- Total Calories used = BMR + ACTIVITY
+ DIT + other factors.
- KCAL:
- The energy content of foods is described in terms of kilocalories (kcal)
or Joules (J). One kilocalorie (kcal) is defined as the amount of heat
required to raise the temperature of 1 kg water by 1 degree C
while it is in the temperature
range of 15 degrees C to 16 degrees C. 1 kcal = 4.128 kJ.
The term ``Calorie'' in common usage (capital ``C'') is 1 kcal.
1-9% of food energy is non-digestible. About 10% goes to DIT.
About 50% is lost as heat.
25-40% is converted to high energy phosphate band energy for use in basal
metabolism (BMR) and physical activities.
Energy Intake, kcal/day
-----------------------
age male female
----------------------------------------
20 2900 1700
40 2550 1550
60 2100 1400
- BMR:
- Basal metabolic rate, or RMR - Resting
Metabolic Rate,
is the rate of energy utilization in
the resting state is most closely related to lean body mass.
Liver and brain, 4% of body mass, account for 40% of BMR.
BMR is measured from O2 consumption (CO2 production)
of a person awake, at rest, after an overnight fast.
Useful average for quick estimates:
- Men: BMR = 1.0 kcal/(kg hr)
- Women: BMR = 0.9 kcal/(kg hr)
BMR = 1.3 kcal/(kg hr) fat-free body weight
(irrespective of sex and age) 1kg = 2.21 lbs. 100 lbs = 45.2 kg.
- This figure
- shows that BMR may be independent of
a person's training status and aerobic level. High intensity
resistance or endurance training also has no effect on BMR.
(Broeder, C.E. et al., (1992) Amer. J. Clin. Nut.,
55, 795-811.)
BMR can be changed by uncouplers of oxidative phosphorylation
such as 2,4-dinitrophenol (DNP).
(Stryer, pp. 421-2; Voet & Voet, pp. 552-4)
``In spite of warnings from the Stanford scientists,
some enterprising physicians started to administer dinitrophenol to
obese patients without proper precautions.
The results were striking. Unfortunately in
some cases the treatment eliminated not only
the fat but also the patients, and several fatalities
were reported in the Journal of the American Medical
Association in 1929. This discouraged physicians for a while...''
(Efraim Racker, A New Look at Mechanisms in Bioenergetics,
p. 155)
- ACTIVITY:
- Energy expenditures above Basal
for Physical Activities, kcal/(kg hr). Examples:
Bicycling (moderate) 2.5 Dishwashing 1.0
Reading, writing 0.4 sitting, eating 0.4
Running 7.0 Walking slowly 2.0
Stone masonry 4.7 Rowing (race) 16.0
Swimming (2 mph) 7.9 Standing at attention 0.6
Walking (4 mph) 3.4 Boxing 11.8
Walking (5.3 mph) 9.3 Lying still, awake 0.1
- DIT:
- Diet Induced Thermogenesis, or TEF -
Thermal Effect of Food, is the
obligation to expend energy to digest, absorb, distribute, and
store nutrients.
Food can activate brown adipose tissue. DIT = 10% of calories
ingested for most americans. DIT from fat = 4% , carbohydrate = 31%
(stored as fat), protein = 15-30% .
- This figure
- shows how free fatty acids uncouple oxidative phosphorylation
in the brown fat mitochondrion (from Voet & Voet p. 554.):
Energy production is the consequence of
the oxidation of food by atmospheric O2 to produce CO2
and excreted nitrogen. (Energy use is measured by
monitoring these three things.)
- CARBOHYDRATES - 4 KCAL/GRAM:
-
Metabolic energy produced from carbohydrate is about
4 kcal/gram.
The chief metabolic role of carbohydrates in the diet
is for energy production. Carbohydrate in excess of that needed
for energy is converted to glycogen and triglyceride for storage.
- FATS - 9 KCAL/GRAM:
- Metabolic energy derived from fat is 9 kcal/gram.
Triglycerides, or fats, can be directly
utilized by many tissues
of the body as an energy source and are an important part of membrane
structure. Excess fat in the diet can be stored as triglyceride only.
- PROTEINS - 4 KCAL/GRAM:
- The metabolic energy derived from protein is about 4 kcal/g.
Although protein contains more energy than
carbohydrate, the metabolic energy derived from protein is the same
because products of nitrogen metabolism are not completely oxidized.
Dietary proteins are broken down to amino acids which are
taken up by the cells for the synthesis of new proteins and other
nitrogen containing compounds. Excess dietary protein is treated as
a source of energy with glycogenic amino acids being converted to
glucose and ketogenic amino acids being converted to fatty acids and
keto acids.
Although there is no separate class of ``storage'' protein, a certain
percentage of muscle and structural protein is considered as
expendable. In the fasting state the breakdown of this store of body
protein is enhanced, and the resulting amino acids are utilized for
glucose production, for the synthesis of non-protein nitrogenous
compounds and essential proteins. Even in the fed state, some of
these amino acids will be utilized for energy production and as
biosynthetic precursors. The turnover of body protein is a normal
process - an essential feature of nitrogen balance.
- NITROGEN BALANCE:
- A comparison between the intake of nitrogen, mostly
in the form of protein, and the excretion of nitrogen, mostly as
undigested protein in the feces, and urea and ammonia in the urine.
- UUN, 24 hour Urinary Urea Nitrogen:
- Normal: <5g/day.
Usefulness: Determine level of catabolism (breakdown paths).
Low UUN can be caused by low protein intake, active fluid
retention, increasing BUN (blood urea nitrogen), and
incomplete urine collection.
High UUN can be caused by high protein intake, stress,
corticosteroid therapy, active diuresis (increased secretion
of urine), decreasing BUN, and >24-hr urine collection.
- Question:
-
A mountaineer walks 8 hrs/day at a rate that consumes
5 kcal/(kg hr), stands or sits for 8 hrs/day,
and sleeps during the remainder.
He weighs 150 lbs.
He eats 1 kg of dry Kellog's low fat granola during the day,
composed by weight of 20% fat, 5% protein, 70% carbohydrates,
and 5% nondigestible fiber. In the evening he eats
a freeze-dried chicken tetrazini dinner for two before retiring.
The dinner contains ...
He is
(A) not eating enough.
(B) eating just about enough.
(C) eating too much.
- EPB, Estimated nitrogen (Protein) Balance:
-
![[image]](/biochem/images/le1-1-icon.gif)
(from Weinsier, R. L., and Morgan, S. L. (1993)
Fundamentals of Clinical Nutrition, Mosby, St. Louis)
EPB = protein intake - protein loss.
Protein loss = [24-hr UUN(g) + 4 (The 4 grams is an allowance
for stool and nonurea nitrogen losses.)] X 6.25
(The 6.25 is for converting from urea to protein losses.)
There are exceptions to this formula for burn patients and others
with large nonurinary nitrogen losses.
- BUN, Blood Urea Nitrogen:
- Normal - 8-23mg/dl. Usefulness - measurement of protein intake;
if serum creatinine is normal, use BUN for protein intake;
if serum creatinine is high, use BUN/creatinine.
BUN/creatine < 8 suggests poor proteine intake.
A low value may also result from severe liver disease.
A high value may occur despite low protein intake
during renal failure, congestive heart failure,
gastrointestinal hemorrhage, corticosteroid therapy,
dehydration, and shock
- Serum Creatinine:
- Normal - 0.6 - 1.6 mg/dl. Usefulness - a value
less than 0.6 mg/dl indicates muscle wasting due to calorie deficiency.
A high value may be seen despite muscle wasting due to renal failure
or severe dehydration (when creatinine simply cannot be excreted
as it normally is in the urine).
- Question:
- Why is urinary creatinine not included in measurements
of protein (nitrogen) loss?
- Case Study 1:
-
A 63 year old woman was hospitalized for cervical cancer therapy.
Prior to admission, her diet consisted of cornbread,
grits, mustard greens (boiled for several hours), and cereals.
She had no teeth. Her weight fell from 54 to 47 kg over the past
two months. She ate little in the hospital and was maintained
only on intravenous saline solutions.
Five days days after removal of her lower abdominal organs,
she had bloody fluid leaking from a poorly healing surgical wound
(see slide in lecture).
A physical examination revealed that her hair could be
easily and painlessly plucked. There were perifolicular petechiae
over the lower extremities, large areas of bleeding into the
skin at needle puncture sites, and widespread pitting edema
(excess fluid in the tissues that show prolonged existence of
pits produced by pressure). Her temperature was high at
39.5 deg. C. Weight was 63 kg, height 150 cm (reference
ideal weight is 47 kg).
Laboratory results showed a very low lymphocyte count
(120 cells/mm3, normal is > 1500/mm3,
total lymphocyte count is used in nutrition to suggest
immunocompromise associated with protein-calorie malnutrition)
BUN was 6 mg/dl, and serum albumin was 2 g/dl.
(Normal is 3.5-5.5 g/dl, 2.8 to 3.5 indicates compromised
protein status; <2.8 suggests kwashiorkor.
Low values may also be caused by infection and other stress,
especially with poor protein intake, burns, trauma,
congestive heart failure, fluid overload, chronic lying down,
and severe hepatic (liver) insufficiency.)
UUN was 16 grams.
A reasonable estimate of her protein needs (the amount needed
to be in protein balance) is (A) 185 g/day. (B) 125 g/day.
(C) 80 g/day.
Read pp. 1126-1136 in Devlin.
To prepare for next lecture on macronutrients
and the clinical correlation on malnutrition,
read Devlin pp. 1097-1111, and
1059-1090, and work problems 6-17 on p. 1112
and 1-16 on p. 1090.
Other references: Voet & Voet pp. 730-739.
The vitamins are organic molecules that the body requires in small amounts for
its metabolism,
yet cannot make for itself at least in sufficient quantities.
In these sections, we describe the major vitamins known today, the nature of
their biological effects, the coenzymes in which the vitamins are essential
components, and examples of coenzyme function in specific enzyme catalyzed
reactions.
Thiamine, Riboflavin, Niacin, Pyridoxine, Pantothenic acid, Biotin:
Because these vitamins are cofactors to enzymes in energy metabolism,
deficiencies show up in quickly growing tissues such as epithelium.
Typical symptoms for this whole group include:
- DERMATITIS
- - inflamation of the skin
- GLOSSITIS
- - inflamation of the toung (swollen, red)
- CHEILITIS
- - (kil it'tis) inflamation of lips as in angular stomatitis
- DIARRHEA
- - inflamation of intestinal epithelium
Nerve cells use lots of energy, so symptoms also show up in nervous tissue:
- PERIPHERAL NEUROPATHY
- - tingling of nerves at extremities
- DEPRESSION
- MENTAL CONFUSION
- LACK OF MOTOR COORDINATION
- MALAISE
- - vague feeling of bodily discomfort
Coenzyme form: thiamine pyrophosphate.
- Biochemical functions promoted:
- Thiamine pyrophosphate serves as
coenzyme for two classes of enzyme-catalyzed reactions in which
aldehyde groups are removed and/or transferred.
- Deficiency:
- Thiamine deficiency in humans is called beriberi. It
is characterized biochemically by accumulation of pyruvic and lactic
acid in body fluid. There is impairment of the cardiovascular,
nervous, and gastrointestinal systems. Beriberi can be separated
into three forms:
- wet beriberi
- - generalized edema, acute cardiac symptoms and
prompt response to thiamine administration.
- dry beriberi
- - edema not present, neurological disorders are
present. The condition is similar to peripheral neuritis.
- infantile beriberi
- - seen in infants under 6 months of age
receiving inadequate thiamine in milk. In acute form, the
infant develops dyspnea and cyanosis and dies of cardiac
failure. Aphonia may be present and the infant may appear to be
crying without emitting much sound. Diarrhea, wasting, vomiting
and edema may be present.
- Wernicke-Korsakoff syndrome
- is the most common CNS-related neurological
problem in alcoholics. Characteristic findings include weakness of eye
movement, ataxia of gait and mental disturbance. The Wernicke syndrome
responds dramatically to thiamine administration.
Thiamine has also been successfully used to treat depression.
- Sources and requirement:
- Riches sources are pork, whole grain,
enriched cereal grains and legumes.
From 1.2 to 1.5 mg daily intake is recommended.
No known toxicity.
Coenzymes: nicotinamide adenine dinucleotide
(NADH) and nicotinamide adenine dinucleotide phosphate
(NADPH)
- Biochemical function promoted:
- Hydrogen atom and two-electron
transfer.
Coenzymes containing niacin are an essential part of enzyme systems
concerned with oxidation and reduction in living cells.
The co-factor NAD+, nicotinamide adenine dinucleotide,
NAD+ is a major carrier of electrons in the oxidation of fuel
molecules. The reactive site is the carbon atom para- to the
positively charged nitrogen atom in the nicotinamide ring.
When a fuel molecule is oxidized, this reactive site accepts
a hydrogen atom and two electrons, forming the reduced
molecule NADH. (The other major carrier is FAD/FADH2.)
- Deficiency:
-
Pellagra is the disease caused by niacin deficiency.
The disease involves the skin (photosensitivity),
gastrointestinal tract and central nervous system. It progresses
through dermatitis, diarrhea, depression and death.
Pellagra was endemic in the southern United States (and many other
parts of the world) in the early 1900s, particularly among children.
It was found to be a dietary deficiency by Joseph Goldberger,
a U.S. Public Health Service physician at about the time of the first
world war.
Pellagra was carried to europe in the years following Columbus' discovery
of the new world as maize (corn) was discovered and became the staple
for Europe's poor.
- Sources and requirement:
- Rich sources include meat,
peanuts and legumes,
whole grain and enriched breads and cereals. Part of the niacin
requirement is met by synthesis of niacin from tryptophan.
Corn is poor in niacin and tryptophan.
The allowance recommended for an adult of niacin is 6.6 mg per 1000
kcal and not less than 13 mg at caloric intake of less than 2000
kcal. Niacin is relatively nontoxic.
It can impare liver function in high dosages of time-release
formulations. It acts as a vasodilator.
Coenzymes: Flavin mononucleotide (FMN) and
flavin adenine dinucleotide (FAD)
- Biochemical function promoted:
- Hydrogen atom (electron) transfer.
Like nicotinamide nucleotides, the flavin nucleotides are 2 electron
carriers.
- Deficiency:
-
Riboflavin deficiency usually occurs with a deficiency
of other members of the B-complex. Ocular symptoms, such as eye
strain and fatigue, itching, burning, and sensitivity to light may
precede other symptoms. Characteristic lesions of the lips, the most
common of which are angular stomatitis and cheilosis (cracks at the
corners of the mouth). Localized seborrheic dermatitis of the face
may result. Behavioral changes have been reported.
- Sources and requirements:
- Rich food sources include liver, meat,
eggs green leafy vegetables, enriched and whole grain breads and
cereals.
The allowance recommended for adults is 0.6 mg /per 1000 kcal and
not less than 1 mg per day to maintain tissue saturation. No
evidence of toxicity.
Coenzyme form: Coenzyme A (CoA)
- Biochemical function promoted:
- Acyl-group transfer. Involved in
fatty acid oxidation, fatty acid synthesis, pyruvate oxidation and
biological acetylations.
- Deficiency:
- Dietary deficiency of pantothenic acid has not been
clinically recognized. Deficiency can be induced by metabolic
antagonists. Symptoms in pantothenic acid deficiency include
fatigue, sleep disturbance, personality changes, nausea, abdominal
distress, numbness and tingling of hands and feet muscle cramp, and
impaired coordination.
- Sources and requirement:
- Pantothenic acid is readily available
in most food.
A daily intake of 5 to 10 mg is thought to be adequate. No evidence
of toxicity.
Coenzyme: lipoamide
- Biochemical function promoted:
- Hydrogen atom and acyl-group
transfer.
- Deficiency:
- unknown
- Sources and requirement:
- lipoic acid is ubiquitous and no recommended
allowance has been established.
Coenzyme: Biocytin
- Biochemical function promoted:
- carrier of activated CO2 (carboxyl
transfer) Part of the enzyme systems participating in conversion of
pyruvate to oxaloacetate (gluconeogenesis) and in fatty acid
synthesis.
- Deficiency:
-
Experimentally induced biotin deficiency is
characterized by hair loss (alopicia), dermatitis,
atrophy of lingual papillae, muscle pain, paresthesias,
hypercholesterolemia, and electrocardiogram abnormalities.
Nutritional biotin deficiency is rare, but is observed
in patients on long term high dose antibiotics,
total parenteral nutrition
without biotin suplementation, and in people who consume
large amounts of raw eggs. Raw egg white induces a biotin deficiency
because it contains a protein, avidin, which specifically binds
biotin very tightly and prevent its absorption from the intestine.
Two types of biotin related dermatitis,
Leiner's disease and seborrheic
dermatitis (occurs in infants) respond to biotin therapy.
- Sources and requirement:
- Biotin is present in most food and is
synthesized by the intestinal flora. A recommended allowance has not
been established. Biotin has no toxicity.
Coenzyme forms: pyridoxal phosphate and
pyridoxamine phosphate
- Biochemical functions promoted: Amino-group transfer.
Vitamin B-6 is
involved in the synthesis and catabolism of amino acids, synthesis
of neurotransmitters, porphyrins and niacin. PLP enzyme catalyzes
transaminations, decarboxylations, deaminations, racemizations and
aldol cleavages. PLP enzymes form covalent Schiff-base intermediates
with their substrate, the aldehyde group of PLP is in Schiff-base
linkage with the epsilon-amino
group of a specific lysine residue at the
active site. The amino acid-PLP Schiff base that is formed remains
tightly bound to the enzyme.
- Deficiency:
- Three different types of symptoms can be observed in
vitamin B-6 deficiency:
- neuropathic: due to insufficient neurotransmitter synthesis.
- anemic: due to low porphyrin synthesis
- pellagrous: due to low endogenous niacin synthesis.
Genetic diseases involving pyridoxal phosphate enzymes may require
treatment with large quantity of vitamin B-6
(e.g. subtype of homocystinuria).
- Sources and requirement:
- Vitamin B-6 is widespread in nature.
Rich sources include yeast, whole wheat, corn, egg yolk,
liver and lean meat.
Firm requirement for vitamin
B-6 has not been established.
Recommended
daily requirement for adults is about 2 mg per day. Toxicity in
humans has been described when taken at extremely high doses.
Folic acid, B-12;
Hematopoiesis, development of blood cells.
Coenzyme form: tetrahydrofolic acid
- Biochemical function promoted:
- Tetrahydrofolate derivatives
serve as donors of one-carbon units in a variety of
biosynthesis.
Various one-carbon tetrahydrofolate derivatives are used in
biosynthesis reactions. They are required in the synthesis of choline,
serine, glycine, methionine, purines and dTMP. Since adequate amounts
of choline and amino acids can be obtained in the diet, the
participation of folates in purine and dTMP synthesis appears to be
metabolically most significant. The folate dependent conversion of
homocysteine to methionine makes a significant contribution to the
methionine pool. Methionine is converted to S-adenosylmethionine which
is used in a number of biologically important methylation reactions.
- Deficiency:
-
The most pronounced effect of folate deficiency is
inhibition of DNA synthesis due to decreased availability of purines
and dTMP. This leads to an arrest of cells in S phase and a
characteristic "megaloblastic" change in the size and shape of the
nuclei of rapidly dividing cells. This block in DNA synthesis slows
down the maturation of red blood cells, causing production of
abnormally large "macrocytic" red blood cells with fragile membranes.
The rapid hemolysis of these macrocytes leads to a hemolytic anemia.
A macrocytic anemia associated with megaloblastic changes in the bone
marrow is fairly characteristic of folate deficiency. Deficiencies are
often induced by anti-cancer drugs such as aminopterin and
methotrexate.
Recent epidemiological studies predict that
between 50% and 70% of the birth defects in this country could
be eliminated if all pregnant women took folic acid supplements
during pregnancy. The average diet includes only about half
the required amount.
- Sources and requirement:
- Rich sources include green leafy vegetables,
liver, kidney, lima beans, asparagus, whole grain cereals, nuts,
legumes and yeast.
The minimum need for adults is believed to be approximately 0.05 mg per
day. Higher levels are recommended for children and during pregnancy.
No toxicity has been observed.
The crystalline forms of B-12 used in
supplementation are usually hydroxocobalamin or cyanocobalamin.
In food B-12 (extrinsic factor)
usually occurs bound to protein in the
methyl or 5'-deoxyadenosyl forms.
To be utilized the B-12 must first
be removed from the protein by acid hydrolysis in the stomach or
trypsin digestion in the intestine. It then must combine with
"intrinsic factor", a glycoprotein secreted by the stomach, which
carries it to the ileum for absorption. Patients with pernicious
anemia lack the intrinsic factor. Pernicious anemia in elderly
patients may be caused by lack of gastric acid.
- Biochemical functions promoted:
- Catalyzes 1,2 shift of hydrogen atoms ( methylmalonyl CoA mutase
catalyzed conversion of methylmalonyl CoA to succinyl CoA, the
coenzyme is the methyl derivative of B-12 )
- Transfer of methyl-group
from N5-methyl tetrahydrofolate to homocysteine
to form methionine (coenzyme form is the 5'-
deoxyadenosyl derivative).
- Deficiency:
- In man there are two major symptoms
associated with B-12 deficiency, hematopoietic and neurological.
- Sources and requirement:
- Best sources are liver, kidney, whole milk,
eggs, oyster, shrimp, pork and chicken.
Plants cannot synthesize B-12.
Intestinal bacteria can synthesize B-12,
but the site of synthesis does not allow absorption.
The recommended amount in the diet is 3 mg per day of which about 50%
is absorbed.
- Biochemical functions promoted:
- The main biological role of vitamin C
appears to be as a reducing agent in a number of important hydroxylation
reactions in the body.
- Ascorbic acid is required for the hydroxylation of proline and lysine on
the polypeptide chains of protocollagen. Without the hydroxylation of
these amino acids, the protocollagen is unable to properly cross-link
into normal collagen fibrils. Collagen is the major connective tissue
in the body. It is also a component of the organic matrix for bone
tissue as well as a component of the ground substance surrounding
capillary walls.
- Vitamin C is required for the hydroxylation reactions in the synthesis
of steroids, and epinephrine. The concentration of ascorbic acid is
high in the adrenal gland especially during periods of stress.
- Ascorbic acid acts as a reducing agent in non-enzymatic reactions: e.g.,
it aids in absorption of iron by reducing it to ferrous state in the
stomach, it spares vitamin A, vitamin E and some B vitamins by
protecting them from oxidation, and it enhances the utilization of folic
acid by aiding the conversion of folate to tetrahydrofolate.
- Deficiency:
-
Most of the symptoms of vitamin C deficiency can be directly
related to its metabolic roles. Symptoms of mild vitamin C deficiency
include ecchymoses (large areas of bleeding into the skin),
corkscrew hairs,
and the formation of petechiae (small pinpoint
hemorrhages in the skin) due to increased capillary fragility. These
symptoms can be explained by weaken collagen fibrils. Severe deficiency
results in scurvy.
Scurvy itself is associated with decreased wound
healing, osteoporosis, hemorrhaging, bleeding into the skin
(petichiae and ecchymoses),
anemia, and friable bleeding gums with
loosened teeth (gingivitis). A child with scurvy may prefer
to lie on its back with legs and arms layed out in the so
called ``frog position'' because of pain in joints.
The osteoporosis results from the inability
to maintain organic matrix of the bone followed by demineralization. The
anemia results from the extensive hemorrhaging coupled with defects in iron
absorption and folate activation.
- Sources and requirement:
- Fruits, especially citrus fruits, tomatoes and
green vegetables are rich sources of vitamin C.
An intake of 30 mg per day is sufficient to replenish the quantity of
ascorbic acid metabolized daily. An intake of 45 mg per day maintains an
adequate body pool. There is some uncertainty over the need for vitamin C
in periods of stress and trauma. Smoking has been shown to cause lower
serum vitamin C. Aspirin appears to block uptake of vitamin C by
platelets. Oral contraceptives and corticosteriods also lower serum levels
of vitamin C. The possibility of marginal C deficiencies should be
considered with any patient under these circumstances.
Large doses of vitamin C (0.5 to 5 gm per day) have been claimed to reduce
the discomfort caused by the common cold. The claim is substantiated
in a few double-blind studies. The number of colds experienced by vitamin
C supplemented groups appears to be the same as the control groups, but the
severity and the duration of the colds were significantly decreased.
Megadoses of vitamin C have not been shown to be harmful except for the
potential of formation of oxalate kidney stones in predisposed individuals.
Oxalate is a major metabolite of ascorbic acid.
Read Devlin pp. 1097-1111, and
1059-1090.
Work problems 6-17 on p. 1112
and 1-16 on p. 1090.
- Enterocyte:
- Most digestion occurs from pancreatic enzymes acting in the small intestine.
Final digestion occurs from enzymes bound to the luminal membrane of
epithelial cells in the small intestine called enterocytes.
Parasites such as Giardia lablia and other factors can damage
the enterocyte membrane, causing malabsorption of
many nutrients that can lead to malnutrition.
- Microvilli, Brush Border:
- The surface area of each enterocyte is increased by tubular projections
of the membrane called microvilli.
Under the microscope they give the cell border a brush like appearance.
- Exocrine secretion:
- Salivary glands, gastric mucosa (stomach), and the pancreas contain
cells that secrete enzymes into the lumen. Refer to figures 26.2 and
26.3 in Devlin.
- Zymogens:
- Inactive precursors of proteases and phospholipase A
called zymogens are produced and stored in
zymogen granules.
These granules fuse with the plasma membrane to release
their secretory proteins in a process called exocytosis.
- Secretagogues:
- The secretion of enzymes and electrolytes is regulated through the
binding of secretagogues to receptors on the contraluminal surface of
exocrine cells. Examples are: acetylcholine, histamine, gastrin, and
cholecystokinin (secretin).
Cholera toxin
secreted by Vibrio cholerae is a secretagogue that does not bind to
a cell receptor.
Acetylcholine is the major secretagogue, causing secretion in the
salivary gland, stomach, and pancreas.
Figure below - The Gastrointestinal Tract:
See also figure 26.1 in Devlin.
Chewing and crushing moistens protein-rich foods and mixes
them with saliva to be swallowed.
The salivary glands add water to disperse
and carry food.
Stomach acid uncoils protein strands and activates
stomach enzymes such as pepsin that partly cleave proteins
to smaller polypeptides.
Intrinsic factor attaches to vitamin B-12.
Stomach acid (HCL) acts on iron to reduce
it, making it more absorbable.
The stomach secretes watery fluid.
Pancreatic and small intestinal enzymes split
polypeptides further into dipeptides, tripeptides, and amino acids.
Then enzymes on the surface of the small intestinal cells hydrolyze
these peptides and the cells absorb them by carrier mediated transport.
There are at least five different transport systems for L-amino acids:
one for neutral, basic, imino and glycine, acidic,
and beta-amino acid side chains.
Bile emulsifies fat-soluble vitamins and aids in their
absorption with other fats.
Water-soluble vitamins are absorbed.
The small intestine, pancreas, and liver
add enough fluid so that the total secreted into the intestine in a
day approximates 2 gallons.
Many minerals are absorbed.
Vitamin D aids in the absorption of calcium.
Bacteria in the colon produce vitamin K, which is absorbed.
More minerals and most of the water is absorbed in the colon.
Fetal and neonatal small intestines can absorb intact proteins,
including maternal antibodies contained in the colostrum
by endocytosis or pinocytosis.
Figure below - Human protein metabolism for one day:
(1) Absorption of free amino acids and peptides;
(2) uptake of dietary amino acids by liver;
(3) synthesis of liver and plasma proteins, especially albumin;
(4) catabolism of excess amino acids;
(5) distribution of amino acids to other organs;
(6) uptake by muscle, pancreas, epithelial cells;
(7) excretion of amino acid nitrogen in various forms.
(from Linder, 1991)
Essential amino acids:
Any (arg) help (his) in (ile) learning (leu) these (thr) little (lys)
molecules (met) proves (phe) truly (trp) valuable (val).
The salivary glands
secrete a watery fluid into
the mouth to moisten the food.
The salivary enzyme amylase begins
digestion: Starch -> Small polysaccharides and maltose.
Digestion of starch continues as swallowed food moves down esophagus.
Stomach acids and enzymes start to digest
salivary enzymes, halting starch digestion. To a small extent,
stomach acid hydrolyzes maltose to glucose
and Sucrose to glucose and fructose.
The pancreas produces carbohydrates and releases
them through the pancreatic duct into the small intestine:
Pancreatic amylase catalyzes the breakdown of
polysaccharides to maltose.
Enzymes on the surface of the small intestinal cells break
these into monosaccharides and the cells absorb them.
Most fiber passes intact through the digestive tract to the large
intestine (colon).
Here, bacterial enzymes digest some fiber to glucose which is absorbed.
Fiber holds water, regulates bowel activity, binds cholesterol and
some minerals, carrying them out of the body.
Figure below: Absorption and distribution of carbohydrate.
Everything passes into the liver, but some glucose passes through
the liver and into the peripheral circulation.
This releases insulin from the pancreas and lowers the secretion
of glucagon. Insulin stimulates uptake of glucose from the blood
by muscle and adipose cells. In the liver, glucose is trapped by
phosphorylation to G6P, which is then converted to glycogen and
also used for energy in glycolysis and the TCA cycle.
Excess glucose is converted into fatty acids and incorporated into
triglyceride. This glucose-derived fat is sent for storage
to adipose tissue via VLDL.
Abbreviations: CHO, carbohydrate; G6P, glucose-6-phosphate;
G1P, glucose-1-phosphate; UDPG, uridine diphosphate glucose;
VLDL, very low-density lipoprotein; FFA, free fatty acids; TG, triglyceride:
Figure below: Carbohydrate metabolism in early fasting.
(1) Decreased plasma glucose stimulates release of glucagon
from the pancreas (and decreases secretion of insulin);
(2,3) glucagon goes to the liver and stimulates breakdown of glycogen via cAMP;
(4) decreased insulin also enhances breakdown of muscle glycogen leading to its utilization for energy by muscle cells in glycolysis and the TCA cycle
(exercise and catecholamines have the same effect,
also beginning the release of free fatty acids from adipose cells;
(5) breakdown of liver glycogen results in dephosphorylation of
glucose-6-phosphate which allows release of glucose into the blood to maintain
blood glucose concentrations. Blood glucose is needed especially by
the central nervous system and by blood cells.
Glands in the base of the tongue
secrete a lipase known as lingual lipase.
The lingual lipase hydrolyzes one bond of triglycerides to
produce diglycerides and fatty acids - slight for most fats
appreciable for milk fats.
The stomach's churning action mixes fat with water and acid.
A gastric lipase accesses and hydrolyzes a very little fat.
Bile flows in from the liver (via the common bile duct) to emulsify fat.
Pancreatic lipase flows in from the pancreas to turn
emulsified fat into monoglycerides, glycerol, and fatty acids.
Some fat and cholesterol, trapped in fiber, exits in feces.
Figure below: Disposal of dietary fat after a meal.
Nutritional deficiency diseases can be classified as primary and secondary.
- Primary deficiency disease:
- Disease that results directly from dietary lack
of a specific essential nutrient. For example, scurvy results if the diet is
deficient in vitamin C; beriberi results if the diet is deficient in thiamine.
- Secondary deficiency disease:
- A disease that results from the inability of the
body to use specific nutrients properly. Such inability may result from (1)
failure to absorb the nutrient from the alimentary tract into the blood (e.g.,
malabsorption syndrome) or (2) failure to metabolize
the nutrient normally after it has been absorbed (e.g., phenylketonuria).
- Extent of malnutrition:
- Widespread, especially in developing nations with
rapid population growth. Results of survey studies in US showed one of
six persons have low serum protein (protein malnutrition), one-third
children under 6 had low blood hemoglobin levels and signs of vitamin
deficiency, 4% of children under 6 had signs of vitamin D deficiency,
serum vitamin C levels were found in 12% of all age groups.
Several studies of the nutritional status of patients in American
hospitals since 1974 have found protein-calorie malnutrition in 40 to
50% of patients on general medicine and surgical wards.
One study in 1979 found a deterioration of the nutritional status of
69% of the patients who remained hospitalized for more than two weeks.
These problems were seen again in a 1990 study. (Weinseir, R.L.
and Morgan, S.L., (1992) ``Fundamentals of
Clinical Nutrition,'' Mosby, St. Louis)
- The ecology of malnutrition:
- Many factors work together to produce malnutrition.
A disease caused by malnutrition may exist in many varieties. It is
often complicated by the presence of other diseases, such as tuberculosis, or
intestinal parasites. A synergism is known to exist between malnutrition and
infection. Each compounds the other, and together they cause more serious
illness than either alone. For example, measles and infectious diarrhea could
be fatal in a severely malnourished child. Some of the related causes of
malnutrition are:
a lack of food quantity or quality;
the presence of other disease;
increased dietary needs during growth, pregnancy, lactation, injury, etc.;
congenital defects - premature birth or anatomic defects;
personal factors such as ignorance of food needs or food values,
carelessness, emotional problems, poor eating habits, etc.;
and environmental factors, including sanitary, cultural, social,
psychological, economic, political, agricultural, and medical factors.
Millions of children throughout the world
are exposed to various degrees of potential malnutrition which causes a
high rate of morbidity and death. In protein-calorie malnutrition a broad
clinical spectrum exists between kwashiorkor on one hand and marasmus on
the other, with many continuous overlapping conditions in between where
features of both are found.
Malnutrition state in which the diet supplies adequate
calories as carbohydrate, but the protein content is qualitatively and
quantitatively inadequate. Kwashiorkor is usually seen in children in the
post-weaning years, ages 1 to 4. Kwashiorkor occurs in tropical and
subtropical areas usually in regions where economic, social and cultural
factors combine to make sufficient protein unavailable to the child. The
word kwashiorkor comes from the Ghanian language meaning
``the sickness the
older child gets when the next baby is born.'' The name is appropriate,
for kwashiorkor is the syndrome that develops in a child who, after being
weaned from the breast at about 1 year, on the birth of the next sibling,
is given a diet consisting largely of starchy gruels or sugar water. The
sharply curtailed diet, based on carbohydrates results in protein
deficiency. Note: An identical situation exists in hospitalized patients
being fed via I.V. glucose.
- General symptoms:
-
The classical syndrome comprises retardation of growth
and development with peevishness, mental apathy, edema, muscular wasting,
depigmentation of hair and skin, characteristic scaly change of skin
texture, hypoalbuminemia, reversible fatty infiltration of liver, atrophy
of the acini of the pancreas with the reduction of enzyme activities of
the duodenal juice, diarrhea, and moderate anemia. Frequently associated
are infections and severe vitamin A deficiency, resulting in permanent
blindness. Serious deterioration of patients with kwashiorkor is caused
by infections and diarrhea.
- Metabolic disturbances:
- A consistent characteristic of kwashiorkor is the
disturbance in water and electrolyte balance. Total body water
increases, and there is marked reduction of total body potassium and
retention of sodium. Factors probably responsible for these fluid and
electrolyte disturbances are hypoalbuminemia, endocrine dysfunction, and
circulatory failure.
An abnormal blood lipid transport in kwashiorkor patients may account
for the vitamin A deficiency which characterizes this syndrome. An
extreme protein depletion reaches different degrees in different organs
and tissues. Those tissues with faster protein turnover (such as the
mucosa and secretory glands in the gastrointestinal system) are affected
most. Protein concentrations important to metabolic function, as in blood
plasma, are greatly disturbed, and there is an extreme decrease in plasma
free amino acids.
- Treatment:
- In severe cases, the following course of treatment is used:
- correction of water and potassium depletion and transfusion of blood and
plasma on the first day;
- skimmed milk at a dilution of 10 calories
per 30 ml be given for about a week at spacings and intervals to provide
a total intake of 50 gm of protein per day (l50 gm dried skimmed milk);
- the caloric content of the diet is increased by addition of mixed
food suitable for the child's age, which also supplies sufficient vitamins
and minerals.
The word marasmus comes from the Greek word ``marasmos'', which
means wasting. It is applied to the state of chronic total
undernutrition in children, which represents a deficiency of both
protein and calories invarious severity and produces a gradual wasting
away of body tissue. Marasmus is most common in infants 6 to 18 months
of age. It occurs in slum conditions in any country (including the US).
- General symptoms:
-
Marasmus is characterized by gross underweight.
There is atrophy of muscle mass and subcutaneous fat. Edema is
minimal or absent. Diarrhea is common. It may result from
infection or from pathogenic microorganisms in the stools, or there
may be preexisting nutritional diarrhea complicated by superimposed
infection. Growth rate declines progressively; there is both
physical stunting and mental and emotional impairment. Body
temperature may be subnormal, the heart is weak and urine scanty,
prostration is common.
- Metabolic disturbances:
- Little or no water retention is present.
Potassium and sodium depletion may occur if diarrhea persist. Serum
protein levels are diminished. As general wasting occurs and
metabolism approaches basal levels, the liver suffers acute and
severe protein depletion and loss of its amino acid pool.
- Treatment:
- As in kwashiorkor, first correct the electrolyte
imbalance followed by a gradual feeding program.
M.C. Linder ``Nutritional Biochemistry and Metabolism'' (M.C. Linder,
ed.) Elsevier, New York, NY, 1991.
Whitney, E.N., Cataldo, C.B. and Rolfes, S.R. ``Understanding Normal
and Clinical Nutrition'', West Publishing Co, New York.
Gornall, A. G. ``Applied Biochemistry of Clinical Disorders''
Harper & Row, Hagerstown, MD, 1980.
The active forms of vitamin A are retinol, retinaldehyde, and
retinoic acid. These substances are synthesized by plants as the more
complex carotenoids which is cleaved to retinol by most animals and stored
in the liver as retinol palmitate.
- Biochemical functions promoted:
- Only in the case of vision is the biochemistry well understood.
Vitamin A becomes reversibly associated with the visual pigments in the
D11-cis-retinal form.
When light strikes the retina, a number of
biochemical changes take place, resulting
in a nerve impulse, conversion of the retinal
to the all-trans form, and dissociation from the visual pigment.
Regeneration of more visual pigment requires isomerization back to
the D11-cis-form.
Some of this material can be regenerated in a slow process in the
retina and by other pathways involving retinal reductase in the eye
and retinal isomerase in the liver.
Other important metabolic roles have been identified to require
vitamin A; they are bone development and cell growth, reproduction, health
of epithelial cells, and maintaining stability of cell membranes.
Carotenoids appear to lower the risk of getting cancer.
- Deficiency:
-
Since vitamin A is stored in the liver, deficiencies of
this vitamin can develop only over prolonged periods of inadequate
uptake. Mild vitamin A deficiencies are characterized by follicular
hyperkeratosis (rough keratinized skin resembling "goosebumps"), anemia
and increased susceptibility to infection.
Night blindness is also an early symptom.
Severe vitamin A deficiency leads to progressive
keratinization of the cornea of the eye. This condition is known as
Bitot's spots in its mildest form (localized spots), xerosis
conjunctivae in moderately severe form and xerophthalmia in its most
advanced stages. In final stages, infection usually sets in, with
resulting hemorrhaging of the eye and permanent loss of vision.
- Absorption and Metabolism:
- Both vitamin A and carotenoids are fat
soluble. Preformed vitamin A in food is usually present as retinyl
palmitate which has to be hydrolyzed by pancreatic enzymes before
absorption by the intestinal mucosa cell as retinol. The carotenoids are
absorbed intact in the presence of bile salts and are converted to
retinol by a cleavage enzyme in the intestinal mucosa cell. The retinol
is then esterified with palmitic acid in the intestinal mucosa cells,
and the retinyl palmitate is then incorporated in chylomicrons and
carried into the blood stream via the thoracic duct. Retinyl palmitate
is stored in the liver.
- Figure below - Mechanism of vitamin A absorption and hormone action.
- Key: RBP, retinol binding protein; CRBP, cellular retinol binding protein;
CRABP, cellular retinoic acid binding protein;
Rx, retinoid receptor; RAR, retinol (or retinoid) receptor;
IBRP, retinoid binding protein in retina; CM, chylomicrons;
RApoE, receptor for CM remnants;
TTR, transthyretin; +, stimulates transcription.
- Sources and requirement:
- Preformed vitamin A is available only in
animal products which include liver, kidney, cream, butter, and egg
yolk. The major dietary sources of the provitamin is yellow and green
vegetables and fruits.
Recommended allowance for vitamin A is 1000 retinol equivalents for
adult males and 800 retinol units for adult females. One retinol
equivalent is defined to be equal to 1 mg of retinol or 6 mg of b-
carotene or 12 mg of other provitamin A carotenoids. Requirements are
different for infants, children, pregnant and lactating women.
Doses of 15,000 to 50,000 retinol equivalents per day of preformed
vitamin A over a period of months or a single dose of 350,000 IU have
been proved to be toxic for children and adults. The usual symptoms
include headache, dizziness, nausea, vomiting, diarrhea, scaly
dermatitis, enlargement of liver and spleen, and hydrocephalus
(abnormal accumulation of fluid in the cranial cavity, results in
enlargement of the head, atrophy of the brain and convulsion).
Excessive intake of carotenes (carotenoids) does not appear to be harmful even though
it may result in deposition of yellow pigments in the soles of the
feet, palms of the hands, and nasolabial folds.
Because of the toxicity that can be induced by high concentrations of
vitamin A, the FDA has imposed a ceiling of 2000 retinol equivalents or
l0,000 IU (international units) on the amount of vitamin A that can be
included in a multivitamin preparation available without prescription.
Vitamin K is found naturally as K1
(phytylmenaquinone) in green vegetables, and K2
(multiprenylmenaquinone),
which is synthesized by intestinal bacteria. The body is also able to
convert synthetically prepared menaquinone (Menadione) to biologically
active K1.
- Biochemical function promoted:
- Vitamin K1 has been shown to be required
for the conversion of several clotting factors and prothrombin to the
active state. Prothrombin is synthesized in an inactive form.
Conversion to the active form requires a vitamin K-dependent
carboxylation of certain glutamic acid residues to gamma-carboxyglutamic
acid. The gamma-carboxyglutamic acid residues are good chelators and allow
prothrombin to bind calcium. The prothrombin: Ca+2 complex in turn
binds to the phospholipid membrane, where proteolytic conversion to
thrombin can occur. The mechanism of the carboxylation reaction
appears to involve the intermediate formation of a 2,3-epoxide
derivative of vitamin K. Dicumarol, a naturally occurring
anticoagulant, may inhibit the reductase which converts the epoxide
back to the active vitamin.
- Figure below - Involvement of vitamin K in blood clotting and
gamma-carboxylation.
- AAs are amino acids. Vitamin K-dependent
gamma-carboxylation of glutamate residues results in a high
affinity of the proteins for Ca2+. This Ca2+ is important
for the function of these proteins. (from Linder)
- Deficiency:
-
The only known symptom of vitamin K deficiency in man is
increased coagulation time. The most common deficiency is seen in
newborn infants when the intestinal flora have not been established.
Vitamin K deficiency is also seen in patients with obstructive jaundice
and other diseases leading to severe fat malabsorption and patients on
long-term antibiotic therapy (which may destroy vitamin K synthesizing
bacteria in the intestine). Vitamin K deficiency should be suspected
in any patient demonstrating easy bruising and prolonged clotting time.
As with vitamin C, deficiency can result in petichiael bleeding,
but other signs of scurvy, such as corkscrew hairs, impacted
hair follicles, pain in joints (frog position), are missing.
- Sources and requirement:
- The synthesis of vitamin K by intestinal
bacteria and levels obtained in a diet from vegetables normally
supplies sufficient vitamin K. Rich sources include green leafy
vegetables.
No daily allowance of intake of vitamin K is recommended. Adults are
believed to required 0.3-l5 mg/kg/day. A daily of 0.2 mg appears to be
adequate for newborn. No toxicity of vitamin K has been demonstrated.
Cholecalciferol (vitamin D3) is produced in the skin
by ultraviolet irradiation of 7-dehydrocholesterol,
a normal metabolite of cholesterol.
Figure below - metabolism and function of vitamin D3.
Cholecalciferol is transported in the blood (bound to a specific transport
globulin), and it is taken up and stored in the liver.
A 25-hydroxylase in
the endoplasmic reticulum hydroxylates cholecalciferol
to form 25-hydroxycholecalciferol (25-(OH)D3).
The 25-(OH)D3 is carried by the same transport
globulin to the kidney.
The kidney contains both a 1 alpha- and a 24-hydroxylase
that act on 25-(OH)D3.
l alpha,25-dihydroxycholecalciferol (l,25-(OH)2D3) is
physiologically active, whereas 24,25-dihydroxycholecalciferol
(24,25-(OH)2D3) is inactive,
and 1,24,25-trihydroxy-derivative is less active.
The synthesis of the 1,25-(OH)2D3 in the kidney
is stimulated by low calcium and/or low phosphate levels in the blood.
High calcium levels cause the synthesis of 24,25-(OH)2D3.
- Biochemical functions promoted:
- The 1,25-(OH)2D3 is carried through
the blood to target cells by the cholecalciferol-transport protein.
The apparent action of the compound is to promote the transcription
of genes that facilitate transport of calcium and phosphate ions.
1,25-(OH)2D3 acts in concert with parathyroid hormone (PTH), and
calcitonin, which is produced in response to low serum calcium. Once
l,25(OH)2D3 is formed, it acts alone as a typical steroid hormone in
intestinal mucosa cells, where it induces synthesis of a calcium binding
protein required for calcium transport. In the kidney, PTH causes
increases in the activity of 1-alpha-hydroxylase
that produces 1,25(OH)2D3,
and it increases the absorption of calcium from the glomerular filtrate
and decreases the absorption of phosphate. In the bone 1,25-(OH)2D3 and
PTH can act synergistically to promote resorption (demineralization).
The response to low serum calcium levels is characterized by elevation
of PTH and 1,25(OH)2D3, which act to stimulate resorption of calcium
by the kidney, loss of calcium from bone,
and inhibit calcium excretion. High serum calcium levels cause
production of the hormone calcitonin, which inhibits bone resorption and
enhances calcium excretion. High levels of serum calcium and phosphate
increase the rate of bone mineralization. The bone serves as a
reservoir of the calcium and phosphate needed to maintain homeostasis of
serum levels.
- Deficiency:
-
When exposure to sunlight is inadequate and dietary intake
is restricted, deficiency in vitamin D occurs. The major symptoms of
vitamin D deficiency are rickets in young children and osteomalacia in
adults. Rickets is characterized by deficient calcification of the bones
resulting in deformation of bones - bow legs, knock-knees, deformities
of ribs, etc. Osteomalacia is characterized by accumulation of
uncalcified osteoid tissue in the rib joints.
- Sources and requirement:
- Rich sources of vitamin D include fatty fish,
eggs, liver, butter, cod-liver and other fish-liver oils. Milk is a
poor source unless fortified. Because vitamin D is normally synthesized
from cholesterol, irradiation of skin with sunlight ensure an adequate
daily human supply.
The minimum requirement for vitamin D has not yet been established. An
uptake of 100 IU (One international unit of vitamin D equals 0.025 mg
cholecalciferol) per day is sufficient in infants although 300-400 IU of
vitamin D per day promote better calcium absorption and some increase in
growth. Thus, the recommended daily allowance is 300-400 IU.
Ingestion of vitamin D in excess of the recommended amounts can be
harmful. Vitamin D is probably the most toxic of all vitamins. Infants
are especially sensitive to large doses of vitamin D. Daily doses equal
to 10 to 100 times the recommended amount may produce toxic symptoms
such as hypercalcemia, loss of appetite, retarded growth, nausea,
vomiting and deposition of calcium in many organs such as kidneys,
arteries.
During chronic overdose,
bones in general show a decrease in density and may break easily,
while density at the growth plates increases.
Very high doses for long period could be fatal.
Vitamin E occurs in the diet as a mixture
of several closely related compounds called tocopherols.
alpha-Tocopherol is the most potent.
- Biochemical functions promoted:
- Vitamin E appears to play an important
role as a naturally occurring anti-oxidant. Due to its lipophilic
structure it tends to accumulate in circulating lipoproteins such as
LDL, cellular membranes, and fat deposits, where it reacts very readily with
molecular oxygen and free radicals. It acts as a scavenger for these
compounds, protecting unsaturated fatty acids (especially those in
membranes) from peroxidation reactions. Because of its anti-oxidant
properties, vitamin E stabilizes coenzyme Q and enhances a number of
enzyme activities.
- Recent retrospective epidemiological studies
- have shown that
men and women who take at least 100 IU of vitamin E per day have
a 40% lower risk of major coronary disease than those who don't
(N Engl J Med 1993;328:1444-9, 1450-6).
100 IU is far above what can be obtained from a normal diet.
The significance of these results are difficult to exaggerate
in light of the following facts:
``Cardiovascular disease, including myocardial infarction
(heart attack) and stroke, is the major cause of death
in Western society, accounting for more than 50 percent of
all deaths in the United States, with 60 percent of deaths
in individuals 65 years and older. This death rate is
three times that from all forms of cancer.'' (M. C. Linder, 1991)
Considering the main results from the female nurses' study
and the male health professionals' study, (N Engl J Med 1993;328),
and that the total death rate in the US for 1992 was 2,177,000,
can you make some extrapolations about how many lives might
be saved or about how much the quality of life might be
improved every year as a consequence of all adults taking
100 mg of vitamin E per day?
- Figure below: superoxide anions
- are produced by the interaction of various oxidizable substrates and molecular
oxygen. Superoxide is either converted to peroxide (H2O2),
or interacts with peroxide to form radicals such as
or 
.These radicals can initiate chain reactions within cell membranes
involving the unsaturated fatty acid chains of the phospholipids.
Vitamin E inhibits these processes.
Symbols: GSH, glutathione (reduced); GSSG, glutathione (oxidized);
NADP+/NADPH, oxidized/reduced nicotinamide adenine dinucleotide phosphate;
MetHb, methemoglobin.
- Deficiency:
- Symptoms of vitamin E deficiency vary widely from one
animal species to another. In various animals vitamin E deficiencies
can be associated with sterility, muscular dystrophy, central nervous
system changes, and megaloblastic anemia. In humans, the symptoms are
limited to increased fragility of red blood cell membrane. Premature
infants fed on vitamin E deficient formulas often develop a form of
hemolytic anemia. Adults suffering from fat malabsorption show a
decreased red blood cell survival time, but seldom anemia.
- Sources and requirements:
- Rich sources of vitamin E include vegetable
oils, wheat germ oil, beef liver, milk, eggs, butter and leafy
vegetables. Absorption of vitamin E requires the presence of bile and
the bulk of vitamin E is transported to the bloodstream via the lymph
system.
The recommended allowance for vitamin E is 12-l5 IU for adults and
5 IU for infants. Large doses of vitamin E have not been found to be
toxic.
Reference: Schneider et. al., Chapter 3
Mineral and inorganic elements
may be divided into classes on the basis of either
function or the magnitude of the daily turnover.
Dietary minerals and inorganic
elements are generally divided into four classes.
- The essential
macronutrients are the bulk elements
which include the major electrolytes and the
constituents of bone and teeth.
The essential macronutrients are required in
amounts of 100 mg/day or more.
- The essential micronutrients are elements
required in amounts no more than a few mg/day.
Many of the essential micronutrients
are used in the body as prosthetic groups of enzymes.
- Some micronutrients
may be essential since animals deficient
of these nutrients develop abnormalities.
These group of elements include tin, nickel, silicon and vanadium.
- Elements present in the diet and in the environment as trace
contaminants include lead, cadmium, mercury,
arsenic, barium, strontium, and etc.
Many of these contaminants are toxic to humans.
Calcium, Phosphorus,
Sodium, Potassium, Chlorine, Magnesium, Sulfur
1-2 kg per adult - 99% found in the skeleton
- Physiological function for calcium
- Bone and teeth formation - about 600-700 mg Ca turned over daily.
- Required for normal neuromuscular irritability - transmission of
nerve impulses, release of neurotransmitter and muscle contraction all
require Ca. About 50% of Ca in the plasma is present in the ionized
form, the remainder are bound to plasma proteins and diffusible
compounds. Substantial reduction in serum Ca could result in tetany,
respiratory or cardiac failure. Substantial increase in serum Ca
could result in anorexia, nausea, vomiting, constipation, hypotonia
and depression.
- Required for blood clotting.
- Essential for maintenance of the integrity of intracellular structures
and various membrane functions, including transport.
- Necessary for the activation of certain enzymes including pancreatic
lipase and plasma lipoprotein lipase.
- Figure below - Nutrition and Metabolism of Calcium:
- Absorption is promoted by vitamin D-hormone, probably via
calcium-binding proteins. Transport is to all cells where
it participates in regulation,
and especially to the
Blood Ca++ levels
are kept within certain limits
through regulation by PTH, vitamin D, and thyroid-derived
calcitonin.
Mineralization and demineralization of bone involves activation
of osteoblasts and osteoclasts, respectively,
and production of inorganic phosphate (Pi) via alkaline phosphatase.
Amounts are mg/day. (from Linder)
- Absorption of Ca:
- Only about 20 to 40% of dietary Ca is absorbed.
Absorption of Ca from human intestinal tract is enhanced by acidic pH,
vitamin D, lactose, citric acid, and certain amino acids (lysine
and glycine). Absorption is inhibited by oxalate, phosphate, phytic
acid and fatty acids. Ca is present in feces, urine and sweat. Fecal
Ca is primarily unabsorbed dietary Ca. Urinary Ca reflects Ca
absorbed but not retained by the tissues.
- Sources and requirement:
- Among common food, milk and cheese are the
richest sources. Leafy vegetables, legumes, nuts and whole grain
cereal all contain Ca.
The recommended allowance for adults in the US is 800 mg per day.
Additional amounts should be allowed during growth, pregnancy and
lactation.
- Signs, symptoms of deficiency:
- paresthesias (pins and needles), increased neuromuscular excitability,
muscle cramps, tetany, and convulsions. Bone fractures and loss of height
may occur. These signs are not specific to a calcium deficiency, but
may also be the result of a vitamin D deficiency (osteomalacia).
Prolonged bed rest or immobilization can cause osteoporosis (loss of
bone mass) because of loss of calcium from bones and increased urinary calcium
excretion.
- Physiological functions for P:
- Bone and teeth formation
- Regulation of release and transfer of energy - Energy generated
by oxidation of carbohydrates, fat and amino acids are trapped in
the form of high energy phosphate bonds (i.e., ADP ATP; creatine
phosphate), this chemical energy is then used to performed work.
- Absorption and transportation of nutrients - Simple carbohydrates
(e.g. glucose) are trapped in the cell and metabolized in the
cells as phosphorylated intermediates. P containing lipids
(phospholipids) are required for transport of fat in chylomicrons
and lipoproteins.
- Components of essential metabolites - Phospholipids are
constituents of biomembranes. Phosphate is a part of nucleic acids
(DNA and RNA). Phosphate is also part of vitamin containing
coenzymes (e.g. TPP, NAD, NADP, FAD, etc.).
- Regulation of acid-base balance - Because of the buffering
capacity of phosphorylated compounds, they serve as important
blood and tissue buffer
- Absorption of P:
- Organic phosphates must be hydrolyzed before
absorption. This is accomplished in the intestinal tract by actions of
phosphatases and phosphodiesterases. Unabsorbed P (organic and
inorganic) can account for 30% of dietary P. The control of P in the
body is exercised through excretion in the urine. Ca and P are
influenced by the same metabolic factors and hormones. The
parathyroid, which regulates the level of blood Ca, also affects the
level of blood P and its rate of absorption from the kidney. Vitamin
D facilitates absorption of Ca and P from the gut and also increases
the rate of resorption from the kidney. In this way, the levels of Ca
and P, both needed for bone formation, are regulated simultaneously.
- Sources and requirement:
- Rich sources of P include fish, poultry, eggs,
cheese, and cereal products.
Since P is widespread, deficiencies only occur due to starvation or
malabsorptive state. Phosphate deficiency does occur in infants with
genetic defects in the mechanism of absorption of phosphate in the
renal tubule. They develop a vitamin D-resistant rickets.
Hypophosphatemia occasionally occurs as a result of metabolic
acidosis, chronic intake of antacids, and chronic alcoholism.
- Signs of deficiency:
- Phosphorus is abundant and nutritional
deficiencies are rare. Renal hypophosphatemia may occur in people with abnormalities of renal tubular function.
- Physiological functions for Na:
- Na is the principal cation of extracellular fluid. Na is
associated with chloride and bicarbonate in the regulation of
acid-base equilibrium.
- Maintenance of osmotic pressure of body fluids.
- Preservation of normal muscle irritability, contractibility and
permeability of the cells.
- Transport and co-transport of nutrients.
- Sources and requirement:
- Na is widespread. The chief source in US is
table salt. Na in well balanced diet without added salt is sufficient
to maintain Na levels in the body. Na ion concentration in the
extracellular fluids is maintained with narrow limits by the
adrenocortical steroids. In a deficiency of these steroids, a decrease
of serum Na and an increase of Na excretion occurs. Excessive
sweating may lead to signs of Na depletion. Symptoms of Na depletion
include nausea, giddiness, apathy, exhaustion, cramps and vomiting.
Respiratory failure may be a consequence. These symptoms can be
prevented by adding a little more salt to food.
Intake of Na in the US averages about 5 g per day per person. Because
Na retain water in the body, the recommended amount is not more than
1 gm per day per person with family history of hypertension.
- Physiological functions for K
- K is the principal cation in the intracellular fluid. Within the
cell, K functions by regulating acid-base balance and osmotic
pressure including water retention.
- Regulates neuromuscular excitability and muscle contraction.
- Functions as cofactor of metabolic enzymes (e.g. pyruvate kinase)
- Sources and requirement:
- K is present in most food, deficiency is
unlikely. The normal dietary intake is 4 gm per day which is adequate
for normal losses in the urine. Excretion of K is regulated by
adrenocortical hormone.
Abnormal losses caused by vomiting, diarrhea, excessive aldosterone
secretion, or treatment with some diuretics would cause hypokalemia
which is characterized by muscle cramps, weakness of skeletal muscle
and cardiac arrest in severe cases. Mild supplementation can be
provided by feeding orange juice (5 mM K). More intensive
supplementation with K requires care, not only because of local
irritation of the gastrointestinal tract but also because the amount
of potassium necessary to restore intracellular balance can create
toxic extracellular levels as it passes through the blood.
Hyperkalemia is characterized by cardiac arrhythmia, and muscle
weakness.
- Physiological functions for Cl:
- Regulation of water balance, osmotic pressure, and acid-base
equilibrium.
- Is a component of gastric HCl.
- Functions as an activator of enzymes (e.g. pancreatic amylase)
- Sources and requirement:
- Cl is usually taken in table salt.
Intake of
Cl is generally adequate as long as Na intake is adequate. Excretion
is controlled by the kidney.
Abnormal losses caused by vomiting, pyloric or duodenal obstruction
lead to hypochloremic alkalosis. In Cushing's disease, or after
administration of excess of corticotropin (ACTH) or cortisone,
hypokalemia with accompanying chloremic alkalosis may be observed.
20-25 gm in adults of which about 70% is combined with Ca
and PO4 in bone.
- Physiological functions of Mg
- Bone and teeth formation
- Activator and coenzyme for metabolic enzymes - concerns with a
large number of enzymes involved in transfer of phosphate bonds
(MgATP).
- Intracellular fluid cation.
- Maintains structural integrity of cellular components.
- Sources and requirement:
- Most foods contain Mg.
Because Mg is a part
of chlorophyll, most common dietary sources are green vegetables. The
recommended intake for adults is 350 mg per day.
- Signs of deficiency:
- Deficiencies in
humans occur in such conditions as chronic malabsorption syndromes,
acute diarrhea, chronic renal failure, chronic alcoholism and protein-
calorie malnutrition. Symptoms of Mg deficiencies include emotional
lability and irritability, tetany, hyperreflexia, and occasional
hyporeflexia. Magnisium deficiency can be an associated
complication of kwashiorkor. Hypomagnesemia is most often seen
in alcoholics and in patients with fat malabsorption syndromes.
- Physiological functions for S:
- A large part of S is present in the amino acids (methionine,
cysteine and cystine) in proteins including some polypeptide
hormones.
- A component of essential compounds such as glutathione,
taurocholic acid, coenzyme A, thiamine pyrophosphate, biotin, etc.
- Thioesters are high energy bonds used in transfer of metabolic
energy. Iron sulfide proteins are involved in transfer of
electrons.
- A component of constituents of mucopolysaccharides.
- Involved in the detoxification reactions.
- Sources and requirement:
- The sources of S are S containing amino
acids resulted from digestion of proteins from both animal and
vegetable sources. No requirement has been established for sulfur
intake. The urinary output of sulfur is about 2 gm per day in the
form of inorganic sulfur compounds.
Iron, Copper, Cobalt, Zinc,
Manganese, Iodine, Molybdenum, Selenium, Fluorine, Chromium
- Physiological functions of Fe:
- Major role in human is in oxygen
transport, electron transport and cellular respiration.
- Component of hemoglobin (60-70% of total body iron) and myoglobin.
- Component of iron porphyrin enzymes (e.g., catalase, cytochromes,
peroxidase, etc.)
- Components of iron:proteins (e.g., transferrin, ferritin, iron
sulfide proteins, hemosiderin, and etc.)
- Absorption and excretion:
- The bulk of Fe absorption takes place in the
small intestine. Ascorbic acid, sulfhydryl compounds and other
reducing compounds convert the Fe+3
form normally present in the food
to Fe+2 form which is readily absorbed.
Fe released from storage in the
mucosa cell as ferritin is transferred to the plasma or tissues as
transferrin. Normally, all the iron bound to transferrin is rapidly
taken up by the bone marrow cells actively synthesizing hemoglobin.
The storage form of iron, ferritin, is found in the intestine, liver,
spleen and bone marrow. Excess Fe is stored as hemosiderin in the
liver.
The amounts of Fe excreted in the urine are very small (less than 0.1
mg per day). Daily loss of iron is less than 1 mg per day for male
and 1.5 to 2.0 mg for female during child bearing age. Because of no
excretion mechanism the absorption of iron in the intestine is
carefully controlled.
- Figure below - Nutrition and metabolism of iron.
- Most iron is involved
in red cell production and function (as hemoglobin), some 20-24 mg of iron
turning over through red cell destruction and replacement daily, mainly
as reticuloendothelial (RE) cells.
Excess iron is stored as ferritin and hemosiderin,
especially in liver, spleen, and bone marrow.
- Sources and requirement:
- The daily recommended allowance for iron is
about 10 mg for adult males which is readily obtainable from a normal
diet. Allowances for adult females is about 18 mg per day. The need
for iron varies with age. The best dietary sources of iron are organ
meat, egg yolk, fish, oyster, clams, whole wheat, beans, and green
leafy vegetables.
- Signs of deficiency:
-
Iron deficiency is one of the most
common nutritional deficiencies in the world.
Iron intake is often inadequate in: (l) infancy, (2) during the female
reproductive period, and (3) pregnancy. Iron deficiency could also
result from GI disturbances, surgery, and excessive loss of blood.
Chronic deficiency in iron results in anemia.
General symptoms include
hypochromic microcytic anemia,
fatigue, pallor, listlessness, burning sensation of the toung,
glossitis,
dyspnea, especially upon exertion, the heart rate increases
(tachycardia), palpitations may occur, and there is general fatigue.
Because of the lack of an excretory pathway for iron, patients
receiving many transfusion over long periods or with excessive
capacity for iron absorption accumulate iron in the liver in a
condition known as hemochromatosis.
- Physiological functions of Cu:
- Cu is a essential component of enzymes
such as cytochrome oxidase, tyrosinase, catalase, dopamine hydroxylase,
ascorbic acid oxidase. lysyl oxidase, ferroxidase.
- Sources and requirement:
- Cu is widely distributed in the food and a diet
containing 2-3 mg per day is sufficient. Rich sources of Cu include
liver, kidney, shellfish, nuts and raisins. Milk is a poor source for Cu.
Cu deficiencies have been reported in infants. These infants manifest
pallor, retarded growth, edema and suffer from anorexia.
- Signs of deficiency:
- Two genetic disturbances of Cu metabolism are known. Wilson's disease or
hepatoenticular degeneration, is an autosomal recessive condition with a
gene frequency that may be as high as 0.02. This condition involves some
uncharacteristic disturbance of Cu within liver so that the excretion and
formation of ceruloplasmin are below normal. The failure in excretion
causes an accumulation of Cu in various tissues. A sign for this disease
is the occurrence of greenish-brown deposit in a ring around the outside
edge of the cornea (Kayser-Fleicher ring). The disease is usually
diagnosed in the first or second decade, and early diagnosis is important
to minimize the cirrhosis of the liver and neurological degeneration.
Treatment involves the administration of a chelating agent, usually
penicillamine.
Menke's disease, the kinky-hair or steely hair syndrome, results from
defects in utilization of dietary Cu, which affects the formation of
normal connective tissue because of the resultant loss of lysyl oxidase
activity. The fundamental defect appears to be an inability to transport
copper out of the intestinal mucosa and into the bloodstream. The loss
of other enzymes has more widespread effects, and death within the first
three years is expected if untreated. This X-linked recessive trait may
have an incidence as high as 1 in 35,000 births. Diagnosis has usually
been made too late to determine if intravenous Cu supplements would be an
effective treatment.
Co is a component of vitamin B-12.
- Physiological functions:
- A component of more than 80 metalloproteins
including carbonic anhydrase, carboxypeptidase, alcohol dehydrogenase,
alkaline phosphatase, RNA polymerase, insulin, nucleic acid binding
proteins, particularly transcription factors.
- Sources and requirement:
- Rich sources of Zn include meat, egg, milk
products, shellfish, whole grains, cerials, legumes, root and leafy
vegatables. An intake of 8-l0 mg per day is adequate
and this amount can be obtained in a normal diet. Frank deficiencies
of Zn are rare. Several dwarf males in Iran and Egypt were found to
have retarded sexual development, anemia, enlargement of liver and
spleen, and mental lethargy. The anemia can be corrected with iron
supplement, but improvement of the arrested growth and development
required supplementation with Zn.
- Signs of deficiency:
-
Signs, symptoms of deficiency:
growth retardation and hypogonadism,
impaired taste and/or smell acuity, poor wound healing,
mental lethargy, and dry scaly skin (see image).
Deficiency in adults causes a loss of normal taste. The saliva
contains gustin, a 27K molecular weight polypeptide that is high in
histidine and contains two Zn atoms. Gustin is required for normal
development of taste buds.
Mental lethargy, poor appetite, and dry, scaly skin may occur
(see slide). Reduced immune competence is frequently noted.
A hereditary defect in Zn absorption, acrodermatitis enteropathica,
a disease marked by severe chronic diarrhea, loss of skin around anus
and mouth, and rash on the extremities. The condition is alleviated
by human milk, but not by cow milk, and the apparent reason is that Zn
in human milk is bound to a low molecular weight polypeptide which
makes Zn more accessible for absorption. A similar condition has been
observed upon feeding with formula deficient in Zn.
Within the last two to three years the role that Zn plays in the
activity of a number of nucleic acid binding proteins, particularly
transcription factors has been determined.
These proteins contain several
(3-9) Zn+2 atoms bound in ``zinc finger'' domains.
Depletion of Zn from these proteins results in an inhibition of their
ability to bind to DNA and hence a loss of their regulatory activity.
Thus the stunting of growth and fetal wastage observed in chronic Zn
deficiency is at least in part due to the inactivation of these
transcription factors.
- Figure below - Zinc speeds healing of wounds.
- Twenty young airmen with surgical wounds were tested, ten as controls
and ten receiving 150 mg zinc sulphate daily.
Wounds in the patients receiving zinc healed nearly three times faster
than those in the controls.
(Pories et al., 1967, The Lancet, 1:121)
This element is known to be required for normal bone structure,
reproduction, and normal functioning of the central nervous system.
Deficiency in humans has not been described.
Iodine is an integral component of thyroxine and triiodothyronine.
Deficiency in iodine results in goiter. In areas where soil is low in
iodine, foods produced are deficient of iodine. Seafoods are rich source of
iodine. In US, a ready source of iodine is iodized salt. The RDA intake is
1 mg per kg body weight per day.
A component of xanthine oxidase and aldehyde oxidase. No
deficiency in humans has been described.
A component of glutathione peroxidase. Deficiency diseases have
been produced in experimental animals.
Inadequate selenium in the diet increases the risk of getting cancer.
The presence of trace amounts of fluoride protects teeth from
dental caries. Fluoride has also been implicated in the protection of the
elderly against osteoporosis.
Required for maintaining normal glucose metabolism in experimental
animals.
Reference: Schneider et. al., Chapter 4
Reference: Maria C. Linder,
``Nutritional Biochemistry and Metabolism'', Elsevier, New York (1991).
- Table below - Correlations between Diet and Cancer:
- Animal products versus total fat intake show (+) correlations,
plant products versus fat intake show negative correlations.
Plant fats show positive correlations. Olive oil, hydrogenated fats, and
fish oil do not appear to promote carcinogenesis.
The table includes diet information from 41 countries, 1964-66,
cancer rates from 1973. Lag between exposure and cancer is 25-30 years.
- Figure below - Death rates from breast cancer versus fat intake:
- Data are from mid 1960s.
- Figure below - Whole milk
- increases relative risk by 1.5 to 2 fold in
several types of cancer.
- In human breast cancer, fat has no effect:
- U.S. Nurses' Health Study: JAMA (1992) 268, 2037-2044.
(Experimental animal models show a significant effect.)
- Figure below - High fat acts at the stage of tumor promotion:
- A high fat diet fed after, rather than during, exposure to the
carcinogen has the same effect as feeding it throughout. (from Linder)
- Figure below - Animal models
- show that fat may act also at the stage of initiation. (from Linder)
(The Nurses Health study shows no effect in humans.)
- Table below - Type of fat makes a difference:
- For experimental colon cancer,
plant oils high in linoleic acid (the important essential fatty acid)
show higher tumor rates than more saturated or shorter fatty acids
(olive oil), or than animal fat.
Table below - Insoluble fiber reduces -
soluble fiber sometimes increases carcinogenesis: (from Linder)
Figure below - Dietary fiber
reduces the mutagenic activity of fecal extracts:
Reddy, B.S. (1990) Adv. Exp. Med. Biol., 270, 159-67.
Cummings, J. (1985) ``Cancer of the large bowel'' in
Dietary Fibre, Fibre-Depleted Foods and Disease,
(H. Trowell, et al., eds) pp 161-185, Academic Press, New York.
Figures below - Fiber reduces colon cancer death rates:
- Both fat and fiber alter biliary secretion.
- Fat intake increases bile acid secretion and excretion.
Some bile acids and derivatives promote carcinogenesis.
The most bulk-producing forms of fiber are the most effective
at reducing colon carcinogenesis in experimental animals.
It is thought that bulk forming fiber ``dilutes'' bile acids.
Certain bile acids appear to stimulate cell proliferation.
It is thought that this uncontrolled cell proliferation leads
to cancerous cells.
- Figure - Calcium has a protective effect.
- Milk and dairy products, and calcium per se are associated
with decreased risk of colon cancer in man.
It is thought that Ca2+ forms less soluble salts of
bile acids that are excreted.
- Figure below - Vitamins C and E
- can prevent carcinogenic nitrosimine formation
and may lower levels of fecal mutagens.
- Table below - Retinoids and carotinoids
- can lower the risk of getting cancer.
- Figure below - Selenium
- can inhibit the growth of tumors.
Selenium is an oxygen radical scavanger, acting like vitamins C and E.
Lower selenium intake is (+) correlated to cancers of colon,
rectum, prostrate, breast, and leukocytes.
- Copper
- inhibits malignant tumor growth in rodents, and is
toxic to tumor cells in culture.
Reference: Maria C. Linder, ``Nutritional Biochemistry and Metabolism'',
Elsevier, New York (1991)
The following events are thought to occur during the genesis
of atherosclerotic plaques:
- 1.
- The Endothelial cell layer is mechanically or chemically injured.
LDL entering the injured tissue may become oxidized to
a cytotoxic, atherogenic product.
Oxidized LDL attracts monocytes and macrophages.
- 2.
- Injured endothelial cells produce less
prostacyclin (PGI2), which normally inhibits
platelet aggregation.
Activated platelets release thromboxane A2,
which stimulates their aggregation, and
platelet-derived growth factor (PDGF),
which stimulates smooth muscle cell proliferation.
- 3.
- Cells of the developing plaque release similar growth factors
and leukotriene B2 (LTB2),
an attractant for blood monocytes and leukocytes.
Smooth muscle cells, monocytes, and lipids enter the intima.
Collagen and elastin are secreted by smooth muscle cells.
- 4.
- Collagen and elastin are secreted by smooth muscle cells.
Scar tissue traps lipid and cells.
Crystalline cholesterol appears.
- 5.
- Necrosis of trapped cells promoted (?) by oxidized LDL.
This step may be irreversible.
- 6.
- Calcification may also begin as part of the injury response.
Here is a nice picture: Figure 1.-Early Events in Atherogenesis.
Native LDL becomes trapped in the subendothelial space,
where it can be oxidized by resident vascular cells such
as smooth-muscle cells, endothelial cells, and macrophages.
Oxidized LDL stimulates (plus sign) monocyte chemotaxis (A)
and inhibits (minus sign)
monocyte egress from the vascular wall (B).
Monocytes differentiate into macrophages that internalize oxidized LDL,
leading to foam-cell formation (C).
Oxidized LDL also causes endothelial dysfunction and injury (D),
as well as foam-cell necrosis (E), resulting in the release of
lysosomal enzymes and
necrotic debris. Broken arrows indicate adverse effects of oxidized LDL.
Adapted from Quinn et al. (Ref. 15)
There is a strong positive correlation between cholesterol
and atherosclerosis, but it may be fortuitous.
The cause may be animal protein, low micronutrients (B-6),
homocystine...
Some populations have low heart disease and consume high cholesterol
(2 g/day). (The French paradox, for example)
Lowering cholesterol definitely lowers the risk of heart disease.
Anticalcifying drugs stop atherosclerosis.
Oxidized cholesterol is very atherogenic.
Risk Factors and Dietary Trends in Atherosclerosis: (from Linder)
Figure below - High Stored Iron Levels
Are Associated With Excess Risk of Myocardial
Infarction. Iron can induce lipid peroxidation in vitro and in vivo
in humans and has promoted ischemic myocardial injury in experimental
animals. In this study, 1,931 men were tested for serum ferritin
levels, and were followed for an average of 3 years.
Serum ferritin levels in excess of 200 micrograms/liter (
)were found to be associated with a greatly increased risk of
heart disease. (Salonen et al., 1992, Circulation, 86, 803-811)
- Figure below - Anticalcifying drugs
- lower atherogenesis in monkeys on an
atherogenic diet. The figure shows the composition
of the intimal and medial layers. (from Kramsch et al., 1981)
- Figures below - Prostaglandins, Fish Oils, Aspirin:
- Triacylglycerols in fish oils
are high in EPA and DHA (eicosapentaenoic and docosahexaenoic acids).
These tend to lower VLDL, blood pressure, and increase levels of
prostaglandins, thromboxanes, and leukotrienes that reduce platelet
aggregation and migration of monocytes and macrophages
into arterial injuries. Cyclooxygenase controls production
of many of these factors and is irreversibly inhibited by aspirin.
Fish oil lowers triglycerides, and may lower insulin resistance.
- Ethanol, Coffee, Protein, Fiber, Micronutrients:
- Ethanol and coffee have no effect on atherosclerosis.
Correlation of animal protein consumption and atherosclerosis is as
strong as those for cholesterol or animal fat.
Homocystine is a potent atherogenic agent.
Deficiency of B-6 promotes homocystine accumulation.
Fiber absorbs bile acids and cholesterol.
Vitamins B-6 and E, copper, chromium, vanadium, silicon, Mg2+,
and zinc have beneficial effects.
- Vitamin E:
-
Figure 2.
-LDL-Specific and Tissue-Specific Mechanisms of Antioxidant Action.
Incorporation of antioxidants into LDL protects LDL
against oxidation and leads
to the reduced formation of oxidized LDL.
In addition, incorporation of
antioxidants into vascular cells may reduce the
clinical expression of vascular
disease by reducing vascular-cell oxidation of LDL
and the cellular responses to
oxidized LDL, resulting in less monocyte adhesion,
less foam-cell formation, less
cytotoxicity to vascular cells, and improved vascular
function. Small vertical arrows indicate increases.
There is now clear evidence, both epidemiological and
from random clinical trials, that vitamin E, 100 IU per
day or more, dramatically reduces the risk of heart disease.
It is difficult to overstate the importance of this
result given that heart disease kills about 1 million
Americans per year (13 million world wide),
causes suffering to many more,
and costs in excess of 100 Billion.
The important results are summarized in a recent
review by Diaz et. al. in The New England Journal of Medicine,
vol 337, Aug 7, 1997, pp 408-416. Here is an excerpt:
There is a wealth of epidemiologic data linking the dietary
and supplemental intake of antioxidant vitamins
with a reduction in the clinical manifestations of
atherosclerosis (*(Table 1)*). Initially, these data were limited
to descriptive studies in European and North American
populations (reviewed by Gaziano et al. (12)).
Subsequent case-control studies indicated that patients
with angina pectoris have lower plasma concentrations
of vitamin E than normal subjects (13) and that reduced
concentrations of vitamin C in the leukocytes are
predictive of angiographically evident coronary artery disease. (4)
These results have been confirmed in recent prospective
cohort studies. In the Nurses' Health Study (5) and the
Health Professionals' Follow-up Study, (6) there was a 35
to 40 percent reduction in the incidence of major
coronary events (nonfatal myocardial infarction and death
from cardiac causes) among the subjects in the
highest quintile of vitamin E intake over a four-to-eight-year
follow-up period, as compared with those in the
lowest quintile. The benefit was greatest in subjects
taking 100 to 250 IU of supplemental vitamin E per day,
with little further benefit at higher doses. There was no
relation between vitamin C intake and major coronary
events in either study, but in another study, subjects
whose vitamin C intake exceeded 50 mg per day had a
lower rate of death from all cardiovascular diseases. (7)
The results of recent randomized trials to investigate whether
there is a cause-and-effect relation between
antioxidant intake and a reduction in coronary artery disease
have been mixed. In the Alpha-Tocopherol, Beta
Carotene Cancer Prevention Study, Finnish smokers were treated
with beta carotene, (alpha)-tocopherol
(vitamin E), both, or neither daily for five to eight years.
There was no benefit with respect to coronary artery
disease for either compound, (9) but the dose of (alpha)-tocopherol
(50 mg per day) was below the protective
range suggested by both the Nurses' Health Study and the Health
Professionals' Follow-up Study. (5,6) There
was no reduction in deaths from cardiovascular causes among
physicians receiving supplemental beta carotene
over a 12-year period in the Physicians' Health Study. (10)
In contrast, in the Cambridge Heart Antioxidant
Study, in which 2002 patients with angiographically evident
coronary artery disease were treated with
(alpha)-tocopherol (400 to 800 IU per day) or placebo,
there was a 77 percent reduction in nonfatal myocardial
infarction in the group receiving (alpha)-tocopherol during
a median follow-up period of 510 days. (11)
In summary, descriptive, case-control, and prospective cohort
studies have found inverse associations between
the frequency of coronary artery disease and dietary intake of
antioxidant vitamins. Randomized therapeutic
trials have thus far shown no benefit with beta carotene and a
possible benefit with vitamin E.
Their summary does not adequately address the very
important public health policy and ethical issues:
Given the considerable and unanimous epidemiological
evidence showing an approximately 40 percent reduction in risk
for vitamin E takers, together with
the one clinical intervention trial using
more than 50 IU per day vitamin E showing
a 77 percent reduction
in non-fatal MIs, and that the only known side effect is
an extended blood clotting time (as one would expect to
see when taking an aspirin every other day),
should physicians recommend to their
patients that they take vitamin E to lower
their risk of heart disease?
- Table below - Effects of Fiber
- on Human Plasma Cholesterol Concentrations:
Table - A drastic lowering of cholesterol by diet and drugs
can cause atherogenesis to reverse. The table below lists studies that
show evidence of regression of atherosclerotic lesions in humans.
Summary of Dietary Sources of Fats and their Effect
on Factors Influencing Atherosclerosis.
Summary of the Effects of Drugs and Resins on Hypercholesterolemia
Structures of Dietary Fats:
Synthesis of Prostaglandins, Thromboxanes, Leukotrienes,
and Levuglandins:
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![[image]](/biochem/images/le1-1.jpeg)
A 63 year old woman was hospitalized for cervical cancer therapy.
Prior to admission, her diet consisted of cornbread,
grits, mustard greens (boiled for several hours), and cereals.
She had no teeth. Her weight fell from 54 to 47 kg over the past
two months. She ate little in the hospital and was maintained
only on intravenous saline solutions.
Five days days after removal of her lower abdominal organs,
she had bloody fluid leaking from a poorly healing surgical wound
(see slide in lecture).
