Ch. 9 - environmental diseases Flashcards
1
Q
climate change
A
- 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
2
Q
xenobiotics
A
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)
3
Q
detoxification process?
A
- 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
4
Q
CYP
A
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
5
Q
what induces CYP activity?
A
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
6
Q
what do you see in radiation?
A
leukemias and lyphomas (and some thyroid cancers)
7
Q
ozone
A
- 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
8
Q
particulate matter
A
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
9
Q
CO poisoning?
A
- 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
10
Q
symptoms of CO poisoning
A
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
11
Q
formaldehyde
A
used to manufacture cabinetry, furniture, adhesives
o causes difficulty breathing, burning in eyes and throat, can trigger asthma attacks
12
Q
plumbism
A
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
13
Q
what do you see besides neural problems in lead poisoning?
A
- 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)
14
Q
blood changes seen in lead poisoning?
A
- 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
15
Q
where do you see macrocytic anemia?
A
folate deficiency
16
Q
brain damage seen in lead poisonining?
A
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
17
Q
other effects of pb poisoning?
A
- GI tract: abdominal pain, “colic”
- Gingiva: lead line
- Bones: radiodense deposits in children
- Kidneys: chronic tubulointerstitial disease
18
Q
glutathione reductase
A
scavenger of free radicals
- protecting mechanism for mercury
19
Q
mercury poisoning
A
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)
20
Q
arsenic poisoning
A
“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
21
Q
CN- poisoning
A
Symptoms:
• toxicity due to CN- blocking cellular respiration by binding to mitochondrial cytochrome oxidase (Cyt a3)
• acts as an asphyxiant
• “bitter almond-scented” breath
22
Q
cadmium poisoning
A
• 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
23
Q
Itai-Itai
A
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
24
Q
carbon tetrachloride
A
• 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
25
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
26
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
27
DDT
Organochlorines:
• DDT (dichlorodi-phenyltrichloroethane)
o used as pesticide, and banned in US
o anti-estrogenic or anti-androgenic activity
28
Dioxins/PCBs
PCB - used in coolant fluid
29
pneumoconiosis
from Coal/Mining Dust: coal dust, silica, asbestos, beryllium
pneumoconiosis = chronic, non-neoplastic lung disease
30
Vinyl Chloride
used in synth of polyvinyl resins
| • angiosarcoma of liver (typically affects children under 5 y/o)
31
asbestos
bronchogenic carcinomas and mesotheliomas
32
pthalates
flexible plastics, such as medical containers (ill infants using IV bag admin.)
• endocrine disruption and testicular dysgenesis syndrome
• hypospadias, cryptorchidism, testicular cell abnormalities
33
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
34
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
35
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
36
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
37
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
38
what other cancers are related with tobacco?
tobacco → oral cavity, esophageal, pancreas and bladder cancers
39
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
40
metabolism of ethanol
done almost exclusively in liver:
1. ADH: turns ethanol --> acetaldehyde in cytosol.
2. 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
41
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
42
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
43
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
44
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.
45
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
46
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
47
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
48
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
49
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.
50
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)
51
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.
52
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
53
opiod narcotics
ex. heroin
| targets Mu opioid receptor (agonist)
54
psychomotor stimulants
ex. cocaine - antagonist of dopamine transporter
| ex. amphetmines/MDMA - toxicity via serotonin receptors
55
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
56
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
57
methanphetamine
Amphetamines: psychomotor stimulants - Methamphetmine
• closely related to amphetamine but with a stronger effect in CNS
• Acts by releasing dopamine in the brain, which inhibits presynaptic neurotransmission at corticostriatal synapses, slowing glutamate release
• produces a feeling of euphoria followed by a crash, leads to violent behaviors, confusion and psychotic features, paranoia and hallucinations
58
MDMA
MDMA, aka Ecstasy – psychomotor stimulant
• hallucinations due to increase in serotonin release in CNS
• interference in serotonin synthesis, causes a reduction in serotonin that is only slowly replenished
- causes increased serotinin in the space for a small period of time
59
marijuana
Cannabinoids
• agonist of CBI cannabinoid receptor: participates in regulation of hypothalamic-pituitary-adrenal axis, and modulates control of appetite, food intake, energy balance and sexual behavior
• used to treat nausea secondary to cancer chemotherapy, decreases pain, increases appetite
• distorts sensory perception and impairs motor condition
• with continued use may result in impairments such as inability to judge time, speed and distance
• increases the heart rate and sometimes blood pressure → angina in people with CAD
60
salicylates pulmonary effects?
cause asthma
61
blemomycin
used for tx. cancer
| - can cause interstitial fibrosis
62
adverse effects of salicylates on CNS
aspirin can cause tinnitus/dizziness
63
abrasion
wound made by scraping, rubbing, and removal of superficial layer of skin
64
contusion
bruise, produced by blunt object characterized by damage to blood vessels and extravasation of blood into tissues
65
laceration
tear or stretching of tissue caused by application of a blunt force object – see tissue bridging
66
incised wound
caused by sharp instrument
67
puncture wound
caused by penetrating narrow instrument
68
three different types of burns?
Superficial = first degree burn – confined to epidermis
partial thickness= second degree burn – involves injury to dermis: burns arepink and mottled with painful blisters
Full-thickness burns = (third degree) – extend into subcutaneous tissue, may also damage muscle underneath (4th degree). Look white/charred and dry
69
third degree burn effects on system?
Full-thickness burns = (third degree) – extend into subcutaneous tissue, may also damage muscle underneath (4th degree). Look white/charred and dry
• result in shock, sepsis and respiratory insufficiency
• hypovolemic shock: protein from blood is lost into interstitial tissue, generalized edema and pulmonary edema result
• hypermetabolic state: excess heat loss and an increased need for nutritional support (when 40% of the body surface is burned, the resting metabolic rate doubles)
• Opprotunistic infections: via Psuedomonas aeruginosa, S. aureus, Candida fungus
• organ system failure may result from burn sepsis
• Injury to airways and lungs may develop within 24-48 hours after burn, due to direct affect of inhalation of heated and noxious gases
• hypertrophic scars
70
heat cramps vs. head exhaustion
* heat cramps due to loss of electrolytes via sweating
| * heat exhaustion due to failure of CV system to compensate for hypovolemia, secondary to water depletion
71
heat stroke
thermoregulatory mechanisms fail, sweating ceases, core body temp increases
o due to generalized vasodilation → peripheral pooling of blood and decreased circulating blood volume → hyperkalemia, tachycardia, arrthymias
o necrosis of muscles (rhabdomyolysis) and myocardium may occur as consequence of nitrosylation of ryanodine receptor type 1 (RYR1) in skeletal mm.
o inherited mutation in RYR1 → malignant hyperthermia: rise in body temp and muscle contractures in response to exposure to common anesthetics
72
hypothermia
* seen in places with high humidity, wet clothing and dilation of superficial vessels resulting from ingestionof alcohol, lowering of body temp
* at 90 F → loss of consciousness, bradycardia, atrial fibrillation
direct effects:
o physical disruptions within cells by high salt concentrations caused by crystallization of intra and extracellular water
indirect effects:
o circulatory changes, due to vasoconstriction and increased vascular permeability, leading to edema and hypoxia
o with sudden persistent chilling, vasoconstriction and increased viscosity of blood in local area may cause ischemic injury and degenerative changes in peripheral nn.
73
electrical injury
* injuries result in burns and ventricular fibrillation or cardiac and respiratory center failure
* alternating current – seen in most homes – induces tetanic mm. spasm so that irreversible clutching occurs → prolonged exposure to current flow
74
ionizing radiation
• ionizing radiation = x-rays and gamma rays: cause electrons to be removed
o dissipate energy over a longer, deeper course and produce considerably less tissue damage than alpha and beta particles
o can cause fibrosis, mutagenesis, carcinogenesis and teratogenesis
75
rate of deliver, field size, cell proliferation in ionizing radiation?
• Rate of delivery: divided doses may allow cells to repair some of the damage b/w exposures
• field size: body can sustain high doses of radiation when delivered to small, carefully shielded fields, where as smaller doses delivered to larger fields may be lethal
• Cell proliferation: rapidly dividng cells are more vulnerable to injury than quiescent cells – DNA damage is compatible with survival in nondividing cells such as brain and myocardium
o tissues with high rates of cell division: gonads, bone marrow, lymphoid tissue and mucosa of GI tract are extremely vulnerable to radiation
76
ROS of ionizing radiation?
* produces ROS → DNA damage: thus poorly vascularized tissues with low O2 (i.e. rapidly growing tumors), are less sensitive to radiation therapy than nonhypoxic tissues
* causes impaired healing, fibrosis and chronic ischemic atrophy
77
morphology of cells affected by IR?
* show deletions, breaks, translocations and fragmentation of chromosomes
* nuclear swelling and chromatin clumping
* membrane breakdown
* apoptosis occurs
* giant cell formation
* **similarity b/w radiation-injured cells and cancer cells, b/c see markers of cell death
78
total body irradiation
• exposure of large areas to small doses → hematopoietic, GI and CNS disorders
79
IR --> hematopoietic/lymph systems
Hematopoietic and Lymphoid Systems:
• lymphopenia appears within hours of irradiation, shrinkage of lymph noes and spleen
• shrinkage of lymph nodes and spleen – destruction of lymphocytes
• destruction of hematopoietic precursors in bone marrow → aplastic anemia
• granulocytes count may increase at first, but becomes near zero by end of second week (takes 2-3 weeks to recover)
• Platelets are destroyed
80
fibrosis seen with IR
* replacement of dead parenchymal cells by CT, leading to formation fo scars and adhesions
* vascular damage, killing of tissue stem cells and pro inflamm. cytokines are released
* seen in lungs, salivary glands → neck cancers and prostate cancers
81
DNA damage/carcinogenesis of IR?
* most serious damage to DNA is double-stranded breaks
* can be repaired via homologous recombination and nonhomologous end joining (NHEJ) – often results in mutations and deletions and tranlocations
* “bystander effect” abnormal cells may promote growth of non-irradiated surrounding cells through production of growth factors and cytokines
82
cancer risks b/c of IR?
• increased incidence in leukemias, lymphomas,, and tumors (thyroid, breast, lungs) -
Hiroshima/Nagasaki
thyroid cancer – Chernobyl accident
acute myeloid leukemia, myelodysplastic syndrome, Hodgkin lymphoma
increased risk of cancer may also be due to exposure to Radon gas
83
PEM
Malnutrition = “protein energy malnutrition” PEM = inadequate intake of proteins and calories, or deficiencies in digestion or absorption of proteins resulting loss of fate and mm. tissue, weight loss, lethargy and generalized weakness
Dietary Insufficiency: BMI<16
- due to poverty, increased risk of infections, due to chronic illnesses (AIDS), chronic alcoholism (deficiency of vitamins)
84
marasmus
"melting"
• somatic compartment is affected
- decreased T cell counts --> viral infections
• child suffers from growth retardation and loss of muscle, resulting from catabolism and depletion of somatic protein compartment – which provides the body with AA’s as a source of energy
• subcutaneous fat is mobilized and letptin is low, with high levels of cortisol contributing to lipolysis
• extremities are emaciated, head appears large
• anemia, and immune deficiencies are present
85
kwashiorkor
* visceral compartment is affected
* protein deprivation nis greater than reduction in total calories → hypoalbunimeia giving rise to generalized edema
* weight loss is masked by increased fluid retention
* sparing of subcu. fat and mm. mass
* children has skin lesions, hyperpigmentation, desquamation, and pale hair changes
* see fatty liver that is enlarged and development of apathy, listlessness and loss of appetite
* see defects in immunity and secondary infections
* small bowel shows a decreases in mitotic index in crypts of the glands
86
secondary PEM
• develops in chronically ill, elderly, and bedridden patients
87
morphology seen in malnourished children
* bone marrow in both may be hypoplastic, due to decreased number of RBC precursors →anemia
* brain shows cerebral atrophy and reduced number of neurons with impaired myelinization of white matter
* thymic and lymphoid atrophy
88
cachexia
* PEM is a common complication in patients with AIDS or advanced cancers- and is responsible for a large amount of deaths with people that have cancer
* Cachexia = extreme weight loss, fatigue, mm. atrophy, anemia, anorexia, edema
* mortality is often caused by atrophy of the diaphragm and respiratory mm.
89
cachetic agents produced by tumors?
1. PIF: proteolysis-inducing factor – polypeptide excreted in urine of weight-losing patients with breast, pancreatic and colon cancer … etc.
o causes skeletal mm. breakdown through the NF-kB induced activation of ubiquitin- proteasome pathway, leading to degredation of myosin heavy chain.
o Also see loss of dystrophin caused by alterations in the dystrophin-glycoprotein complex
2. LMF: lipid-mobilizing factor – increases FA oxidation and pro-inflammatory cytokines such as TNF, IL2 and IL6. TNF and IL6 trigger acute phase response from the host increasing the secretion of CRP and fibrinogen and decreasing plasma concentrations of albumin.
90
anorexia nervosa
self-induced starvation → weight loss
*** see Amenorrhea, (almost always)resulting from decreased secretion of GNRH, and subsequent decreased secretion of LH and FSH
• decreased thyroid hormone releas → cold intolerance, bradycardia, constipation and changes in skin and hair
• dehydration and electrolyte abnormalities
• skin is dry and scaly
• decreased bone density
• anemia, lymphopenia, hypoalbunimia
• **increased susceptibility to sudden death resulting from hypokalemia
91
bulimia
patient induces vomiting (this is more common)
• see 50% with amenorrhea
• electrolyte imbalances – hypokalemia → cardiac arrhythmias
• pulmonary aspiration of gastric contents
• esophageal and gastric cardiac rupture
• teeth imprints on backs of hands
92
retinol in body
* retinoids: the various forms of Vit A: retinol, retinal, retinoic acid
* found in liver, fish, eggs, milk, butter and yellow and leafy green vegetables
* fat-soluble vitamin, its absorption requires bile, pancreatic enzymes and some antioxidant activity in the food
* retinol and Beta-carotene are absorbed in the intestine where B-carotene is converted to retinol
* retinol is transported in chylomicrons to the liver for esterification and storage
* uptake in liver cells takes place through apolipoprotein E receptor
* more than 90% of bodys vitamin A reserves are stored in the liver, predominantly in the perisunusoidal stellate (Ito) cells
* before being released retinol binds to specific retinol binding protein (RBP) which is synthesized in the liver, and is taken up in peripheral tissues
93
function of Vitamin A?
1. Maintenance of Normal vision: rhodopsin of the rods requires oxidation to all-trans-retinal, isomerization to 11-cis retinal and covalent association with the 7-transmembrane rod protein opsin to form rhodopsin. a photon of light causes the isomerization of 11-cis retinal to all-tran-retinal, which dissociates from rhodopsin and triggers a down stream impulse. Most retinol is lost to the retina and thus needs the continuous supply of retinol.
2. Cell growth and differentiation: Vit A plays an important role in orderly differentiation of mucus-secreteing epithelium. Deficiency causes epithelium to undergo squamous metaplasia, differentiating into keratinizing epithelium. The RAR/RXR heterodimers bind to retinoic acid response elements located in promoter regions of genes that encode receptors for growth factors, tumor suppressor genes and secreted proteins → thus retinoids play in cell growth and differentiation, cell cycle control.
3. Metabolic Effects of retinoids: RXR is activated by retinoic acid and is involved in drug metabolism. PPARs are regulators of fatty acid metabolism, and their association with RXR explains effects of retinoids on adipogenesis and obesity
4. Host resistance to infections: helps diarrheal diseases through maintenance and restoration of the integrity of the epithelium of the gut and through stimulation of the immune system
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retinoids used clinically?
• Retinoids are used clinically for the treatment of skin disorders; acne, psoriasis, acute promyelocytic leukemia
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Vit A deficiency?
• occurs due to undernutrition or secondary deficiency due to malabsorption of fats
• Ault patients with malabsorption see Vit. A deficiency due to → Celiac disease, Crohn’s Disease, Colitis
• Symptoms:
o night blindness
o epithelial metaplasia and keratinization
o xeropthalmia (dry eyes)
o xerosis conjunctivae (dryness of conjunctiva) is seen first as the normal lacrimal and mucus secreting epithelium are replaced by keratinized epithelium
o Bitot Spots: these are as keratin debris build up into small opaque plaques
o Keratomalacia: softening and destruction of the cornea, occurs through erosion of the roughened corneal surface → total blindness
o squamous metaplasia of respiratory/urinary tract: epithelium lining these areas is replaced by keratinizing squamous cells. loss of mucociliary epithelium → pulmonary infections in lungs and predisopes to renal and urinary bladder stones
o hyperkeratinization of the epidermis: due to plugging of the ducts of the adnexal glands causing follicular and popular dermatosis
o immune deficiency: common infections are prevalent
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vit a toxicity
* ex. man who ate polar bear liver
* Acute Toxicity Symptoms: headache, dizziness, vomiting, stupor, blurred vision, symptoms may be confused with that of a brain tumor (psuedotumor cerebri)
* Chronic Toxicity symptoms: weight loss, anorexia, nausea, vomiting, and bone and joint pain
* Retinoic acid stimulates osteoclast production and activity which lead to increased bone resorption and high risk of fractures
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metabolism of vitamin D
o about 90% of vitamin D comes through skin, darker skinned individuals have lower vitamin D production
o 1. 7-dehydrocholesterol + UV light → Vitamin D (cholecalciferol) or Vitamin D aborbed through gut
o 2. binding of vitamin D with alpha1-globulin (D-binding protein DBP) and transport to liver
o 3. conversion of vitamin D → 25,hydroxycholecalciferol (25-OH-D) in liver through 25-OHases, including CYP27A1
o 4. conversion of 25-OH-D to 1,25 dihydroxyvitamin D in the kidney (the most active form of vitamin D through alpha1-hydroxylase)
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regulation of vitamin D
o 1. hypocalcemia stimulates secretion of PTH, which in turn augments conversion of 25-OH-D into 1,25dihydroxyvitamin D by activating 1alpha-0hydroxylase
o 2. hypophosphatemia directly activates alpha1-hydroxylase and increases the production of 1,25dihydroxyvitamin D
o 3. feedback mechanisms: increased levels of 1,25 dihydroxyvitamin D down-regulate its own synthesis through inhibition of 1alpha-hydroxylase activity
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mechanism of vit D action?
o 1,25 dihydroxyvitamin D is a steroid hormone
o It binds to high-affinity D receptor (VDR) which associates with RXR
o The receptors transduce signals that regulate plalsma levels of Ca2+ and P- through action of the small intestine, bones and kidneys
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Effects of Vitamin D on Ca2+ and P- homeostasis
o 1. Stimulation of intestinal Ca2+ absorption: 1,25 Vit D stimulates absorption in duodenum via interaction of 1,25 Vit D with VDR and formation of complex with RXR – this complex activates the TRPV6 txn, which encodes a Ca2+ transport channel
o 2. Stimulation of Ca2+ reabsorption in the kidney: 1,25, Vit D increases CA2+ influx in distal tubules through increased expression of TRPV5, - this expression is also regulated by PTH in response to hypocalcemia
o 3. Interaction with PTH in the regulation of blood Cad2+ : Vit D maintains Ca2+ and P- at supersatured levels in the plasma – both 1,25 Vit D and PTH enhance the expression of RANKL on osteoblasts. RANKL binds RANK in preosteoclasts and induces differentiation into osteoclasts. → osteoclasts dissolve bone and release Ca2+ and P- into circulation
o 4. Mineralization of bone: vit D contributes to laying down of osteoid matrix and epiphyseal cartilage – stimulates osteoblasts to synthesize the Ca2+ binding protein osteocalcin, involved in deposition of CA2+ during bone formation.
• flat bones develop via intramembranous formation – where mesenchymal cells differentiate into osteoblasts and deposit osteoid matrix
• Long bones develop by endochondral ossification through growing cartilage at epiphyseal plates
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vitamin D deficiency
* can be due to renal disorders causing decreased synth. of 1,25 Vit D, P- depletion, or malabsorption disorders
* Vit D deficiency also leads to increased risk of bone loss and hip fractures
* in both Rickets and Osteomalacia you see an excess of unmineralized matrix
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Rickets
* seen in children, resulting from limited sun exposure of diet deficient in Ca2+ and Vitamin D
* Rickets is most common during the first year of life: during nonambulatory stage head and chest change:
* softened occipital bones become flattened and pariparietal bones can buckle→ craniotabes.
* Excess of osteoid produces frontal bossing and squared appearance of head.
* Also see deformation of chest → “rachitic rosary”
* Pigeon Breast deformity:
During ambulatory stage:
• deformities are seen in spine pelvis and tibia causing lumbar lordosis and bowing of the legs
* overgrowth of epiphyseal cartilage due to inadequate provisional calcification occurs and there is a failure of cartilage cells to mature and disintegrate
* see persistence of distorted irregular masses of cartilage which project into marrow cavity
* deposition of osteoid matrix is seen on inadequately mineralized cartilaginous remnants
* see disruption of orderly replacement of cartilage by osteoid matrix – with abnormal overgrowth of capillaries and fibroblasts in disorganized zone resulting from microfractures and weak bones
* deformation of skeleton
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osteomalacia
seen in adults
• deranges the normal bone remodeling that occurs throughout life
• newly formed osteoid matrix is inadequately mineralized, resulting in bones that are weak and vulnerable to gross fractures/microfractures (often seen at vertebral bodies and femoral necks)
• unmineralized osteoid can be visualized as thickened layer of matrix arranged about normally mineralized trabeculae
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hypocalcemic tetany
Hypocalcemic tetany: convulsive state caused by insufficient extracellular concentration of ionized CA2+ - which is reqd for normal neural excitation and relaxation of mm.
• When hypocalcemia occurs in vitamin D deficiency you see:
o a. PTH is elevated → activation of renal 1alpha-hydroxylase, increasing the amount of active Vitamin D and calcium absorption
o b. increase resorption of Ca2+ from bone via osteoclasts
o c. decreased renal Ca2+ excretion
o d. increased renal excretion of P-
• FGF23 is a phosphatonin which blocks absorption of phostphate in intestine and P- reabsorption by kidney → increased P- excretion
• increased FGF23 may be responsible for tumor-induced osteomalacia and hypophosphatemic rickets
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nonskeletal effects of vitamin D
Skeletal Effects of Vitamin D:
• Important for immunity: macrophages synth of 1,25 Vit D is through CYP27B → stimulates the synthesis of cathelicidin (an antimicrobial peptide from defensing family, which is effective against infection of M. tuberculosis )
• Pathogens and LPS stimulate TLRs in macrophages, causing txn of vVDR and increased cYP27B activity in mitochondria. This causes production of 1,25 Vitamin D, which stimulates synth of cathelicidin.
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vit D toxicity
can cause hypervitaminosis D: see metastatic calcifications of soft tissues in the kidney, in adults it causes bone pain and hypercalcemia
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Vitamin C
Ascorbic Acid
• Collagen function: Vit C is necessary for activation of prolyl and lysyl hydroxylases from inactive precursors, providing for hydroxylation of procollagen. Inadequately hydroxylated procollagen cannot acquire stable configurations, so it is poorly secreted from the fibroblast
o molecules secreted lack tensile strength and are vulnerable to enzymatic degredation
o Collage deposition is most affected -→ accounts for hemorrhages in scurvy
• antioxidant properties: Vit C can scavenge free radicals and regenerate the antioxidant form of Vit E
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Scurvy
= Vitamin C deficiency
• characterized by bone disease in growing children and hemorrhages/healing defects in children and adults
• occasionally occurs in people undergoing peritoneal dialysis and hemodialysis or amongst food faddists or in infants who are maintained on formulas of evaporated milk without Vit C supplementation
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Vitamin C toxicity?
may cause relief of colds due to mild antihistamine action. However, the physiologic ability of Vit C is limited and is promptly excreted in the urine
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Vitamin A
fn: Component of visual pigment, Maintenance of specialized epithelia
deficiency: Resistance against infection Night blindness, xeropthalmia, blindness, squamous metaplasia, vulnerability to infection (particularly measels)
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Vit D
fn: Facilitates intestinal absorption of Ca2+ and P- and mineralization of bone
deficiency: Rickets in children
Osteomalacia in adults
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beri-beri
weightloss, emotional disturbances, weakness and pain in limbs, irregular heart beat
- affects the PNS and CV system
- results from thiamine deficiency (seen in alcoholics) (aka Vitamin B1)
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WErnickes encephalopathy
thiamine def. (seen in alcoholics)
| - occular disturbances, dementia, ataxia
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Korsakoff Syndrome
- thiamine def. (seen in alcoholics)
| - amnesia, aphasia, apraxia, memory deficits, agnosia
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Vit E
Cofactor of hepatic carboxylation of procoagulants : factors II, VII, IX and X and protein C and protein S
Bleeding diathesis
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Vit B
Vit B1 (thiamine)
As pyrophosphate, is coenzyme in decarboxylation rxns
Dry and wet beriberi, Wernicke syndrome, Korsakoff syndrome
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Vit B2
Vit B2 (riboflavin)
Converted to coenzymes which are cofactors for many enzymes in intermediary metabolism
Ariboflavinosis, cheilosis, stomatitis, glossitis, dermatitis, corneal vascularization
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vit B3
Vit B3 (Niacin)
Incorporated into NAD / NAD phosphate: important for redox rxns
Pellagra – “three D’s”: dementia, dermatitis, diarrhea
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Vit B12
Rqd. for folate metabolism and DNA synthesis
Maintentance of myelinization of spinal cord tracts
Megaloblastic pernicious anemia, degeneration of posterolateral spinal cord tracts
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Vit C
Serves in many redox rxns and hydroxylation of collagen
| Scurvy
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Folate
Essential for transfer and use of one-carbon units in DNA synth
Megaloblastic anemia, neural tube defects
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Zinc
Component of enzymes and oxidases
- Deficiency seen with inadequate supplementation
- see rash around eyes, moth, nose and anus called acrodermatitis enteropathica
- anorexia and diarrhea
growth retardation in children
- depressed mental fn
- depressed wound healing/immune response
- impaired night vision
- infertility
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iron
Essential component of Hgb
- Deficiency seen with inadequate diet/chronic blood loss
Hypochromic microcytic anemia
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Iodine
Component of thyroid hormone
- Deficiency seen with inadequate supply in food and water
Goiter and hypothyroidism
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Copper
Component of cytochrome C oxidase, dopamine hydroxylase cross-linking of collage
- Deficiency due to inadequate absorption
Muscle weakness
Neurologic deficits
Abnormal collagen cross-linking
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Fluoride
Deficiency due to inadequate supply in soil and water and inadequate supplementation
Dental caries
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Selenium
Component of glutathione peroxidase and Vit E antioxidant
Myopathy
Cardiomyopathy (Keshan disease)
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BMI
BMI > 30 = obese
| BMI between 25 and 30 = overweight
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central obesity
visceral obesity = fat accumulates in trunk and abdominal cavity (in mesentery and around viscera)
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Leptin
(from fat cells)
o product of ob gene
o mice deficient in leptin (ob/ob mice) or leptin receptors (db/db mice) fail to sense adequacy of fat stores, overeat, gain weight and behave as if undernourished
o leptin secretion is stimulated with fat stores are abundant, insulin-stimulated glucose metabolism is important factor in leptin regulation
o leptin stimulates POMC/CART in hypothalamus to produce anorexigenic neuropeptides and inhibits NPY/AgRP neurons
o abundance of leptin simulates physical activity, heat production and energy expenditure
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adiponectin
(from fat cells)
o stimulates FA oxidation in mm, causing decrease in fat mass
o “fat burning molecule” – directs FA’s to mm. for their oxidation
o decreases influx of FA’s to liver, causes increase in insulin sensitivity
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Ghrelin
(from stomach)
o produced in stomach and only known gut hormone that increases food intake (orexigenic effect)
o stimulates NPY/AgRP neurons to increase food take
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Peptide YY
(PYY) (from ileum and colon)
o secreted from endocrine cells, levelsare low during fasting and increase shortly after food intake
o PYY reduces energy intake
o Prader-Willi Syndrome: PYY is decreased in these individuals, contributing to development of hyperphagia and obesity in these people
o stimulates POMC/CART
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Amylin
(peptide secreted with insulin that reduces food intake and weight gain)
o stimulates POMC/CART
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POMC/CART
o enhance energy expenditure and weight loss through production of anorexigenic hormone (MSH) and activation of MC3/4R
o mutations in MC4R are associated with severe obesity – individuals can’t sense being full
o BDNF is an important signal in MC4R and is altered in WAGR syndrome, resulting in marked obesity
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NPY/AgRP
o neurons promote food intake (orexigenic effect) and weight gain
• activation of Y1/5 receptors
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adipose and inflammation
• in addition to leptin/adiponectin, adipose tissue produces cytokines such as TNF, IL-6 and IL-1, IL-18, chemokines and steroid hormones
o creates a chronic inflammatory state – and elevation of CRP levels
• total number of adipocyte cells is established during childhood/adolescence, higher in obese rather than lean individuals
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metabolic syndrome
“metabolic syndrome”: visceral/intra-abdominal adiposity, insulin resistance, hyperinsulinemia, glucose intolerance, HTN, hypertriglyceridemia, low HDL cholesterol
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obesity leads to...
* insulin resistance and hyperinsulinemia → increased sodium retention→ HTN
* Low HDL → Coronary artery disease
* nonalcoholic fatty liver disease
* cholelithiasis (gallstones): 6x more common in obese individuals
* Hypoventilation syndrome: respiratory abnormalities in very obese persons = pickwickian syndrome
* hypersomnolence: apneic pauses during sleep and right sided heart failure
* Osteoarthritis: effects of increased load on weight bearing joints
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obesity and cancer
• Men: increased adenocarcinoma of esophagus, cancers of thyroid, colon and kidney
• Women: increased incidence of adenocarcinoma of esophagus, endometrial, gallbladder and kidney cancers
• increased cancer risk may be due to hyperinsulinemia and insulin resistance
o hyperinsulinemia causes increase in insulin-like growth factor → mitogenic and anti-apoptotic agent. IGF-1 activates many cell growth pathways
o obesity increases synth of estrogen from androgen and increases androgen synth in ovaries and adrenals
o decreased levels of adiponectin in obese contribute to hyperinsulinemia
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diet and cancer
* Exogenous synthesis of toxins: aflotoxin: seen in hepatocellular carcinomas → causes mutation in p53 gene
* Endogenous synthesis of carcinogens: ex. Nitrosamines and nitrosamides
* high animal fat intake with low fiber intake → colon cancer (increased level of bile acids in gut, modifies intestinal flora, favoring growth of microaerophilic bacteria. high fiber diets increase stool bulk and transit time thereby protecting the mucosa)
