Chapter 9

Question 1

Xenobiotics

Answer 1

-exogenous chemicals in the air, water, etc that are inhaled, ingested, etc

Question 2

Phase I reactions

Answer 2

• first step of either metabolizing xenobiotics to inactive metabolites or activating them into toxic compounds
• involved hydrolysis, oxidation, or reduction reactions
• most important catalyst is cytochrome p-450 enzymes

Question 3

Phase II reactions

Answer 3

• metabolism of phase I products into excretable water-soluble compounds
• glucuronidation, sulfation, methylation or glutathione conjugation

Question 4

Carbon monoxide

Answer 4

• product of incomplete oxidation of carbonaceous materials
• systemic asphyxiant that causes CNS depression
• hemoglobin has 200x greater affinity for CO than for oxygen, and so does not carry oxygen resulting in hypoxia at low concentrations, and unconsciousness and death at high concentrations (in 5 min in a garage)
• chronic CO poisoning: ischemic changes in CNS especially basal ganglia
• acute CO poisoning: cherry-red skin and mucus membranes; may see cerebral edema, punctate hemorrhages and hypoxia induced neuronal changes (changes not specific for CO but seen in any hypoxic injury)

Question 5

Mercury

Answer 5

• main sources: contaminated fish, mercury vapours from dental amalgams
• methyl mercury (organic compound) accumulates in CNS and can cause deafness, mental retardation etc (Minamata disease), cerebral palsy, and kidney damage
• CDC recommends low mercury intake in pregnancy to protect against fetal brain damage
• ?autism link

Question 6

Arsenic

Answer 6

• found in herbal supplements, wood preservers, herbicides
• causes cardiovascular, CNS and gastrointestinal toxicity
• arsenic keratoses and SCC

Question 7

Cadmium

Answer 7

• from batteries, soil contamination (most commonly ingested)
• causes obstructive lung disease and renal tubular damage that can progress to end stage renal disease

Question 8

Vinyl chloride risk and who is at risk

Answer 8

• angiosarcoma of the liver

- risk to producers of polyvinyl resins

Question 9

Main steps in alcohol metabolism

Answer 9

• converted to acetaldehyde by alcohol dehydrogenase in hepatocytes
• acetaldehyde converted to acetate by acetaldehyde dehydrogenase
• acetate then utilized by mitochondrial respiratory transport chain

Question 10

Effects of chronic alcoholism

Answer 10

Liver: steatosis, steatohepatitis, cirrhosis
GI tract: gastritis, ulcers and varices can cause life-threatening bleeding; pancreatitis
CNS/PNS: thiamine deficiency causing Wernicke-Korsakoff syndrome and peripheral neuropathy
CV system: dilated cardiomyopathy
FAS
Cancer: oral cavitiy, esophagus, liver
Malnutrition and nutritional deficiencies

Question 11

Mechanism of injury in acetaminophen toxicity

Answer 11

• accumulation of NAPQI which binds to hepatic proteins causing damage to membranes and mitochondria, and depletion of GSH (which normally conjugates NAPQI), making hepatocytes more susceptible to ROS-induced injury
• because alcohol induces CYP2E1 which metabolizes some acetaminophen to NAPQI, toxicity occurs at lower doses in alcoholics
• in the normal setting, 95% of acetaminophen is detoxified by phase II enzymes, but in larger doses, the NAPQI pathway gets activated more

Question 12

Histologic features of acetaminophen overdose

Answer 12

-centrilobular necrosis that may extend to involve entire lobules

Question 13

Acute ASA overdose

Answer 13

• respiratory alkalosis due to stimulation of medullary respiratory centres
• then, metabolic acidosis producing nausea, coma

Question 14

Effects of cocaine

Answer 14

Generally: blocks reuptake of dopamine and norepinephrine and epinephrine
Cardiovascular effects: acts as a sympathomimetic causing tachycardia, hypertension and peripheral vasoconstriction; also induces myocardial ischemia via coronary artery vasoconstriction; also lethal arrhythmias from ion transport disruption
CNS: hyperpyrexia
Pregnancy: fetal hypoxia due to vasoconstriction in placenta

Question 15

Effects of heroin

Answer 15

Opioid agonist (Mu receptor)

Sudden death due to respiratory depression, arrhythmia and cardiac arrest and severe pulmonary edema
Pulmonary edema
Infections including endocarditis due to injections
Renal disease

Question 16

Features determining the significance of a burn injury

Answer 16

• depth of burn
• percentage body surface involved
• internal injuries caused by inhalation of hot and toxic fumes
• promptness and efficacy of therapy, especially fluid resuscitation

Question 17

Types of electrical injuries

Answer 17

• burns
• ventricular fibrillation
• cardiac/respiratory centre failure
• tetanic muscle spasm resulting in prolonged grabbing in alternating currents

Question 18

Damage to DNA caused by ionizing radiation

Answer 18

• double strand breaks, single base damage, single strand breaks, DNA-protein cross links
• double strand breaks are the most serious because repair often produces mutations, which, if not corrected, may initiate carcinogenesis

Question 19

Marasmus

Answer 19

• growth retardation and loss of muscle but visceral protein compartment (liver) is only marginally depleted, therefore albumin levels near normal
• subcutaneous fat is mobilized for fuel
• emaciated extremities; large head for body

Question 20

Kwashiorkor

Answer 20

• protein deprivation > calorie deprivation
• severe loss of the visceral protein compartment, leading to hypoalbuminemia and generalized edema
• relative sparing of subcutaneous fat and muscle mass
• enlarged fatty liver

Question 21

Functions of vitamin A

Answer 21

• maintaining vision (required to build pigments)
• differentiation of mucus-secreting epithelium (becomes keratinized without vitamin A)
• roles in fatty acid metabolism
• involved in host resistance to infections

Question 22

Effects of vitamin A deficiency

Answer 22

• night blindness
• xerophthalmia (dry eye)
• squamous metaplasia of respiratory tissues causing loss of mucociliary epithelium and infection
• follicular plugging in skin
• immune deficiency

Question 23

Vitamin D deficiency

Answer 23

• Rickets in children
• Osteomalacia in adults
• both due to an excess of unmineralized matrix

Question 24

Rickets

Answer 24

• due to lack of Vitamin D
• overgrowth of cartilage due to inadequate calcification with deposition of osteoid on inadequately mineralized cartilage with subsequent fractures and skeletal deformation
• flattened occipital bones, frontal bossing, rachitic rosary (overgrowth of cartilage at the costochondral junction)

Question 25

Osteomalacia

Answer 25

- deranged normal bone remodelling due to lack of vitamin D - excess persistent inadequately mineralized osteoid - histology: thickened matrix around normal basophilic mineralized bone - susceptible to fractures

Question 26

Main function of vitamin C

Answer 26

- production of prolyl and lysyl hydroxylases that result in hydroxylation of procollagen - antioxidant properties: free radical scavenging

Question 27

Features of vitamin C deficiency

Answer 27

- poor vessel support: bleeding gums, joints, skin - inadequate synthesis of osteoid - impaired wound healing

Question 28

Leptin

Answer 28

- synthesized by fat cells - stimulates POMC/CART neurons in the hypothalamus that produce anorexigenic neuropeptides (MSH) - inhibits NPY neurons thereby inhibiting feeding-inducing neuropeptides - leptin is dimished when there are inadequate stores of body fat - leptin resistance may be a cause for obesity

Question 29

Ghrelin

Answer 29

- produced in stomach and arcuate nucleus | - only known gut hormone that increases food intake

Question 30

Malformation

Answer 30

- primary error of morphogenesis with an intrinsically abnormal developmental process - usually multifactorial rather than related to a single chromosomal defect - e.g. anencephaly

Question 31

Deformation

Answer 31

- extrinsic disturbance of development caused by localized or generalized compression of the fetus by abnormal biomechanical forces - e.g. uterine constraint (maternal factors such as 1st pregnancy, leiomyomas, or placental factors such as oligohydramniosis, or fetal factors such as twins) - e.g. clubfeet

Question 32

Syndrome

Answer 32

- constellation of congenial anomalies believed to be pathologically related but that cannot be explained by a single initiating defect - e.g. viral or specific chromosomal abnormalities that affect multiple tissues

Question 33

Aplasia

Answer 33

-absence of an organ due to failure of development of the primordium

Question 34

What three enzyme systems are responsible for metabolizing alcohol?

Answer 34

- alcohol dehydrogenase - the microsomal ethanol oxidizing system - catalase -latter two come into play at high blood alcohol concentrations

Question 35

Differentiate heat cramps, heat exhaustion and heat stroke.

Answer 35

Cramps: loss of electrolytes via sweating with cramping (usually after exercise) Exhaustion: Collapse because of failure of CV system to compensate for hypovolemia Stroke: Failure of thermoregulatory mechanisms resulting in high body temperature, generalized vasodilation with peripheral pooling, tachycardia, arrhythmia, and muscle necrosis (rhabdomyolysis)

Question 36

What are cachectic agents produced by tumors?

Answer 36

- PIF (proteolysis inducing factor): causes muscle breakdown via NF-KB - LMF (lipid-mobilizing factor)

Question 37

What is the possible mechanism whereby obesity contributes to carcinogenesis?

Answer 37

May be through hyperinsulinemia and insulin resistance; with increase in IGF1, which is mitogenic and antiapoptotic and is highly expressed in many cancers May also have an effect on steroid hormones that regulate cell growth in certain organs (e.g. estrogen for breast or uterus)

Question 38

How might sirtuins (increased by calorie restriction) prolong life?

Answer 38

May lower IGF1 levels with resistance to carcinogenesis | -also less oxidative damage and less decline in immunologic function