Path Chapter 9: Environmental and Nutritional Diseases (pages 420-444)
All soft tissues react similarly to mechanical forces that cause trauma, and lead to abrasions, contusions,
lacerations, incised wounds, and puncture wounds
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Abrasion – wound produced from scraping or rubbing, causing removal of the superficial layer
of skin
Contusion (bruise) – injury usually from blunt trauma, that causes damage to blood vessels that
then extravastate blood into the tissues
Laceration – tear of tissue from force from a blunt object
o Unlike incisions, most lacerations have intact bridging blood vessels and jagged
irregular edges
Incision – break in tissue from a sharp object, that severs the bridging blood vessels
Puncture – break in the skin from a long narrow instrument
o Penetrating puncture – when it pierces the tissue
o Perforating puncture – when it traverses the tissue and also creates an exit wound (so
it goes all the way through the tissue)
In a car accident, the most common things seen are they bang their head, chest, or knees off something
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So common chest injuries from a car accident include sternal and rib fractures, heart
contusions, and aortic lacerations, which are all internal wounds to look for
Burns are classified as superficial, partial thickness, and full thickness, and no longer as “degree burns”
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Superficial burns (aka 1st degree burns) – confined to the epidermis
Partial thickness burns (aka 2nd degree burns) – injure the epidermis and dermis
o Partial thickness burns are pink or mottled with blisters, and are painful
Full-thickness burns (3rd degree burns) – injure the epidermis, dermis, and subcutaneous tissue
o A full-thickness burn can also involve the muscle under the subcutaneous tissue (aka 4th
degree burn)
o Full thickness burns are white or charred, dry, and anesthetic (nerves are destroyed)
The most severe effects of a burn are shock, sepsis, and respiratory insufficiency
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In burns of more than 1/5 of the body surface, there’s rapid (within hours) shift of body fluids
into the interstitial compartments at both the burn site and systemically, which can cause
hypovolemic shock (volume left the blood vessels)
Protein from the blood is then lost into the interstitial tissue, causing generalized edema that
includes pulmonary edema, which can be severe
An important effect of burns is they can cause a hypermetabolic state causing excessive heat
loss, and increased need for nutritional support
o When 40% of the body surface is burned, the resting metabolic rate can double
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A burn site is ideal for growth of microorganisms – the serum and debris provide nutrients,
while the burn injury compromises blood flow, blocking immune response
o The most common infection in burns is opportunist pseudomonas aeruginosa, and
hospital-acquired infection like staph and candida are also common
o Spread from the burn site and/or release of endotoxin can result in really bad problems
o The most often result is pneumonia or septic shock with renal failure and/or acute
respiratory distress syndrome
o Removing the burn wound with excision decreases infection and need for graft surgery
Injury to the airways and lungs can develop 24-48 hours after the burn, and happen from direct
effect of heat on the mouth, nose, and upper airways, or from inhalation of heated air and
noxious gases in smoke
o Water soluble gases like chlorine, sulfur oxides, and ammonia, can react with water in
the airway to form acids or bases that cause inflammation and swelling in the upper
airway, causing partial or complete airway block
o Lipid soluble gases like NO and stuff from burning plastic are more likely to get to the
deeper airways and cause pneumonitis
In burn survivors, the burn can develop hypertrophic scars from continuous angiogenesis in the
wound caused by excess neuropeptides, like substance P, released from injured nerve endings
Hyperthermia – prolonged high body temperature, and it can cause heat cramps, heat exhaustion, heat
stroke
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Heat cramps – happen from loss of electrolytes from sweating, leading to cramping of voluntary
muscles
o Often caused by exercise
o Heat-dissipating mechanisms are able to maintain normal core body temperature
Heat exhaustion – sudden collapse from failure of the cardiovascular system to compensate for
low blood volume, secondary to water depletion
o Most common symptom of hyperthermia
o Eventually, equilibrium is reestablished and they recover
Heat stroke – caused by high body temperature, high humidity, and exertion
o In heat stroke, attempts to regulate the heat fail, sweating stops, and core body temp
rises above 40⁰C, leading to multi-organ dysfunction that can be rapidly fatal
o This is caused by generalized vasodilation, with peripheral pooling of blood and
decreased circulating blood volume
o Other effects are hyperkalemia, tachycardia, and arrhythmias
o Rhabdomyolysis – necrosis of the muscles and myocardium from nitrosylation of the
ryanodine receptor of the sarcoplasmic reticulum (SR) of skeletal muscle
 The ryanodine receptor regulates release of Ca2+ from the SR into the cytoplasm
 Malignant hyperthermia – mutation to the ryanodine receptor that cause a rise
in body temp and muscle contractions when they’re exposed to anesthetics
 Ryanodine receptor mutations also increase their susceptibility to heat stroke
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Major people at risk for heat stroke are the elderly, athletes, and people with
cardiovascular disease
Hypothermia – prolonged exposure to low body temperature
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Hypothermia can be promoted by high humidity, wet clothing, and dilation of superficial blood
vessels from ingestion of alcohol, which all lower body temperature
At a body temp below 90⁰F, you lose consciousness, which is followed by bradycardia and afib
Hypothermia can cause direct injury by causing high salt levels due to water crystalizing to ice
Slow developing coldness can induce vasoconstriction and increased vascular permeability,
leading to edema and hypoxia
When your insides get cold more suddenly, the vasoconstriction and increased viscosity of the
blood in the local area can cause ischemic injury and degenerative changes in peripheral nerves
Electrical injuries are often fatal, and can result in burns, or ventricular fibrillation or heart or
respiratory failure
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The strength of an electric current is measured in amps
Voltage in things we use in houses and buildings is high enough that, when you lower the
resistance at the site of contact (like when skin is wet), enough current can pass through the
body to cause serious injury
If current flow goes on long enough, it can generate enough heat to produce burns at the site of
entry and exit, and in internal organs
Alternating current (the type at home) characteristically induces tetanic muscle spasm, so that
when you touch the source of the current, you can’t let go of it, which increases the period of
current flow, increasing burns and can cause spasm of the chest wall muscles, causing death
from asphyxia
High-voltage sources, like lightning, are more likely to cause paralysis of the medullary centers,
and extensive burns
Electric and magnetic fields, and microwave radiation, when intense enough, can cause burns
Radiation – energy that travels in the form of waves or high-speed particles
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Radiation can be ionizing or non-ionizing
Non-ionizing radiation energy can move atoms in a molecule or cause them to vibrate, but isn’t
enough to displace electrons from the atom
o Non-ionizing radiation includes UV and infrared light, and microwave and sound waves
Ionizing radiation has enough energy to remove electrons
o Collision of electrons with other molecules releases electrons, called ionization
o The main sources of ionizing radiation are x-rays and gamma rays, neutrons, and alpha
and beta particles
 Alpha particles induce heavy damage in a restricted area
 X-rays and gamma rays dissipate energy over a longer, deeper course, causing
less damage per area of tissue
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Adverse effects of ionizing radiation include fibrosis, mutagenesis, carcinogenesis, and
teratogenesis
Curie (Ci) –meausrement of the amount of radiation emitted by a source
Gray (Gy) – measurement of the amount of energy absorbed by the target tissue per unit mass
Sievert (Sv) – measurement of potent a dose of the radiation is compared to the same dose in
another type of radiation (so how potent is that radiation compared to others)
The rate of delivery is important in determining the effect of radiation on you, because even
though the effect of radiation is cumulative over the years, divided doses allow cells to repair
some of the damage between exposures
o So the cumulative effect of fractioned doses is only what wasn’t repaired in between
doses
o Radiation therapy on tumors exploits that normal cells can repair themselves and
recover quicker than tumor cells, so they don’t sustain as much cumulative radiation
damage
The size of the field exposed to radiation also has a lot to do with the consequences
o The body can handle higher doses of radiation when given to smaller more shielded
areas, while small doses to larger fields can be lethal
Ionizing radiation damages DNA, making rapidly dividing cells more vulnerable to injury from
radiation than quiescent (dormant, nondividing) cells
o The brain and heart cells are nondividing, so they can survive DNA damage
o In dividing cells, the DNA damage is recognized by cell cycle checkpoints, either stopping
growth or causing apoptosis
o So tissues with a high rate of cell division, like the gonads, bone marrow, lymph tissue,
and the mucosa of the GI tract, are all very vulnerable to radiation, and show injury
earlier after exposure
The most important way ionizing radiation causes DNA damage is by radiolysing water into
reactive oxygen species (ROS)
o Tissues with poor blood supply and so less oxygen, like the center of a growing tumor,
are less sensitive to radiation therapy than well oxygenated tissues
Endothelial cells are sensitive to radiation, which can cause narrowing or occlusion of the blood
vessel, leading to impaired healing, fibrosis, and chronic ischemic atrophy, months to years after
exposure
Page 424-425 – effects of radiation at parts of the body
Nucleus changes from radiation:
o Cells that survive radiant energy damage have lots of structural changes in their
chromosomes, like breaks, deletions, and translocations
o Radiation causes the mitotic spindle to get messed up, causing polyploidy and
aneuploidy
o Radiation can cause the nucleus to swell, and chromatin to clump and condense, and
cell death by apoptosis can happen
Since radiation can cause cell pleomorphism, giant-cell formation, changes to the nuclei, and
mitotic figures, radiation injury definitely looks like cancer
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Irradiated tissues usually show vascular changes and interstitial fibrosis, with endothelial
changes that start as swelling of the vessels, and progress to degeneration of the vessel wall, or
thickening that occludes lumens along with thrombosis
The hematopoietic (blood making) and lymphoid (WBC making) systems are very susceptible to
radiation injury
o High doses of radiation or those that affect large areas can cause decreased
lymphocytes within hours, with shrinkage of lymph nodes and the spleen
o Radiation directly destroys lymphocytes, in both the blood and lymph tissues
o If the radiation dose isn’t lethal, the lymph precursors are regenerated quickly to restore
normal lymphocyte levels in weeks to months
o Radiation can cause bone marrow aplasia by hurting the hematopoietic cells
 High doses kill marrow stem cells causing permanent aplasia (aplastic anemia)
 In lower doses the aplastic anemia is transient
o So radiation decreased RBCs, WBCs, and platelets, and can cause aplastic anemia
A common consequence of radiation treatment for cancer is development of fibrosis in the
tissues included in the irradiated field
o Fibrosis can happen weeks to months after irradiation from replacement of dead
parenchymal cells by connective tissue, leading to formation of scars and adhesions
o The radiation causes vascular damage, kills tissue stem cells, and causes release of
inflammatory cytokines, all leading to activation of fibroblasts
o Common sites of fibrosis after radiation therapy are the lungs, salivary glands, and
colorectal and pelvic areas
Ionizing radiation can cause many types of DNA damage, which usually get repaired by the cell
o The most serious type is double-stranded breaks, which get fixed by homologous
recombination, and nonhomologous end joining (NHEJ, more common)
o DNA repair through the NHEJ often produces mutations
o If the DNA damage isn’t fixed, cells with chromosome damage persist and can initiate
carcinogenesis years later
o They can also have “bystander effect” where they promote growth of non-irradiated
surrounding cells
Any cell that can divide, and that has been mutated, can become cancerous
o Sources of radiation can cause cancer
o X-rays and gamma rays have a risk for cancer at high enough doses
o Radon gas is made from decay of uranium, and decays into things with alpha particles,
so it can cause radiation when inhaled, increasing risk for lung cancer
Vitamins and minerals function as coenzymes or hormones in metabolic pathways
Primary malnutrition – the nutrient is missing from the diet
Secondary malnutrition – it’s in the diet, but there’s insufficient intake, malabsorption, impaired use or
storage, excess loss, or increased need for nutrients
Protein malnutrition can increase the risk for infection, and infections can make protein malnutrition
worse
The basal metabolic rate is increased in many illnesses, increasing your need for nutrients, and the lack
of them can delay recovery
Protein malnutrition happens in wasting diseases, like cancers and AIDS
Alcoholics can be deficient in protein, but are more often deficient in taking in, absorbing, or using
vitamins
Protein-energy malnutrition (PEM) – not taking in or absorbing enough protein, causing loss of fat and
muscle tissue, weight loss, lethargy, and generalized weakness
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Sometimes just malnutrition is aka protein energy malnutrition
A BMI less than 16 is considered malnutrition (normal BMI is 18.5-25)
A kid who’s weight is less than 80% of normal is malnourished
Marasmus
o They’re said to have marasmus when their weight is 60% of normal
o Marasmus causes growth retardation and loss of muscle, due to catabolism and
depletion of the somatic (muscle) protein compartment
 The body’s protein storage is divided into somatic (muscle) and visceral
 The visceral storage is more is more critical for survival
o Serum albumin is normal in marasmus, showing that visceral protein isn’t affected
o Along with the body protein, subcutaneous fat is mobilized and used as fuel
 Not much leptin is being made, which can stimulate the release of cortisol from
the adrenals, causing more lipolysis (adipose triglyceride fat breakdown)
o Because of the eating away of muscle and subcutaneous fat, the extremities are
emaciated, and the head looks too large for the body
o They’ll have anemia and immune deficiency, especially in T cells, allowing easy
infection, which increases demand for nutrients more
Kwashiorkor – when they’re really deficient in just protein, and not so much calories
o Kwashiorkor is common in African kids weaned too early, and fed mostly carbs
o Kwashiorkor can happen in severe diarrhea (not absorbing protein), nephrotic
syndrome, or extensive burns
o In kwashiorkor, their lack of protein causes them to draw from the visceral protein
compartment, causing hypoalbuminemia that leads to edema
o So any weight they would lose is then masked by increased fluid retention
o In kwashiorkor, the subcutaneous fat and muscles are spared, and they can show
apathy, listlessness, and loss of appetite
o Kwashiorkor has a characteristic skin lesion, with alternating zones of
hyperpigmentation, areas of desquamation, and hypopigmentation, giving it a “flaky
paint” appearance
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Changes in hair include loss of color or alternating bands of pale and darker hair
Kwashiorkor has an enlarged fatty liver, from decreased making of carrier lipoproteins
to get the fat out of it
 This doesn’t happen in marasmus
o Vitamin deficiencies and problems with the immune systems are common, often
leading to a secondary infection
o In kwashiorkor, the small bowel shows a decrease in the mitosis happening in the crypts
of the glands, causing mucosal atrophy and loss of villi and microvilli
 This leads to loss of small intestine enzymes, usually seen as a lack of
disaccharidase deficiency
 Because of this, a kid with kwashiorkor may not respond at first to getting them
milk with complete nutrition, but then these changes are reversible
Secondary protein-energy malnutrition is most common in chronically ill, elderly, and bedridden patients
o Half the elderly in nursing homes in the US are malnourished
o The most obvious signs of secondary protein-energy malnutrition are depletion of
subcutaneous fat in the arms, chest wall, shoulders, or metacarpals, wasting of the
quadriceps femoris and deltoid muscles, and ankle or sacral edema
The main changes protein-energy malnutrition cause are growth failure, peripheral edema in
kwashiorkor, and loss of body fat and atrophy of muscle (more in marasmus)
The bone marrow in both kwashiorkor and marasmus can be hypoplastic, from decreased RBCs
o So they have mild to moderate anemia, caused by deficiencies in protein, iron, and
folate, as well as the suppressive effects of infection (anemia of chronic disease)
The brain of a baby born of a mom who was malnourished during pregnancy, can be atrophied
with less neurons and impaired myelinization
Protein-energy malnutrition is common in people with AIDS or advanced cancers, and in this
case is called cachexia
o Cachexia happens in about half of cancer patients, and causes 1/3 of cancer deaths
o Cachexia is most common in GI, pancreatic, and lung cancers
o Cachexia is characterized by extreme weight loss, fatigue, muscle atrophy, anemia,
anorexia, and edema
o The main way cachexia causes death is by atrophy of the diaphragm and other
respiratory muscles
o Tumors release things to encourage cachexia, including proteolysis-inducing factor
(PIF), lipid-mobilizing factor (LMF), which increases fatty acid oxidation, and cytokines
like TNF, Il-2, and Il-6
 Il- 6 triggers an acute phase response that increases release of C-reactive
protein and fibrinogen, and decrease plasma albumin
 PIF and pro-inflammatory cytokines cause skeletal muscle breakdown through
inducing NF-Kb, which activates the ubiquitin proteasome pathway, leading to
the degradation of myosin heavy chain
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Inducing the ubiquitin-proteosome pathway involves making of muscle-specific
ubiquitin ligases MuRF1 and MAFBx
Muscle atrophy is also promoted by loss of dystrophin
Anorexia nervosa – self induced starvation, causing weight loss
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Anorexia nervosa has the highest death rate of any psychiatric disorder
Anorexia nervosa shows a lot of the same things as protein-energy malnutrition, and more
endocrine findings
o Decreased gonadotropin-releasing hormone (GnRH) decreases pituitary release of LH
and FSH, causing amenorrhea
 This is so common in anorexia, that it’s used to diagnose anorexia nervosa
o They also often show decreased thyroid hormone release, causing cold intolerance,
bradycardia, constipation, and skin and hair changes
o They’ll have dehydration and electrolyte changes, and the skin will be dry and scaly
o The low estrogen will cause bone density to decrease
Both anorexia and bulimia show an increased susceptibility to heart arrhythmia and sudden
death from hypokalemia
Bulimia – they binge on food, and then induce vomiting
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Bulimia is more common than anorexia nervosa, and has a better prognosis
Menstrual irregularities are common in bulimia, but amenorrhea happens in less than half of
bulimics, because their weight and gonadrotropin levels are near normal
The major medical problems from bulimia are from the excessive vomiting
o Includes electrolyte imbalances like hypokalemia, which can lead to arrhythmia and
heart failure, aspiration of gastric stuff into the lungs, and esophageal & gastric rupture
The fat soluble vitamins are vitamins A, E, D, and K; and all the rest are water-soluble
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Fat soluble vitamins are more readily stored int eh body, but they need fat to absorb them
Vitamin D can be made from precursor steroids from cholesterol
Vitamin K and biotin can be made colon bacteria
Niacin can be made from tryptophan
Deficiency of a single vitamin is uncommon, & often vitamin deficiencies are associated w/ malnutrition
Vitamin A – name for a group that includes retinol (vitamin A alcohol), retinal (vitamin A aldehyde), and
retinoic acid (vitamin A acid)
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Retinol is the chemical name for vitamin A, and is the transport and storage form
Retinoids – things structurally similar to vitamin A
Animal foods like milk, eggs, and fish have pre-formed vitamin A
Carotenoids – provitamins that can be converted into active vitamin A in the body
o Carotenoids are big in yellow and leafy green vegetables, like carrots and spinach
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o The most important carotenoid is β-carotene
Vitamin A is fat soluble, so it needs bile and pancreatic enzymes to be absorbed
β-carotene is converted to retinol in the intestine, and this and dietary retinol are absorbed then
in the intestine
Retinol is then transported in chylomicrons to the liver to be stored
o The liver takes up vitamin A with its apolipoprotein A receptor
o Most (90%) of vitamin A is stored in the liver, mostly in stellate (ito) cells
o The liver stores enough vitamin A to supply us for up to 6 months
To move retinol esters from the liver, retinol is bound to a specific retinol-binding protein (RBP)
that’s made by the liver
The RBP/retinol complex is then taken up by receptors in the tissues, then retinol detaches and
binds to an RBP in the cell, and the original RBP is released back into the blood
In the tissues, retinol can be stored as retinol ester, or oxidized into retinoic acid
Jobs of vitamin A - vision, cell growth, metabolism, immune defense, and antioxidant
o Maintenance of normal vision – pigments in the eye use vitamin A
 This includes rhodopsin pigment in the rods, which is the most light sensitive
pigment and so important in reduced light, & also certain things in cones need it
 To make rhodopsin, retinol is oxidized to all-trans-retinal, then isomerized to 11cis-retinal, and then bound to the rod protein opsin
 A photon of light causes the isomerization of 11-cis-retinal back to all-transretinal, which then dissociates from the rhodopsin, causing a shape change in
opsin that triggers a nerve impulse to be sent through neurons from the retina
to the brain
 When it gets dark, most of the retinol is lost, so you need a continuous supply
to replace this
o Cell growth and differentiation of mucus-secreting epithelium
 Without vitamin A, the epithelium undergoes squamous metaplasia and
differentiates into a keratinizing epithelium
 When vitamin A activates a retinoic acid receptor (RAR), it makes stuff to bind
the retinoic X receptor (RXR), and both the RAR and RXR then go and bind to
retinoid acid response elements on genes for regulating growth
o Metabolism – the activated RXR can bind receptors in the nucleus for drug metabolism,
the peroxisome proliferator-activated receptors (PPARs), and vitamin D receptors
 PPARs are big for fatty acid metabolism, including fatty acid oxidation in fat
tissue and muscle, adipogenesis, and lipoprotein metabolism
o Immune defense – vitamin A supplements can help in diarrheal diseases and measles
 In diarrhea, vitamin A helps to maintain and restore gut epithelium
 Vitamin A can also stimulate the immune system, to fight infections
 Infections try to counter this by inhibiting the making of retinol binding
protein (RBP)
o Antioxidants – vitamin A and carotenoids can act as photoprotective agents and
antioxidants
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Retinoids are used in medicine for treating skin disorders like acne and psoriasis, and also for
acute promyelocytic leukemia
o In acute promyelocytic leukemia, the retinoic acid receptor (RAR) gene is translocated to
fuse it onto the PML gene, forming an abnormal RAR that blocks myeloid cell
differentiation
 Giving them all-trans retinoic acid overcomes the block, causing the leukemia
cells to differentiate into neutrophils, which then die by apoptosis
Vitamin A deficiency can be caused by poor diets, fat malabsorption, and infections
o Malabsorption stuff includes celiac disease, Crohns diseae, and colitis
 Bariatric surgery can cause malabsorption and vitamin A deficiency
o Vitamin A deficiency causes impaired vision, especially in reduced light (night blindness)
o Vitamin A deficiency also can cause epithelial metaplasia and keratinization
o Vitamin A deficiency can cause xerophthalmia (dry eye) (xero means dry)
 This starts with dryness of the conjunctiva (xerosis conjunctivae) since the
normal lacrimal and mucus-secreting epithelium is replaced by keratinized
epithelium – page 432
 This is followed by buildup of keratin debris in small opaque plaques called
Bitot spots, and then eventually erosion of the roughened corneal surface with
softening and destruction of the cornea (keratomalacia) and total blindness
o In the upper respiratory and urinary tracts, vitamin A deficiency can cause squamous
metaplasia of the mucociliary epithelium to keratinizing squamous cells
 This predisposes to pulmonary infections, and stones in the urinary tract
o Hyperplasia and hyperkeratinization of the epidermis with plugging of the ducts of the
adnexal glands can cause follicular or papular dermatosis
o Lack of vitamin A also causes the immune system to be weaker
Acute symptoms from too much vitamin A include headache, dizziness, vomiting, stupor, and
blurred vision
Chronic vitamin A toxicity causes weight loss, anorexia, nausea, vomiting, & bone & joint pain
Retinoic acid stimulates osteoclasts making and activity, which can lead to increased bone
resorption and high risk of fractures
Synthetic retinoids used for acne don’t cause these symptoms, but shouldn’t be used during
pregnancy because retinoids are teratogens
Vitamin D’s main job is to make sure there’s enough calcium and phosphorous in the plasma to support
metabolic functions, bone mineralization, and neuromuscular transmission
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Lack of vitamin D causes rickets (in kids), osteomalacia (after epiphyses close), and hypocalcemic
tetany (convlusive state from too little ECF calcium)
The major source of vitamin D is endogenous making of it in the skin, from UV sunlight
o Sunlight converts 7-dehydrocholesterol to cholecalciferol, which is then bound to
plasma α1-globulin (aka D-binding protein or DBP)
o Vitamin D from the diet also gets bound to DBP
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DBP then goes to the liver, where the cholecalciferol is converted to 25-OH
cholecalciferol (calcidiol) by cytochromes (CYP’s)
o Calcidiol is then taken to the kidneys to be converted to 1-25 (OH)2 cholecalciferol
(calcitriol), which is the active form of vitamin D, by 1-α-hydroxylase
o Conversion to calcitriol is regulated by 3 things:
 Parathyroid hormone (PTH) – hypocalcemia will trigger release of PTH, which
promotes conversion to 1,25-OH-cholecalciferol by activating 1-α-hydroxylase
 Low phosphate – directly triggers 1-α-hydroxylase to make vitamin D
 Vitamin D – vitamin D does feedback, so when there’s enough vitamin D it
down-regulates its making at 1-α-hydroxylase
People with more melanin and darker skin usually have less vitamin D because of all the
melanin pigmentation
1,25-(OH)2-cholecalciferol acts like a steroid, and binds to the high-affinity vitamin D receptor
(VDR), which then can work with the retinoic X receptor (RXR)
o The VDR-RR complex then goes to response elements on the promoter of target genes
o Most cells of the body have the VDR, and transduce signals to regulate plasma calcium
and phosphorous, especially in the small intestines, bones, and kidneys
The main job of active vitamin D is to regulate calcium and phosphorous homeostasis:
o Vitamin D stimulates the intestines to absorb calcium at the duodenum – vitamin D
binds the VDR in the cytoplasm, which binds the RXR, which binds to genes to cause
making of TRPV6, which codes for a calcium channel
o Vitamin D stimulates calcium reabsorption in the kidney at the distal tubules, by
increasing expression of TRPV5
 TRPV5 is also regulated by PTH in response to hypocalcemia
o Vitamin D works with PTH to regulate blood calcium and phosphorous
 The parathyroids have a calcium receptor that senses any change in blood Ca2+
 PTH and vitamin D combine to absorb calcium in the GI and kidney, and also
increase expression of RANKL (receptor activator of NF-kB ligand) on
osteoblasts
 RANKL binds to RANK on preosteoclasts, inducing them to differentiate
into mature osteoclasts, which then resorb bone with HCl and
proteases, releasing calcium and phosphorous into the blood
o Vitamin D also helps mineralize the bone by working in mineralizing the osteoid matrix
and epiphyseal cartilage in the making of both flat and long bones in the skeleton
 Vitamin D stimulates osteoblasts to make the calcium-binding protein
osteocalcin, which works in depositing calcium during bone development
 Flat bones form from intramembranous bone formation, where mesenchymal
cells differentiate directly into osteoblasts and make the collagenous osteoid
matrix that calcium is deposited on
 Long bones form from endochondral ossification, where growing cartilage at the
epiphyseal plates is mineralized and then progressively resorbed and replaced
by osteoid matrix that is mineralized to create bone
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When vitamin D deficiency causes hypocalcemia, PTH will be increased, causing increased
activation of renal 1α-hydroxylase to increase the amount of vitamin D made and increase
calcium absorption
o It will also increase resorption of calcium from bone by osteoclasts, decrease renal
calcium excretion, and increase renal excretion of phosphate
o Phosphatonins like fibroblast growth factor 23 (FGF-23) block absorption of phosphate
in the intestine and kidney, to increase urinary excretion of phosphate
 So all of this may restore blood calcium, but you have low phosphate, which
impairs mineralization of bone
Vitamin D deficiency can be caused by diets deficient in it, and not enough exposure to sunlight
o Fish oils are high in vitamin D and can be used to help fix this
o Other causes of vitamin D deficiencies are caused by kidney problems making active
vitamin D, loss of phosphates, and malabsorption
o Rickets in kids, and osteomalacia in adults, are the most common serious results of
vitamin D deficiency, while mild low vitamin D, called vitamin D insufficiency, is common
in elderly people
o The main problem in rickets and osteomalacia is excess unmineralized matrix
o Rickets shows:
 Overgrowth of epihphyseal cartilage – due to not enough calcification, and
failure of cartilage cells to mature and disintegrate
 Persistence of distorted, irregular masses of cartilage, which project into the
bone marrow cavity
 Deposition of osteoid matrix in inadequately mineralized cartilage remnants
 Disruption of the normal replacement of cartilage by osteoid matrix, with
enlargement of the osteochondral junction – page 435
 Abnormal overgrowth of capillaries and fibroblasts in the disorganized zone –
from microfractures and stresses on the poorly mineralized weak poorly formed
bone
 Deformation of the skeleton due to loss of structural rigidity of the developing
bones
o Rickets is most common during the first year of life
 Before they learn to walk, the head and chest are most affected
 The bones are softened, so the occipital bones can become flattened,
and the parietal bones can buckle inwards from pressure
 An excess of osteoid causes frontal bossing (protrusion) and a squarelooking head
 The chest shows a “rachitic rosary” from overgrowth of cartilage or
osteoid tissue at the costochondral junction
 The ribs are weakened, and so can be pulled by respiratory muscles
and bend inward, causing anterior protrusion of the sternum called
”pigeon chest” deformity
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When they learn to walk, rickets starts to affect the spine, pelvis, and tibia,
causing lumbar lordosis and bowing of the legs
o Osteomalacia in adults deranges normal bone remodeling
 The newly formed osteoid matrix laid down by osteoblasts is inadequately
mineralized, causing characteristic excess of persistent osteoid
 Osteomalacia makes the bone weak and vulnerable to fractures, especially in
the vertebral bodies and femoral necks
Vitamin D also works in things not involved with bone:
o Macrophage make vitamin D when pathogens activate their toll-like receptors, which
then stimulates making of cathelicidin
 Cathelicidin is an antimicrobial defense that works well against M. tuberculosis
Prolonged exposure to normal sunlight will not cause excess vitamin D
Ingesting too much vitamin D can cause metastatic calcifications of soft tissues in kids, and bone
pain and hypercalcemia in adults
Vitamin C (ascorbic acid):
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Lack of vitamin C causes scurvy, which is characterized by bone disease in growing kids, and
hemorrhages and healing problems in both kids and adults
We can’t make vitamin C, so we depend entirely on our diet for vitamin C
Vitamin C is water soluble, & works in pathways by accelerating hydroxylation & amidation rxns
The best known function of vitamin C is it activates prolyl and lysyl hydroxylases from inactive
precursors, to allow for hydroxylation of procollagen
o If procollagen isn’t hydroxylated, it can’t turn into a stable helix or be cross-linked, so
then it’s poorly secreted from the fibroblast
 What is secreted lacks tensile strength, and is more soluble and vulnerable to
enzymes breaking it down
 So collagen is very effected, especially in blood vessels, leading to easy
hemorrhages in scurvy
o Decreased vitamin C also decrease the rate of making of procollagen
Vitamin C is also an antioxidant that can directly scavange free radicals, and indirectly
regenerate the antioxidant form of vitamin E
Vitamin C is found in many fruits and easily gotten from food, making scurvy rare
There is no proof that megadoses of vitamin C boosts the immune system or cancer
Page 438 – table fo the vitamins, what they do, and what happens in their deficiencies
Page 439 – table of the mineral and trace elements, what they do, and their deficiencies
Obesity – accumulation of enough adipose to impair health
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BMI from 25-30 is overweight, BMI over 30 is obese
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Central (visceral) obesity – when fat accumulates in the trunk and abdominal cavity (so in the
mesentery and around the viscera), and is associated with a much higher risk for disease than
just excess subcutaneous fat anywhere else
The neurohumoral mechanisms to regulate energy balance are divided into 3 groups:
o Peripheral (afferent) system – generates signals from peripheral sites
 The peripheral system mainly works through leptin and adiponectin made by
adipose cells, ghrelin from the stomach, peptide YY (PYY) from the ileum and
colon, and insulin from the pancreas
o The arcuate nucleus in the hypothalamus processes and integrates peripheral signals to
generate efferent signals
 The arcuate nucleus uses pro-opiomelanocortin (POMC) and CART neurons,
and neurons w neuropeptide Y & AgRP, as first-order neurons, which then
sends signals to second-order neurons
o Efferent system – carries the signals generated by the second-order neurons of the
hypothalamus to control food intake and energy expenditure
 Signals also go to the forebrain and midbrain to control the autonomics
POMC/CART neurons enhance energy expenditure and weight loss through making
anorexigenic α-melanocyte-stimulating hormone (MSH) and stimulating melanocortin
receptors in second-order neurons
NPY/AgRP neurons promote food intake (called orexigenic effect) and weight gain, by also
activating receptors on secondary neurons
Leptin – hormone made by the ob gene in fat cells, that tells the brain you have enough energy
and don’t need to eat
o Came from the greek word “leptos” which means “thin”
o The leptin receptor (OB-R) is made by the diabetes (db) gene
o Leptin levels are regulated by how much fat you have stored
 Leptin is released when you have plenty of fat stored
o In the hypothalamus, leptin stimulates POMC/CART neurons that produce anorexigenic
neuropeptides (mainly melanocyte-stimulating hormone, MSH), and inhibits NPY/AgRP
neurons that would make you want to eat from releasing orexigenic neuropeptides
o In people with stable weight, the activities of POMC/CART vs NPY/AgRP are balanced
o When there isn’t enough fat stored in the body, leptin isn’t released, and you want to
eat more
o People with loss-of-function mutations in the leptin system develop early-onset severe
obesity, but this is rare
o Mutation of melanocortin receptor 4 (MCR4) is more common, and these people can’t
sense that you have enough fat stored (satiety), so these people respond as if they’re
undernourished
o Leptin also regulates energy expenditure
 So excess leptin stimulates physical activity, heat production, and energy
expenditure
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The thermogenesis causes catabolism, and is stimulated by the hypothalamus
causing release of norepinephrine from symps at the adipose
Adiponectin – hormone made by adipocytes that directs fatty acids to the muscle to be oxidized
o Adiponectin decreases movement of fatty acids to the liver and the amount of fat in the
liver
o Adiponectin also decreases glucose making in the liver, and increases insulin sensitivity
o Adiponectin levels are very high in the blood, but are decreased though in obese people
compared to thin people
o Receptors for adiponectin are in most body cells, but especially in the skeletal muscle
and liver
o When adiponectin binds its receptor, it triggers activation of cAMP, which activates
protein kinase A (cAMP-activated protein kinase), which then phosphorylates and
inactivates acetyl CoA carboxylase, which is a key enzyme needed to make fatty acids
Adipose can also make cytokines like TNF, Il-6, Il-1, and Il-18, chemokines, and steroids
o Increased making of cytokines and chemokines by adipose in obese people causes a
chronic but asymptomatic inflammatory state, that includes increased C-reactive
protein
So adipose works in control of energy balance and metabolism
The total # of adipocytes is established during childhood and your teens, and is higher in obese
than in lean people
In adults, the # of adipocytes stays constant, even after weight changes
o There is adipocyte turnover to replace adipocytes, but this is not affected at all by
weight or metabolism, and stays constant
So the fat mass of an adult can increase through the adipocytes enlarging, but their # is tightly
controlled, and predetermined in childhood and your teens
People who lose weight have difficulty maintaining the weight loss, due to the fact you never
decreased the # of adipocytes, and because appetite is increased by leptin deficiency
Gut peptides can act as short-term meal initiators and terminators, and include ghrelin, PYY,
pancreatic polypeptide, insulin, and amylin
Ghrelin – the only gut hormone that increases food intake
o Ghrelin is made by the stomach and in the arcuate nucleus of the hypothalamus
o Ghrelin works by binding the growth hormone (GH) receptor in the hypothalamus and
pituitary
o Ghrelin then probably stimulates NPY/AgRP neurons to increase food intake
o Ghrelin levels increase before meals, and fall within 1-2 hours after eating
o In obese people, the levels of ghrelin after eating don’t decrease as much
PYY – secreted by the ileum and colon, that works to decrease energy intake
o PYY levels are low during fasting, and increased shortly after food intake
Amylin is secreted along with insulin from pancreatic β cells, and decreases food intake and
weight gain
PYY and amylin both work by stimulating POMC/CART neurons in the hypothalamus to
decrease food intake
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Metabolic syndrome – excess visceral or intra-abdominal adipose, insulin resistance,
hyperinsulinemia, glucose intolerance, hypertension, hypertriglyceridemia, and low HDL
o Obesity causes insulin resistance and hyperinsulinemia
o Obesity increase the risk for hypertension
o Hypertriglyceridemia and low HDL from obesity can increase the risk for coronary artery
disease
o Obesity causes non-alcoholic fatty liver disease, which can progress to fibrosis and
cirrhosis
 Gallstones (cholelithiasis) are way more common in obese people, due to an
increase in body cholesterol and problems excreting it in bile
o Obesity causes hypoventilation and hypersomnolence (sleepiness)
 Hypersomnolence is associated with apneic pauses during sleep, polycythemia,
and eventual right-sided heart failure
o Obesity predisposes to the development of degenerative joint disease (osteoarthritis),
due to the increased load on the weight-bearing joints
Obesity increases the risk for cancers of the esophagus, thyroid, colon, and kidney in men, and
esophagus, endometrium, gallbladder, and kidney in women
It’s thought obesity increases the risk for cancer due to hyperinsulinemia and insulin resistance
o Insulin promotes cell growth
o Hyperinsulinemia causes an increase in insulin-like growth factor-1 (IGF-1), because
insulin inhibits the making of IGF-binding proteins
 IGF-1 stimulates growth and inhibits apoptosis, and is highly expressed in many
cancers
 IGF-1 stimulates many of the same pathways as insulin,a nd also increases
making of vascular endothelial growth factor (VEGF) by inducing expression of
hyopoxia-inducible factor 1 (HIF-1)
o Obesity also increases the making of estrogen in adipose aromatases, and insulin
increase the making of androgens from the ovaries and adrenals
 The estrogen is made more available by obesity inhibiting making of sexhormone-binding globulin (SHBG)
o Obesity also decreases adiponectin, decreasing insulin sensitivity which raises insulin
levels
Aflatoxin is made by asperigillus in Asia in Africa, and ingesting it in rice and nuts can lead to the
development of hepatocellular carcinoma, especially when there’s already hepatitis B (HBV)
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Aflatoxin has a characteristic mutation on p53 that nothing else causes
Nitrosamines and nitrosamides can cause gastric cancer
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They’re made in the body from ingested nitrites and amines or amides from digested proteins
Sources of nitrites include sodium nitrite added as a preservative to foods
Nitrates are common in vegetables
High animal fat intake combined with low fiber intake can lead to colon cancer
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High fat intake increases the level of bile acids int eh gut, which adjusts the gut bacteria to favor
their growth and use the bile acids
o The metabolites they make from these bile acids can act as carcinogens
High fiber increases stool bulk and decreased time it takes before you poop, which both
decrease exposure of mucosa to these carcinogens, and also the fiber can bind the carcinogens
to get rid of them
Vitamins C, E, carotenoids, and selenium are antioxidants that can prevent cancer, but can’t be used to
treat it