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Information for healthcare professionals
Dietary food for special medical purposes
Micronutrients and the Immune System
3
4 The immune system – a complex system needs optimum support 6 What is orthomolecular nutritional medicine?
7 Micronutrients – nutritional support for the immune system
14 Oxidative stress – the threat posed by free radicals14 Formation of free radicals
16 Which people need a particularly large supply of antioxidant
micronutrients?
18 Increased need for micronutrients in case of illness18 Micronutrients as nutritional support
20 Dietary treatment of infectious diseases
24 Keeping inflammation under control
24 Micronutrients and wound healing
28 Allergies, asthma and COPD
31 Reducing the cancer risk – supporting tumor therapy
35 Micronutrients in oncology
40 Literature
Contents
5
Lymphatic organs and tissues
4
The immune system is one of the most complicated and complex networks
in the human body’s organ systems (Fig. 1). Its principal functions include
the defense against infections and tumors and the involvement in tissue
regeneration.
Like all body systems, the immune system is based on biochemical meta-
bolic processes and cellular mechanisms that depend on the external supply
of energy and micronutrients. As the immune system, compared with other
systems of the human body, mainly consists of rapidly proliferating cells, it
is particularly sensitive to an inadequate supply of micronutrients. Before
the clinical or subclinical symptoms of an insufficient micronutrient supply
can be recognized, the functional impairment of the immune response may
already be observed.
The immune system has an especially high turnover rate in chronic diseases
or infections. Immune cells must be activated rapidly in the right place at
the right time. This is why the immune system is particularly vulnerable to
a lack of micronutrients in such cases.
Any shortage in the supply of micronutrients to the immune system should
therefore be prevented by a regular, appropriate intake. This is where ortho-
molecular nutritional medicine comes in. The organism is provided with an
additional quantity of certain vitamins and trace elements in the right com-
position and dosage.
The immune system – a complex system needs optimum support
Palatine and pharyngeal tonsils
Secondary lymphatic organs
Waldeyer’s tonsillar ring
Bone marrow
Axial lymph nodes
Spleen
Intestinal mucosa lymph nodes
Peyer’s patches
Inguinal lymph nodes
Primary lymphatic organs
Thymus
Fig. 1. Locations of human lymphoid tissues
Bone marrow
76
This brochure gives you an impression of the importance of micronutrients
for the immune system. It also shows what orthomolecular nutritional medi-
cine (Fig. 2) can do to support the treatment of diseases. With orthomolec-
ular nutritional medicine, doctors have an effective opportunity to recom-
mend to their patients a supplementary nutritive therapy above and beyond
the established methods. Many ill people feel the need to actively contribute
to the healing process themselves in addition to the therapeutic measures
taken by their doctor.
What is orthomolecular nutritional medicine?“Orthomolecular nutritional medicine is the preservation of good health and treatment of disease by varying the concentrations in the human body of substances that are normally present in the body, and that are required for good health.” (Linus Pauling)65
The functions of orthodox medicine and orthomolecular medicine
Orthodox medicineCombatting disease and
restoring health
Orthomolecular medicineProtecting and restoring health and maintaining the body’s functions (e.g. immune defense and regeneration) as well as supporting the treatment of diseases
We have known for decades that malnutrition or undernourishment may
impair the function of the immune system. But even in a generally adequate
nutritional situation, an increased need for vitamins and trace elements, often
going unrecognized, may considerably weaken the immune system (Table 1).
Micronutrients, with their nutritional and physiological properties and charac-
teristics, may influence the immune system in many different ways.
Thus, for instance, a lack of vitamin A can impair the formation of antibodies
against certain bacterial antigens. In animal experiments, fewer granulocytes,
B cells and natural killer cells were generated.12 Moreover, a lack of vitamin A
will aggravate inflammatory reactions, and experimental studies have shown
that this vitamin can inhibit various types of inflammatory reactions.16
Micronutrients – nutritional support for the immune system
Table 1. Features of important micronutrients related to the immune system30,31,36,53,74,80,84
Proliferation and activation of lymphocytes
Activation of macrophages
Phagocytosis
Proinflammatory cytokines (TNFα, IL-1β, IL-6)
Free radicals
Cancer risk
Zinc Beta-carotene
Selenium, copper, manganese
Vitamin
Fig. 2. Differentiating orthodox medicine from orthomolecular medicine
C E D3 A
98
Animal experiments and studies in humans suggest that a vitamin B6 defi-
cit will have a negative effect on the humoral as well as the cell-mediated
immune response. Thus, for instance, a vitamin B6 deficiency will change
the differentiation and maturation of lymphocytes, reduce the delayed-
type hypersensitivity reaction and may impair antibody production.70 In
a recent study it was shown that a vitamin B6 intake above the recom-
mended RDA* (2.1–2.7 mg per day), however, will significantly increase
lymphocyte proliferation and may therefore have a beneficial influence
on the immune response.50
The physiological function of various cell types of the immune system
depends on an adequate supply of vitamin C. As vitamin C has a strong
antioxidant capacity, it protects many types of tissue. Vitamin C plays an
important part in the immune function, the modulation of the body’s
resistance against infection pathogens and it can reduce the risk, severity
and duration of infectious diseases and accelerate recovery.85
A particularly high vitamin C concentration is found in neutrophilic granu-
locytes where the vitamin protects the intracellular compartments, such
as the phagocytic cell membrane, against the damaging effect of oxygen
radicals.12 Moreover, the proliferation of T lymphocytes can be enhanced by
vitamin C supplementation, and the activity of leukocytes and natural killer
cells can be improved.85
In addition, in several case-control studies it was found that a high vitamin C
intake will reduce the risk of gastric cancer. This is supposed to be due to
the neutralization of the carcinogenic nitrosamines by this vitamin, among
other reasons.
Vitamin C is also important for the healing process, as it boosts the function
of specific immune defense cells (Fig. 4).57 Besides, vitamin C enhances the
iron absorption in the intestines and thus influences iron transport and iron
storage.12
Vitamin E has an antioxidant effect and thus protects the tissues and
blood cells. Adequate vitamin E levels are essential for the function of the
immune cells. Vitamin E improves both the humoral and cellular immune
response as well as phagocytosis.84 Many studies have shown that vitamin E
has a beneficial effect on the immune function of older people. Thus, a
correlation was found between the plasma vitamin E level and the course
of a delayed-type hypersensitivity reaction (type-IV reaction) on the skin
and the response to a hepatitis-B vaccination. In addition, various clinical
trials and animal studies indicate that supplementary vitamin E intake can
improve resistance in old age, especially to viral infections of the upper
respiratory tract including influenza.56
There are probably two mechanisms that are responsible for the immuno-
modulatory effects of vitamin E: on the one hand, vitamin E has an indirect
effect by reducing the formation of immunosuppressive factors, such as
PGE2, and on the other it promotes cell division and the interleukin-2 pro-
duction of naive T cells.56
Antioxidants are complementary to each other in their effects. For exam-
ple, vitamin E, which oxidizes itself and becomes ineffective when oxygen
radicals are inactivated, can be reduced again by vitamin C and can thus
be “recycled” to its active version.15 Vitamin C in its turn is reduced by the
selenium-containing glutathion peroxidase.27
* RDA: recommended dietary allowance
ZincInfluences phagocytosis of macrophages
Supports NK activity
Increases cytokine production
Stimulates lymphocytes
Fig. 3. Functions of zinc for immune defense10,26,43
10
The last link in the chain is the enzyme superoxide dismutase (SOD) which
needs zinc as a cofactor.2
Vitamin A has many important characteristics that are essential to maintain-
ing the basic functions of the human body: it regulates cell division and
tissue growth. Moreover, it strengthens the barrier function of the skin and
mucosa and plays an essential part in adaptive immunity as it is needed for
the development of helper T cells and B cells.12
The carotenoid beta-carotene, as provitamin A, is a vitamin A precursor. As
an antioxidant it is able to scavenge aggressive oxygen radicals, it protects
the body cells against their damaging effect, and it helps prevent cancer.80
Carotenoids can, for instance, contribute to the protection against the
detrimental oxidative impact of ozone. Among other functions, ozone leads
to the formation of free radicals that attack the lung tissues and causes a
significant reduction in plasma carotenoids. Carotenoid intake can increase
the carotenoid concentration in the plasma and lung macrophages and
thus counteract their depletion under an ozone load.76 In addition, beta-
carotene enhances the immune defense and weakens the skin reaction
in patients with light dermatosis.
The trace element selenium, as a component of the glutathion peroxidases
and thioredoxin reductases, which both have an antioxidant effect, pro-
tects the tissues against oxidative stress. Thus, glutathion peroxidase, for
instance, is very important for the degradation of lipid peroxide. Moreover,
more than 20 selenoproteins have meanwhile been identified that are
involved in the cell and thyroid metabolism and the immunofunction.9
11
By influencing phagocytosis, selenium helps eliminate harmful micro-
organisms.9 It is an important factor for many functions of the immune
system (Table 2)9 and thus also contributes to the immune defense against
degenerated cells. In many studies it could be shown that selenium intake
is associated with a reduced cancer risk (e.g. cancer of the intestines and
prostate gland).31,46
Zinc is an important cofactor of more than 300 metalloenzymes that would
be unable to function without zinc.26 It promotes the development and
integrity of the immune system (Fig. 3, Table 2).26 Zinc, for instance, is essen-
tial for the activation of thymoduline (thymic hormone) which regulates
lymphocyte maturation.26 Zinc also seems to play a role in cytokine activity,
as the biologic activity of IL-1, 2, 3, 4 and 6, IFN-β and TFN-α is impaired in
people with a zinc deficiency.26 A lack of this micronutrient leads to a higher
susceptibility to infections and a decline in T lymphocytes (cytotoxic T cells,
helper T cells), reduces the activity of natural killer cells and impairs the
phagocytosis of macrophages and neutrophils.43
Wound matrix
Macrophage
Epithelial cell
Procollagen• Vitamin C
• Thiamin
• Pantothenic acid
• Manganese
Glycoproteins• Vitamin C
• Vitamin A
• Manganese
Metabolism• B vitamins
Replication• Vitamin A
• Zinc
Cross-linking• Zinc
• Copper
Phagocytosis• Vitamin C
• Selenium
Morphology• Vitamin A
Replication• Vitamin A
• ZincAntioxidants• Vitamin E
Chemotaxis• Vitamin C
More rapid healing
Growth factors
Lymphocyte Hypophysis
Collagen formation
Micronutrients involved in relevant metabolic processes
Fig. 4. Role of micronutrients in relevant metabolic processes57
12 13
Iron deficiency is one of the most frequent nutritional deficiencies. Iron is
an essential component of the enzyme myeloperoxidase which granulo-
cytes require for phagocytosis.30,84 In children with a lack of iron the number
of immunocompetent T cells is drastically reduced and the susceptibility
to infections increased.84 A recent study with older women has shown
that iron deficiency is associated with a disorder of the cell-mediated and
congenital immunity.4 Besides, iron is essential to the transport of oxygen
because every hemoglobin molecule consists of 4 subunits with one hem-
group each containing a central iron atom.77 As a cofactor of peroxidases
and catalases, iron helps eliminate detrimental peroxides.32
Copper as a component of many metalloproteins is involved in various meta-
bolic reactions. They include the respiratory chain (cytochrome-C-oxidase), the
antioxidant defense (superoxide dismutase, coerulo plasmin), the synthesis and
degradation of catecholamine (dopamine-β hydroxylase, monoamine oxidase),
and the formation of connective tissue (lysyloxidase). As this trace element has
an important position in the iron metabolism, it plays a role in the hemoglobin
synthesis and thus the transport of oxygen.32,38
Table 2. Immune function with deficiency of certain trace elements9,26,43
+
+
(number of T cells)
Anergy*
Zinc Selenium
* anergy = lack of response for an antigen + occurs - not specified decreased
-
Activity of natural killer cells
Thymus atrophy
Lymphocytes
Antibody formation
Phagocytosis
Helper T cell activity
-
(proliferation)
(IgG, IgM)
Collagen Fibroblast
1514
A study by Cheng et al. 200121 showed that a short-term supply of vitamins
and minerals (for 16 weeks) improved the antioxidant status and increased
the activity of antioxidant enzymes. The resistance of the red blood cells to
peroxidation processes was also significantly higher.
Oxidative stress – the threat posed by free radicals
Besides noxious substances, bacteria and viruses, the formation of free radi-
cals also threatens the organism. Free radicals react very easily with other
molecules through unpaired electrons and thus have a detrimental effect on
tissues and cells (Fig. 5). They interfere with the correct plication of impor-
tant proteins, oxidize the lipid membranes of the cells and affect the ideo-
plasm. The sum of all these effects is called oxidative stress.
Formation of free radicals• Free radicals can develop either endogenically as metabolic products,
especially in inflammatory processes such as chronic respiratory tract diseases (asthma, COPD*) and hepatic diseases (hepatitis)
• Or they are of exogenic origin generated by environmental pollutants, ozone, high-energy radiation (e.g. X-rays or sunlight), certain drugs, and smoking
To protect itself against the free radicals and their detrimental effects,
the organism can make use of two antioxidant systems (Table 4):
• Antioxidant enzymes which are formed by the body itself; an adequate
supply of the trace elements selenium, copper, iron, zinc and manganese
is needed for their synthesis, or
• Non-enzymatic antioxidants which have to be ingested through food;
these include in particular vitamins C and E as well as phytonutrients such
as carotenoids and bioflavonoids
To ensure that the body has an adequate supply of antioxidant systems at all
times, the micronutrients required for this purpose, such as vitamins C and E,
phytonutrients (carotenoids and bioflavonoids) and trace elements (seleni-
um, zinc, manganese and copper), must be taken regularly (Fig. 6).
Table 3. Sources of important micronutrients
Micronutrients Sources
Vitamin C Fruit, vegetables (paprika, broccoli, etc.)
Vitamin E Vegetable and fish oils, nuts, eggs, giblets
Vitamin A Liver, carrots, tuna, cheese
Selenium Seafish, meat, eggs, cereals
Zinc Meat, fish, milk
Iron Meat
Copper Liver, nuts
Iodine Seafish
Folic acid Green vegetables, giblets
Vitamin B12 Meat, liver, kidney, milk, fish(cyanocobalamin)
Vitamin B6 Meat, fish, vegetables (Brussels sprouts, avocado)(pyridoxine)
Vitamin D3 Fish, milk
Vitamin K1 Green vegetables (curly kale, broccoli, etc.)
Manganese Cereals
Carotenoids Vegetables and fruit
Bioflavonoids Vegetables and fruit
* COPD: chronic obstructive pulmonary disease
Detrimental effects of free radicals
Lipid peroxidation
Lipid cell membrane
Radical
Denaturation of proteins
Protein in pleated-sheet structure
Radical
DNA damage
DNA double helix
Radical
Fig. 5. Effects of free radicals on DNA, proteins and lipids
Vitamin E
Free radicals
Bioflavonoids
Selenium
Manganese Copper
Zinc
Carotenoids
Vitamin C
Antioxidants control free radicals
Fig. 6. Antioxidants as radical scavengers
Table 4. Features of antioxidant systems
Vitamin C Water-soluble, reaction with toxic oxygen radicals, prevents the penetration of free radicals in the lipid phase
Non-enzymatic antioxidants
Vitamin E Fat-soluble, especially in cell membranes, prevents oxidation of unsaturated fatty acids
Selenium Central component of the antioxidant enzyme glutathione peroxidase, important for the protection of erythrocytes
Trace elements in antioxidant enzymes
Zinc, manganese, copper Components of superoxide dismutases having antioxidant efficacy
Iron Component of catalases, a group of antioxidant enzymes
1716
Which people need a particularly large supply of antioxidant micronutrients?8,35,48,49,56,62,69,73,79,81,84
• People with acute or chronic infections• People with chronic illnesses, such as respiratory tract diseases
(asthma, COPD), or hepatic diseases (hepatitis)• Elderly people• Top-performance athletes• People who are exposed to special environmental pollutants
(e.g. smog, ozone)• People who smoke and/or regularly consume alcohol• People with metabolic disorders• People who are exposed to intense sunlight• People who mingle with many other people and are therefore
exposed to an elevated risk of infection
Carotenoids Fat-soluble, especially effective against singlet oxygen, protect DNA against radical chain reaction (provitamin A)
Bioflavonoids Antioxidants from vegetables
1918
In certain illnesses the need for micronutrients may increase, for instance in
people with infectious or chronic diseases who have to take a certain medica-
tion regularly. Often this increased need for micronutrients cannot be covered
with normal eating habits. You would have to eat 2 kg of oranges in order to
ingest 950 mg of vitamin C. 350 ml of thistle oil contains 150 mg of vitamin E.
For a dose of 5 mg of mixed carotenoids you would have to eat 50 g of carrots
and 50 g of tomatoes.71 In Germany, however, a person’s average consumption
of fruit and vegetables only amounts to 309 g per day and thus is far below the
amount of 650–700 g recommended by the German Nutrition Society (DGE
– Deutsche Gesellschaft für Ernährung).29 A large proportion of the population
therefore does not receive a sufficient supply of micronutrients. For example,
the intake of vitamin D3, folic acid, pantothenic acid and iodine is much lower
than the nutrient supply reference levels of the DGE. According to the recent
DGE nutrition report, for instance, 45% of women and 45.5% of men do not
reach the DGE reference level for folic acid.29 Moreover, many foods lose impor-
tant micronutrients over a long storage period or when they are prepared.71
Micronutrients as nutritional support Micronutrients help support the defense system and maintain good health.
In prospective studies, for instance, it was shown that the supplementation
of combinations of vitamins and trace elements can reduce the risk of
infection.11,20,44 But even patients who are already ill will benefit from an
increased supply because micronutrient supplementation can:
• Cover the higher demand due to an acute disease or a certain medication
(Table 5)18
• Contribute to stimulating the immune system and wound healing, and
also support drug therapy5,57,68,81
• Mitigate drug side effects68
• Have a beneficial influence on the antibody reaction after an influenza
vaccination20,51
Increased need for micronutrients in case of illness
Table 5. Vitamin supply affected by pharmaceuticals18
Amiodarone
Antacids
Anticoagulants
Anticonvulsants
Antidiabetics, oral
Antimicrobials
Antineoplastic agents
Antituberculous agents
Colchicine
H2 receptor antagonists
Hydralazine
Laxatives
Lipid lowering agents
MAO inhibitors
Orlistat
Proton pump inhibitors
Psychiatric agents
A B1 B2 Nicotin- amide
B6 B12 C D E KFolic acid
VitaminsPharmaceuticals
a Colestyramine b Fibrates c Methotrexate
• • • • • • • • • (•) (•) • • • • • • • • • • • • • • •c • • • • • • • • • • • • • • • • •a •a • a •a,b •a • • • • • • •
•
• • • • • •
Anticontraceptives, oral
Glucocorticoids
Nitroglycerin
Barbiturates
Salicylates, NSAIDs
Theophylline
Loop diuretics
Days
Distribution pattern of infectious diseasesSubjects (n)
10 20 30 40 50 60 70 80
Fig. 8. Infection-related annual days with symptoms under supplementation of micronutrients (MN) or placebo in elderly patients19
2
12
10
8
6
4
With MN supplementation
Without MN supplementation
n=96p=0.002
21
Absence rate in comparison with previous year
Previous year Following year0
Previous year Following year
1
2
3
4
5
6 6.3
1.5
5.7 5.8
Intervention:Orthomol® Immun powder daily 4 months(n=27)
Previous year or control group without supplementation(n=27)
Fig. 7. Absence rates (days off sick in the previous year vs. following year; p<0.001)42
-75.6 %
20
Vitamins and trace elements are essential for the functions of the immune
system. Therefore, the need for them greatly increases in people with infec-
tions. Many studies have shown that the optimum supply of these substances
can support the treatment of infections and the defense against pathogens.
Moreover, antioxidants scavenge harmful free radicals of which a higher
number is produced during infectious diseases and can thus have a beneficial
influence on the course of the disease.
In an interventional trial, the intake of a micronutrient combination (Orthomol® Immun) could improve general health and strengthen the
immune defense.42 Thus, after taking the micronutrients for four months,
vitality improved by 39.5%, the quality of life by 29.6%, and the general
health was 31.7% better than before. Within the reference values the blood
test demonstrated a significant multiplication of immunoactive cells and a
significant improvement in the immune status. Thanks to the micronutrient
combination, the absence rate due to illness could be reduced significantly
by 75.6% compared to the previous year (p<0.001, Fig. 7). In the control
Dietary treatment of infectious diseases
21
group, the number of days lost due to illness increased. Common colds also
dropped by 48.6% compared to the previous year.42
In a placebo-controlled double-blind trial the preventive effect of a micro-nutrient supplementation on a group of subjects aged >65 years (Fig. 8)
was investigated. In the observation period (1 year) the test group subjects’
immune status improved considerably (increase in T and NK cells with higher
activity of these immune cells, more interleukin-2 production and enhanced
antibody response). In comparison with the placebo group, the number of
days of illness due to infections could be reduced by more than 50%.19
In another study of the same design, the 12-month administration of a
micronutrient combination to a group of subjects aged 50 to 65 led to
a significantly higher antibody response after influenza vaccination and
a decline in the number of influenza infections.20 Jain et al. (2002)44 also
showed that the 12-month administration of a micronutrient combination
led to a significant reduction in the number of days of illness due to respi-
(Intervention period: Dec. 2002–Mar. 2003)
Intervention group Control group
Days (n)
AIDS is also associated with a malfunction of the immune system and
malnutrition. The levels of vitamins A, B6, B12, C and E, beta-carotene and
selenium are often lowered in this group of patients.5,53 The supplemen-
tation of these micronutrients has an immunomodulating effect and
strengthens the cellular defense.53 In some studies the administration of
vitamins C and E reduced the oxidative stress and the viral load.5,53 In addi-
tion, an in-vitro study has shown that vitamin C inhibits the proliferation of
HIV-infected cells39 (14±2 days vs. 29±4 days in the placebo group; p=0.03).
Fawzi et al. (2004)33 demonstrated that the nutritive effect of multivitamins
will slow down the progression of an HIV infection. Moreover, the risk of
developing HIV-associated symptoms could be markedly reduced. These
symptoms include oral thrush, ulcers or aphthae, difficulty in swallowing,
nausea and vomiting, exhaustion and skin rashes. Taking the multivitamin
product also led to much higher CD4+ and CD8+ cell counts. As a result of
the significant reduction in the viral load (by 0.18 Log10) the time to the out-
break of AIDS or death could be prolonged by about 30%.
Chronic diseases or infections, such a pancreatitis55 or viral hepatitis, are
associated with high oxidative stress.69,89 Accordingly, in two prospective
double-blind trials a high vitamin E intake to support the treatment of
hepatitis B and C infections led to an improvement in the following clinical
parameters: ALT*, AST** and/or only ALT*.8,81 Chronic pancreatitis could also
be improved by supplementary intake of antioxidants (vitamin E, beta-
carotene, selenium).55 Another study showed that patients with chronic
active hepatitis, cirrhosis of the liver and liver cell carcinoma have low
serum levels of the antioxidant vitamin C.89
22 23
ratory tract diseases (14±2 days vs. 29±4 days in the placebo group; p<0.03).
Moreover, the supplement group took fewer antibiotics over the observation
period (supplement group 27±4 days vs. placebo group 58±5 days; p<0.02).
In the study by Barringer et al. (2003)11, a 12-month supplementation with a
micronutrient combination reduced the general risk of infection significant-
ly by 41%.
In the study by Langkamp-Henken et al. (2004)51, older people who had
taken a micronutrient combination for 183 days had a considerably better
immune function than the placebo group and recovered from respiratory
tract infections much faster. They also formed more antibodies after an
influenza vaccination.
Athletes have an increased risk of infection, mainly due to the oxidative
stress under great physical exertion. Also, the body’s own production of cor-
ticosteroids, which depresses the activity of the immune system, increases
under high-level physical strain. The preventive benefit of antioxidants was
clearly demonstrated in placebo-controlled studies. Thus, the infection rate
of athletes declined by about 50% after they had taken vitamin C.41
In several clinical trials it was shown that taking vitamin A markedly reduces
the morbidity and mortality involved in various infectious diseases, among
them measles, pneumonia, malaria and HIV infection.72 Animal studies have
shown that a deficiency in selenium and vitamin E may increase the virulence
of viruses. The assumed mode of action is probably the genetic mutation of
the pathogen caused by the excess amount of free radicals.13 People infected
with HIV and AIDS patients have an increased need for micronutrients. These
patients display elevated oxidative stress.
* ALT: Alanine Aminotransferase
** AST: Aspartate Aminotransferase
Inflammatory phase
Erythrocytes
Neutrophils
Plasma cells
Giant cells
Remodelling phase
Proliferative phase
Fibroblasts
Macrophages
Fig. 9. Wound healing phases and cell types involved
2524
The body reacts to detrimental irritations by releasing a large number of
mediators. In this complex reaction, the various proinflammatory cytokines
and free radicals become fully effective. A very strong defensive reaction
may cause extended tissue damage and/or chronicity of inflammatory
processes. Endogenic antioxidants, such as glutathion, and exogenic anti-
oxidants, such as vitamins C and E, phytonutrients (carotenoids and bioflavonoids) as well as trace elements (zinc, selenium and copper) can
regulate cytokine production and protect the tissues against the damage
caused by free radicals. Therefore, micronutrient supply is one of the factors
influencing the outcome of inflammatory processes.34
Patients with chronic inflammation, such as hepatitis, pancreatitis or COPD,
also suffer from increased oxidative stress and therefore benefit from an
extra supply of antioxidants as well.3,8,69,78,79,81
Patients with pressure ulcers show signs of a systemic inflammatory reac-
tion. Thus, they demonstrate an elevated level of oxidative stress and re-
duced serum concentrations of important antioxidants. This should be
taken into account in the treatment of pressure ulcers.25 In general, smaller
or larger wound areas after accidents, inflammatory processes or surgery
do not heal as fast as would be possible under optimum circumstances.
The cause may be a micronutrient deficiency. As the immune system is
under an immense strain during the phase of wound healing (Fig. 9), it is
important to ensure an adequate supply of vitamins and trace elements.
Keeping inflammation under control
Micronutrients and wound healing
2726
Vitamins C, B6, copper and manganese are essential to the collagen syn-
thesis because, as enzyme cofactors, they are responsible for cross-linking
the collagen fibers.12,57 Vitamin A promotes the differentiation of epithelial
cells. Vitamin E protects the lipids of the cell membrane against oxidation
and thus reduces the oxidative stress caused by injuries. Selenium, a trace
element and a building block of antioxidant enzymes, also counteracts
oxidative stress.57
The B vitamins, especially pantothenic acid, promote wound healing by
stimulating the synthesis of fatty acids and collagen.57
A lack of zinc, on the other hand, will disturb wound healing.1,57 Zinc, as a
component of various metalloenzymes, is absolutely necessary for protein
biosynthesis and cell division and thus accelerates wound healing. In addi-
tion, zinc stimulates the lymphocytes and activates the macrophages.74
The iron of the hemoglobin is important for the transport of oxygen to
the wound area.14 It also supports collagen synthesis.14 Thus, the optimum
supply of micronutrients is a crucial factor for rapid wound closure and
tissue regeneration (Table 6).
Table 6. Role of important micronutrients for wound healing
Vitamin A Liver, milk, eggs Supports cell division and cell differentiation, stimulation of epithelial cells
Yellow and orange fruits and dark green leafy vegetables
Micronutrient Sources Features and characteristics
Selenium Radical scavenger
B vitamins Components of enzymes of the energy metabolism, collagen synthesis (vitamin B6)
Vitamin C Collagen formation, enhance- ment of immune defense, radical scavenger, contributes to the regeneration of vitamin E
Vitamin E Enhancement of immune defense, radical scavenger
Vitamin K1 Stimulation of blood clotting
Copper Cofactor of enzymes which cross-link collagen and elastin
Zinc Increase of cytokine formation, stimulation of lymphocytes, activation of macrophages, radical scavenger
Meat, cereals, milk, green vegetables, fish, potatoes
Seafish, eggs, meat, cereals
Citrus fruits, vegetables, potatoes
Oils, nuts, eggs, giblets
Milk, giblets, green vegetables
Liver, nuts, wholemeal products, legumes
All foods of animal origin
Beta-carotene High antioxidant potential
COPD and increased oxidative stress
COPD exacerbation Stable phase Control
2.5
0
2
1.5
1
0.5
Vitamin A (µg/dl) Vitamin C x10 (µg/ml) Vitamin E (µg/ml) MDA (nmol/ml)
2928
In an allergy the reactivity of the immune system is pathologically in-
creased. The contact with the antigen triggering the allergy will lead to
an excessive formation of IgE-antibodies and/or, with a time delay, to
the release of lymphokines from specifically sensitized T lymphocytes.
Histamine released from mast cells causes typical symptoms, such as
swelling, urtication and itching.
In animal experiments it was found that high vitamin E doses can suppress
allergic symptoms.92 Moreover, vitamin C acts as a histamine antagonist.
People with a low vitamin C level have elevated plasma histamine concen-
trations.
In patients with a histamine, intolerance foods like red wine or cheese that
contain this biogenic amine will cause headaches and other allergic symp-
toms. It is suggested that this may be due to a reduced activity of diamin-
oxidase, an enzyme that degrades histamine. Besides a low-histamine diet,
a larger supply of vitamin B6 will improve the symptoms because vitamin B6
increases the diaminoxidase activity.45
A number of studies have shown that patients with chronic inflammation
of the respiratory tract (asthma and COPD*) suffer from elevated oxidative
stress.35,58,79,82 In asthma and COPD patients the impaired pulmonary func-
tion is reflected by an imbalance in oxidant and antioxidant substances.60
In the study by Tug et al. (2004)79 the oxidative stress of COPD patients rose
during an acute episode and remained high also in the subsequent stable
phase. The rise in oxidative stress was reflected by an increase in lipid per-
oxidation, i.e. elevated malondialdehyde (MDA) levels, a reduced glutathion
peroxidase activity, and a low vitamin C level.35,79,82
Interestingly, the vitamin A and E serum concentrations declined in the
acute phase of a COPD attack (Fig. 10).79 In the study by Kelly et al. (1999)49
asthma patients also had lower vitamin C and E concentrations, larger quan-
tities of oxidized glutathione in the respiratory tract secretion and elevated
oxidative stress. Compared with healthy controls, COPD patients had greatly
increased MDA values, and thus higher oxidative stress, after physical exer-
tion. After taking vitamins E and C for one month, the same COPD patients
no longer displayed increased MDA levels after physical exertion, and the
maximum physical load period was significantly longer.3 Thus, antioxidants
can mitigate the detrimental effects of oxidative stress if patients with a
chronic pulmonary disease take nutritive measures.
Ocht-Balcom (2006)60 was able to show that a similarly high intake of anti-
oxidants ingested through food by patients with chronic respiratory tract
diseases obviously leads to lower plasma levels than it does in healthy
subjects.
Allergies, asthma and COPD
Fig. 10. Mean serum level of stress markers and antioxidant vitamins79
* p<0.01: COPD exacerbation vs. stable phase, COPD exacerbation vs. control
Mean serum level
31
This may be due to an elevated need for antioxidants in patients with asth-
ma and COPD, which probably results from the higher oxidative stress (e. g.
due to inflammatory processes).60 The results of the study suggest that an
insufficient supply of antioxidants may play a role in asthma development
and intensity. Low antioxidant levels could make these patients more
susceptible to inhaled allergens.49 An increased intake of antioxidants
ingested through food or as supplementation might thus have a beneficial
influence on the pulmonary function of asthma patients.22
It appears that carotenoids also play an important part in asthma patho-
genesis. Asthma patients have lower blood carotenoid levels. If the caro-
tenoid levels are raised by means of supplementation, the carotenoid
concentration in the respiratory tract will also rise.88
Selenium as a component of the antioxidant enzyme glutathione peroxi-
dase is important for the antioxidant protection and immune system of
asthma patients. Asthma patients with increased oxidative stress tend to
have a lower selenium status and a reduced glutathione peroxidase ac-
tivity. Supplementation with selenium in combination with the standard
asthma medication helps reduce the oxidative stress, improve the immune
response and thus mitigate the asthma symptoms.
The modulation of the antioxidant potential by the intake of antioxidants
and selenium through food or as supplements could therefore help reduce
the asthma severity and the secondary damage caused by COPD and
increase the physical strength of COPD patients.3,35,49,58,60,79
30
Reducing the cancer risk – supporting tumor therapy
Vitamins and other micronutrients are not a cure for malignant tumor
diseases. Under no circumstances must they take the place of the appro-
priate therapeutic methods of orthodox medicine, such as surgery,
chemotherapy or radiation therapy. But, combined with other elements
of a healthy lifestyle, they can contribute to primary and secondary preven-
tion and in many cases actively support medical therapy. The reports over
the last decades dealing with the beneficial effects especially of antioxidant
micronutrients were repeatedly confirmed by controlled studies over the
past few years.
Besides environmental factors and genetic disposition, lifestyle and nutri-
tion are important factors for the development of cancer. According to
some estimates, the Western diet is responsible for about 40 % of all tumor
diseases. It is a high-fat diet deficient in dietary fibers, polyunsaturated fatty
acids, vitamins and trace elements.67 The insufficient consumption of fruit
and vegetables is associated with a higher cancer risk probably connected
with the resulting inadequate supply of vitamins and trace elements.
A deficit of iron, zinc, folic acid, vitamins B6, B12 and C can damage the
DNA and thus promote the development of cancer.7
In addition, a large number of epidemiological studies were able to show
a correlation between the lack of certain antioxidants, trace elements (such as selenium) or vitamins and the risk of developing various types of
cancer. Thus, a deficit of vitamins A, C and E or carotenoids was correlated
to the cancer incidence just as frequently as an undersupply of vitamins D3,
B6, B12 and folic acid (Table 7).80 Numerous studies have demonstrated that
vitamin C helps prevent cancer of the bladder, breast, cervix and colon and
a number of other tumors.48 People with a deficiency of vitamin D were
found to have an elevated colon cancer risk.7
3332
Other studies with people at risk showed a significantly lower risk for cer-
tain tumor diseases when micronutrient consumption was high:
• A nutrition intervention study in Linxian (China) including 30,000 subjects
showed that the daily intake of beta-carotene, vitamin E and selenium
could considerably reduce the esophageal and gastric cancer risk which
is particularly high in that part of the world. The mortality of both types of
cancer declined by about 20 %, the number of cases by 10 %.17 Total mor-
tality and the mortality due to cerebrovascular diseases were also lower.17
• The daily consumption of a combination of vitamins A, C and E led to a
lower recurrence rate after the removal of colorectal polyps.86
• A recent meta-analysis of 14 studies including a total of 351,077 subjects
(thereof 8,816 cancer patients and 342,261 healthy subjects) proved that
the daily intake of 1,000 IU (= 25 μg) of vitamin D reduced the colon
cancer risk by 50%.36
• Over an average period of 14.8 years, Larsson et al. (2005)52 observed
61,433 Swedish women aged between 40 and 76 who did not show any
signs of cancer at the beginning of the trial. When the study started (in
1987-90) and in 1997 the vitamin B6 quantity ingested through food and
the alcohol consumption were determined by means of a questionnaire.
After an average period of 14.8 years, 805 colon cancer cases were iden-
tified. The long-term intake of vitamin B6 was significant and inversely
correlated to the colon cancer risk.
• A prospective cohort study (Nurses’ Health Study) found that folic acid counteracts the elevated breast cancer risk resulting from regular alcohol
consumption. Women who consumed alcohol had a 50 % lower relative
breast cancer risk if they took at least 600 μg of folic acid daily. This high
amount of folic acid was mostly taken in the form of multivitamin prod-
ucts.91
• Other studies have shown that a high folic acid intake and/or high folic
acid blood levels are associated with a low relapse risk of colorectal ade-
noma (reduction of 34 % and 39 %, respectively). A low homocysteine level
and a high vitamin B6 intake were also associated with a lower relapse
rate.54
• In a recent pilot study with patients suffering from precarcinomatous
laryngeal leukoplaquia who were given folic acid (3 x 5 mg per day) over
a 6-month period, a beneficial effect was noted. In 72 % of the treated
patients the precarcinomatous leukoplaquia shrank by at least 50 % or
even disappeared completely. According to the investigating scientists,
folic acid products could therefore be used for the secondary prevention
of such risks.6
People who are suffering from cancer have increased oxidative stress and
low antioxidant concentrations. This was found, among others, for breast,
cervix and colon cancer.64,75,90 The authors assume that oxidative stress has
an influence on cancer development.64,75,90 Such patients therefore have an
elevated need for antioxidants.
Thus, the nutritive supplementation of antioxidants can counteract oxidative
damage resulting, for instance, from increased lipid oxidation.75,90 Thanks to their
nutritive and physiological characteristics,68 antioxidants are able to:
• Increase the effectiveness of chemotherapy, radiation therapy and hyperthermia
• Reduce the expression of oncogenes in cancer cells• Induce differentiation of cancer cells• Strengthen the body’s own defenses• Mitigate the toxicity of cancer therapy
35
Chemotherapy and radiation therapy make use of the difference between
normal tissue and uncontrollably growing tumors in order to destroy the
cancer cells as selectively as possible. Many studies have shown that
micronutrients:
• Differ in their effect on cancer and normal cells In cultured rodent and human cancer cells, the treatment with antioxidant
vitamins (vitamins C and E) and beta-carotene induces cell differentiation
and inhibits cell growth. The underlying mechanisms are complex. Vitamins
A and E, for instance, enhance growth-inhibiting signals (e. g. by protein
kinase C inhibition) and lead to a reduction in oncogene expression (e. g.
c-myc and H-ras). Moreover, vitamin E increases the production and release
of TGF-β, a growth inhibitor, and reduces the phosphorylation and activity of
transcription factor E2F which plays a central role in cell proliferation.68 Beta-
carotene, for instance, inhibits the growth of cell lines from human prostate
gland carcinomas.87 In vitro vitamins D, E and K as well as beta-carotene
induce in many tumor cell lines the “programmed cell death” (apoptosis),
whereas this effect is not observed in healthy cells.23 The most powerful
proaptotic effect is reached by a combination of vitamins C and E.23
• Support the effect of standard therapiesInitial results show that individual antioxidant vitamins or a combination of
several vitamins enhance the growth-inhibiting effect of radiation therapy,
chemotherapy and hyperthermal treatment.68 A large number of cell and
animal studies indicate that vitamins A, C and E and beta-carotene increase
the growth-inhibiting effect of many cytostatic drugs (such as cisplatin) or
radiation therapy.24,68
Micronutrients in oncology
34
37
Effects of anticancer therapy on nutritional status
Mucosal irritation through antineoplastic agents
• Inflammations• Vomiting, diarrhea
• Loss of appetite
Fig. 11.
Surgical interventions• Difficulty with chewing and swallowing • Malabsorption
Chemotherapy • Anorexia• Nausea• Vomiting• Infections• Malabsorption• Reduction of white blood cell and platelet numbers
Formation of free radicals
Radiation therapy• Nausea• Difficulty with chewing and swallowing • Taste disturbance or loss• Dryness of the mouth
37
Moreover, the synergies between vitamin A and tamoxifen increase the apoptosis
of cultivated breast cancer cells.83 Prasad et al. (1994)66 also found that the growth
of human melanoma cells can be inhibited much more effectively by chemo-
therapeutic drugs, such as cisplatin, as well as by decarbazin and tamoxifen, when
vitamin C alone, a combination of beta-carotene with a vitamin E and vitamin A
derivative, and the combination of vitamin C, beta-carotene and the vitamin E
and A derivative was taken. The combined administration of several vitamins had
the most powerful effect.66 These micronutrients support each other functionally.
Thus, for instance, vitamin C restores the antioxidant function of vitamin E.15
• Counteract many adverse effects of cancer therapyIn animal experiments vitamins C and E reduce the toxic effect of the antineo-
plastic drugs doxorubicin and bleomycin on healthy cells.68 Healthy body cells
seem to accumulate far lower antioxidant levels than cancer cells, so that healthy
cells are protected against the growth inhibiting effects of standard cancer ther-
apy, whereas the high antioxidant levels in the cancer cells trigger the growth
inhibiting signals and differentiations mentioned. Thanks to this selective action,
chemotherapy can be made less toxic.68
• Diminish the side effects of the therapyChemotherapy and radiation therapy are a considerable strain on the immune
system. Tumor surgery that may be required also burdens the immune system.
Micronutrients are then needed, e. g. for wound healing. At the same time, the
intake and resorption of nutrients may be impaired by lack of appetite, vomiting
and diarrhea. Therefore, tumor treatment should be supported by an adequate
supply of micronutrients helping the immune system to recover, strengthening
the defense against infections and promoting wound healing (Fig. 11).
36
39
Micronutrients Sources Features and characteristics
Carotenoids
Bioflavonoids
Selenium
Zinc
Copper
Manganese
Iron
Iodine
Fruit and vegetables
Fruit and vegetables
Seafish, meat, eggs, cereals
Meat, fish, cheese
Liver, nuts
Cereals
Meat
Seafish
Antioxidant effects Supports the immune system
Antioxidant effects, as natural antioxidants support the effect of vitamin C
Important for the blood formation and oxygen transport in the blood
Important effect on thyroid function
38
Micronutrients Sources Features and characteristics
Table 7. Sources of micronutrients and their features and characteristics, especially related to cancer diseases
Vitamin B1
(thiamin)
Vitamin B2
(riboflavin)
Pantothenic acid
Nicotinamide
Vitamin B6
(pyridoxine)
Vitamin B12
(cyanocobalamin)
Folic acid
Biotin
Vitamin K1
Vitamin D3
Vitamin C
Vitamin A
Vitamin E
Pork, cereals
Cheese, meat, fish
Meat, fish, cheese, eggs
Meat, fish, mushrooms, cereals
Meat, fish, vegetables (Brussels sprouts, avocado)
Meat, liver, kidney, milk, fish
Green vegetables, giblets
Eggs, fish, giblet
Green vegetables (curly kale, broccoli)
Fish, milk
Fruit, vegetables (esp. paprika, broccoli)
Liver, carrots, tuna, cheese
Vegetable and fish oils, nuts, eggs, giblets
Optimization of cell functions Important for the energy metabolism
Optimization of cell functions Important for the energy metabolism
Optimization of cell functions Important for the energy metabolism
Important for the energy metabolism
Optimization of cell functions Important for the energy metabolism
Important for blood formation
Stimulation of cell formation
Optimization of cell functions
Essential factor in the blood clotting system Supports the bone metabolism
Supports the bone metabolism
Antioxidant, supports the immune system Involved in the regeneration of vitamin E Required for the collagen synthesis
Supports cell division and function Important for the immune system
Antioxidant, supports the immune system
Components of antioxidant enzymes Support the immune system
41
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