What are the leading causes of death in developed countries?
Ischemic heart disease and cerebrovascular disease
Postnatally, what are the 3 conditions that are preventable that cause deaths in children under 5 y/o?
2) Diarrheal diseases
Activation of Xenobiotics to generate toxic compounds occurs in 2 phases, what are they?
Phase I: chemicals undergo hydrolysis, oxidation, or reduction (by CYP 450)
Phase II: often metabolized to water soluble compounds through glucuronidation, sulfation, methylation, and conjugation w/ glutathione
Xenobiotics are metabolized by what?
- CYP-450 system in ER of liver
- Either detoxification or conversion into active compounds that cause cell injury –> ROS
What are the inducers of CYP? (mnemonic)
What decreases CYP activity?
Fasting and/or starvation
Which size particles are the most harmful?
What happens when inhaled?
- Fine or ultrafine particles less than 10 μm in diameter
- Readily inhaled into alveoli where they are phagocytosed by macrophages and neutrophils,respond by releasinginflammatory mediators
Acute poisoning by CO is marked by which characteristic morphology?
Cherry-red color of the skin and mucous membranes
Lead is a readily absorbed metal that binds to what?
Leads to what kind of toxicities?
- Binds to sulfhydryl groups in proteins and interferes with CALCIUM metabolism
- Leads to: hematologic, skeletal, neurologic, GI, and renal toxicities
Most absorbed lead is incorporated into?
- Bones and teeth
- Competes with calcium
High levels of lead cause CNS disturbances in both adult and children, but what condition is predominant in adults?
Lead inhibits the activity of what 2 enzymes involved in heme synthesis?
Causes what type of anemia?
- δ-aminolevulinic acid dehydratase and Ferrochelatase
- Microcytic hypochromic anemia
What morphological blood and bone marrow changes are present in lead poisoning?
- Ring sideroblasts —> red cell precursors w/ iron-laden mitochondria that are detected with Prussian blue stain
- Punctate basophilic stippling of the red cells
What kind of brain/CNS damage is associated with children in lead poisoning?
- In children = brain damage
- In adults = peripheral demyelinating neuropathy (wrist drop and foot-drop)
Mercury mostly affects what organs?
Arsenic affects what organs most commonly?
Arsenic trioxide is a frontline treatment for?
Acute promyelocytic leukemia
Cadmium is toxic to what systems?
Due to increased production of?
- Kidneys and Lungs
- Increased production of ROS
The principal toxic effects of excess cadmium take the form of what diseases?
- Obstructive lung disease caused by necrosis of alveolar epithelial cells
- Renal tubular damage that may progress to end-stage renal disease
BPAs have been known to be a potential ________ disruptor.
Elevated urine BPA linked to?
- Endocrine disruptor
- Elevated urine BPA linked to heart disease
What are among the most potent carcinogens and are released during the combustion of fossil fuels, particularly coal and gas at high temps?
Implicated in the development of what diseases?
- Polycyclic Hydrocarbons
- Lung and bladder cancer
Organochlorines (i.e., DDT, PCB, dioxins) disrupt what?
Hormonal balance due to antiestrogenic and antiandrogenic activity
Dioxins and PCBs can cause what skin disorder?
Affect CYPs how?
- Folliculitis and a dermatosis known as chloracne, characterized by acne, cyst formation, hyperpigmentation, and hyperkeratosis of face and behind ears
- Induce CYPs, may shown abnormal drug metabolism
Which components of cigarette smoke are potent carcinogens and are directly involved in the development of lung cancer?
Carcinogens from cigarette smoke are processed by CYPs, but some of the intermediates produced are electrophilic and form what?
DNA adducts; persistence of these adducts can cause mutations in oncogenes and tumor suppressors
What are the causal mechanisms for the development of atherosclerosis in smokers?
- Increased platelet aggregation
- Decreased myocardial O2 supply
- Increased O2 demand
- Decreased threshold for ventricular fibrillation
Passive smoke inhalation (second-hand smoke) in non-smokers can be estimated by measuring the blood levels of?
Cotinine, a metabolite of nicotine
How does alcohol potentiate the depressant effects of narcotic, sedative, and other psychoactive drugs?
- Alcohol induces CYPs
- Competes with other CYPE21 substrates and delays drug catabolism
What is the direct, and toxic, product of alcohol oxidation?
About 50% of Asians have very low alcohol dehyrogenase activity, due to what?
What is the normal allele and the inactive variant?
What effect does the inactive variant have?
- Substitution of lysine for glutamine at residue 487
- Normal allele = ALDH2*1
- Inactive variant = ALDH2*2 = dominant negative
Oxidation of ethanol by ADH (alcohol dehydrogenase) takes place in the?
Cytosol = most important route
The cytochrome P-450 system and its CYP2E1 isoform are located?
In the ER (microsome)
Oxidation of alcohol by alcohol dehydrogenase causes the reduction of which molecule?
What is this molecule important for?
- Reduction of NAD to NADH (decreased NAD and increased NADH)
- NAD is required for fatty acid oxidation in the liver and for the conversion of lactate —> pyruvate
The main cause of accumulation of fat in the liver of alcoholics is deficiency of?
What else does this cause in alcoholics?
- Deficiency of NAD, required for fatty acid oxidation in liver
- Increased NADH/NAD ration also causes lactic acidosis
How does alcohol consumption lead to lipid peroxidation of hepatocyte cell membranes?
Metabolism of ethanol in the liver by CYP2E1 produces ROS, causes lipid peroxidation
What effect does alcohol have on gram negative bacteria in the intestinal flora?
Stimulates the production of?
- Causes the release of endotoxin (lipopolysaccharide)
- Stimulates production of TNF and other cytokines from macrophages and Kupffer cells, leading to hepatic injury
Menopausal hormone therapy (MHT) increases the risk for?
- Breast cancer (after 5-6 yrs use), ovarian and endometrial cancers
- Stroke and venous thromboembolism, including DVT and pulmonary embolism
What is the effect of oral contraceptives on development of breast carcinomas, endometrial cancer, and ovarian cancers?
- Do not increase breast cancer risk
- Have a protective effect against endometrial and ovarian cancers
What is the relationship between oral contraceptives and thromboembolism?
- Associated with a threefold to sixfold INCREASED risk of svenous thrombosis and pulmonary thromboembolism
- Due to hypercoagulable state induced by elevated hepatic synthesis of coagulation factors
There is a well-defined association between the devlopment of what type of tumor in older woman who have used OCs for prolonged periods?
Rare benign hepatic tumor (hepatic adenoma)
What is the cause of 50% of cases of acute liver failure, with 30% mortality, in the US?
At therapeutic doses, 95% of acetaminophen undergoes detoxification in the liver by what?
- Phase II enzymes
- Excreted as glucuronate or sulfate conjugates
How is the other 5% of acetaminophen metabolized and what is the product of this metabolism?
How is this product usually dealt with?
Large doses of this toxic metabolite lead to?
- Through CYP2E –> NAPQI (N-acetyl-p-benzoquinoneimine) = highly reactive metabolite
- NAPQI is usually conjugated with glutathione (GSH)
- In large doses, unconjugated NAPQI accumulates and causes hepatocellular injury, leading to centrilobular necrosis that may progress to liver failure
What are the 2 mechanisms in which the toxic metabolite of acetaminophin, NAPQI, produces injury within the liver?
1) Covalent binding to hepatic proteins which causes damage to cellular membranes and mitochondrial dysfunction
2) Depletion of GSH, making hepatocytes more susceptible to ROS induced injury
Why does acetaminophen toxicitiy occur in lower doses in chronic alcoholics?
Due to alcohol inducing CYP2E in liver
A patient presents to the ED with nausea, vomiting, diarrhea, and eventually shock after ingesting unknown pills from the medicine cabinet, a few days later they develop jaundice.
What do you suspect the culprit to be?
How can acetaminophen toxicity (ODs) be treated within 12 hours of ingestion?
Administration of N-acetylcysteine, which restores GSH levels
In serious overdoses of acetaminophen, how does liver failure occur?
Beginning with centrilobular necrosis that may extend to entire lobules
*Liver transplantation will be the only hope for survival
Often Aspirin overdose results from accidental ingestion of a large number of tablets by children or attempted suicide by adults. What is a much less common cause?
Ointments containing oil of wintergreen (methyl salicylate)
Acute salicylate overdose causes what acid-base shift, due to?
- Alkalosis as a consequence of stimulation of the respiratory center in the medulla (ASA is an acid)
- Followed by metabolic acidosis and accumulation of pyruvate and lactate, due to uncoupling of OxPhos and inhibition of the Krebs cycle
A patient presents to the ED with a hx of headaches, dizziness, ringing in the ears (tinnitus), hearing impairment, mental confusion, drowsiness, nausea, vomiting, and diarrhea.
They tell you they take an OTC for chronic pain management, what do you suspect is the culprit of their symptoms?
Chronic aspirin toxicity (salicylism)
Chronic aspirin toxicity may lead to what GI issues?
- Acute erosive gastritis, leading to:
- Overt or covert GI bleeding and lead to gastric ulceration
Bleeding disorders can be caused by chronic aspirin ingestion, what are the signs of this?
Petechial hemorrhages may appear in skin and internal viscera, and bleeding from gastric ulcerations may be exaggerated.
*Remember that primary hemostasis disorders = defects in platelets = mucocutaneous bleeding = petechia, purpura, and ecchymosis
Proprietary analgesic mixtures of aspirin and phenacetin or its active metabolite, acetaminophen, when taken over several years, can cause?
Tubulointerstitial nephritis w/ renal papillary necrosis, referred to as analgesic nephropathy
Cocaine blocks the reupatake of?
Stimulates release of?
- Dopamine in the CNS
- Epi and NE at adrenergic nerve endings; while stimulating presynaptic release of NE
What are the pulmonary complications that can arise as a result of Heroin use?
- Moderate to severe edema
- Septic embolism from endocarditis
- Lung abscess
- Opportunistic infections
- Foreign-body granulomas (from talc and other adulterants)
What are the 4 most common places of infection complications as a result of heroin use?
1) Skin and subcutaneous tissue
2) Heart valves
Endocarditis in heroin abusers often takes a distinctive form involving?
Most cases causes by what bacteria?
- Right-sided heart valves, particularly tricuspid
- Most cases, caused by S. aureus
What is the most common infection among individuals addicted to heroin?
Viral hepatitis acquired through sharing needles
What 2 forms of kidney disease are most frequently encountered in heroin/opiate abusers?
1) Amyloidosis (secondary to skin infections)
2) Focal and segmental glomerulosclerosis
What kind of burns involve injury to the dermis?
Partial thickness burns (2nd degree)
What kind of burns extend to the subcutaneous tissue?
Those that involve damage to the muscle tissue?
- Full-thickness (3rd degree)
- Now called full-thickness, but damage to muscle beneath subcutaneous tissue were formerly called 4th degree burns
Which type of burn is confined to the epidermis?
Superficial (1st degree)
What are the greatest threats to life in burn patients?
Shock, sepsis, and respiratory insufficiency
Shift of the body’s fluid into the interstitial compartment, both at the burn site and systemically, following a severe burn, is due to?
- Due to the Systemic inflammatory response syndrome (SIRS)
- Leads to shock
An important pathophysiologic effect of burns is the development of what state?
Hypermetabolic state associated with excess heat loss and increased need for nutritional support
*Estimated that when >40% of body surface is burned the RMR may double
Burn sites are ideal growth enviornments for microorganisms and virtually all burns become colonized with bacteria. Which is the most common offender?
- Pseudomonas aeruginosa = most common
- S. aureus (methicillin-resistant) = MRSA
- Fungi, particularly Candida species
What are the most common serious complications produced by direct bacteremic spread in burn victims?
- Septic shock w/ renal failure and/or acute respiratory distress syndrome
Which gases are more likely to reach the deeper airways and produce pneumonitis?
Lipid-soluble gases, such as NO and products of burning plastics
What type of scarring is a common complication of burn injury?
Marked by excessive?
- Hypertrophic scarring
- Marked by excessive deposition of collagen in the healing wound bed
Morphologically how do full-thickness burns appear in comparison to partial-thickness burns?
Full-thickness = white or charred, dry, and painless (destruction of nerve endings)
Partial-thickness = pink or mottled with blisters and painful
Histologically what is seen with devitalized tissue and the vital tissue surrounding burns?
Quicky accumulates what?
Coagulative necrosis, adjacent to vital tissue that quickly accumulates inflammatory cells and marked exudation
In heat stroke, the hyperthermia is accompanied by?
Marked generalized vasodilation, with peripheral pooling of blood and decreased effective circulating blood volume
Sustained contractions of skeletal muscle can exacerbate hyperthermia in someone suffering a heat stroke, leading to muscle necrosis known as?
- Nitrosylation of ryanodine receptor 1 (RYR1), located in SR of skeletal muscle
- Heat stroke deranges RYR1 function and allows calcium to leak into the cytoplasm, stimulating muscle contraction and heat production
Inherited mutaitons in RYR1 occur in a condition called?
- Malignant hyperthermia
- Characterized by a “heat-stroke-like” rise in core body temp and muscle contractures following exposure to common anesthetics
High humidity, wet clothing, and dilation of superficial blood vessels resulting from ingestion of alcohol all contribute to?
Lowering of body temperature —> Hypothermia
Hypothermia causes injury by 2 mechanisms, what are they?
Direct = physical disruption within cells by high salt concentrations caused by the crystallization of intra- and extracellular water
Indirect = result from circulatory changes; vary depending on rate and duration of the temperature drop
Slow chilling (indirect mechanism) may have what physiologic effects?
May induce vasoconstriction and increase vascular permeability, leading to edema, and hypoxia
*Typical of “trench foot” seen in soldiers during WWI, frequently causing gangrene
Sudden, persistent chilling (indirect mechanism) may have what physiologic effects?
What type of injury can occur?
- Vasoconstriction and increased viscocity of the blood in the local area mau cause ischemic injury and degenerative changes in peripheral nerves
- Vascular injury and edema become evident only after the temp begins to normalize
Ionizing radiation such as that used in diagnostic imaging can produce what short- and long-term effects?
Teratogenesis (malformation in a developing fetus)
Differentiate Curie (Ci) vs. Gray (Gy) vs. Sievert (Sv) units of radiation.
Curie (Ci) = amount of radiation emitted by a source
Gray (Gy) = energy absorbed by the target tissue per unit mass
Sievert (Sv) = depends on the biologic rather than the physical effects of radiation
Which tissues are extremely vulnerable to radiation?
- Tissue with high rate of cell division:
- Bone marrow
- Lymphoid tissue
- Mucosa of GI tract
What is the major mechanism by which DNA is damaged by ionizing radiation?
Production of ROS from rxns with free radicals generated by radiolysis of water
What are the acute effects of marrow irradiation on peripheral blood counts of granulocytes, neutrophils, and platelets (i.e., neutropenia, anemia, thrombocytopenia)?
- Neutropenia appears within several days; often near zero by end of 2nd week
- Recovery of normal granulocyte count may require 2-3 months
- Thrombocytopenia appears by end of first week
- Anemia appears after 2-3 weeks and may persist for months
Very high doses of radiation kill marrow stem cells and induce?
Permanent aplasia (aplastic anemia) = failure of blood count recovery
What is the “bystander effect” produced by damaged cells from radiation?
- Abnormal cells are able to alter the behavior of nonirradiated surrounding cells through the production of GFs and cytokines
- Referred to as non-target effects of radiation
What are common sites of fibrosis following radiation therapy?
- Salivary glands
- Pelvic areas
What is the main site of injury from 1-2 Sv ionizing radiation?
1-2 Sv = Lymphocytes
2-10 Sv = Bone marrow
10-20 Sv = Small bowel
>50 Sv = Brain
What is the most common repair pathway for double-stranded breaks of DNA caused by ionizing radiation?
What common mutations result from this pathway?
- Nonhomologous end joining (NHEJ)
- Short deletions or duplications, or gross chromosomal aberrations such as translocations and inversions
A BMI less than _____ kg/m2 is considered malnourished?
A child whose weight falls less than ______% of normal is considered malnourished?
A BMI less than 16 kg/m2 is considered malnourished
A child whose weight falls less than 80% of normal is considered malnourished
Marasmus affects which protein compartment of the body?
Which hormone is low and what does this trigger?
What occurs to the extremities and head?
- Catabolism and depletion of the somatic protein compartment
- Production of leptin is low, may stimulate H-P-A axis to produce high levels of cortisol, which contributes to lipolysis
- Extremities are emaciated, by comparison the head appears too large for the body
Kwashiorkor occurs when?
Depletion of which protein compartment?
Levels of albumin?
- Occurs when protein deprivation is relatively more severe than the deficit in total calories
- Marked protein deprivation of the visceral compartment, with resultant hypoalbuminemia —> generalized or dependent edema
Albumin levels in Marasmus and Kwashiorkor?
- In Marasmus, the albumin levels are normal
- In Kwashiorkor, there is hypoalbuminemia –> generalized or dependent edema
What are the characteristics of the skin and hair in children with Kwashiorkor?
- Skin lesions, with alternating zones of hyperpigmentation, areas of desquamation, and hypopigmentation, giving a “flaky paint” appearance
- Hair changes include overall loss of color or alternating bands of pale and darker hair
What is the liver like in Kwashiorkor?
Enlarged, fatty liver from reduced synthesis of the carrier protein component of lipoproteins
What morphological changes occur to the small bowel of a child with Kwashiorkor?
Most often manifested as?
- Decrease in the mitotic index in the crypts and glands, associated with mucosal atrophy and loss of villi and microvilli
- Loss of small intestinal enzymes, most often manifested as disaccharide deficiency
*Infants w/ Kwashiorkor initially may not respond well to full-strength, milk-based diets
Which mediators secreted by tumors and during chronic inflammatory reactions contribute to development of Cachexia?
- Proteolysis-inducing factor: glycosylated polypeptide excreted in urine of weight-losing patients w/ pancreatic, breast, colon, and other cancers
- Lipid-mobilizing factor: increases fatty acid oxidation and proinflammatory cytokines, such as TNF and IL-6
Proteolysis-inducing factor and proinflammatory cytokines cause skeletal muscle breakdown in cachexia through what?
NF-kB induced activation of the ubiquitin proteasome pathway, promoting degradation of structural proteins such as myosin heavy chain by upregulating expression of several muscle-specific ubiquitin ligases
What clinical finding is so common in Anorexia that its presence is considered a diagnostic feature?
What are major complications that may result from Anorexia?
Cardiac arrhythmia and sudden death, resulting from hypokalemia
What are the 3 major medical complications associate with Bulimia?
1) Electrolyte imbalance (hypokalemia), predisposing pt to cardiac arrhythmias
2) Pulmonary aspiration of gastric contents
3) Esophageal and gastric rupture
Which vitamins can be synthesized endogenously?
- Vit D from steroids
- Vit K from biotin by intestinal microflora
- Niacin from tryptophan
What are the 3 major functions of Vitamin A?
1) Maintenance of vision
2) Regulation of cell growth and differentiation
3) Regulation of lipid metabolism
Vitamin A supplmentation can reduce the morbidty and mortality from some forms of?
Also in preschool children with what disease?
- Some forms of diarrhea
- Improve clinical outcome of measles
Vitamin A used in the treatment of what disorders?
- Severe acne and some forms of psoriasis
- Tx of acute promyelocytic leukemia
What are the most devastating consquences of Vitamin A deficiency?
- Xerophthalamia (dry eye) gives rise to epithelial metaplasia
- Followed by buildup of keratin debris in small opaque plaques (Bitot spots)
- Progresses to erosion of the roughened corneal surface, softening and destruction of the cornea (keratomalacia) and blindness
Effect of Vitamin A deficiency on the immune system?
Immune deficiency, responsible for higher mortality rates from common infections such as measles, pneumonia, and infectious diarrhea
Why should synthetic retinoids, such as those used to tx acne, be avoided in pregnant woman?
Well-established teratogenic effects of retinoids
Deformation of the chest results from overgrowth of cartilage or osteoid tissue at the costochondral junction, producing what characteristc morphology in Rickets?
What skeletal deformities are commonly seen in Rickets?
- Pectus carinatum (“pigeon” brest deformity)
- Excessive Lumbar lordosis
- Bowing of the legs
Spinocerebellar degeneration is a deficiency syndrome of what vitamin?
Cheilosis, stomatitis, glossitis, dermatitis, and corneal vascularization are all associated with what vitamin deficiency?
Riboflavin (vitamin B2)
Megaloblastic pernicious anemia and degeneration of posterolateral spinal cord tracts are a result of what vitamin deficiency?
What is the deficiency syndrome of Niacin? (The 3 D’s)
Megaloblastic anemia and neural tube defects are a result of what vitamin defect?
Cheilosis, glossitis, dermatitis, peripheral neuropathy, and dismaintenance of myelinization of spinal cord tracts is a result of what vitamin deficiency?
Vitamin B6 (pyridoxine)
A rash around the eyes, mouth, nose, and anus called acrodermatitis enteropathica results from a deficiency in what vitamin?
Hypochromic microcytic anemia results from a deficiency in what vitamin?
Muscle weakness, neurologic defects, and abnormal collagen crosslinking due to a deficiency in what vitamin?
Myopathy and cardiomyopathy (Keshan disease) due to a deficiency in what vitamin?
Vitamin C deficiency has what consequences?
- Impaired collagen formation leads to:
- Impaired wound healing
- Inadequate synthesis of osteoid
- Mucosal bleeding (gums) and joints
Which immune cell can synthesize 1,25-dihydroxyvitamin D?
- Macrophages, through the activity of CYP27B in the mitochondria
- Pathogen-induced activation of TLR in macrophages causes increased expression of vitamin D receptor and CYP27B, leading to local synthesis and activation of vitamin-D-dependent gene expression
POMC/CART producing α-MSH that activates MC3/4R in second order neurons regulate what component of hunger and food intake?
NPY/AgRP activating Y1/5 receptors in second order neurons regulate what component of hunger and food intake?
Promote food intake (orexigenic effect)
Haploinsufficiency of brain-derived neurotrophic factor (BDNF), an imoortant component of signaling downstream of MC4R in the hypothalamus is associated with obesity in patients with what syndrome?
WAGR syndrome (Wilms tumor, aniridia, genitourinary defects, mental retardation, and obesity) = very rare
What are levels of PYY like in Prader-Willi syndrome?
What is 6 times more likely in obese people than lean people, especially women?
In very obese individuals the constellation of respiratory abnormalities encompassing Hypoventilation syndrome, is known as?
Obesity causes what kind of cancer in women?
Due to what?
- Uterine and breast
- Increased estrogen synthesis
Aflatoxin is involved in the development of what cancer in parts of Asia and Africa?
What cancers are associated with nitrosamines and nitrosamides?
What is the single leading global cause of health loss (defined as morbidity and premature death)?
Exposures of a fetus to high levels of mercury in utero may lead to what disease?
- Minamata disease
- Cerebral palsy, deafness, blindness, and mental retardation
Naphthylamines, 4-aminobiphenyl, benzidine, and rubber products have all be implicated in the development of what cancer?
Silica, nickel, arsenic, chromium, mustard gas, and uranium have all be implicated in the devlopment of what cancer?
Effectivness of all-trans-retinoic acid in the Tx of acute promyelocytic leukemia lies in its ability to bind what?
The PML-RARα fusion protein