agriculture
What are the symptoms of CHEI intoxication?
- cholinesterase inhibitors increase muscarinic and nicotinic activity.
- The signs and symptoms include pinpoint pupils, sweating, salivation, bronchoconstriction, vomiting and diarrhea, CNS stimulation followed by depression, and muscle fasciculations, weakness, and paralysis.
- The most common cause of death is respiratory failure.
- Chronic exposure to some organophosphates (not carbamates) has resulted in a delayed neurotoxicity with axonal degeneration
What is the treatment of Cholinesterase Inhibitors intoxication?
- Atropine is used in large doses to control muscarinic excess;
- pralidoxime is used to regenerate cholinesterase.
- Mechanical ventilation may be necessary
What are the three Botanical Insecticides?
What are the health of effects of botanical pesticide?
- NICOTINE: excitation followed by paralysis of ganglionic, CNS, and neuromuscular transmission). Treatment is supportive.
- ROTENONE: GI distress when ingested and conjunctivitis and dermatitis after direct contact
- PYRETHRUM: contact dermatitis (MC). Ingestion or inhalation of large quantities may cause CNS excitation (including seizures) and peripheral neurotoxicity.
What are the important herbicide and their effects?
- Chlorophenoxy Acids: The 2 most important members of this group are 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid, the compound in Agent Orange.( Acute--> muscle hypotonia and coma. Long-term -->NHL)
- Glyphosate (the most widely used herbicide in the world)--> skin and eye irritation
- Paraquat, a bipyridyl herbicide, is used extensively to kill weeds on farms and for highway maintenance. nontoxic unless ingested. After ingestion, the initial effect is GI irritation with hematemesis and bloody stools. Within a few days, signs of pulmonary impairment occur and are usually progressive, resulting in severe pulmonary fibrosis and often death
What are the effects of Inhalation of mineral dusts?
- Causes chronic, non-neoplastic lung diseases known as pneumoconioses.
- This term also includes diseases induced by organic and inorganic particulates, and chemical fume- and vapor-induced non-neoplastic lung diseases.
- The most common pneumoconioses are caused by exposures to coal dust (from mining of hard coal), silica (sandblasting, stone cutting, etc.), asbestos (mining, fabrication, insulation work), and beryllium (mining, fabrication).
- Exposure to these agents nearly always occurs in the workplace. However, the increased risk of cancer as a result of asbestos exposure extends to the family members of asbestos workers and to other individuals exposed outside the workplace
What is the health effect of vinyl chloride?
- Used in the synthesis of polyvinyl resins
- angiosarcoma of the liver
What occupational exposure increase the risk of heart disease?
CO, lead, solvents, cobalt
What occupation agent can cause respiratory illness?
- Nasal cancer: Isopropyl alcohol, wood dust
- Lung cancer: Radon, asbestos, silica, bis(chloromethyl)ether, nickel, arsenic, chromium, mustard gas, uranium
- Chronic obstructive lung disease: Grain dust, coal dust, cadmium
- Hypersensitivity: Beryllium, isocyanates
- Irritation: Ammonia, sulfur oxides, formaldehyde
- Fibrosis: Silica, asbestos, cobalt
Which occupational exposure are associated with CNS symptoms?
- Peripheral neuropathies/ataxic gait: Solvents, mercury, lead, arsenic, DDT(tremor seizure)
- Central nervous system depression: Chlordane, toluene, mercury
- Cataracts: Alcohols, ketones, aldehydes, Ultraviolet radiation
What are the toxic effect of occupational exposure on urinary system?
- Toxicity: lead, glycol ethers, solvents, cadmium
- Bladder cancer: Naphthylamines, 4-aminobiphenyl, benzidine, rubber products
What are the effects of occupational exposure on reproduction?
- Male infertility: Lead
- Female infertility/stillbirths: Lead, mercury
- Teratogenesis: Mercury, polychlorinated biphenyls
What are the effects of occupational exposure on skin?
- Folliculitis and acneiform dermatosis: PCB, dioxins, herbicides
- Cancer: UV, arsenic
What is the treatment of lead exposure?
- oral succimer in outpatients and with parenteral agents (eg, EDTA with or without dimercaprol) in more severe cases.
- Succimer is generally used in such children.
- In workers exposed to lead, prophylaxis with oral chelating agents is contraindicated because some evidence suggests that lead absorption may be enhanced by the presence of chelators.
- In contrast, high dietary calcium is indicated because it impedes lead absorption
What is the treatment of arsenic toxicity?
What are the symptoms of arsenic poisoning?
- ACUTE ARSENIC POISONING: severe GI discomfort, vomiting, "rice-water" stools, and capillary damage with dehydration and shock. A sweet, garlicky odor may be detected in the breath and the stools.
- CHRONIC ARSENIC POISONING: skin changes, hair loss, bone marrow depression and anemia, and chronic nausea and gastrointestinal disturbances. Arsenic is a known human carcinogen.
- ARSINE GAS: an occupational hazard, is formed during the refinement and processing of certain metals and is used in the semiconductor industry. Arsine causes a unique form of toxicity characterized by massive hemolysis. Pigment overload from erythrocyte breakdown can cause renal failure.
What are the symptoms of mercury poisoning?
- ACUTE MERCURY POISONING: through inhalation of inorganic elemental mercury. It causes chest pain, shortness of breath, nausea and vomiting, kidney damage, gastroenteritis, and CNS damage. Acute ingestion of mercuric chloride causes a severe, life-threatening hemorrhagic gastroenteritis followed by renal failure.
- CHRONIC MERCURY POISONING: may occur with inorganic or organic mercury. Poisoning from inhalation of mercury vapor presents as a diffuse set of symptoms involving the gums and teeth, gastrointestinal disturbances, and neurologic and behavioral changes (erethism).
- ORGANIC MERCURY POISONING:Minimata
What is the treatment of mercury poisoning?
- oral succimer or with intramuscular dimercaprol (for acute)
- Dimercaprol may redistribute mercury to the CNS and should not be used in chronic exposure to elemental mercury
What are the symptoms of iron toxicity?
The initial symptoms of iron poisoning include vomiting, gastrointestinal bleeding, lethargy, and gray cyanosis. These can be followed by signs of severe gastrointestinal necrosis, pneumonitis, jaundice, seizures, and coma
..............is the most common exogenous cause of human cancers
What are the important types of tobacco?
- The main culprit is cigarette smoking, but smokeless tobacco (snuff, chewing tobacco, etc.) is also harmful to health and an important cause of oral cancer.
- The use of tobacco products not only creates personal risks, but passive tobacco inhalation from the environment (“second-hand smoke”) can cause lung cancer in nonsmokers.
................is the most preventable cause of human death
What are the changes following cessation of smoking?
Cessation of smoking greatly reduces, within 5 years, the overall mortality and the risk of death from cardiovascular diseases. Lung cancer mortality decreases by 21% within 5 years, but the excess risk lasts for 30 years.
What are the cancers whose association have been proven with smoking?
- Head and neck cancers, including esophagus
- Lower urinary tract, including renal pelvis, ureter, and bladder
- Myeloid leukemia
- Nasal cavity and paranasal sinuses
- Uterine cervix
What are the effects of nicotine?
- Mainly addictive
- Nicotine binds to receptors in the brain, and through the release of catecholamines, 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
What are the major problems associated with tobacco smoking?
- The most common diseases caused by cigarette smoking involve the lung and include COPD, and lung cancer.
- Cigarette smoking is also strongly associated with the development of atherosclerosis, myocardial infarcts, and cancers of the lip, mouth, pharynx, esophagus, pancreas, bladder, kidney, and cervix
Which compounds in tobacco are mainly carcinogens?
- Polycyclic aromatic hydrocarbons
Which compound in the tobacco is tumor promoter?
Which compounds in the tobacco are toxic and irritant to cilia?
- Oxides of nitrogen
- Phenol (also promoter)
Which component of tobacco is associated with Impaired oxygen transport and utilization?
What are the roles of nicotine?
Ganglionic stimulation and depression
What are the non carcinogenic effects of tobacco on respiratory system?
- Agents in smoke have a direct irritant effect on the tracheobronchial mucosa, producing inflammation and increased mucus production (bronchitis).
- Cigarette smoke also causes the recruitment of leukocytes to the lung, with increased local elastase production and subsequent injury to lung tissue, leading to emphysema.
What are the mechanisms underlying carcinogenesis of tobacco?
- Components of cigarette smoke, particularly polycyclic hydrocarbons and nitrosamines, are potent carcinogens are likely involved in the development of lung cancer in humans.
- CYPs (cytochrome P-450 phase I enzymes) and phase II enzymes increase the water solubility of the carcinogens, facilitating their excretion
- However, 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,.
- The risk of developing lung cancer is related to the intensity of exposure, frequently expressed in terms of “pack years”.
- Moreover, smoking multiplies the risk of other carcinogenic influences. Witness the ten-fold higher incidence of lung carcinomas in asbestos workers and uranium miners who smoke over those who do not smoke, and the interaction between tobacco consumption and alcohol in the development of oral cancers
What are the carcinogens involved in each type of tobacco related cancer?
- Lung, larynx: Polycyclic aromatic hydrocarbons 4-(Methylnitrosoamino)-1-(3-pyridyl)-1-buta-none (NNK), polonium 210
- Esophagus: N′-Nitrosonornicotine (NNN)
- Bladder: 4-Aminobiphenyl, 2-naphthylamine
- Oral cavity (smoking): Polycyclic aromatic hydrocarbons, NNK, NNN
- Oral cavity (snuff): NNK, NNN, polonium 210
What is the mechanism of smoking in CAD?
- The causal mechanisms probably relate to several factors, including increased platelet aggregation, decreased myocardial oxygen supply (because of significant lung disease coupled with the hypoxia related to the CO content of cigarette smoke) accompanied by an increased oxygen demand, and a decreased threshold for ventricular fibrillation.
- Smoking has a multiplicative effect on the incidence of myocardial infarction when combined with hypertension and hypercholesterolemia.
What is the effect of smoking in pregnancy?
- Maternal smoking increases the risk of spontaneous abortions and preterm births and results in intrauterine growth retardation.
- Birth weights of infants born to mothers who stopped smoking before pregnancy are, however, normal
What are the effects of passive smoking?
- increased risk of coronary atherosclerosis and fatal myocardial infarction
- Risk of lung cancer
- respiratory illnesses and asthma
Passive smoke inhalation in nonsmokers can be estimated by measuring the blood levels of .........................
cotinine, a metabolite of nicotine
What are the symptoms of tobacco use disorder?
- Problematic pattern of tobacco use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period:
- 1. Tobacco is often taken in larger amounts or over a longer period than was intended.
- 2. There is a persistent desire or unsuccessful efforts to cut down or control tobacco use.
- 3. A great deal of time is spent in activities necessary to obtain or use tobacco.
- 4. Craving, or a strong desire or urge to use tobacco.
- 5. Recurrent tobacco use resulting in a failure to fulfill major role obligations at work, school, or home (e.g., interference with work).
- 6. Continued tobacco use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of tobacco (e.g., arguments with others about tobacco use).
- 7. important social, occupational, or recreational activities are given up or reduced because of tobacco use.
- 8. Recurrent tobacco use in situations in which it is physically hazardous (e.g., smoking in bed).
- 9. Tobacco use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by tobacco
- 10. Tolerance, as defined by either of the following:a. A need for markedly increased amounts of tobacco to achieve the desired effect.b. A markedly diminished effect with continued use of the same amount of tobacco.
- 11. Withdrawal, as manifested by either of the following:a. The characteristic withdrawal syndrome for tobacco (refer to Criteria A and B of the criteria set for tobacco withdrawal).b. Tobacco (or a closely related substance, such as nicotine) is taken to relieve or avoid withdrawal symptoms
What is the criteria for tobacco withdrawal?
- A. Daily use of tobacco for at least several weeks.
- B. Abrupt cessation of tobacco use, or reduction in the amount of tobacco used, followed within 24 hours by four (or more) of the following signs or symptoms:1. Irritability, frustration, or anger.2. Anxiety.3. Difficulty concentrating.4. Increased appetite.5. Restlessness.6. Depressed mood.7. Insomnia.
What is the diagnostic criteria for alcohol use disorder?
- A problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period:
- 1. Alcohol is often taken in larger amounts or over a longer period than was intended.
- 2. There is a persistent desire or unsuccessful efforts to cut down or control alcohol use.
- 3. A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recovôr from its effects.
- 4. Craving, or a strong desire or urge to use alcohol.
- 5. Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home.
- 6. Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol.
- 7. Important social, occupational, or recreational activities are given up or reduced because of alcohol use.
- 8. Recurrent alcohol use in situations in which it is physically hazardous.
- 9. Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol
- 10. Tolerance, as defined by either of the following:a. A need for markedly increased amounts of alcohol to achieve intoxication or desired effect.b. A markedly diminished effect with continued use of the same amount of alcohol.
- 11. Withdrawal, as manifested by either of the following:a. The characteristic withdrawal syndrome for alcohol (refer to Criteria A and B of the criteria set for alcohol withdrawal, pp. 499-500).b. Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms
What are some diagnostic clues to alcohol related disorder?
- blood alcohol concentration (>200 in non tolerant--> severe intoxication): can judge the degree of tolerance
- GGT and CDT--> sensitive and return to normal upon abstinence
- MCV (elevated): not normalized readily
- Elevated TG, uric acid and HDL
What are the symptoms of alcohol intoxication?
- A. Recent ingestion of alcohol.
- B. Clinically significant problematic beliavioral or psychological changes (e.g., inappropriate sexual or aggressive behavior, mood lability, impaired judgment) that developed during, or shortly after, alcohol ingestion.
- C. One (or more) of the following signs or symptoms developing during, or shortly after, alcohol use:1. Slurred speech.2. Incoordination. 3. Unsteady gait.4. Nystagmus.5. Impairment in attention or memory.6. Stupor or coma.
Highest intoxication with alcohol is seen with ....
other substance intoxication, especially in individuals with conduct disorder or antisocial personality disorder
What are the symptoms of alcohol withdrawal?
- A. Cessation of (or reduction in) alcohol use that has been heavy and prolonged.
- B. Two (or more) of the following, developing within several hours to a few days after the cessation of (or reduction in) alcohol use described in Criterion A:1. Autonomic hyperactivity (e.g., sweating or pulse rate greater than 100 bpm).2. Increased hand tremor.3. Insomnia.4. Nausea or vomiting.5. Transient visual, tactile, or auditory hallucinations or illusions.6. Psychomotor agitation.7. Anxiety.8. Generalized tonic-clonic seizures.
What is the mcc of alcohol-related death?
accidents caused by drunken driving and alcohol-related homicides and suicides
How is ethanol distributed and absorbed?
- After consumption, ethanol is absorbed unaltered in the stomach and small intestine. It is then distributed to all the tissues and fluids of the body in direct proportion to the blood level.
- Less than 10% is excreted unchanged in the urine, sweat, and breath.
What is the legal concentration for alcohol?
The amount exhaled is proportional to the blood level and forms the basis of the breath test used by law enforcement agencies. A concentration of 80 mg/dL in the blood constitutes the legal definition of drunk driving in the United States. For an average individual, this alcohol concentration may be reached after consumption of three standard drinks, contained in about 3 (12 ounce) bottles of beer, 15 ounces of wine, or 4–5 ounces of 80 proof distilled spirits
By drinking alcohol ..............occurs at 200 mg/dL, ................at 300 mg/dL, and coma, with possible respiratory arrest, at higher levels. The rate of metabolism affects the blood alcohol level
How is alcohol metabolized?
- Most of the alcohol in the blood is biotransformed to acetaldehyde in the liver by three enzyme systems consisting of alcohol dehydrogenase (ADH), the microsomal ethanol-oxidizing system (MEOS), and catalase.
- The main enzyme system involved in alcohol metabolism is ADH, located in the cytosol of hepatocytes.
- At high blood alcohol levels, the microsomal ethanol-oxidizing system participates in its metabolism.
- Catalase, which uses hydrogen peroxide as substrate, is of minor importance, since it metabolizes no more than 5% of ethanol in the liver.
- Acetaldehyde produced by alcohol metabolism through ADH or MEOS is converted to acetate by acetaldehyde dehydrogenase (ALDH), which is then utilized in the mitochondrial respiratory chain
What are the features of alcohol dehydrogenase?
- This cytosolic, NAD+-dependent enzyme, found mainly in the liver and gut, accounts for the metabolism of low to moderate doses of ethanol.
- Because of the limited supply of the coenzyme NAD+, the reaction has zero-order kinetics, resulting in a fixed capacity for ethanol metabolism of 7–10 g/h.
- Gastrointestinal metabolism of ethanol is lower in women than in men
Acetaldehyde produced by alcohol metabolism through ADH or MEOS is converted to ....................
acetate by acetaldehyde dehydrogenase (ALDH), which is then utilized in the mitochondrial respiratory chain
What are the features of MICROSOMAL ETHANOL-OXIDIZING SYSTEM (MEOS)?
- At blood ethanol levels higher than 100 mg/dL, the liver microsomal mixed function oxidase system that catalyzes most phase I drug-metabolizing reactions contributes significantly to ethanol metabolism.
- Chronic ethanol consumption induces cytochrome P450 enzyme synthesis and MEOS activity; this increase may be partially responsible for the development of tolerance to ethanol.
- The primary isoform of cytochrome P450 induced by ethanol—2E1—converts acetaminophen to a hepatotoxic metabolite
The primary isoform of cytochrome P450 induced by ethanol is ..............
2E1 which converts acetaminophen to a hepatotoxic metabolite
What are the features of aldehyde dehydrogenase?
- Aldehyde dehydrogenase, a mitochondrial enzyme found in the liver and many other tissues.
- Aldehyde dehydrogenase is inhibited by disulfiram and metronidazole, oral hypoglycemics (chlorpropamide), and some cephalosporins (Cefoperazone ).
- Some individuals, primarily of Asian descent, have genetic deficiency of aldehyde dehydrogenase.
- After consumption of even small quantities of ethanol, these persons experience nausea and a flushing reaction from accumulation of acetaldehyde
What is the significance of CYP2E1 in alcohol metabolism?
- Located in SER
- 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, potentiating the depressant effects of narcotic, sedative, and psychoactive drugs in the central nervous system
What are the toxic effects of alcohol mediated by aldehyde?
- Acetaldehyde has many toxic effects and is responsible for some of the acute effects of alcohol and for the development of oral cancers.
- The efficiency of alcohol metabolism varies between populations, depending on the expression levels of ADH and ALDH isozymes, and the presence of genetic variants that alter enzyme activity.
- About 50% of Asians have very low ALDH activity, due to the substitution of lysine for glutamine at residue 487 (the normal allele is termed ALDH2*1 and the inactive variant is designated as ALDH2*2).
- The ALDH2*2 protein has dominant-negative activity, such that even one copy of the ALDH2*2 allele reduces ALDH activity significantly.
- Individuals homozygous for the ALDH2*2 allele are completely unable to oxidize acetaldehyde and cannot tolerate alcohol, experiencing nausea, flushing, tachycardia, and hyperventilation after its ingestion
What are the effects of alcohol metabolism on NADH?
- Alcohol oxidation by ADH causes the reduction of NAD to NADH, with a consequent decrease in NAD and increase in NADH.
- NAD is required for fatty acid oxidation in the liver and for the conversion of lactate into pyruvate.
- Its deficiency is a main cause of the accumulation of fat in the liver of alcoholics.
- The increase in the NADH/NAD ratio in alcoholics also causes lactic acidosis
NAD is required for .....................................
fatty acid oxidation in the liver and for the conversion of lactate into pyruvate
What are the toxic consequences of Metabolism of ethanol in the liver by CYP2E1 ?
- produces reactive oxygen species and causes lipid peroxidation of cell membranes.
- Alcohol also causes the release of endotoxin (lipopolysaccharide) from gram-negative bacteria in the intestinal flora, which stimulates the production of TNF and other cytokines from macrophages and Kupffer cells, leading to hepatic injury
Acute alcoholism exerts its effects mainly on the ......
What are the effects of acute alcoholism?
- Acute alcoholism exerts its effects mainly on the CNS, but it may induce hepatic and gastric changes that are reversible if alcohol consumption is discontinued.
- Even with moderate intake of alcohol, multiple fat droplets accumulate in the cytoplasm of hepatocytes (fatty change or hepatic steatosis).
- The gastric changes are acute gastritis and ulceration.
- In the CNS, alcohol is a depressant, first affecting subcortical structures (probably the high brain stem reticular formation) that modulate cerebral cortical activity. Consequently, there is stimulation and disordered cortical, motor, and intellectual behavior.
- At progressively higher blood levels, cortical neurons and then lower medullary centers are depressed, including those that regulate respiration. Respiratory arrest may follow
Chronic alcoholism affects mainly the ......
Which organs are affected by chronic alcoholism?
- Peripheral neuropathies and the Wernicke-Korsakoff syndrome
- Dilated congestive cardiomyopathy
- Acute and chronic pancreatitis
- fetal alcohol syndrome
- Increased incidence of cancer of the oral cavity, esophagus, liver, and, possibly, breast in females
- Malnutrition and nutritional deficiencies, particularly of the B vitamins
What are the features of alcohol on the liver?
- The liver is the main site of chronic injury. In addition to fatty change, chronic alcoholism causes alcoholic hepatitis and cirrhosis.
- Cirrhosis is associated with portal hypertension and an increased risk for the development of HCC
What are the effects of chronic alcoholism in GI?
massive bleeding from gastritis, gastric ulcer, or esophageal varices (associated with cirrhosis), which may prove fatal
What is the major modulator of alcohol-related neurological symptoms?
Thiamine (vitamin B1) deficiency.
What are the main neurological lesions in chronic alcoholics?
The principal lesions resulting from this deficiency are peripheral neuropathies and the Wernicke-Korsakoff syndrome; cerebral atrophy, cerebellar degeneration, and optic neuropathy
What are the effects of alcohol on CV system?
- Direct Injury to the myocardium may produce dilated congestive cardiomyopathy (alcoholic cardiomyopathy).
- Moderate amounts of alcohol (about 20–30 gm of daily intake, corresponding to approximately 250 mL of wine) have been reported to increase HDL levels and inhibit platelet aggregation, thus protecting against coronary heart disease.
- However, heavy alcohol consumption, with attendant liver injury, results in decreased levels of HDL, increasing the likelihood of coronary heart disease.
What are the features of FAS?
- It consists of microcephaly, growth retardation, and facial abnormalities in the newborn, and reduction in mental functions as the child grows older.
- It is difficult to establish the minimal amount of alcohol consumption that can cause fetal alcohol syndrome, but consumption during the first trimester of pregnancy is particularly harmful
................is considered to be the main agent associated with alcohol-induced laryngeal and esophageal cancer
What is the effect of alcohol on cancer?
- Chronic alcohol consumption is associated with an increased incidence of cancer of the oral cavity, esophagus, liver, and, possibly, breast in females.
- Acetaldehyde is considered to be the main agent associated with alcohol-induced laryngeal and esophageal cancer, in that acetaldehyde-DNA adducts have been detected in some tumors from these tissues.
- Individuals with one copy of the ALDH2*2 allele who drink are at a higher risk of developing cancer of the esophagus
red wine contains .............., a polyphenolic compound that increases life span in worms and flies, promotes longevity in mice, and protects mice against diet-induced obesity and insulin resistance
The effects of resveratrol on longevity have been attributed to ...............................................
its activation of protein deacetylases of the Sir2 (sirtuin) family of enzymes, which include histone deacetylases
What are the interaction of alcohol with neurotransmitters?
- It facilitates the action of GABA at GABAA receptors, inhibits the ability of glutamate to activate NMDA (N-methyl-D-aspartate) receptors, and modifies the activities of adenylyl cyclase, phospho-lipase C, and ion channels.
- It has been suggested that alcohol "blackouts" may result from interference with NMDA receptors.
What are the effects of ethanol on smooth muscle?
Vascular smooth muscle is relaxed, which leads to vasodilation, sometimes with marked hypothermia. Ethanol relaxes uterine smooth muscle
What is the effect of ethanol on glucose?
Reduced gluconeogenesis can lead to hypoglycemia
What are the effects of ethanol on endocrine system?
Gynecomastia, testicular atrophy, and salt retention occur, partly because of altered steroid metabolism in the cirrhotic liver
Which drugs are used in acute alcohol withdrawal?
What are the drugs used for chronic alcoholism?
- The opioid receptor antagonist naltrexone has proved to be useful in some patients, presumably through its ability to decrease the effects of endogenous opioid peptides in the brain.
- Acamprosate , an NMDA glutamate receptor antagonist, is also FDA approved for treatment of alcoholism.
- The aldehyde dehydrogenase inhibitor disulfiram is used adjunctively in some treatment programs. If ethanol is consumed by a patient who has taken disulfiram, acetaldehyde accumulation leads to nausea, headache, flushing, and hypotension
What are the major functions and deficiency syndromes associated with vitamin A?
- A component of visual pigment, Maintenance of specialized epithelia, Maintenance of resistance to infection
- Def: Night blindness, xerophthalmia, blindness, Squamous metaplasia, Vulnerability to infection, particularly measles
What are the major functions and deficiency syndromes associated with vitamin D?
- Facilitates intestinal absorption of calcium and phosphorus and mineralization of bone
- Def: Rickets in children/ Osteomalacia in adults
What are the major functions and deficiency syndromes associated with vitamin E?
- Major antioxidant; scavenges free radicals
- DEf: Spinocerebellar degeneration
What are the major functions and deficiency syndromes associated with vitamin K?
- Cofactor in hepatic carboxylation of procoagulants—factors II (prothrombin), VII, IX, and X; and protein C and protein S
- Def: Bleeding diathesis
What are the major functions and deficiency syndromes associated with vitamin B1?
- As pyrophosphate, is coenzyme in decarboxylation reactions
- Def: Dry and wet beriberi, Wernicke syndrome, Korsakoff syndrome
What are the major functions and deficiency syndromes associated with vitamin B2?
- Converted to coenzymes flavin mononucleotide and flavin adenine dinucleotide, cofactors for many enzymes in intermediary metabolism
- Def: Ariboflavinosis, cheilosis, stomatitis, glossitis, dermatitis, corneal vascularization
What are the major functions and deficiency syndromes associated with vitamin B3?
- Incorporated into nicotinamide adenine dinucleotide (NAD) and NAD phosphate, involved in a variety of redox reactions
- Def: Pellagra—“three Ds”: dementia, dermatitis, diarrhea
What are the major functions and deficiency syndromes associated with vitamin B6?
- Derivatives serve as coenzymes in many intermediary reactions
- Def: Cheilosis, glossitis, dermatitis, peripheral neuropathy
What are the major functions and deficiency syndromes associated with vitamin B9,12, 5,8?
- B12: Required for normal folate metabolism and DNA synthesis/ Maintenance of myelinization of spinal cord tracts Def: Megaloblastic pernicious anemia and degeneration of posterolateral spinal cord tracts
- Folate: Essential for transfer and use of one-carbon units in DNA synthesis Def: Megaloblastic anemia, neural tube defects
- Pantothenic acid: Incorporated in coenzyme A
- Biotin: Cofactor in carboxylation reactions
What are the major functions and deficiency syndromes associated with vitamin C?
- Serves in many oxidation-reduction (redox) reactions and hydroxylation of collagen
- Def: Scurvy
Which test has the best performance in alcoholism diagnosis?
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