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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