ProHealth health Vitamin and Natural Supplement Store and Health
Home  |  Log In  |  My Account  |  View Cart  View Your ProHealth Vitamin and Supplement Shopping Cart
800-366-6056  |  Contact Us  |  Help
Facebook Google Plus
Fibromyalgia  Chronic Fatigue Syndrome & M.E.  Lyme Disease  Natural Wellness  Supplement News  Forums  Our Story
Store     Brands   |   A-Z Index   |   Best Sellers   |   New Products   |   Deals & Specials   |   Under $10   |   SmartSavings Club

Trending News

10 Fibro-Friendly Foods with a Bonus: Beautiful Skin

Fight Back! Win the War Being Waged Against Your Immune System

Studies Show that Magnesium L-threonate Improves Brain Plasticity, Leading to Direct and Significant...

The role of microbiota and intestinal permeability in the pathophysiology of autoimmune and neuroimm...

Clary Sage Oil May Be Pricey, but Its Benefits Are Priceless

Component of red wine, grapes can help to reduce inflammation, study finds

Poly MVA: A Novel Therapy for Increasing Energy, Repairing DNA, and Promoting Overall Health

Pumpkin Pie Turmeric Breakfast Smoothie - Vegan + Gluten-Free

Vitamin D supplementation extends life in mouse model of Huntington's disease

What’s Fenugreek Good For?

Print Page
Email Article

The Role of Vitamin A Deficiency in Autoimmune Diseases Including Gulf War Syndrome, Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, and Fibromyalgia

  [ 280 votes ]   [ Discuss This Article ] • November 25, 2002

By Frederick W. Plapp, Jr. Ph.D.  Professor Emeritus of Insecticide Toxicology, Texas A&M University,


Immune system dysfunction may be a cause of multiple human autoimmune
diseases, ranging from rheumatoid arthritis to multiple chemical
sensitivities and Gulf War Illness. A lack of vitamin A hormone (retinoic
acid) appears to play a key role in autoimmune disease. The deficit may be
the result of a genetic deficiency in synthesis of the hormone, of exposure
to environmental chemicals which interfere with hormone synthesis, or of a
combination of the two. Prevention may be achieved by the use of vitamin
A-rich diets and/or by avoidance of exposures to appropriate environmental


Vitamin A (retinol) and vitamin A hormone (retinoic acid) comprise one of
the major human hormone systems. The importance of vitamin A in regulating
visual accommodation as measured by both dark adaptation and photosensitivity
has been known for many years.

Additional roles for vitamin A/retinoic acid have been recognized more
recently. These include activation of synthesis of immune system proteins,
activation of enzyme synthesis relative to apoptosis (killing off old cells)
and drug metabolism, activation of protein synthesis related to
neurotransmission, and activation of protein synthesis relating to
reproduction. These findings suggest that quantitative changes in the
vitamin A system may relate to health problems involving these areas.
Without normal levels of vitamin A hormone, these systems are not fully

Variations between individuals in levels of vitamin A are known to occur
in human populations and, as described below, deficiency in vitamin A may
relate to increased frequencies of autoimmune diseases as compared to the
general population. Sub-populations such as those who served in the 1990-1991
Persian Gulf War also seem to be at greater risk than the general population.
In addition, exposure of humans to various environmental chemicals such as
pesticides and other endocrine disrupters may result in poisoning both the
transport and synthesis of vitamin A. Individuals at greatest risk of
autoimmune disease appear to be those who combine the genetic deficiency with
chemical exposures. Material in support of this hypothesis follows.


The occurrence of diseases associated with malnutrition/vitamin A
deficiency is well established in developing countries. Vitamin A deficiency
is clearly associated with blindness in children (xerophthalmia) (see ref.
1). Higher infant mortality rates (2) and morbidity and mortality associated
with infectious diseases (3) have also been demonstrated in vitamin A
deficient children.

Vitamin A deficiency is associated with a predisposition to
Staphylococcus aureus infection in rats (4). The authors also reported that
host defense mechanisms are “profoundly affected” by Vitamin A deficiency.

Vitamin A deficiency is “strongly associated” with impaired immunity and
infectious disease (5). Vitamin A deficiency impairs innate immunity and is
also related to adaptive immunity (6).

Examples of autoimmune diseases associated with vitamin A deficiency
include rheumatoid arthritis (7), juvenile arthritis (8), Lyme disease (9),
systemic lupus (7), and insulin dependent diabetes mellitus (10, 11).
Evidence has been reported from several studies that low vitamin A levels
occurred in affected individuals before they became ill. In other words, the
lack of vitamin A is associated with development of the disease and is not a
consequence of them.

Several human cancers have been reported to be associated with vitamin A
deficiency (e.g. 12). Similarly, vitamin A levels are depleted in individuals
with HIV/AIDS (13).

A number of neurological conditions may also relate to vitamin A
deficiency. Lack of retinoic acid depresses synthesis of dopamine D2
receptors in mice suggesting a key role for retinoic acid in central nervous
system gene expression (14). Further, a lack of retinoic acid induces a
Parkinsonism-like condition in rats (15). The mouse hippocampus is a site of
robust retinoid synthesis and retinoids are essential competence factors in
the adult mouse brain (16). Similarly, retinoids are required for normal
brain signaling in aged mice (17), suggesting a role for retinoids in optimal
brain functioning in older individuals.

As described above, a possible role of vitamin A deficiency seems well
established for a number of human illnesses. To the best of my knowledge,
there have not been studies directly investigating the relationships between
vitamin A and any of the several Gulf War Illnesses. Similarly, there seem
to be a dearth of studies involving vitamin A and more recently recognized
conditions as chronic fatigue syndrome, fibromyalgia, and multiple chemical
sensitivity. I propose such studies are badly needed. At the very least, the
ideas presented here represent testable hypotheses and thus, are amenable to
scientific study.


Deficiency of vitamin A occurs frequently in humans and wildlife exposed
to a wide array of environmental chemicals. Several processes appear to be
involved. One is the binding of environmental chemicals to transthyretin,
the protein which transports thyroid hormones and the retinol-retinol binding
protein complex from sites of synthesis to sites of action. Evidence for
poisoning of this process by environmental chemicals was first reported by
Brouwer and Van Den Berg (18).

The second process, poisoning of proteins involved in the synthesis of
vitamin A, has not been systematically investigated. The apparent crucial
step is inhibition of the esterases that hydrolyze fat-soluble retinyl esters
such as retinyl acetate and retinyl palmitate. This inhibition blocks the
conversion of these esters to retinol.

The third process involves interference with the oxidation of retinol, the product of retinyl ester hydrolysis, to retinoic acid, the active hormone. Retinol is oxidized via a two step process. The first step converts retinol to retinaldehyde and the second step converts retinaldehyde to retinoic acid (19,20). This step is also subject to poisoning. The synthetic chemicals, formaldehyde and acetaldehyde, both used in resin components of building products such as plasterboard and carpeting, are oxidized by the same process that converts retinaldehyde to retinoic acid. The presence of these competitors blocks the final step in hormone production and may be responsible for the human illness known as Sick Building Syndrome.

Different types of chemicals are involved in the different poisoning
processes. Chlorinated phenoxyphenyls such as tetrachlorodioxin (TCDD), the
major chemical involved in Agent Orange poisoning in Viet Nam, and
polychlorinated biphenyls (PCB), a widely used plasticizer, both bind to
transferrin and are well known as causes of human health problems. Hepatic
vitamin A depletion in TCDD-treated rodents is a sensitive marker of TCDD
exposures (21). Similar findings have been reported with exposures to PCBs
and polybrominated biphenyls (22). Several types of insecticides, notably
diphenyl ethanes such as DDT, and the phenoxybenzyl chlorinated pyrethroids
such as permethrin and cypermethrin are potential transferrin poisons, but
have not apparently been evaluated in this regard.

The second process, inhibition of retinyl ester hydrolysis by chemicals
used in the Persian Gulf, has not been evaluated. It is well known that
organophosphate and carbamate insecticides are poisons of many esterases,
blocking reactions ranging from hydrolysis of acetylcholine to hydrolysis of
long chain fatty acid esters. Pyrethroid insecticides are known as
substrates for multiple esterases and may reduce esterase activity via
competition for active sites.

Human exposure to subacute doses of esterase inhibitors is widespread in
both military and civilian populations. Permethrin aerosol formulations were
routinely made available to personnel in the Persian Gulf for self treatment
of uniforms to protect against biting and disease carrying insects. I have
not been able to determine if pretreated uniforms were issued to personnel in
the Gulf or if uniforms were retreated with these chemicals at military
laundry facilities in the Gulf. However, it is well established that the
military has been developing the use of permethrin for treatment of uniforms
since the early 1980s.

High rates of Gulf War illnesses occurred in rear area personnel such as
nurses. Sanitation and regular clothing changes are necessary for hospital
service and laundry treatment of uniforms with permethrin is a possible cause
of their health problems (personal communications with Gulf War veterans).

Exposures to residues of insecticides applied to interior living and
working areas, and to lawns and gardens have produced similar responses in
civilians (numerous personal communications). Based on my knowledge of the
action of potential esterase inhibitors in combination with low dose
exposures to chemical toxicants, these residue treatments offer a plausible
explanation for health problems in civilians similar to those seen in Persian
Gulf veterans.


The only biochemical variations clearly shown to relate to Gulf War
Illness are the several mutations in the sequence of the esterase gene PON-1,
also known as paraoxonase or paraoxonase-1, as well as mutations in upstream
promoter regions. PON1 is an esterase capable of metabolizing paraoxon, the
active form of the organophosphate insecticide parathion, as well as oxon
forms of other phosphorothionate insecticides. Sick Gulf War veterans from a
small test population were shown to have lower levels of PON1 activity than
their healthy peers (23) and also to have a greater frequency of the less
frequent R allele as compared to the Q allele than healthy veterans. Low
PON1 activity is also characteristic of individuals with type 1 diabetes
(24). Evidence of mutations in promoter sequences has been reported (25)
along with evidence the mutations can cause large changes in PON1 activity.

The natural function of the PON1 esterase is not known. The idea it
evolved in order to react with insecticides developed in the 20th century is
not evolutionarily sound. There are suggestions that PON1 functions to
protect against oxidative damage associated with high and low density
lipoproteins (26) and other evidence it may relate to coronary disease (27).
Alternative functions such as hydrolyzing lipophilic hormone precursors, e.g.
retinyl esters, seem not to have been considered. It may be worthwhile to
determine if competition between endogenous hormone-related chemicals and
xenobiotics could increase our knowledge of the esterase and its possible
role in Gulf War Syndrome and other autoimmune diseases.


1. McLaren DS. 1999, J Indian Med Assoc 97:320

2. Semba RD et al. 1998, J Trop Pediatr 44:232

3. Donald PR et al. 1995, S Afr Med J 85:373

4. Wiedermann U et al. 1996, Infect Immun 64:209

5. Harbige LS. 1996, Nutr Health 10:285

6. Stephenson CB. 2001, Annu Rev Nutr 21:167

7. Comstock GW et al. 1997, Ann Rheum Dis 56:323

8. Helgeland M et al. 2000, Clin Exp Rheumatol 18:637

9. Cantorna MT, Hayes CE. 1996, J Infect Dis 174:747

10. Krill D et al. 1997, Hum Biol 69:89

11. Baena N et al. 2002, Eur J Clin Nutr 56:44

12. Sun SY, Lotan R. 2002, Crit Rev Oncol Hematol 41:41

13. Kafwembe EM et al. 2001, East Afr Med J 78:451

14. Samad TA et al. 1997, Proc Natl Acad Sci 94:14349

15. Wolf G. 1998, Nutr Rev 56:354

16. Misner DL et al. 2001, Proc Natl Acad Sci 98:11714

17. Etchamendy N et al. 2001, J Neurosci 21:6423

18. Brouwer A, van den Berg KJ. 1986 Toxicol Appl Pharmacol 85:301

19. LaBrecque J et al. 1993, Biochem. Cell Biol. 71:85

20. Tomita S et al. 1993, FEBS Lett. 336,272

21. Fletcher N et al 2001, 62:166

22. Hallgren S et al. 2001, Arch Toxicol 75:200

23. Haley RW et al. 1999, Toxicol Appl Pharmacol 157: 227

24. Mackness B et al. 2002, Eur. J Clin Invest 32:259

25. Furlong CE et al. 2000, Neurotoxicology 21:91

26. Brophy VH et al. 2001, Pharmacogenetics 11:77

27. Mackness B et al. 2000, Eur J Clin Invest 30:4

(c) 2002 Frederick W. Plapp, Jr. Ph.D. Reprinted with permission from the author.

Post a Comment

Featured Products From the ProHealth Store
Energy NADH™ 12.5mg Vitamin D3 Extreme™ Ultra ATP+, Double Strength

Looking for Vitamins, Herbs and Supplements?
Search the ProHealth Store for Hundreds of Natural Health Products

Article Comments

Be the first to comment on this article!

Post a Comment

Natural Pain Relief Supplements

Featured Products

Optimized Curcumin Longvida® Optimized Curcumin Longvida®
Supports Cognition, Memory & Overall Health
FibroSleep™ FibroSleep™
The All-in-One Natural Sleep Aid
Energy NADH™ 12.5mg Energy NADH™ 12.5mg
Improve Energy & Cognitive Function
Vitamin D3 Extreme™ Vitamin D3 Extreme™
50,000 IU Vitamin D3 - Prescription Strength
Ultra EPA  - Fish Oil Ultra EPA - Fish Oil
Ultra concentrated source of essential fish oils

Natural Remedies

Thyroid Health and Fibromyalgia Thyroid Health and Fibromyalgia
Nutrients to Combat the Modern Stress Epidemic Nutrients to Combat the Modern Stress Epidemic
Coenzyme Q10 - The Energy Maker Coenzyme Q10 - The Energy Maker
Coping When Colds or Flu Catch Up with You Coping When Colds or Flu Catch Up with You
Guarding Against the Dangers of Vitamin D Deficiency Guarding Against the Dangers of Vitamin D Deficiency

ProHealth, Inc.
555 Maple Ave
Carpinteria, CA 93013
(800) 366-6056  |  Email

· Become a Wholesaler
· Vendor Inquiries
· Affiliate Program
Credit Card Processing
Be the first to know about new products, special discounts and the latest health news. *New subscribers only

CONNECT WITH US ProHealth on Facebook  ProHealth on Twitter  ProHealth on Pinterest  ProHealth on Google Plus

© 2016 ProHealth, Inc. All rights reserved. Pain Tracker App  |  Store  |  Customer Service  |  Guarantee  |  Privacy  |  Contact Us  |  Library  |  RSS  |  Site Map