Five Stages of Nutrient Deficiency Leading to Disease
by Richard Gerber

In 1964 Myron Brin published a classic analysis of the five stages in the development of a vitamin or nutrient deficiency. He illustrated the schema with reference to vitamin B1 (thiamin).

  1. In the first, or preliminary stage, inadequate B1 availability due to faulty diet, malabsorption or abnormal metabolism leads to a greatly reduced urinary B1 loss.
  2. In the second, or biochemical stage, the activity of a key enzyme—transketolase—which is activated by B1, is significantly reduced. Adding B1 to a blood sample from a person at this stage increases his or her transketolase activity.
  3. In the third, or physiologic stage, various general symptoms develop, such as lessened appetite, insomnia, increased irritability, and malaise.
  4. In the fourth, or clinical stage, a constellation of symptoms classically specific to B1 deficiency disease (beri-beri) develops: e.g., intermittent claudication, polyneuritis, bradycardia, peripheral edema, and ophthalmoplegia (paralysis of eye muscles).
  5. In the fifth, or anatomical stage, histopathological changes due to cellular structural damage are seen, such as cardiac hypertrophy, degeneration of the cerebellar granule layer, and swelling of the microglia.8

    Although Brin’s five-stage deficiency schema is exemplified with regard to B1, it is in principle applicable to any nutrient, as Brin himself notes. Brin’s schema is especially illuminating with regard to the RDAs, since the “just preventing failure of specific functions” and “just preventing specific deficiency signs” criteria of nutritional requirement, which is the basis of the RDA concept, are only evidenced in the fourth (clinical) and fifth (anatomical) stages of developing nutritional deficiency disease.

    The first three stages, although they are objectively, empirically measurable and observable phases of a developing nutrient deficiency, do not involve either “specific deficiency symptoms” or “failure of a specific nutrient-related function.” What follows from this is quite simple. The RDA level of nutrient intake may keep most people out of the severe illness-leading-to-death fourth and fifth nutrient deficiency stages, but RDA nutrient levels cannot be presumed to be adequate to keep one out of the first three stages of “subclinical” deficiency, let alone in a more optimal, vibrant, energized state of health.

    Genetic Need for High-Dose Vitamins
    A recent major scientific review article by famed nutrition researcher Bruce Ames and colleagues makes it clear that for many people, the RDAs will not be sufficient even to avoid major nutrient-related illness and death. Noting that a key function of many vitamins, minerals and nutrients is to activate the metabolic enzymes on which all life depends, the Ames group reports that about 50 human genetic diseases caused by defective enzymes can be remedied or ameliorated through high-dose nutrient therapy, which at least partially restores defective enzyme activity.9

    Ames and coworkers point out that an alternate form of a gene which is present in 1 percent or more of the population is called a “polymorphism.” They state:

    Our analysis of metabolic disease that affects cofactor [nutrient] binding, particularly as a result of polymorphic mutations, may present a novel rationale for high-dose vitamin therapy, perhaps hundreds of times the normal dietary reference intake (DRI) in some cases. This area should interest the entire health community because of the considerable percentage of the population affected by polymorphisms…. The setting of a DRI may become more complicated if a sizable percentage of the population in fact has a higher B-vitamin requirement because of a polymorphism…. It also seems plausible that for each example of a genetic disease or polymorphism clearly involving derangement of metabolism, multiple forms of the disease exist that reflect [only] slight changes in [genetically defective enzyme activity] but that are not commonly thought of as genetic diseases…. The administration of high doses of vitamins may reverse, at least partially, many more genetic diseases than those described here.... Provided safe dosages are used…there is potentially much benefit and possibly little harm in trying high-dose nutrient therapy because of the…low level of risk. Most of the vitamins discussed here appear safe in relatively high doses because the body can discard excess.”9

    Given the large number of case reports analyzed in the Ames article, the question becomes less “Are high dose vitamins safe?” than “For many people, are RDA-only vitamin levels safe?” The Ames group reports a myriad of cases with people being snatched from the jaws of death or crippling disease by megadose (10-500X RDA) nutrient therapy, who would have perished or suffered irreparable harm on mere RDA vitamin doses. And some of the genetic enzyme defects discussed in the Ames article may affect millions of people—e.g., those leading to homocysteinemia.

    The Ames group also comments on the safety of even megadose levels of many nutrients. They report that 500 mg of B6 per day for two years appears to be safe, but that 1,000 mg/day is probably the maximum.9 No safe upper limit (UL) for B1 has been set because of its relative safety.9 No UL has been set for B2 because there have been few reports of adverse effects even with doses in the hundreds of milligrams.9 Adverse effects of niacin (B3) usually occur at doses over 1,500 mg, with the niacinamide form of B3 being even safer.9 No toxicity of biotin has been reported with doses of 200 mg/day or less.9 B12 therapy with 5000 mcg or less has resulted in few adverse effects.9 Due to a lack of reports of adverse effects, no UL has been set for pantothenic acid.9 Adverse effects with vitamin E are rare below 1,500 IU/day.9 (In a 1988 review article on vitamin E safety, Bendich and Machlin noted virtually no side effects in six double-blind human studies even up to 3,200 IU/day).10 Vitamin D side effects typically occur at doses of 10,000-50,000 IU.9

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    How did we qualify them ?

    1. Natural Products Insider, vol. 9 no. 1, 2004:p. 19.
    2. Ibid:p. 4.
    3. Institute of Medicine. Dietary Reference Intakes for Thiamin…and Choline. National Academies Press, 2000:p. 18.
    4. Ibid:pp. 18-19.
    5. Subar, A. et al, “Folate intake and food sources in the US population”, Am J Clin Nutr, 1989, 50:508-16.
    6. Crayhon, R. The Carnitine Miracle. NYC:M. Evans, 1998.
    7. National Academy of Sciences. Recommended Dietary Allowances. Wash. D.C.:National Acad. Sci. Press, 1980:1-3.
    8. Brin, M. “Erythrocyte as a biopsy tissue for functional evaluation of thiamin adequacy”. JAMA, 1964, 187:762-66.
    9. Ames, B. et al, “High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased Km): relevance to genetic disease and polymorphisms”. Am J Clin Nutr, 2002, 75:616-58.
    10. Bendich, A. & Machlin, L. “Safety of oral intake of vitamin E”. Am J Clin Nutr, 1988, 48:612-619.

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