Toxins Flashcards
(24 cards)
Smoking can cause pneumonia, mostly due to pneumococcus. How?
Toxins, which:
1) Injure mucociliary apparatus via squamous metaplasia, so bacteria no longer pushed out
2) Cause inflammation, and therefore recruitment of macrophages that leak their proteases
3) Inhibit anti-proteases needed to protect against protease tissue injury
4) Cause mucous production and secretion
5) Inhibit phagocytosis
6) Kill respiratory epithelial cells, removing barrier to bacterial invasion.
Smoking can cause emphysema. How?
Toxins inhibit alpha-1-antitrypsin, which normally stops elastase from degrading elastin in the lungs. Meanwhile, toxins cause neutrophil migration into tissues, and these neutrophils up-regulate elastase. Inflammatory cells release proteases and cytokines that wreck the ECM, kill epithelial cells, and cause parenchymal cells to apoptose. Alveolar parenchymal destruction causes emphysema.
Gross appearance: abnormal, permanent enlargement of airspaces due to the destruction of the walls between alveoli.
Do smoking and drinking have synergistic toxicity?
Yes, especially with formation of laryngeal cancer.
Respiratory bronchiolitis
Occurs as smoking injures bronchioles.
Microscopic: large numbers of macrophages stuffed with “dusty” granular brown/black pigment
Smoking can cause thrombosis due to rupture of an atherosclerotic plaque. How?
Toxins, which:
1) Injure endothelial cells, increasing permeability of lipids into arteries
2) Induce procoagulant state
3) Increase HR, BP, and myocardial contractility, which increases heart’s need for blood
4) Decreases blood O2-carrying capacity
5) Cause 1/3 of MIs
Smoker’s macrophages
These contain a very light brown/black pigment located in tiny granules.
Hemophages
These are hemosiderin-laden macrophages in the heart. They are also called heart failure cells. They contain dark brown pigment in large, chunky refractile granules
Carbon monoxide poisoning
1) CO binds hemoglobin 200x better than O2, blocking O2 binding and transport to tissues
2) Clinical presentation: look for red discoloration of skin and mucous membranes, dyspnea, headache, coma, and death
3) How it kills: induces CNS depression, leading to coma and death.
Lead poisoning
Microscopic: Look for basophilic stippling (clumping of ribosomes) of RBCs due to degradation of ribosomal RNA
Pathology:
Electropositivity: Lead is positively charged and therefore attracted to negatively-charged enzymes. It inhibits sulfhydryl-dependent enzymes involved in heme synthesis, leading to HIGH FREE ERYTHROCYTE PROTOPORPHYRINS
Competition with Calcium: Neurotoxicity due to lead’s interference with calcium-dependent processes
Clinical Presentation in children: Low Conc => behavior, cognitive impairment, irritability, lethargy, anemia; High Conc => abdominal pain, kidney damage, tremor, seizures, coma, death
Clinical Presentation in adults: Low Conc. => Short-term memory loss, anxiety, phobias, irritability, depression; High Conc. => Peripheral neuropathy, anemia, abdominal pain, constipation, and anorexia.
Minamata disease
Occurs in a fetus that has exposure to high mercury levels
Clinical Presentation: cerebral palsy, deafness, and blindness
Arsenic poisoning
Pathophysiology: arsenic interferes with mitochondrial oxidative phosphorylation and the function of a variety of proteins.
Result: Toxicity in GI tract, CNS, and cardiovascular system
Alcohol causes steatosis. How?
Pathophysiology: Alcohol oxidation by alcohol dehydrogenase to acetaldehyde depletes NAD, which is needed for fatty acid oxidation. Fatty acids are no longer oxidized and instead accumulate in the liver. There is also impaired assembly and secretion of lipoproteins, as well as increased peripheral catabolism of fat. This condition also causes metabolic acidosis.
Gross pathology: tan-yellow liver, as opposed to a healthy red-brown
Microscopic pathology: hepatocytes will be distended with a clear cytoplasm (in vivo, they are distended with lipid, but the lipid is dissolved out during slide processing)
Main effects of chronic alcoholism
Fatty liver, alcoholic hepatitis, and cirrhosis. These lead to portal hypertension and increased risk of carcinoma.
Bleeding from gastric ulcers, pancreatitis, peripheral neuropathy
Cancers of the oral cavity, larynx, and esophagus
Legal limit?
80 mg/dL
Alcohol is absorbed unaltered in the stomach and small intestine
Chronic alcoholism causes steatohepatitis. How?
Pathophysiology:
1) Acetaldehyde, a major metabolite of ethanol, induces lipid peroxidation, which can disrupt cytoskeletal and membrane functions.
2) Alcohol directly affects cytoskeletal organization, mitochondrial function, and membrane fluidity
3) ROS are generated during oxidation of ethanol.
4) Alcoholic hepatitis and alcoholic liver disease cause cytokine-mediated inflammation that injures cells.
4) TNF: THE MAIN EFFECTOR OF INJURY, as well as IL-1, IL-6, and IL-8.
Microscopic Pathology: You’ll see steatosis in the liver, as well as neutrophilic inflammation and dead hepatocytes with pyknotic nuclei. You’ll also see Mallory-Denk bodies, which are tangled skeins of deranged cytoskeletal elements.
Cirrhosis
Pathophysiology: A distinctive form of fibrosis in the liver with regenerative nodules of hepatocytes that are not properly connected to arterial supply, venous supply, or the biliary system. The hepatocytes end up surrounded by fibrous tissue.
Microscopic Pathology: Look for round/oval nodules of regenerating hepatocytes completely surrounded by fibrous tissue.
Time table? 15 years of chronic alcoholism to get cirrhosis.
Hepatocellular carcinoma
Gross Pathology: rounded, variegated, green, brown, tan mass with background cirrhosis.
Microscopic Pathology: Glandular cells that look like hepatocytes, but with bigger nuclei, less cytoplasm, and bile in some of the lumens.
Fetal Alcohol Syndrome
Clinical presentation: growth retardation, dysmorphic facial features, neurobehavioral problems like cognition issues, adaptive functioning, and impairment of self-regulation.
Menopausal hormone therapy
Increases risk of endometrial and breast cancers, as well as thromboembolism
Oral contraceptives
Have protective effect against endometrial and ovarian cancers
Increases risk of thromboembolism and hepatic adenomas
Overdose of acetaminophen (Tylenol)
Causes centrilobular liver necrosis, leading to liver failure. Recall that Tylenol is metabolized to toxic NAPQI via CYP450s. Glutathione produced from methionine is required to take care of NAPQI. A dose of Tylenol too large for glutathione to manage leads to liver necrosis.
Restore GSH levels within 12 hrs to limit toxicity and possibly save life.
Scope of problem: 50K ER visits annually; causes 50% of the cases of liver failure; 30% mortality rate
And of course, alcohol and acetaminophen have synergistic toxicity.
Aspirin
Effect: Blocks production of thromboxane A2, which may lead to gastric ulceration and bleeding.
Cocaine
Induces myocardial ischemia by: 1) causing coronary artery vasoconstriction (decreasing blood flow) and enhancing platelet aggregation and thrombus formation. 2) At the same time, it increases myocardial oxygen demand by its sympathetic action
Smoking makes this worse.
These toxic actions are not necessarily dose-related and a fatal event could occur with first use of “reasonable amount”
Radiation Injury
Effect: Ionizing radiation generates free radicals, damages DNA (so rapidly dividing cells like those in GI tract are very susceptible), and causes vascular damage and sclerosis (resulting in ischemic necrosis of parenchymal cells that are replaced by fibrous tissue). It also causes neoplasm when cells with damaged DNA do not repair properly.
Microscopic Presentation: Look for pleomorphism, giant-cell formation, conformational changes in nuclei, and abnormal mitotic figures.
Look also at vasculature: you might see a totally obliterated artery without a lumen, an increase in interstitial collagen with scarring, and a blurred border between the tunica intima and tunica media.
