This article consists of excerpts from Nutritional Medicine (Fritz Perlberg Publishing), a comprehensive textbook by Alan Gaby, MD. This new, landmark book is a thorough and practical compendium on the use of dietary change, nutritional supplements, and other natural products for the prevention and treatment of more than 400 health conditions.
Written for busy practitioners who need reliable but clinically-relevant information to guide patient care, Nutritional Medicine combines literature reviews, case reports, thorough background material and Dr. Gaby’s lifetime of clinical experience in applying nutritional approaches to manage complex disorders and to promote health and wellbeing.
In addition to thorough reviews of nutritional interventions for nearly all of the common chronic disorders, the book also includes 61 chapters on specific vitamins, minerals, amino acids, and other compounds, reviewing in detail the biochemical effects, clinical indications, interactions, preparations, dosage and administration.
Nutritional Medicine contains 1,374 pages and more than 15,000 references. It is priced at $295. For further information, visit www.doctorgaby.com or call 603-225-01354. The following excerpts give a sense of the scope of material in the book, and the clinically-focused way in which it is presented.
Vitamin K and Warfarin: Misunderstood Interaction
Warfarin works by inhibiting the vitamin K-dependent activation of coagulation factors II, VII, IX, and X. Because this inhibition is competitive in nature, the effect of warfarin is influenced by dietary vitamin K intake. Increasing vitamin K intake inhibits the action of warfarin, whereas decreasing vitamin K intake has the opposite effect. For this reason, patients taking warfarin should keep their dietary intake of vitamin K consistent. 1
Studies have shown that supplementation with 100-150 µg/day of vitamin K1 results in fewer fluctuations of the International Normalized Ratio (INR) outside the normal range, thereby reducing risk of thrombotic events resulting from under-treatment, and risk of hemorrhagic events resulting from over-treatment. Vitamin K supplementation probably improves the stability of anticoagulation by decreasing the relative change in total vitamin K intake associated with variations in dietary vitamin K.
Seventy warfarin-treated patients with fluctuating INRs were randomly assigned to receive, in double-blind fashion, 150 µg/day of supplemental vitamin K1 or placebo for 6 months. The percentage of time patients were within the target INR range increased to a significantly greater extent in the vitamin K group (from 59% at baseline to 87%) than in the placebo group (from 63% at baseline to 78%; p < 0.01 for the difference in the change between groups). More patients achieved stable control of anticoagulation in the vitamin K group than in the placebo group (54% vs. 21%; p value not stated). 2
Eight patients (aged 45-79 years) receiving warfarin, whose INRs had been fluctuating for reasons that were not clear, were given 100 µg/day of supplemental vitamin K1 for 8-72 weeks. After vitamin K supplementation, INR fluctuations decreased in nearly all patients. A significant decrease was seen in the INR standard deviation (p < 0.05), and more INRs were within 0.2 units of the target range (57% vs. 32% prior to supplementation). 3
Despite this evidence, many practitioners advise patients taking warfarin to restrict dietary vitamin K intake. That advice is inappropriate for 2 reasons. First, as noted above, lower vitamin K intake results in greater fluctuations of INR values. Second, restricting vitamin K intake requires the avoidance of leafy green vegetables, which decreases the quality of the diet.
1. Franco V, Polanczyk CA, Clausell N, Rohde LE. Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols. Am J Med 2004;116:651-656.
2. Sconce E, Avery P, Wynne H, Kamali F. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood 2007;109:2419-2423.
3. Reese AM, Farnett LE, Lyons RM, et al. Low-dose vitamin K to augment anticoagulation control. Pharmacotherapy 2005; 25:1746-1751.
Dementia and Vitamin B12
Vitamin B12 deficiency is well recognized as a cause of cognitive decline and dementia.4 Dementia due to vitamin B12 deficiency responds to vitamin B12 therapy, unless it has progressed to the point of irreversible brain damage.
The presence of a normal serum vitamin B12 level does not rule out vitamin B12 deficiency as a possible cause of cognitive impairment. Some patients with dementia who had normal serum vitamin B12 concentrations and normal hematological parameters were found to have subnormal or undetectable levels of the vitamin in their cerebrospinal fluid (CSF), suggesting that they had a defect in the transport of vitamin B12 across the blood-brain barrier or accelerated breakdown of the vitamin in brain tissue.5-6
In one study, subnormal CSF vitamin B12 levels were found in 9 of 12 patients with senile dementia, 5 of 6 with alcoholic dementia, and 0 of 5 patients with multi-infarct dementia. Vitamin B12 deficiency would have been missed in the vast majority of these patients if only serum vitamin B12 had been measured.
Parenteral vitamin B12 therapy (dosage and duration of treatment not specified) produced “clear” clinical improvement in some of these patients, but oral vitamin B12 was not beneficial.7 The lack of clinical improvement with oral therapy is consistent with the observation that CSF vitamin B12 levels did not increase in demented patients after oral administration of the vitamin, but did increase after intramuscular administration.
4. Hector M, Burton JR. What are the psychiatric manifestations of vitamin B12 deficiency? J Am Geriatr Soc 1988;36:1105-1112.
5. van Tiggelen CJM, Peperkamp JPC, Tertoolen HJFW. Assessment of vitamin B12 status in CSF. Am J Psychiatry 1984;141:136-137.
6. Mitsuyama Y, Kogoh H. Serum and cerebrospinal fluid vitamin B12 levels in demented patients with CH3-B12 treatment – preliminary study. Jpn J Psychiatry Neurol 1988;42:65-71.
7. van Tiggelen CJM, Peperkamp JPC, Tertoolen JFW. Vitamin B12 levels of cerebrospinal fluid in patients with organic mental disorder. J Orthomolec Psychiatry 1983;12:305-311.
Food Addiction and Opioid Peptides
It has been suggested that overeating is related to auto-addiction to endogenous opioid peptides. 8 That possibility is supported by the observation that administration of naloxone (an opioid antagonist) prevented stress-induced eating in rats9 and abolished overeating in genetically obese mice.10 In addition, administration of naloxone decreased ad libitum food intake in obese human volunteers. 11
An interaction with the opioid system might explain, above and beyond the purported allergy/addiction syndrome, why so many patients crave wheat or dairy products. Hydrolysis of wheat gluten and alpha-casein (a milk protein) by pepsin has been reported to yield peptides that have opioid activity.12 Since peptides can be absorbed intact into the bloodstream,13 these molecules have the potential to interact with the endogenous opioid system.
Depending on the efficiency with which a person’s digestive enzymes breaks down peptides into individual amino acids, and depending on the sensitivity of their endogenous opioid system to exogenous opioid peptides, different people may be more or less susceptible to becoming addicted to wheat or dairy products.
Addiction to refined sugar may also be mediated in part by the opioid system. In rats fed a 10% sucrose solution for 21 days or a 25% glucose solution for 8 days in addition to their usual chow, administration of naloxone caused biochemical imbalances in the brain that resembled the effects of morphine withdrawal. Naloxone did not produce these effects in rats fed chow alone.14
The recognition that the opioid system may contribute to addictive eating does not lead to any particular medical strategy for managing obesity, other than maintaining awareness that wheat, dairy products, and refined sugar may be common triggers for addictive eating. However, patients may benefit psychologically from the knowledge that their “lack of willpower” could have a physical basis. Such knowledge often makes it easier for patients to endure withdrawal symptoms, and to resume healthful eating after periodic lapses.
8. Kather H, Simon B. Opioid peptides and obesity. Lancet 1979;2:905.
9. Morley JE, Levine AS. Stress-induced eating is mediated through endogenous opiates. Science 1980;209:1259-1261.
10. Margules DL, Moisset B, Lewis MJ, et al. Beta-endorphin is associated with overeating in genetically obese mice (ob/ob) and rats (fa/fa). Science 1978;202:988-991.
11. Wolkowitz OM, Doran AR, Cohen MR, et al. Effect of naloxone on food consumption in obesity. N Engl J Med 1985;313:327.
12. Zioudrou C, Streaty RA, Klee WA. Opioid peptides derived from food proteins. The exorphins. J Biol Chem 1979;254:2446-2449.
13. Walker WA, Isselbacher KJ. Uptake and transport of macro-molecules by the intestine. Possible role in clinical disorders. Gastroenterology 1974;67:531-550.
14. Colantuoni C, Rada P, McCarthy J, et al. Evidence that intermittent, excessive sugar intake causes endogenous opioid dependence. Obes Res 2002;10:478-488.
Fibromyalgia: A Case Report
I saw a 48-year-old woman who had a 6-year history of fairly constant myalgias and arthralgias. Six months previously she was found to have an elevated sedimentation rate (50 mm/hr). She had been diagnosed by a rheumatologist as possibly having polymyalgia rheumatica, although the possibility of fibromyalgia was also considered. She also had migraines about 8 times per year and chronic nasal congestion.
During her first office visit she was given a therapeutic trial consisting of 6 ml of vitamin C (222 mg/ml), 4 ml of 20% magnesium chloride, 2.5 ml of 10% calcium gluconate, and 1 ml each of vitamin B12 (1,000 µg/ml), pyridoxine (100 mg/ml), dexpanthenol (250 mg/ml), and B complex 100. At the end of the injection reported with amazement that all of her muscle aches and joint pains were gone for the first time in 6 years.
The injection was repeated a week later (at which time her symptoms had not returned), followed by every other week for several months, then once a month for 3 years until I moved out of state. Her treatment regimen also included identification and avoidance of allergenic foods, and empirical administration of desiccated thyroid. She discovered that eating refined sugar caused myalgias and arthralgias, and that thyroid hormone improved her energy level, mood, and overall well-being. During the 3 years of monthly maintenance injections, she reported that mild symptoms would begin to recur if she went much longer than a month between injections.
Does Vitamin E Cause Heart Failure?
Some practitioners reported in the 1940s and 1950s that vitamin E in doses of 200-600 IU/day produced clinical improvement in CHF patients.15 Intramuscular administration of 300-400 IU/day of vitamin E for 4-5 days was said to produce rapid and dramatic diuresis (usually within 12 hours of the first injection) in patients with severe heart failure.16 However, other practitioners found that vitamin E in doses of 150-800 IU/day was not beneficial for patients with CHF.17-20
More recently, controlled trials have shed an unfavorable light on vitamin E. In a double-blind study of patients with advanced CHF (NYHA class III or IV) administration of 1,000 IU/day of vitamin E for 12 weeks did not improve heart function or quality-of-life scores, compared with placebo.21 Moreover, in a double-blind study of patients with vascular disease or diabetes, those who received 400 IU/day of vitamin E for a mean of 7 years had a 19% higher incidence of CHF (14.7% vs. 12.6%; p = 0.007) and a 40% higher incidence of hospitalization for CHF (5.8% vs. 4.2%; p = 0.002), when compared with those who received placebo.22
The negative results observed in many vitamin E studies might be explained by the fact that virtually all of these studies used pure alpha-tocopherol, whereas vitamin E as it occurs naturally in food consists of 4 isomers: alpha-, beta-, gamma-, and delta-tocopherol.
Studies in humans have shown that supplementation with alpha-tocopherol can deplete gamma-tocopherol.23 Gamma-tocopherol is metabolized largely to 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), which may function as a natriuretic hormone, since it is involved in the body’s response to sodium-induced plasma volume expansion. 24-26 It is possible that alpha-tocopherol-induced gamma-tocopherol depletion could lead to impaired regulation of sodium and water balance, potentially increasing the risk for heart failure.
If high-dose alpha-tocopherol does adversely affect cardiac function in some people, one might reasonably expect that mixed tocopherols, which contain all 4 isomers of vitamin E, would not have the same negative effects, and might even be beneficial. The clinical trials that used alpha-tocopherol should therefore be repeated using mixed tocopherols.27
15. Vogelsang A, Shute EV. Effect of vitamin E in coronary heart disease. Nature 1946;157:772.
16. Vogelsang A. Intramuscular administration of vitamin E. Lancet 1950;1:734.
17. Eisen ME, Gross H. Vitamin E in arteriosclerotic heart and peripheral vascular disease. NY State J Med 1949;49:2422-2424.
18. Berger H. The failure of vitamin E to alleviate the signs and symptoms of congestive heart failure. NY State J Med 1950;50:441-443.
19. Levy H, Boas EP. Vitamin E in heart disease. Ann Intern Med 1948;28:1117-1124.
20. Baer S, Heine WI, Gelfond DB. The use of vitamin E in heart disease. Am J Med Sci 1948;215:542-547.
21. Keith ME, Jeejeebhoy KN, Langer A, et al. A controlled clinical trial of vitamin E supplementation in patients with congestive heart failure. Am J Clin Nutr 2001;73:219-224.
22. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005;293:1338-1347.
23. Huang HY, Appel LJ. Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. J Nutr 2003;133:3137-3140.
24. Murray ED Jr, Wechter WJ, Kantoci D, et al. Endogenous natriuretic factors 7: biospecificity of a natriuretic gamma-tocopherol metabolite LLU-alpha. J Pharmacol Exp Ther 1997;282:657-662.
25. Wechter WJ, Kantoci D, Murray ED Jr, et al. A new endogenous natriuretic factor: LLU-alpha. Proc Natl Acad Sci 1996;93:6002-6007.
26. Uto H, Kiyose C, Saito H, et al. Gamma-tocopherol enhances sodium excretion as a natriuretic hormone precursor. J Nutr Sci Vitaminol 2004;50:277-282.
27. Gaby AR. Vitamin E supplementation, cardiovascular events, and cancer. JAMA 2005;294:425.
