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Synergy between Medical and Nutrient Therapies: George Washington Meets Rodney Dangerfield

Department of Nutrition and Food Science, Wayne State University, Detroit, Michigan

Address correspondence to: David M. Klurfeld, PhD, Professor and Chairman, Department of Nutrition and Food Science, Wayne State University, 3009 Science Hall, Detroit, MI 48202. E-mail: dklurfe{at}sun.science.wayne.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION SYNERGY BETWEEN MEDICAL AND... EFFECT OF MEDICAL THERAPY... CONCLUSION DISCUSSION REFERENCES

 
Although medical therapies are widely accepted by health practitioners, sometimes without adequate testing, nutritional therapy is frequently looked upon uniformly as without merit. There are many reasons for this attitude. However, a substantial body of literature has accumulated that objectively demonstrates the value of adding nutritional therapy to the prevention or treatment of some diseases or specific risk factors for diseases. Examples of successful nutrition therapy that can be combined with medical management include treatment of hypertension, hyperlipidemia, intermittent claudication, osteoporosis, respiratory distress syndrome, and arthritis.

Key words: cardiovascular disease, hypertension, diabetes, intestinal diseases, cancer, wound healing, inflammatory conditions, osteoporosis, arthritis, hepatic disease, renal disease, functional foods

Key teaching points:

• Many products sold as nutritional supplements have a long history of use, but little or no data on safety or efficacy. Some are not supported by anything other than testimonials.

• A surprising number of nutrients do provide established benefits that can be combined with medical therapy for specific conditions.

• Generally acknowledged examples in which nutritional and medical therapies synergize include lowering of blood pressure, maintenance of bone mineral density, and inhibition of platelet aggregation.

• Many less well known examples of combined nutritional and medical therapy are summarized in this review.

	INTRODUCTION

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For many years, nutritional therapy has been a stepchild in the armamentarium of most healthcare professionals, even though it has been known for thousands of years that medicine can help prevent and treat disease, as recognized by Hippocrates (460–377 BCE) who is credited with the saying "Let food be your medicine, and medicine your food." Most of the American public and, in fact, many healthcare professionals have a rather jaundiced view of nutritional support for medicine. The usual view of medicine is the cultural equivalent of George Washington, while the typical opinion of nutritional therapy equates with Rodney Dangerfield—it doesn’t get any respect. To many, nutritional therapy means untested or unconventional remedies such as those used by the actor, Steve McQueen, who died from lung cancer twenty years ago today. His death from this disease was hastened by alternative nutritional therapies, such as coffee enemas for detoxification, fasting, and a vegetarian diet combined with raw liver juice, obtained at a clinic in Mexico. His death was due to electrolyte imbalance from these therapies.

Today, I would like to give you an overview of examples of diseases or disorders in which nutritional therapy, supported by science, interacts with medical therapy to result in better disease prevention or treatment. Much to my initial surprise, there is a vast amount of information on this subject.

	SYNERGY BETWEEN MEDICAL AND NUTRIENT THERAPIES

TOP ABSTRACT INTRODUCTION SYNERGY BETWEEN MEDICAL AND... EFFECT OF MEDICAL THERAPY... CONCLUSION DISCUSSION REFERENCES

 
Cardiovascular Disease
With respect to cardiovascular disease, lipid lowering, primarily by increasing the dietary ratio of polyunsaturated to saturated fatty acids, has been well studied. In fact, there is general agreement that this dietary strategy is an effective means to lower serum cholesterol levels that may reduce the risk of cardiovascular disease. Reducing hypertension, a risk factor for cardiovascular disease, is another approach. Recently, attention has focused on dietary patterns to lower blood pressure [1]. The American Heart Association’s revised dietary guidelines promote a dietary pattern called the DASH diet to lower blood pressure and risk for heart disease [2]. DASH is an acronym for "Dietary Approaches to Stop Hypertension." Participants in the DASH study consumed either a control diet typical of the usual American diet, a lowfat diet containing 8 to 10 servings/day of fruits and vegetables, or a combination lowfat diet high in fruits and vegetables and low or nonfat dairy products (3 or more servings/day) [1]. Sodium intake and body weight were held constant in all three groups. The combination diet rapidly (within two weeks) reduced both systolic and diastolic blood pressure. Since this initial study was published in the New England Journal of Medicine in 1997, several follow-up studies have examined the effect of the DASH combination diet on the blood pressure of various subgroups of the population. These studies demonstrate that the DASH combination diet is effective for both hypertensive and normotensive subjects, but is more effective for hypertensives. For minority groups such as African Americans who are at high risk for hypertension, the DASH diet is particularly effective in lowering blood pressure [3].

In addition to lipid and blood pressure lowering, preventing platelet coagulation by consumption of omega-3 fatty acids derived from fish is an area of active investigation [4]. Also, a variety of antioxidants in foods have been shown to reduce oxidation of LDL cholesterol [5]. Intake of arginine may reduce risk for cardiovascular disease by several mechanisms. This amino acid lowers blood cholesterol levels in animal models [6]. It also increases endogenous nitric oxide production, which induces vasodilation and inhibits platelet aggregation [7]. In a recent double-blind, placebo-controlled study, consumption of a granola bar enriched with L-arginine reduced symptoms of intermittent claudication from atherosclerotic peripheral arterial disease and allowed patients to increase their pain-free and total walking distances [8]. Forty-one subjects were given either a placebo granola bar or one or two active bars, with each active bar providing 3.3 g arginine. A two-week double blind period was followed by eight weeks of open therapy. The subjects had severe intermittent claudication and could not walk ten meters without significant pain. Consumption of a single bar almost tripled their pain-free walking distance, while two bars led to a statistically significant, 70-meter pain-free walking distance. In addition to arginine, this bar contains soy protein, 200 mg of potassium, and a variety of antioxidants such as vitamins C and E, and B vitamins, which can reduce homocystine levels. The product is low in sodium, and fairly low in dietary fat.

Congestive heart failure (CHF) has been treated fairly successfully with large doses of coenzyme Q-10 [9]. However, this supplement is of questionable value for other conditions and there is disagreement regarding its efficacy against CHF. Magnesium also may play a role in reducing heart disease risk by preventing conduction abnormalities [10].

Diabetes Mellitus
Diabetes mellitus is a disease in which nutrition and medical therapy play an important role. For example, dietary fiber, as well as other nutrients, is effective in inhibiting glucose absorption [11], whereas other nutrients increase insulin sensitivity. A high polyunsaturated to saturated fatty acid ratio in the diet increases insulin sensitivity both in animal models and in a limited number of human studies [12,13]. Antioxidants have been shown to be effective as well.

In contrast to the above examples, other nutrients or nutritional products are being marketed to diabetics with little scientific evidence to support their efficacy. One is a bar containing a mixture of soluble fiber, psyllium, ginseng, fructose from barley, a soy sterol, willow bark, and chromium picolinate. Although chromium picolinate enhances insulin sensitivity, most people in the United States are not chromium deficient despite numerous claims that 85 per cent of the population is deficient. In fact, what nutritionists would consider a poor diet characterized by frequent consumption of lunchmeat and hot dogs would be a chromium rich diet since these are the richest source of the mineral in our diet. Minute amounts of chromium transfer to the ground meat from the stainless steel grinders. The identity and amount of soy sterol are not disclosed in this product. The willow bark is added as an anticoagulant. This complex mixture is currently being sold as a snack bar to treat Type 2 diabetes with no testing to back up the claims.

Pre-term Deliveries
There are some very interesting data indicating that pre-term deliveries are inhibited by fish oil supplements [14]. The researchers looked at the effect of fish oil on pre-term delivery with intrauterine growth retardation and pre-eclampsia. There was an effect of fish oil on pre-term delivery, but not on intrauterine growth retardation or pre-eclampsia. Women who had previously experienced a pre-term delivery were given 2.7 grams of fish oil a day and experienced a 50 percent reduction in risk of preterm delivery compared to the group receiving placebo capsules. A plausible mechanism is alteration of eicosanoid production subsequent to a change in the dietary n-6/n-3 fatty acid ratio of the diet.

Intestinal Disorders
Intestinal disorders are another area in which nutritional therapy has a very obvious role to play. In particular, probiotics, prebiotics, and synbiotics offer promise in the treatment of gastrointestinal disorders. Probiotics refer to live bacteria that beneficially affect the host by improving its intestinal microbial balance. Certain species of lactic acid bacteria such as L. acidophilus have been demonstrated to shorten the duration of diarrhea and increase resistance to infectious intestinal diseases. In countries such as Japan, probiotic-containing beverages are widely available. Prebiotics are nondigestible food ingredients such as dietary fibers, sugar alcohols, and oligosaccharides that selectively stimulate the growth and/or activity of health-promoting bacteria. Synbiotics contain both probiotics (e.g., bifidobacteria) and prebiotics (e.g., oligofructose). One of the problems with probiotics is that they do not seem to flourish in the colon, so regular intake of the organisms and fermentable substrates is necessary.

Cancer
Nutritional therapy is receiving attention in the prevention and treatment of cancer. Although considerable research focuses on antioxidant nutrients and cancer, there is no consensus regarding their efficacy. In animal models, restriction of single nutrients has been demonstrated to be fairly effective in inhibiting the growth of various tumors [15]. But caloric restriction, which is essentially underfeeding energy while providing all essential nutrients, offers the greatest potential in reducing cancer in laboratory animals. According to long-term studies in nonhuman primates carried out by the National Institute of Aging, 17 deaths occurred in the control animals over the past 13 years, whereas only four deaths occurred in the calorically restricted monkeys [16]. Further, the majority of the deaths in these animals were due to cardiovascular disease, not cancer. Fish oil and other long-chain omega-3 inhibitors of cyclooxygenase may be potential anticancer agents [17].

Ulcers
A variety of nutrients, including a high fiber diet, are effective in treating or preventing gastrointestinal ulcers. Both animal and human studies demonstrate that zinc and vitamin C increase postoperative healing or burn wound healing. The combination of pharmacologic agents, such as injections of IGF-1, and administration of arginine, a growth hormone secretagogue, is an example of combining medical and nutritional therapy. Intestinal anastomoses are a unique type of postoperative healing in which a variety of nutrients have been demonstrated to be beneficial in both animals and patients. Glutamine is considered to be a conditionally essential amino acid under stress, which may be particularly important for healing in the gastrointestinal tract [18]. Dietary fiber and, in particular, pectin increase wound strength in intestinal anastomoses [19]. Also, a variety of peptides and nucleotides have been added to diets to enhance wound healing in the gut [20].

Inflammatory and Autoimmune Conditions
With respect to inflammatory and autoimmune conditions, omega-3 fatty acid formulas have probably been studied most extensively. Also in terms of the common cold, nutrients such as zinc and vitamin C have received considerable attention, although their effectiveness is controversial. Chicken soup has long been regarded as a cold remedy. In fact, a recent study published in the journal, Chest, indicates that chicken soup may help to relieve symptomatic upper respiratory tract infections, possibly by a mild anti-inflammatory effect [21]. Acute respiratory distress syndrome can be favorably influenced by omega-3 fatty acid formulas. For example, intake of a high fat (55%) omega-3 rich enteral formula containing canola oil, medium chain triglycerides, fish oil, borage oil, and a small amount of soy lecithin, as well as several antioxidants, has been demonstrated to be effective for patients with acute respiratory distress syndrome [22]. In this multi-center double-blind placebo controlled study, the patients receiving this formula required significantly fewer days on a ventilator (12.7 vs. 17.6) and in the intensive care unit (11.0 vs. 16.0). These findings suggest significant cost savings for each hospitalization of the patients given this formula. They also point to the tremendous potential for the combination of nutritional and medical support.

Osteoporosis and Arthritis
Osteoporosis is a major chronic disease in which nutrients such as calcium, vitamin D, fluoride, magnesium, and fatty acids play an important role. A variety of nutritional interventions are being investigated for their potential to alleviate arthritis symptoms. Unfortunately, weight management is often overlooked in this disease. Weight loss alone improves mobility of patients with osteoarthritis. Omega-3 fatty acid formulas also have been shown to be effective in rheumatoid arthritis. In animal studies, combining omega-3 fatty acids with antioxidants such as vitamin E significantly reduces inflammation. The effectiveness of vegetarian diets for patients with rheumatoid arthritis is controversial, as is the benefit of chondroitin sulfate and glucosamine sulfate preparations. A meta-analysis in the Journal of the American Medical Association concluded that chrondroitin/glucosamine preparations have a modest effect on arthritis but that most studies have been of poor quality [23].

Gout, Liver and Renal Diseases
Nutrients such as calcium, magnesium, zinc, and fatty acids influence fracture risk [24] and a low purine diet is effective in the treatment of gout. In hepatic diseases, feeding saturated fatty acids to laboratory rats with alcoholic liver damage inhibits and reverses the damage and decreases oxidation in the liver [25]. Antioxidants also reduce liver damage in animal models. Another potential for medical therapy combined with nutrition is evident in renal disease. A low protein diet and intake of B vitamins, particularly folate, may be beneficial for patients with this disease.

	EFFECT OF MEDICAL THERAPY ON NUTRITIONAL STATUS

TOP ABSTRACT INTRODUCTION SYNERGY BETWEEN MEDICAL AND... EFFECT OF MEDICAL THERAPY... CONCLUSION DISCUSSION REFERENCES

 
Medical therapy can induce or contribute to nutritional deficiencies. Diuretics are probably the most widely known group of drugs to cause loss of minerals in the urine. Surgery creates a hypermetabolic state that increases the need for total calories, protein, and a variety of other nutrients. Exposure to radiation therapy for cancer and other disorders increases the requirement for antioxidants. Cancer chemotherapy also increases the need for a variety of nutrients. Patients placed on restricted diets, regardless of the reason, may be at nutritional risk. Likewise, the potential of nutritional shortcomings in patients fed enteral formulas cannot be overlooked. Total parenteral nutrition is another challenge in providing patients with sufficient nutrients.

How Do You Get Nutrients to Patients?
This can be accomplished with diets, foods, and most recently functional foods. Functional foods are receiving considerable attention. Regulations regarding the labeling of functional foods in the U.S. are currently under discussion. In Japan, almost 150 products are certified as FOSHU, which is an abbreviation for "Foods for Specified Health Uses." These foods include a variety of nutrients or components that include a variety of carbohydrates ranging from polydextrose to oligosaccharides, wheat bran, proteins (soy, casein derivatives), minerals, green tea extract, and the bacterial culture Lactobacillus-GG. In addition to functional foods, patients can receive nutrients through nutraceuticals, dietary supplements and medical foods.

	CONCLUSION

TOP ABSTRACT INTRODUCTION SYNERGY BETWEEN MEDICAL AND... EFFECT OF MEDICAL THERAPY... CONCLUSION DISCUSSION REFERENCES

 
The challenge for nutrition researchers and practitioners is to separate the evidence-based products from those supported by testimonials and wishful thinking. Just as we should be open to additional nutrition therapy, we should not blindly accept alternative nutritional therapies just because they have a long history of use in traditional cultures. Likewise, we cannot ignore the strong placebo effect associated with many therapies, but it is our obligation to distinguish this from a specific treatment effect. Often the traditional uses are not based on any scientific evidence, the doses are quite different from those used today, and potential interactions with pharmacological therapy are often unanticipated. An example of this latter phenomenon is the influence of St. John’s wort on levels of several medications. It has been found that this is mediated via modulation of the p450 enzyme system with subsequent influence on the half-lives of many compounds. Another example to demonstrate that this type of effect may not only be related to nutritional supplements is that consumption of grapefruit has similar effects. Therefore, both nutrition and nutritional supplements may modulate levels of pharmaceuticals in the blood, may have independent effects on risk factors for many conditions, and will interact with a variety of medical therapies.

	DISCUSSION

TOP ABSTRACT INTRODUCTION SYNERGY BETWEEN MEDICAL AND... EFFECT OF MEDICAL THERAPY... CONCLUSION DISCUSSION REFERENCES

 
Dr. David J. Strobl.
Are you aware of any research on the ability of L-arginine supplements to restore endothelial func-tion and on the benefit of L-arginine for patients with peripheral vascular disease?

Dr. Klurfeld.
I think pieces of evidence point in the direction of a beneficial role for arginine. However, one of the problems in most human studies is that there are no areas in humans in which endothelial cells are totally denuded, as in mice, unless you have a serious injury to the artery. Nevertheless, I think that endothelial function can be restored, and certainly nitric oxide is the primary mediator. Studies have shown relatively clearly that arterial relaxation in the postprandial state occurs with arginine supplements secondary to increased NO, which also functions as an endothelial-derived relaxing factor. The study that I described in patients with intermittent claudication of the leg also points in this same direction. So, to answer your question, I think arginine has a significant role to play.

Dr. Strobl.
If you can’t consume an arginine-containing granola bar, would you have to take 16 capsules of L-arginine a day?

Dr. Klurfeld.
That’s precisely the argument given by people selling these bars. Most of the capsules contain 500 mg arginine, so one would need to take about 12 to 16 capsules/day for a therapeutic dose. However, if someone can’t walk more than ten meters at a time, he or she is probably willing to take a dozen capsules a day, as do many people on conventional therapy. I don’t think this is really a problem.

Dr. Robert P. Heaney.
Could you explain why Rodney Dangerfield doesn’t get the respect he deserves, in this case nutrition.

Dr. Klurfeld.
Part of the reason is gender bias. Nutrition has been a female’s field for many years. In fact, most people know nutrition through exposure to dietitians, 95%% of whom are female. Another part of the reason is the presence of a lot of charlatans in the nutrition field, including people with proper academic credentials such as PhDs and MDs who are pushing all kinds of supplements and writing books for the public, regardless of whether they are harmful or not.

Dr. Heaney.
So, you are saying that nutrition gets some of the disrespect it deserves?

Dr. Klurfeld.
You are absolutely right. I think that’s a good assessment of the situation.

Received April 26, 2001.

	REFERENCES

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