phys chapter 71 [10-24

Phys chapter 71
Energy Intake and Output Balanced Under Steady State Conditions
 Stability of body weight and composition over long periods requires person’s energy intake and energy
expenditure be balanced
o When energy intake persistently exceeds expenditure, most of excess energy stored as fat, and body
weight increases
o Loss of body mass and starvation occur when energy intake insufficient to meet body’s metabolic needs
Dietary Balances
 Each gram of carbohydrate yields 4.1 Calories, each gram of fat yields 9.3 Calories, and each gram of protein as it
is oxidized to CO2, H2O, and urea yields 4.35 Calories
o 98% of carbs in GI tract absorbed, 95% of fat absorbed, and 92% of protein absorbed
o Average physiologically available energy in each gram of foodstuffs is 4 Calories of carb, 9 Calories of fat,
and 4 Calories of protein
o Average Americans receive 15% of their energy from protein, 40% from fat, and 45% from carbohydrate
o In most non-Western countries, quantity of energy derived from carbohydrates far exceeds that derived
from both proteins and fats
 Fat usually exists as nearly 100% fat, whereas both proteins and carbs mixed in watery media so that each of
these normally represents less than 25% of the weight (a pat of butter in an entire helping of potato might have
more energy in the butter than the entirety of the potato)
 Average person can maintain normal stores of protein to replace degraded proteins in cells provided daily intake
is above 30-50 g
o Partial proteins – proteins that have inadequate quantities of certain essential amino acids to replace
degraded proteins
o Proteins derived from animal foodstuffs are in general more complete than those derived from
vegetable and grain sources
o Kwashiorkor – protein-deficiency syndrome seen often in countries where cornmeal is principal source
of protein (lacks tryptophan); symtpoms include failure to grow, lethargy, depressed mentality, and
edema caused by low plasma protein concentrations
 When diet contains abundance of carbs and fats, almost all body’s energy derived from them and very little from
protein, so carbs and fats are protein sparers
o In starvation, after carbs and fats have been depleted, body’s protein stores consumed rapidly for
energy, several times more than normal daily rate
 When carbs metabolized with O2, exactly one CO2 molecule formed for each molecule of O2 consumed
o Ratio of CO2 output to O2 usage is respiratory quotient
 When fat oxidized in body’s cells, respiratory quotient averages 0.70
 When proteins oxidized by cells, average respiratory quotient is 0.80
 Reason respiratory quotients for fats and proteins lower than those for carbs is portion of oxygen metabolized
with foods required to combine with excess hydrogen atoms present in molecules, so less CO2 formed in relation
to O2 used
 Respiratory exchange ratio = (output of CO2 by lungs)/(uptake of O2 during same period)
o Over period of 1 hour or more, respiratory exchange ratio = average respiratory quotient of metabolic
reactions throughout body
 Protein utilization can be determined by measuring nitrogen excretion; then one can calculate almost exactly
utilization of the 3 foodstuffs
 Immediately after a meal, almost all food metabolized is carbs, so respiratory quotient at that time approaches 1
 About 8-10 hours after a meal, body has already used up most of its readily available carbs, and respiratory
quotient approaches 0.70 (that for fats)
 In untreated DM, little carbs can be used by body’s cells under any conditions because insulin is required for
this, so when diabetes is severe, most of time respiratory quotient remains near 0.70
 Average protein contains about 16% nitrogen; during metabolism of protein, about 90% of N excreted in urine in
form of urea, uric acid, creatinine, and other N products; remaining 10% excreted in feces, so rate of protein
breakdown in body can be estimated by measuring amount of N in urine, then adding 10% for N excreted in
feces and multiplying by 6.25 (100/16) to determine total amount of protein metabolism in g/day
o If daily intake of protein is less than daily breakdown of protein, person has negative N balance, which
means their body stores of protein are decreasing daily
Regulation of Food Intake and Energy Storage
 About 27% of energy ingested normally reaches functional systems of cells, and much of this eventually
converted to heat, which is generated as result of protein metabolism, muscle activity, and activities of various
organs and tissues of body
 Deficit of energy intake causes loss of total body mass until energy expenditure eventually equals energy intake
or death occurs
 Deficits of energy stores rapidly activate multiple mechanisms that cause hunger and drive person to seek food
Neural Centers that Regulate Food Intake
 Sensation of hunger associated with craving for food, rhythmical contractions of stomach, and restlessness,
which cause person to seek adequate food supply
 Appetite – desire for food; satiety – successful quest for food; differs by environmental and cultural factors as
well as physiologic controls that influence specific centers of brain, especially hypothalamus
 Lateral nuclei of hypothalamus – feeding center; stimulation of this area causes individual to eat lots, and
destruction causes lack of desire for food and progressive inanition (marked weight loss, muscle weakness, and
decreased metabolism); works by exciting motor drives to search for food
 Ventromedial nuclei of hypothalamus – satiety center; gives a sense of nutritional satisfaction that inhibits
feeding center
 Paraventricular, dorsomedial, and arcuate nuclei of hypothalamus play roles in regulating food intake
o Lesions of paraventricular nuclei often cause excessive eating
o Leasions of dorsomedial nuclei depress eating behavior
o Arcuate nuclei – sites in hypothalamus where multiple hormones released from GI tract and adipose
tissue converge to regulate food intake as well as energy expenditure
 Much chemical cross-talk among neurons on hypothalamus and together, centers coordinate processes that
control eating behavior and perception of satiety
o Hypothalamic nuclei influence secretion of several hormones important in regulating energy balance
and metabolism, including those from thyroid and adrenal glands, as well as pancreatic islet cells
 Hypothalamus receives neural signals from GI tract that provide sensory information about stomach filling;
chemical signals from nutrients in blood (glucose, amino acids, and fatty acids) that signify satiety; signals from
GI hormones; signals from hormones released by adipose tissue; and signals from cerebral cortex (sigh, smell,
and taste) that influence feeding behavior
 Hypothalamic feeding and satiety centers have high density of receptors for neurotransmitters and hormones
that influence feeding behavior
o Orexigenic substances stimulate feeding; stuff such as NPY, AGRP, MCH, orexins A and B, endorphins,
GAL, glutamate and γ-aminobutyric acid, cortisol, ghrelin, and endocannbinoids
o Anorexigenic substances inhibit feeding; stuff such as α-MSH, leptin, serotonin, norepinephrine,
corticotropin releasing hormone, insulin, CCK, GLP, CART, and PYY
 2 types of neurons in arcuate nuclei of hypothalamus that control appetite and energy expenditure
o Pro-opiomelanocortin (POMC) neurons produce α-melanocyte-stimulating hormone (α-MSH) together
with cocaine- and amphetamine-related transcript (CART)
 Activation of POMC neurons decreases food intake and increases energy expenditure
o Neurons that produce orexigenic substances neuropeptide Y (NPY), and agouti-related protein (AGRP)
 Activation of NPY-AGRP neurons increases food intake and reduces energy expenditure
o Neurons of arcuate nuclei are site of convergence of many nervous and peripheral signals that regulate
energy stores
 POMC neurons release α-MSH, which then acts on melanocortin receptors found especially in neurons of
paraventricular nuclei – 5 subtypes of melanocortin receptors (MCR), but MCR-3 and MCR-4 especially
important in regulating food intake and energy balance
o Activation of MCR-3 and MCR-4 reduces food intake while increasing energy expenditure, and inhibition
increases food intake and decreases energy expenditure
Effect of MCR activation to increase energy expenditure in part by activation of neuronal pathways that
project from paraventricular nuclei to nucleus tractus solitarious and stimulate SNS activity
 Hypothalamic melanocortin system plays powerful role in regulating energy stores o fbody, and defective
signaling associated with extreme obesity
o Mutations of MCR-4 represent most common known monogenic cause of human obesity
o Excessive activation of melanocortin system reduces appetite (may be part of anorexia associated with
severe infections, cancer tumors, or uremia
 AGRP released from orexigenic neurons of hypothalamus and is natural antagonist of MCR-3 and MCR-4 and
increases feeding by inhibiting effects of α-MSH to stimulate melanocortin receptors
o Excessive formation of AGRP due to gene mutations, associated with increased food intake and obesity
 NPY released from orexigenic neurons of arcuate nuclei; when energy stores of body low, orexigenic neurons
activated to release NPY, which stimulates appetite; at same time, firing of POMC neurons reduced, decreasing
activity of melanocortin pathway and further stimulating appetite
 Actual mechanics of feeding controlled by centers of brain stem
 Amygdala and prefrontal cortex, closely coupled with hypothalamus, play important roles in control of appetite
o Portions of amygdala are major part of olfactory nervous system; destructive lesions of amygdala show
that some of its areas increase feeding, whereas other inhibit feeding; stimulation of some areas elicits
mechanical act of feeding
 Destruction of amygdala on both sides of brain causes psychic blindness in choice of foods
(individual loses appetite control that determines type and quality of food it eats)
Factors That Regulate Quantity of Food Intake
 when GI tract becomes distended, especially stomach and duodenum, stretch inhibitory signals transmitted
mainly by way of vagi to suppress feeding center, thereby reducing desire for food
 Cholecystokinin (CCK) – released mainly in response to fat and proteins entering duodenum, enters blood and
acts as hormone to influence gallbladder contraction, gastric emptying, gut motility, and gastric acid secretion
o Activates receptors on local sensory nerves in duodenum, sending messages to brain via vagus nerve
that contribute satiation and meal cessation
o Effect short-lived and chronic administration of CCK has no major effect on body weight
o Functions mainly to prevent overeating during meals but may not play major role in frequency of meals
or total energy consumed
 Peptide YY (PYY) – secreted from entire GI tract, especially from ileum and colon; food intake stimulates release
of PYY; peak levels 1-2 hours after ingesting meal and influenced by number of calories ingested and
composition of food, with higher levels of PYY observed after meals with high fat content
 Presence of food in intestines stimulates them to secrete glucagon-like peptide (GLP), which enhances glucosedependent insulin production and secretion from pancreas
o GLP and insulin tend to suppress appetite
o Eating a meal stimulates release of several GI hormones that may induce satiety and reduce further
intake of food
 Ghrelin – hormone released mainly by oxyntic cells of stomach and, to much less extent, by intestine; blood
levels of ghrelin rise during fasting, peak just before eating, and fall rapidly after a meal; administration of
ghrelin increases food intake
 When animal with esophageal fistula fed large quantities of food, even though food is immediately lost again to
exterior, degree of hunger decreased after reasonable quantity of food passed through mouth, so oral factors
(chewing, salivation, swallowing, and tasting) may meter food as it passes through mouth and after certain
amount has passed, hypothalamic feeding center becomes inhibited
o Inhibition caused by metering mechanism considerably less intense and of shorter duration than
inhibition caused by GI filling
 Glucostatic theory of hunger and feeding regulation – decrease in blood glucose concentration causes hunger
o Same effect for blood amino acid concentration and blood concentration of breakdown products of
lipids such as keto acids and some fatty acids, leading to aminostatic and lipostatic theories
o Rise in blood glucose level increases rate of firing of glucoreceptor neurons in satiety center in
ventromedial and paraventricular nuclei of hypothalamus
Same increase in blood glucose level simultaneously decreases firing of glucosensitive neurons
in hunger center of lateral hypothalamus
 Some amino acids and lipid substances affect rates of firing of same neurons or other closely
associated neurons
When animal exposed to cold, it increases feeding, and when exposed to heat, it decreases caloric intake
o Caused by interaction within hypothalamus between temperature-regulating system and food intakeregulating system; important to increase food intake in cold because it increases metabolic rate and
provides increased fat for insulation
Hypothalamus senses energy storage through actions of leptin (peptide hormone released from adipocytes)
o When amount of adipose tissue increases (signaling excess energy storage), adipocytes produce
increased amounts of leptin, which is released into blood
o Leptin circulates to brain, where it moves across BBB by facilitated diffusion and occupies leptin
receptors at multiple sites in hypothalamus, especially POMC neurons of arcuate nuclei and neurons of
paraventricular nuclei
o Stimulation of leptin receptors in hypothalamic nuclei initiates multiple actions that decrease fat
storage, including decreased production in hypothalamus of appetite stimulators (such as NPY and
AGRP), activation of POMC neurons (causing release of α-MSH and activation of melanocortin
receptors), increased production in hypothalamus of substances (such as corticotropin-releasing
hormone) that decrease food intake, increased SNS activity (through neural projections from
hypothalamus to vasomotor centers, which increase metabolic rate and energy expenditure), and
decreased insulin secretion by pancreatic beta cells (which decreases energy storage)
o Mutations that render fat cells unable to produce leptin or mutations that cause defective leptin
receptors in hypothalamus, marked hyperphagia and morbid obesity occur
 Obesity more likely associated with leptin resistance because plasma leptin levels increase in
proportion to increasing adiposity
Long-term regulatory system for feeding, which includes all nutritional energy feedback mechanisms, helps
maintain constant stores of nutrients in tissues
Short-term regulatory stimuli serve to make person eat smaller quantities at each eating session, allowing food
to pass through GI tract at steadier pace so its digestive and absorptive mechanisms can work at optimal rates
rather than becoming periodically overburdened; also help prevent person from eating amounts at each meal
that would be too much for metabolic storage systems once all food has been absorbed
 BMI – surrogate marker for body fat; weight in kg/height in m2
o BMI between 25-29.9 kg/m2 is overweight, and BMI greater than 30 kg/m2 is obese
o Not a direct estimate of adiposity and does not take into account fact that some individuals have high
BMI due to large muscle mass
 Obesity defined as 25% or greater total body fat in men and 35% or greater in women
o Percentage of body fat can be estimated by measuring skin-fold thickness, bioelectrical impedance, or
underwater weighing
 About 65% of adults in U.S. are overweight, and nearly 33% of adults are obese
 Excessive adiposity caused by energy intake in excess of energy output
o For each 9.3 Calories of excess energy that enter body, 1 g of fat stored
 Fat stored mainly in adipocytes in subcutaneous tissue and in intraperitoneal cavity, although liver and other
tissues of body often accumulate significant amounts of lipids in obese persons
 New adipocytes can differentiate from fibroblast-like preadipocytes at any period of life and development of
obesity in adults accompanied by increased numbers, as well as increased size, of adipocytes
o Extremely obese person may have as many as 4x adipocytes that have twice as much lipid each
o Once person has become obese and stable weight obtained, energy intake equals energy output
o For person to lose weight, energy intake must be less than energy expenditure
 About 25-30% of energy used each day by average person goes into muscular activity
o In obese people, increased physical activity usually increases energy expenditure more than food intake,
resulting in significant weight loss
Single episode of strenuous exercise may increase basal energy expenditure for several hours after
physical activity stops
o Muscular activity is by far most important means by which energy is expended in body
 Rate of formation of new fat cells especially rapid in first few years of life, and greater rate of fat storage means
greater number of fat cells
o Overnutrition of children, especially in infancy and to lesser extent during later years of childhood, can
lead to lifetime of obesity
 People with hypophyseal tumors that encroach on hypothalamus often develop progressive obesity
 Obese people may have abnormalities of neurotransmitters or receptor mechanisms in neural pathways of
hypothalamus that control feeding
o Obese person who has reduced to normal weight by strict dietary measures usually develops intense
hunger that is demonstrably far greater than that of normal person
o Set-point of obese person’s feeding control system at much higher level of nutrient storage than that of
normal person
o When food intake restricted in obese animals, there are marked neurotransmitter changes in
hypothalamus that greatly increase hunger and oppose weight loss; some changes include increased
formation of orexigenic neurotransmitters such as NPY and decreased formation of anorexic substances
such as leptin and α-MSH
 20-25% of cases of obesity may be caused by genetic factors – genes can contribute to obesity by causing
abnormalities of one or more pathways that regulate feeding centers and energy expenditure and fat storage
 3 monogenic causes of obesity are mutations of MCR-4 (most common monogenic form), congenital leptin
deficiency (caused by mutations of leptin gene, very rare), and mutations of leptin receptor (also very rare)
o Account for small percentage of obesity
 Current NIH guidelines recommend decrease in caloric intake of 500 Calories per day for overweight and
moderately obese persons to achieve weight loss of about a pound a week
o More aggressive energy deficiet of 500-1000 Calories per day recommended for persons with BMIs
greater than 35 kg/m2 – if deficit can be achieved and maintained, will cause weight loss of 1-2 lbs per
week (10% weight loss after 6 months)
o Increasing physical activity also important component of successful long-term weight loss
 Most reducing diets designed to contain large quantities of bulk (non-nutritive cellulose substances); distends
stomach and thereby partially appeases hunger
 Amphetamines directly inhibit feeding centers in brain
o Sibutramine – sympathomimetic drug that reduces food intake and increases energy expenditure
o Problem is amphetamines simultaneously overexcite SNS and raise blood pressure; person soon adapts
to drug, so weight reduction usually no greater than 5-10%
 Orlistat – lipase inhibitor that reduces intestinal digestion of fat, causing portion of ingested fat to be lost in
feces and therefore reduce energy absorption
o Fecal fat loss may cause unpleasant GI side effects as well as loss of fat-soluble vitamins in feces
 Significant weight loss achieved through increased physical activity
 For morbidly obese patients with BMIs greater than 40 or for those with BMIs greater than 35 and conditions
such as hypertension or type II diabetes that predispose them to other serious diseases, various surgical
procedures can be used to decrease fat mass of body or decrease amount of food that can be eaten each meal
o Gastric bypass surgery – construction of small pouch in proximal part of stomach that is connected to
jejunum with section of small bowel of varying lengths; pouch separated from remaining part of
stomach with staples
o Gastric banding surgery – placing adjustable band around stomach near upper end; creates small
stomach pouch that restricts amount of food that can be eaten at each meal
Inanition, Anorexia, and Cachexia
 Inanition – opposite of obesity; characterized by extreme weight loss
o Can be caused by inadequate availability of food or pathophysiological conditions that greatly decrease
desire for food, including psychogenic disturbances, hypothalamic abnormalities, and factors released
from peripheral tissues
o Reduced desire for food may be associated with increased energy expenditure, causing weight loss
Anorexia – reduction in food intake caused primarily by diminished appetite
Anorexia nervosa – abnormal psychic state in which person loses all desire for food, and even becomes
nauseated by food
 Cachexia – metabolic disorder of increased energy expenditure leading to weight loss greater than that caused
by reduced food intake alone
 Anorexia and cachexia often occur together in many types of cancer or wasting syndrome in AIDS patients or
chronic inflammatory disorders
o Almost all types of cancer cause both anorexia and cachexia, and more than half of cancer patients
develop anorexia-cachexia syndrome during course of their disease
 Central neural and peripheral factors contribute to cancer-induced anorexia and cachexia
o Inflammatory cytokines, including tumor necrosis factor-α, IL-6, interleukin-1β, and proteolysis-inducing
factor, cause anorexia and cachexia
o Most of inflammatory cytokines mediate anorexia by activating melanocortin system in hypothalamus
o Blockade of hypothalamic melanocortin receptors almost completely prevents anorexic and cachetic
effects of cytokines
 Quantity of carb stored in entire body only lasts for half a day, so except fo first few hours of starvation, major
effects are progressive depletion of tissue fat and protein
 Because fat is prime source of energy (100x as much fat stored as carb energy stored), rate of fat depletion
continues unabated
 Protein undergoes rapid depletion first, then greatly slowed depletion, then rapid depletion again shortly before
death; initial rapid depletion caused by use of easily metabolized protein for direct metabolism or for conversion
to glucose and metabolism of glucose mainly by brain
o After readily mobilized protein stores depleted during early phase of starvation, remaining protein not
so easily removed, and rate of gluconeogenesis decreases to 20-33% of its previous rate, and rate of
depletion of protein becomes greatly decreased
o Lessened availability of glucose initiates series of events that leads to excessive fat utilization and
conversion of some fat breakdown products to ketone bodies, producing state of ketosis
o Ketone bodies can cross BBB and be used by brain cells for energy, so 2/3 of brain’s energy now derived
from ketone bodies (principally beta-hydroxybutyrate)
o Comes a time when fat stores almost depleted, and only remaining source of energy is protein, so
protein stores enter stage of rapid depletion; because proteins essential for maintenance of cellular
function, death ordinarily ensues when proteins of body depleted to about half normal level
 Stores of some vitamins, especially water-soluble vitamins (vitamin B group and vitamin C) do not last long
during starvation; after a week or more of starvation, mild vitamin deficiencies usually begin to appear, and
after several weeks, severe vitamin deficiencies can occur, adding to debility that leads to death
 Vitamin – organic compound needed in small quantities form normal metabolism that cannot be manufactured
in cells of body
 Vitamins stored to slight extent in all cells; some vitamins stored to major extent in liver (vitamin A stored in
liver may be sufficient to maintain person for 5-10 months, and quantity of vitamin D stored in liver sufficient to
maintain person for 2-4 months)
 Storage of most water-soluble vitamins relatively slight
o When person’s diet is deficient in vitamin B compounds, clinical symptoms can be recognized within a
few days (except for vitamin B12, which can last in liver in bound form for year or longer)
o Absence of vitamin C can cause symptoms within a few weeks (scurvy)
 Vitamin A – occurs in animal tissues as retinol; doesn’t occur in vegetable foods, but provitamins for formation
of vitamin A occur in abundance in many vegetable foods (carotenoid pigments – because their chemical
structures similar to that of vitamin A, they can be changed into vitamin A in liver)
o Used in formation of retinal pigments of eye; needed to prevent night blindness
o Necessary for normal growth of most cells of body, especially normal growth and proliferation of
epithelial cells – when vitamin A lacking, epithelial structures of body tend to become stratified and
Vitamin A deficiency manifests by scaliness of skin, sometimes acne, failure of growth in young
(including cessation of skeletal growth), failure of reproduction (associated with atrophy of germinal
epithelium of testes and sometimes interruption of female sexual cycle), and keratinization of cornea
with resultant corneal opacity and blindness; damaged epithelial structures often become infected
(conjunctivae of eyes, linings of urinary tract and respiratory passages)
Thiamine (vitamin B1) – operates in metabolic systems of body principally as thiamine pyrophosphate, which
functions as a cocarboxylase, operating mainly in conjunction with protein decarboxylase for decarboxylation of
pyruvic acid and other α-keto acids
o Beriberi – thiamine deficiency; causes decreased utilization of pyruvic acid and some amino acids by
tissues, but increased utilization of fats; decreased utilization of carbs and amino acids responsible for
many debilities associated with beriberi
o Thiamine specifically needed for final metabolism of carbs and many amino acids
o CNS normally depends almost entirely on metabolism of carbs for energy; in thiamine deficiency,
utilization of glucose by nervous tissue may be decreased by 50-60% and replaced by utilization of
ketone bodies derived from fat metabolism
 Neuronal cells of CNS frequently show chromatolysis and swelling during thiamine deficiency;
can disrupt communication in many portions of CNS
o Thiamine deficiency can cause degeneration of myelin sheaths of nerve fibers in both peripheral nerves
and CNS; lesions in PNS frequently cause them to become extremely irritable, resulting in polyneuritis
(pain radiating along course of one or many peripheral nerves)
o Fiber tracts in cord can degenerate to such an extent that paralysis occasionally results; even in absence
of paralysis, muscles atrophy, resulting in severe weakness
o Person with severe thiamine deficiency eventually develops cardiac failure because of weakened cardiac
muscle; venous return of blood to heart may be increased to twice normal because thiamine deficiency
causes peripheral vasodilation throughout circulatory system as a result of decreased release of
metabolic energy in tissues, leading to local vascular dilation
 Cardiac effects partially due to high blood flow into heart and partly to primary weakness of
cardiac muscle
 Peripheral edema and ascites occur in some patients, mainly because of cardiac failure
o GI symptoms include indigestion, severe constipation, anorexia, gastric atony, and hypochlorhydria
(failure of smooth muscle and glands of GI tract to derive sufficient energy from carb metabolism
Niacin (nicotinic acid or vitamin B3) – functions as coenzyme in form of nicotinamide adenine dinucleotide (NAD)
and nicotinamide adenine dinucleotide phosphate (NADP); hydrogen acceptors that combine with hydrogen
atoms as they are removed from food substrates by many types of dehydrogenases
o When deficiency exists, normal rate of dehydrogenation cannot be maintained; therefore, oxidative
delivery of energy from foodstuffs to functioning elements of all cells cannot occur at normal rates
o In early stages of deficiency, muscle weakness and poor glandular secretion may occur, but in severe
deficiency, actual tissue death ensues
o In severe deficiency, pathological lesions appear in many parts of CNS, and permanent dementia or
many types of psychoses may result; skin develops cracked, pigmented scaliness in areas that are
exposed to mechanical irritation or sun irradiation
o Deficiency causes intense irritation and inflammation of mucous membranes of mouth and other
portions of GI tract, resulting in many digestive abnormalities that can lead to widespread GI
hemorrhage in severe cases (results from generalized depression of metabolism in GI epithelium and
failure of appropriate epithelial repair
o Pellagra and canine disease black tongue caused mainly by niacin deficiency
 Pellagra exacerbated in people on corn diet because corn is deficient in tryptophan, which can
be converted in limited quantities to niacin in body
Riboflavin (vitamin B2) – normally combines in tissues with phosphoric acid to form 2 coenzymes (flavin
mononucleotide or FMN and flavin adenine dinucleotide or FAD); operate as hydrogen carriers in important
oxidative systems of mitochondria
o NAD usually accepts hydrogen removed from various food substrates and then passes hydrogen to FMN
or FAD; finally hydrogen released as ion into mitochondrial matrix to become oxidized by oxygen
Deficiency causes severe dermatitis, vomiting, diarrhea, muscle spasticity that finally becomes muscle
weakness, coma and decline in body temperature, and then death – debilities due to generally
depressed oxidative processes within cells
o No known human cases of deficiency severe enough to cause marked debilities, but mild deficiency
common; causes digestive disturbances, burning sensations of skin and eyes, cracking at corners of
mouth, headaches, mental depression, forgetfulness
o Deficiency frequently occurs in association with deficiency of thiamine, niacin, or both
Vitamin B12 – several cobalamin compounds possess common prosthetic group exhibit vitamin B12 activity
(prosthetic gropu contains cobalt, which has bonds similar to those of iron in Hgb molecule; likely cobalt atom
functions in same way iron atom functions to combine reversibly with other substances
o Vitamin B12 performs several metabolic functions, acting as hydrogen acceptor coenzyme
o Most important function is to act as coenzyme for reducing ribnucleotides to deoxyribonucleotides
(necessary in replication of genes)
o Major functions of B12 are promotion of growth and promotion of RBC formation and maturation
o Demyelination of nerve fibers in people with B12 deficiency occurs especially in posterior columns, and
occasionally lateral columns, of spinal cord; as result, many people with pernicious anemia have loss of
peripheral sensation and, in severe cases, become paralyzed
o Usual cause of deficiency is deficiency of formation of intrinsic factor, which is normally secreted by
parietal cells of gastric glands and is essential for absorption of B12 by ileal mucosa
Folic acid (pteroylgutamic acid) – several pteroylglutamic acids exhibit folic acid effect; folic acid functions as
carrier of hydroxymethyl and formyl groups
o Perhaps most important use is in synthesis of purines and thymine, required for formation of DNA
o One of most important functions of folic acid is to promote growth
o Folic acid even more potent growth promoter than B12 and is important for maturation of RBCs
o One of significant effects of folic acid deficiency is development of macrocytic anemia almost identical to
pernicious anemia (often treated with folic acid alone)
Pyridoxine (vitamin B6) – exists in form of pyridoxal phosphate in cells and functions as coenzyme for many
chemical reactions related to amino acid and protein metabolism
o Most important role is as coenzyme in transamination process for synthesis of amino acids
o Acts in transport of some amino acids across cell membranes
o Dietary lack can cause dermatitis, decreased rate of growth, development of fatty liver, aneima, and
evidence of mental deterioration; rarely in children, deficiency can cause seizures, dermatitis, and GI
disturbances such as nausea and vomiting
Pantothenic acid – mainly incorporated in body into CoA, which has many metabolic roles in cells (conversion of
decarboxylated pyruvic acid into acetyl-CoA before its entry into citric acid cycle and degradation of fatty acid
molecules into multiple molecules of acetyl-CoA)
o Lack of pantothenic acid can lead to depressed metabolism of both carbs and fats
o Deficiency of pantothenic acid can cause retarded growth, failure of reproduction, graying of hair,
dermatitis, fatty liver, and hemorrhagic adrenocortical necrosis
o No definite deficiency syndrome has been proved in humans because of wide occurrence in almost all
foods and because small amounts can be synthesized by body
Ascorbic acid (vitamin C) – essential for activating enzyme prolyl hydroxylase, which promotes hydroxylation
step in formation of hydroxyproline (integral constituent of collagen); without ascorbic acid, collagen fibers
formed in virtually all tissues of body are defective and weak; needed for growth and strength of fibers in
subcutaneous tissue, cartilage, bone, and teeth
o Deficiency of ascorbic acid for 20-30 weeks causes scurvy; one of most important effects is failure of
wounds to heal (caused by failure of cells to deposit collagen fibrils and intercellular cement substances,
so healing of wound may require several months instead of several days
o Lack of ascorbic acid also causes cessation of bone growth; cells of growing epiphyses continue to
proliferate, but no new collagen laid down between cells, and bones fracture easily at point of growth
because of failure to ossify; when already ossified bone fractures, osteoblasts cannot form new bone
matrix, so fractured bone doesn’t heal
Blood vessel walls become extremely fragile in scurvy because of failure of endothelial cells to be
cemented together properly and failure to form collagen fibrils normally present in vessel walls;
capillaries especially likely to rupture and as a result, many small petechial hemorrhages occur
throughout body; can cause purpuric blotches, sometimes over entire body
o To test for ascorbic acid deficiency, one can produce petechial hemorrhages by inflating a BP cuff over
upper arm; occludes venous return of blood, capillary pressure rises, and red blotches occur in forearm
o In extreme scurvy, muscle cells sometimes fragment; lesions of gums occur, with loosening of teeth;
infections of mouth develop; vomiting of blood, bloody stools, and cerebral hemorrhage
o High fever develops before death
 Vitamin D – increases calcium absorption from GI tract and helps control calcium deposition in bone
o Mainly promotes active transport of calcium through epithelium of ileum
o Increases formation of calcium-binding protein in intestinal epithelial cells that aids in calcium
 Vitamin E – several related compounds have vitamin E activity, and only rare instances of proved vitamin E
deficiency have occurred in humans
o Lack of vitamin E can cause degeneration of germinal epithelium in testis, causing male sterility
o Deficiency can cause resorption of fetus after conception in female (vitamin E called antisterility vitamin)
o Deficiency prevents normal growth and sometimes causes degeneration of renal tubular cells and
muscle cells
o Plays protective role in prevention of oxidation of unsaturated fats; in absence of vitamin E, quantity of
unsaturated fats in cells becomes diminished, causing abnormal structure and function of mitochondria,
lysosomes, and PM
 Vitamin K – essential co-factor to liver enzyme that adds carboxyl group to factors II (prothrombin), VII
(proconvertin), IX, and X, all important in blood coagulation; without carboxylation, coagulation factors are
inactive, so when vitamin K deficiency occurs, blood clotting is retarded
o Because vitamin K synthesized by bacteria in colon, it is rare for person to have bleeding tendency
because of vitamin K deficiency in diet, but when bacteria of colon destroyed by administration of large
quantities of antibiotic drugs, vitamin K deficiency occurs rapidly because of paucity in diet
Mineral Metabolism
 Magnesium – 1/6 as plentiful in cells as potassium; required as catalyst for many intracellular enzymatic
reactions, particularly those related to carbohydrate metabolism
o Extracellular fluid magnesium concentration slight; increased extracellular concentration of Mg
depresses nervous system activity as well as skeletal muscle contraction (reduction of skeletal muscle
contraction can be blocked with administration of calcium)
o Low Mg concentration causes increased irritability of nervous system, peripheral vasodilation, and
cardiac arrhythmias, especially after acute MI
 Calcium – present in body mainly in form of calcium phosphate in bone
o Excess quantities of Ca2+ in extracellular fluid can cause heart to stop in systole and can act as mental
o Low levels of Ca2+ can cause spontaneous discharge of nerve fibers, resulting in tetany
 Phosphate – major anion of intracellular fluid; phosphates can combine reversibly with many coenzyme systems
and with multiple other compounds necessary for operation of metabolic processes
 Iron – 2/3 of iron in body is in form of Hgb, although smaller quantities present in other forms, especially in liver
and bone marrow
o Electron carriers containing iron (especially cytochromes) present in mitochondria of all cells of body
and are essential for most of oxidation that occurs in cells
o Iron absolutely essential for transport of oxygen to tissues and operation of oxidative systems in tissue
cells, without which life would cease in a few seconds
 Iodine – essential to formation of thyroxine and triiodothyronine (2 thyroid hormones) essential for
maintenance of normal metabolic rates in all cells of body
 Zinc – integral part of many enzymes, including carbonic anhydrase, which is present in high concentration in
RBCs; carbonic anhydrase responsible for rapid combination of CO2 with H2O in RBCs of peripheral capillary
blood and for rapid release of CO2 from pulmonary capillary blood into alveoli
Carbonic anhydrase present in GI mucosa, tubules of kidney, and epithelial cells of many glands of body
Zinc essential for performance of many reactions related to CO2 metabolism
Zinc also component of lactic dehydrogenase and is important for interconversions between pyruvic acid
and lactic acid
o Zinc component of some peptidases and is important for digestion of proteins in GI tract
Fluorine – presence of small quantity in body during period of life when teeth being formed protects against
caries; does not make teeth stronger but has effect in suppressing cariogenic process
o Excessive intake causes fluorosis, which manifests by mottled teeth and in more severe state by
enlarged bones; structural strength of mottled teeth may be considerably lessened
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