Integrative medicine refers to the integration of alternative and complementary medicine with traditional allopathic medicine. I have found that having knowledge and tools in both areas allows me to provide the best care for my patients. It is clear that allopathic medicine provides many powerful lifesaving treatments to our patients. However, we need to offer our patients with chronic medical disorders an integrated approach, taking into account their individual situations, the interactions between the environment, and their particular genetic uniqueness. It is estimated that there are more than 2 million polymorphisms that can potentially affect the way a person experiences health or disease.

Because the breadth of alternative medicine cannot be summarized in a single writing, this chapter focuses on one field in integrative medicine, functional medicine. ¹

Functional medicine is an individualized approach to patient care that focuses on restoring balance to the dysfunctional systems by strengthening the fundamental physiologic processes that underlie them, and by adjusting the environmental inputs that nurture or impair them. Functional medicine looks at the triggers and mediators that lead to a particular clinical state. This takes into account the environmental factors that wash over a patient’s particular genetic uniqueness that then can result in either vitality or dysfunction. The environmental effect can be as broad as the mind’s influence on the psychoneuroendocrine system or as narrow as a conditionally essential nutrient in a metabolic pathway that has been affected by an environmental toxin.

Functional medicine uses a matrix of core clinical imbalances (Figure 1) to organize a structural framework around a patient’s complex presentation. These core imbalances include:

1. Neurotransmitter and hormonal imbalances
2. Oxidation-reduction imbalances and mitochondropathy
3. Detoxification and biotransformational imbalances
4. Immune and inflammatory imbalances
5. Digestive, absorptive, and microbiologic imbalances
6. Structural imbalances from cellular membrane function to the musculoskeletal system

Biochemical individuality is the rule rather than the exception and is the result of having thousands of genetic polymorphisms. One of the exciting frontiers that is emerging in functional medicine is the application of genetic analysis in areas such as inflammation and detoxification. It is the role of the clinician to examine this complex web of interactions and develop a treatment plan to help our patients. Functional medicine provides a robust paradigm to explore each patient’s story in the context of the environment’s influence on his or her particular spiritual, emotional, and biochemical uniqueness.

Oxidative Stress

Processes

Proposed mechanisms of aging as well as neurodegenerative and other organ-specific degenerative diseases have focused on the susceptibility of the cell to oxidative stress. Research in this area has demonstrated the role of oxidative stress–induced mitochondrial dysfunction and the subsequent cascade of mitochondria-initiated cellular apoptosis. Oxidative stress is also related to the development of certain cancers.

Oxidative stress occurs when either endogenously metabolic generated reactive molecules or exogenous reactive substances in the environment interact with biologic structures, resulting in altered cellular physiology. Endogenously produced reactive oxygen species (ROS) include molecules such as superoxide, peroxynitrite, peroxyl radicals, hydroxyl, hydroxyl radicals, and singlet oxygen. Most ROS originate intracellularly in the mitochondria, which converts the energy potential from macronutrients from the diet into cellular energy currency that includes adenosine triphosphate (ATP), reduced nicotinamide adenine dinucleotide (NADH), and reduced flavin adenine dinucleotide (FADH₂). Through the process of oxidative phosphorylation in the mitochondria, molecular oxygen is consumed and reduced to water. However, about 1% of the oxygen is converted to superoxide anion (O₂ ⁻). These ROS molecules, if left unchecked, damage cellular structures such as mitochondrial membranes, proteins, and DNA. Mitochondrial DNA is especially vulnerable to oxidative damage because it lacks the protective and repair mechanisms found in nuclear DNA. Repeated injury to DNA results in a cumulative loss of function. After enough hits, the mitochondria and the bioenergetics of the cell are altered in ways that can result in cellular apoptosis and loss of organ function.

Cells have developed antioxidant defenses to protect cellular proteins, membranes, and nucleic acids. These molecules include coenzyme Q₁₀ (CoQ₁₀), lipoic acid, and glutathione. Enzymatic processes that also contribute to antioxidant defense include superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase.

Oxidative stress can be assessed in the laboratory by measuring oxidized products from cellular damage. The unsaturated component of lipid membranes undergoing oxidative damage releases lipid peroxides. Oxidative injury to arachidonic acid results in the production of isoprostanes. Oxidation of guanosine molecules in DNA produces 8-hydroxydeoxyguanosine (8OHdG), which has a close relation with neuronal oxidative stress. Methods of measuring these products of oxidation are commercially available.

The production of ATP from oxidative phosphorylation depends on organic acids generated from the Krebs cycle. To function correctly, the enzymatic processes in the Krebs cycle depend on cofactors that include nicotinamide dinucleotide derived from niacin, FAD derived from riboflavin, and thiamine pyrophosphate derived from thiamine. The production of energy from fatty acids depends on the transport of free fatty acids across the mitochondrial membrane, which requires conjugation to carnitine by the enzyme carnitine palmitoyltransferase I. The free fatty acids are then deconjugated for use in energy production.

Antioxidants

Today’s standard American diet is poor in nutrients, rich in calories, high in glycemic load, and deficient in antioxidants. These processed foods lack the phytonutrients that provide our cells with the information to orchestrate a balanced cellular physiology to prevent cancer and inflammatory conditions. Antioxidant-rich foods in the diet are the major sources of supplemental antioxidants. The richly pigmented phytochemicals in vegetables and fruits serve antioxidant functions, and intake of vegetables and fruits has been associated with a decreased risk of some cancers. The antioxidant activity produced by whole foods, as measured by products of oxidative stress in humans, outperforms antioxidants taken as supplements. ² Although many substances in vegetables and fruits have been identified, many remain unidentified, and the biologic effect of a parti-cular herb or plant could be related to effects of the particular plant’s various phytochemicals on multiple-cell–signaling biochemical pathways.

Green tea, rich in catechins, has demonstrated antioxidant properties related to the combination of aromatic and hydroxyl groups that make up the structure of these polyphenols. Other biologic effects of green tea include inhibition of arachidonic acid metabolites, thus reducing inflammatory responses; activation of hepatic enzymes that promote the detoxification of xenobiotic compounds; and positive effects on intestinal microflora by raising levels of Lactobacillus and Bifidobacterium while lowering levels of potential pathogenic bacteria. One of the major polyphenols in green tea, (-)-epigallocatechin-3-gallate (ECGC), has been shown to decrease lipopolysaccharide-induced tumor necrosis factor (TNF) production in a dose-dependent manner.

Curcumin (derived from turmeric, the yellow spice in curries) has been shown to have a broad range of cellular effects in addition to its potent antioxidant activity. It has potent anti-inflammatory effects that may be related to its ability to inhibit biosynthesis of inflammatory prostaglandins from arachidonic acid and also its inhibitory effect on neutrophil aggregation. Molecular targets include the inhibition of cell-signaling pathways associated with inflammation that includes nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX). It also affects many pathways associated with cancer. ³

Lycopene, a red carotenoid pigment, is found in a variety of plants including guava, pink grapefruit, watermelon, and tomatoes. Lycopene is a potent antioxidant that might protect vulnerable cellular components from reactive oxygen damage. Epidemiologic data show lycopene to be associated with a reduced risk of prostate cancer. Clinical trials have also demonstrated a prevention or reduction of the progression of high-grade prostate intraepithelial neoplasms into prostate cancer. Serum lycopene levels are inversely related to prostate-specific antigen (PSA) levels. Mechanisms in addition to the antioxidant effects can include inhibition of insulin-like growth factor-1 and other cell-signaling effects. ⁴

In addition to whole foods, dietary supplements used to support these processes include those directed at facilitating energy production at the level of the Krebs cycle and oxidative phosphorylation. They can serve as cofactors in the processes for the generation of ATP and as antioxidants to quench aberrant ROS. Many of the substrates used in these processes are conditionally essential, which implies that under certain conditions, optimal function cannot be maintained through endogenous synthesis alone.

CoQ₁₀ (ubiquinone) is a potent antioxidant and also a bioenergetic enzyme that participates in electron transport during oxidative phosphorylation. CoQ₁₀ biosynthesis is impaired by statin medications that inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, thus producing lower tissue levels of CoQ₁₀. CoQ₁₀ supplementation has been shown to potentially benefit a number of neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. ⁴ Additionally, it has shown benefit in prophylaxis for migraine headache and in treating congestive heart failure, periodontal disease, and hypertension. It has also been shown to reduce doxorubicin-induced myocardial toxicity in patients receiving chemotherapy without compromising the chemotherapeutic effectiveness. Dosages as high as 1200 mg/day have been successfully used in clinical studies in patients with Parkinson’s disease.

α-Lipoic acid (ALA) is a molecule that serves as a coenzyme in several complexes in the mitochondria, including pyruvate dehydrogenase in the Krebs cycle. ALA is also a potent antioxidant in water and in lipophilic solvents. In its reduced form, dihydrolipoic acid has been demonstrated to have distinct antioxidant actions that include free radical–scavenging activity; it also can regenerate endogenous antioxidants such as glutathione, CoQ₁₀, and vitamins E and C. Studies in patients with diabetes have shown improvement in measurements of oxidative stress. ⁵ ALA has also resulted in significant clinical improvement in symptom scores in patients with diabetic polyneuropathy. ⁶ ALA supplementation in animal models has resulted in improvement in outcomes following central nervous system reperfusion injury and protects against cataract formation in animals with induced diabetes. ⁷ ALA has also been used successfully to prevent liver failure in patients with amanita mushroom poisoning. Besides its direct antioxidant effects, ALA might also influence clinical outcomes through other important mechanisms and pathways such as by modulating inflammation through its inhibitory affect on NF-κB activation. ⁸ Therapeutic doses of ALA are in the range of 600 mg daily.

Many foods and supplements that have primarily been believed to have antioxidant properties also play a role in modulating inflammation, have anticancer properties through cell-signaling pathways, and can influence many physiologic effects through a plethora of other mechanisms and processes. Primary prevention of cancer and degenerative diseases through the intake of a whole-foods diet seems prudent. We are beginning to have the tools available to identify persons at increased risk for oxidative damage and development of degenerative disease due to their specific genetic polymorphisms. Targeted dietary and nutraceutical supplemental therapy is possible for these people based on sound scientific data and inferences (Box 1). The ideal of having outcome studies for many of these proposed treatments is a story in progress. Resources are listed in Box 2.

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Detoxification and Biotransformation

Toxins that are present in our bodies originate from environmental exposures including the air we breathe, water we drink, food we eat, and the complex array of molecules we produce in our bodies that are metabolites of physiologic processes. The greatest amount of energy that our bodies use outside of our growing years pertains to detoxifying these toxic molecules to prevent oxidative damage to vital intracellular proteins, DNA, and lipid membranes. This complex process has to be able to recognize thousands of diverse molecules and perform a highly orchestrated synchronous detoxification process that includes molecular modification by phase I enzymes, conjugation to water soluble molecules by phase II enzymes, and then efflux out of the cells by phase III proteins. Hundreds of proteins participate in these processes, which are highly dependent on having the necessary substrate available to complete these processes.

Detoxification begins at the intestinal epithelium. High concentrations of CYP 3A4 (a major cytochrome P-450 enzyme involved in metabolism of many drugs) and phase III antiporter activities are found at the tips of intestinal villi. Other tissues with significant detoxification systems include the lungs, kidneys, reproductive tissues, and nasal epithelium. The ability of the nasal epithelium to detoxify xenobiotics is important so that loss of our ability to detect scents due to habituation does not occur. The fragrance produced by a rose must be metabolized by our detoxification system to allow the system to become resensitized so we can to continue to perceive the fragrance.

Each person has a unique biochemistry to detoxify substrate, which depends on individual genetic makeup, the load of environmental or endogenous toxins, and the substrate available to accomplish this task. Because single nucleotide polymorphisms (SNPs) can occur in any combination of the enzymes involved in these processes, some persons present with signs and symptoms of toxicity such as fatigue, neurologic complaints, and cancer whereas others with similar exposures do not present with any problems. Laboratory testing is currently available for gene panels that are involved in detoxification and biotransformation. Obtaining gene panels on our patients might help us determine this aspect of their risk for developing diseases related to detoxification. Specific minimally processed whole foods or nutritional supplements can be prescribed to optimize the function of these processes.

A classic example of the detoxification process is metabolism of acetaminophen (Figure 2). Acetaminophen is primarily metabolized through a phase II process that includes sulfation to form acetaminophen sulfate and glucuronidation to form acetaminophen glucuronide. These compounds are then safely eliminated. If these pathways are impaired or compromised by depletion of essential cofactors, acetaminophen undergoes phase I biotransformation to N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is a highly reactive molecule, and if it is not rapidly conjugated with glutathione, it will cause cellular toxicity. If the phase I cytochrome P-450 enzyme CYP 2E1 is induced to promote biotransformation to NAPQI, or if essential cofactors for phase II conjugation are lacking, the outcome favors production of this reactive intermediate, which can cause cellular damage and possibly liver failure.

Phase I biotransformation can be induced by various substrates or can be competitively inhibited. Genetic variations through SNPs also occur that can result in either increased or decreased enzyme kinetics. Phase II conjugation may be affected by individual polymorphisms and is also subject to available substrate for conjugation and elimination. For optimal biotransformation, phase I and phase II need to function in a balanced manner. Reactive intermediates produced through phase I processes are conjugated by phase II processes. In the case of acetaminophen toxicity, ethanol induction of CYP 2E1 results in increased production of NAPQI. At the same time, a fasting state can deplete the limited supply of sulfur-containing amino acids used as phase II substrates. This imbalanced state can result in liver toxicity at what we would consider normal doses of acetaminophen.

Although there are many likely processes that ultimately result in altered cellular physiology and the development of malignancies, detoxification and biotransformation play critical roles as a link to make persons either more susceptible or less susceptible to the environmental mediators of cancer development. Our diet can have either a positive or negative effect in this cascade of nutragenomic-influenced events. As an example, estrogen metabolism is influenced by both phase I and phase II processes. A study of the expression of estrogen-metabolizing enzymes in human breast tissue has found increased levels of CYP 1B1(increased enzyme activity) and decreased levels of catechol-O-methyl-transferase (COMT) in patients with breast cancer. ⁹ Both of these are common polymorphisms found in the general population. These changes favor the metabolism of estrogen to its carcinogenic metabolites. Similar findings have been demonstrated in men with prostate cancer, thus suggesting the importance of estrogen metabolism in the development of this malignancy. ¹⁰

Diet and nutritional supplements can be used to help balance the biotransformation of estrogen metabolites toward less-carcinogenic precursors. In general, fruits and vegetables contribute to the upregulation of hepatic detoxification enzymes. Phytonutrients can potentially affect hormone response or metabolism through a variety of mechanisms that include competitive inhibition at receptor sites, induction or inhibition of phase I processes, or upregulation of phase II processes. It remains to be seen through clinical trials whether whole food or supplement use can influence clinical outcomes.

Indol-3-carbinol (I3C) is a compound found in cruciferous vegetables such as broccoli, cauliflower, cabbage, and Brussels sprouts. I3C can shift the metabolism of estrogen to the protective 2-hydroxy estrogens by upregulating the expression of CYP 1A1 that increases the 2-hydroxylation of estradiol and estrone. Research has also shown that I3C induces in vitro tumor cell death by regulating the apoptotic pathway and through selective stimulation of a tumor-suppressor gene.

As mentioned, patients with breast cancer express lower levels of COMT. COMT is important in the metabolism of estrogen to products that have lower potential for oxidative DNA damage and reduced inflammatory properties. S-adenosylmethionine (SAMe) is a substrate for COMT methylation, and availability of SAMe depends on its own set of factors, which include polymorphisms for methylenetetrahydrofolate reductase (MTHFR), nutritional status, and environmental factors. Supplementation with SAMe in patients who have COMT polymorphisms, in addition to folic acid, and vitamins B₁₂, and vitamins B₂, and B₆ for those with MTHFR polymorphisms, can supply the needed substrate to favor the metabolism of estrogen to noncarcinogenic molecules. Moreover, the flora of the colon can influence detoxification and estrogen metabolism through the bacterial production of β-glucuronidase, which deconjugates glucuronyl side chains, resulting in enterohepatic recirculation of the transformed molecule, leading to increased toxic load. This example illustrates the weblike interaction of molecular processes that is the rule rather than the exception in biologic systems.

Curcumin (the principal curcuminoid of turmeric) is another herb that influences detoxification. In vitro and animal studies have shown that curcumin inhibits phase I CYP 1A1 and increases activity of phase II reactions. Curcumin has been shown in animal models to induce apoptosis in colon and breast cancers. It also downs regulates molecules in the inflammatory pathway, includ-ing COX-2, 5-LOX, NF-κB, and TNF. Green tea also affects detoxification by affecting phase I and phase II enzyme activity, has anti-inflammatory effects. Green tea polyphenols have been studied as cardiovascular disease and chemopreventive agents. ^11–13 Many phytonutrients have been demonstrated to have a broad range of effects on a variety of cellular physiologies including detoxification, inflammation, and oxidative stress (Figure 3).

Depending on the clinical presentation of the patient and our underlying knowledge of the various detoxification pathways, we have the opportunity to improve the function of these pathways through nutritional supplementation. This can be illustrated through the following case history. A 50-year-old patient who is a laboratory technician in an area hospital presents with episodic extreme fatigue that would last for several days following the landing of life flight helicopters at the heliport near his laboratory. His physical examination and routine laboratory tests to evaluate the fatigue were unremarkable. Symptoms suggesting a detoxification issue included a perceived heightened olfactory sensitivity to exhaust and diesel fumes (this may be related to enhanced elimination of these substances through phase I detoxification in the nasal epithelium, thus increasing sensitivity due to a reduction of neuronal habituation). Genomic testing on this patient revealed polymorphisms in the phase I enzymes CYP 1B1 and CYP 2E1. Polymorphisms for phase II enzymes included a null genetic expression (no gene present) for hepatic glutathione-S-transferase. This combination of environmental and genetic interactions could result in the rapid conversion of hydrocarbons to reactive intermediates by phase I that could not be optimally conjugated by phase II, resulting in toxic metabolites and the manifestation of his symptoms. Treatment was initiated with a combination of supplements and herbs that supported phase II detoxification through the addition of antioxidants and cofactors. Within weeks, his clinical symptoms resolved completely after years of intermittent fatigue due to environmental exposures. As an additional preventive strategy, this patient should also include in his diet cruciferous vegetables and phytonutrients to favor the conversion of estrogen to safer metabolites, which could also result in a lower risk of prostate and other cancers.

Detoxification and biotransformation illustrate the individual approach we need to take with our patients given their unique genetic determinants that are influenced by powerful environmental factors. This web of complex interactions examined in the functional medicine paradigm gives us an opportunity to offer our patients additional options in their quest for health and wellness.

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Immune and Inflammatory Imbalances

Immune and inflammatory imbalances can affect every organ system and can manifest as common clinical disorders that include neurodegenerative disorders, coronary heart and peripheral vascular disease, asthma, eczema, inflammatory bowel disease, connective tissue disease, and many other disorders. Being able to mount an immune response is critical to our survival, but when the response is perpetuated after the insult has been eliminated or as a result of disordered regulation, destruction to the host occurs and results in chronic inflammatory disease processes. This state of dysfunction was likely present long before the manifestation of the disease process. In many instances, this dysfunction occurs decades before the clinical presentation. The host’s susceptibility to inflammatory processes can be related to genetic uniqueness as manifested by cell membrane proteins involved in antigen presentation and cytokine polymorphisms. Triggers and mediators of inflammatory responses include infections, dietary factors, environmental toxins, and even the bacterial composition of the digestive tract. We again begin to appreciate the weblike interactions that the mediators of inflammation have on virtually all the organ systems of the patient.

Advances in genetics and molecular biology have provided us with many new tools to examine the pathogenesis and propagation of immune and inflammatory disorders. Functional medicine provides a paradigm to examine and to modulate these states of dysfunction by applying our understanding of the underlying pathophysiology and the factors that support optimal function. Factors that support optimal function can be as specific as a nutritional supplement that modulates the inflammatory response or as broad as the mind-body influence on the mediators of inflammation (Box 3).

Inflammation can be identified on the physical examination by the classic signs and symptoms including redness, increased temperature, swelling, and pain. The molecular mediators of inflammation interact in a complex and synchronous array of events that either serve to destroy invading organisms or that hover in an anticipatory mode in ongoing vigilance that serves to protect the host. When this balance is tipped in the direction of activation by any one of a variety of triggers, these processes can then become perpetuated and result in disease processes.

Coronary artery disease (CAD) has evolved from the concept that atherosclerosis was a localized lipid storage disease that resulted in mechanical obstruction of blood flow to a dynamic process. It is now characterized as an inflammatory disorder from its earliest stage in atheroma formation to the clinical hallmark of acute myocardial infarction related to inflammatory-mediated plaque rupture. This process of inflammation has a number of potential triggers and mediators. Modification of unhealthy lifestyle habits remains the single most powerful strategy for preventing CAD. Several studies have shown the positive effect of aerobic exercise on various cytokines that are associated with inflammation. Healthy diets, such as a Mediterranean diet, reduce the intake of saturated fats and thus lower the precursor intake of arachidonic acid and affect the cascade of proinflammatory prostaglandins and leukotrienes. ¹⁴ Whole foods, especially those rich in phytonutrients, have beneficial effects due to their antioxidant and anti-inflammatory properties. Meals with high glycemic loads (which include highly processed or quickly digested macronutrients) can induce an inflammatory response as monitored by levels of C-reactive protein (CRP). A whole-food diet has a lower glycemic index, because foods are digested slowly and the fluctuations of blood glucose levels are less pronounced.

Mind-body interventions, such as meditation, result in modulation of the autonomic nervous system, which in turn influences endothelial function. There is strong evidence of reduced adverse events in patients who have established coronary heart disease and who use stress-reduction techniques. Heart rate variability represents a beat-to-beat variation in the sinoatrial node activation and can be noninvasively measured to determine output of the autonomic nervous system. Patients who have low heart rate variability have increased risks for sudden death as well as recurrent coronary events. ¹⁵ Specific meditative and biofeedback techniques can modulate heart rate variability in subjects who are skilled in using these techniques. ¹⁶

CRP is a marker and possibly a mediator of systemic inflammation. Serum levels of this protein have been shown to be independently correlated with an increased risk of adverse cardiovascular events. Association of elevated CRP levels with stress has also been demonstrated. ¹⁷ There is also evidence of a relation between reduced heart rate variability and subclinical inflammation in patients without apparent heart disease. ¹⁸

In epidemiologic studies, fish intake has been associated with a reduced risk for the development of CAD and for the risk of sudden death in those patients with existing CAD. Fatty acids are essential constituents of and influence the function of cell membranes. They are also precursors of eicosanoids, which through their messenger functions influence the inflammatory response of the organism. Omega-6 and omega-3 fatty acids are the substrates for the production of series 1 and series 3 eicosanoids, respec-tively, which serve to inhibit the inflammatory response, whereas arachidonic acid–derived eicosanoids of the series 2 family are proinflammatory (Figure 4).

Acute inflammation often serves a protective role. Chronic inflammation, on the other hand, is often associated with deleterious affects. Fish oils are mostly composed of the essential fatty acids in the omega-3 family, which includes eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In addition to the influence of omega fatty acids on the production of eicosanoids, EPA also can inhibit both the 5-LOX pathway in neutrophils and monocytes and the leukotriene B4–mediated function in neutrophils. ¹⁹ There is also evidence that omega-3 fatty acids can suppress mononuclear cytokines that includes TNF-α and interleukin (IL) 1b. Like the thiazolidinedione class of drugs used in diabetes management, fish oils are also peroxisome proliferator-activated receptor (PPAR) g agonists that can modulate the expression of this family of genes. An example of this effect is the lowering of triglyceride levels through fish oil supplementation.

Fish oils have demonstrated clinical efficacy in chronic inflammatory conditions. The benefits of supplemental fish oils in the treatment of rheumatoid arthritis are well documented. A diet low in arachidonic acid and the addition of fish oil has been shown to produce a superior result to that of diet alone. ²⁰ Other inflammatory conditions, including inflammatory bowel disease, immunoglobulin (Ig) A nephropathy, psoriasis, and coronary artery disease, are modified by fish oils. In the Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto miocardio (GISSI)-Prevenzione clinical trial, supplementation with only 1 g of omega-3 fatty acids per day resulted in an approximate 20% decrease in cardiovascular mortality. ²¹

Laboratory testing is available to determine the contents and ratios of fatty acids from serum samples. It is important to make sure that the fish oil supplement has been purified and tested for heavy metals and other contaminants. Manufacturers should supply third-party testing results when requested to confirm this. It is also important to review the concentrations of the actual omega-3 components (EPA and DHA) because the potency varies from product to product. Dosing recommendations for specific conditions are varied and range from 1 to 9 g of omega-3 fatty acids. It can take several months to notice a clinical response in patients with active inflammatory disorders. Although omega-3 fatty acids can affect platelet aggregation, no data suggest any increased risk of hemorrhagic events. However, caution is suggested when adding omega-3 fatty acids to the diet of patients who are taking anticoagulants or antiplatelet therapy. Fish oils should be discontinued one week before surgical procedures to decrease the risk of hemorrhage.

With the recent clinical concerns related to the prostacyclin-mediated adverse effect of COX-2 inhibitors and concern over similar issues with COX-1 inhibition, natural anti-inflammatory agents represent another possible treatment modality for inflammatory conditions such as osteoarthritis and rheumatoid arthritis. These herbal preparations might modulate inflammation at various points in the inflammatory pathways, including modulation of cytokine production or production of arachidonic acid proinflammatory products (see Box 3). Clinical trials for specific conditions have been performed with herbal preparations and can help direct the clinician in the use of these agents. An excellent resource to review the quality of supplements can be found at www.consumerlabs.com.

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Gastrointestinal Imbalances

We consume approximately 30 to 60 tons of food in our lifetime. This food intake is composed of macromolecules, micronutrients that include vitamins and minerals, toxins, and other organisms capable of invasion. The gastrointestinal (GI) tract must function in an optimal fashion to be able to process and absorb these molecules and to keep invading organisms or toxins from entering the host. The microflora of the colon, which is composed of approximately 100 billion bacteria, is also intimately involved in intestinal health and generates metabolic byproducts that support the health of the host in a symbiotic fashion. Disruption of this flora (dysbiosis) can result in the production of toxic bacterial metabolites or the reduction in beneficial byproducts. Approximately 60% of the immune system is located in the GI tract and is referred to as the gastrointestinal associated lymphoid tissue (GALT). Activation of GALT can have far-reaching downstream effects, as can be seen in the peripheral manifestations of inflammatory bowel syndrome or gluten sensitivity. The GI system can have large effects on either keeping physiologic processes in balance or initiating and perpetuating imbalances in inflammation, oxidation, and detoxification, which are often manifest in organ systems that seem far removed from the GI system.

Macromolecules must be processed to their basic building blocks to be absorbed via transport mechanisms in the small intestine. Potential disruptions can occur in this process at any of a number of sites. Hydrochloric acid production in the stomach, pancreatic enzyme production, loss of tight junctions of the small bowel intestinal epithelium (causing leaky gut), and dysbiosis can all result in GI dysfunction and downstream effects. Functional disorders such as irritable bowel syndrome can occur as a result of this disordered physiology.

The 4R Model

Remove

One clinical paradigm used extensively in functional medicine is referred to as the 4R model. The first approach in the 4R model, remove, refers to the elimination of pathogenic organisms including fungi, pathogenic bacteria, parasites, and other ingested substances that include environmental toxins and foods. Food allergy is believed to be mediated by the passage of incompletely digested proteins across the intestinal epithelium, where it stimulates an immune response with the production of IgG antibodies. With continued ingestion of these proteins and translocation across the intestinal epithelium due to leaky gut, immune complexes are formed that result in immune activation. This is in contrast to the traditional concept of food allergy, which is IgE mediated and can represent a life-threatening, immediate type of immune reaction.

Infants have been shown to have impaired tight junctions of the enterocytes, and introduction of antigenic foods within the first 6 to 12 months is associated with the development of inflammatory skin conditions. Symptoms suggesting IgG-mediated food allergies include irritable bowel syndrome, apthous ulcers in the oral mucosa, serous otitis media, migraine headaches, asthma, chronic sinusitis, nasal congestion (without rhinorrhea), eczema, and memory loss. IgG-mediated food allergy might trigger other disorders (through stimulation of the immune system via immune complexes) such as rheumatoid arthritis and inflammatory bowel disorders. Peptides produced through the partial hydrolysis of gluten and casein that leak across an impaired GI mucosa have opioid properties and can result in neurobehavioral symptoms.

Leaky gut can be related to infections, use of NSAIDs, and the development of dysbiosis related to antibiotic use. One study has demonstrated a higher incidence of functional GI complaints in patients who had received antibiotics months before the development of symptoms. ²² Studies have also suggested that antibiotics can increase the risk of Crohn’s disease. ²³ Leaky gut can be tested for by ingesting lactulose and mannitol and measuring urinary ratios of these substances in the urine. Lactulose is not normally absorbed, and an elevated ratio might suggest impaired mucosal integrity.

Removal of offending foods by following an oligoantigenic diet and observing clinical improvement is the gold standard for assessing food allergies. Elimination diets are typically continued for approximately 1 month, and then food groups are reintroduced every 4 days or so. If symptoms recur with re-introduction (it can take a week of continued ingestion to develop clinical symptoms due to the delayed type of response from immune complex formation), then that food is identified as a possible trigger. Food allergy testing for IgG antibodies is also commercially available and can help guide decisions regarding dietary modifications. The results from these tests seem to be quite variable, so proceeding straight to the elimination diet is a better practice if possible.

Replace

Replace, the second approach in the 4R program, refers to the supplementation of digestive factors that may be reduced, therefore preventing optimal function. Hydrochloric acid production in the gastric mucosa is necessary for the optimal digestion of proteins and for the absorption of nutrients such as calcium. With increasing age, impairment in the production of HCl becomes more common. Osteoporosis has been described in patients taking proton pump inhibitors, which may be related to this mechanism. Pancreatic enzymes may be functionally deficient in a variety of clinical conditions including eczema and steatorrhea. The symptoms in patients with irritable bowel syndrome can improve with the addition of empirical supplemental pancreatic enzymes.

Reinoculate

Reinoculate is the third step. This refers to the supplementation of desirable microorganisms (probiotics) into the GI tract. This balance, involving hundreds of species of bacteria, can be impaired through the use of antibiotics and through exposure to environmental toxins. The environmental influence on the colonization of the intestinal microflora begins at the time of delivery and continues for the first 2 years of life. The maternal microflora inoculates the infant and influences the development of this symbiotic relation-ship and eventual milieu of the GI tract. Commonly prescribed probiotics include Lactobacillus and Bifidobacteria. Within each of these groups of bacteria, there are many species, and each has its unique characteristics and produces different effects in clinical trials.

Probiotics can inhibit pathogenic bacteria through a variety of proposed mechanisms that include competition for bacterial adhesion sites and bactericidal activity against pathogenic bacteria. Probiotics produce metabolites, such as butyric acid, that are beneficial to barrier function and colonocyte health. Studies have demonstrated the effectiveness of probiotics in children with viral diarrhea illness. Use of probiotics shortened the course of diarrhea and reduced hospitalization. ²⁴ Probiotics have also been shown to modulate the course of ulcerative colitis ²³ Saccharomyces boulardii, when given in conjunction with vancomycin, has been demonstrated to reduce the likelihood of recurrent Clostridium difficile enterocolitis. ²⁵ Caution must be exercised in extremely ill patients because the use of this normally nonpathogenic organism has resulted in fungemia. The use of probiotics together (synbiotics) has been shown to be beneficial in specific clinical situations.

In addition to reinoculation, the addition of prebiotics can provide nutritional substrate for the beneficial bacteria that in turn results in the production of short-chain fatty acids (SCFAs), which are believed to provide up to 70% of the nutritional energy used by colonic cells. Examples of prebiotics include fructans, fructo-oligossaccharides, inulin, and arabinogalactans. Soluble fiber is also an important nutritive source for probiotics.

Repair

Repair is the final step in the 4R program. Nutrients that have been shown to support the repair process of the intestinal epithelium include glutamine, zinc, pantothenic acid, and essential fatty acids. Glutamine represents the major metabolic fuel for the epithelial cells in the small intestine. Pantothenic acid (vitamin B₅) is needed for the production of coenzyme A (CoA) and acyl carrier proteins (ACP). CoA is a cofactor in more than 70 enzymatic pathways, and ACP is an essential cofactor for the fatty acid synthase complex. Essential fatty acids such as omega-3 from fish oils are involved in cell membrane function and also have anti-inflammatory properties.

Laboratory testing to support the clinician is commercially available. Stool testing for meat fibers can imply adequacy of HCl and pancreatic enzymes involved in protein digestion. Stool fat analysis can suggest adequacy of lipase production. SCFA levels can suggest the amount and composition of the beneficial bacteria. Stool cultures can assess quantitative measures of Lactobacillus and Bifidobacteria along with pathogenic bacteria and yeast. Stool should also be examined for ova and parasites. In patients with irritable bowel syndrome, empirical treatments with these supplements in a stepwise fashion can result in significant clinical improvements that might not have been evident based on laboratory results.

Nature and Nurture

The web of interactions expands as we consider the influence of the GI tract on downstream processes such as inflammation, oxidative stress, and detoxification. Imagine the scenario where the patient in our office presents with an inflammatory condition such as eczema or rheumatoid arthritis. We know that approximately 70% of cancers and other disease processes are a result of the environment and 30% are related to genetic predisposition. The environment washes over the genes to result in either an inhibition or potentiation of genetic expression. Our hypothetical patient then received antibiotics or had some other insult that favored the development of a dysbiosis and leaky gut that in turn resulted in immune complex formation and activation of cytokines. He also inherited an SNP that results in the enhanced production of an inflammatory cytokine, which in turn is expressed in this inflammatory condition for which he is now being evaluated. His diet consists of highly processed inflammatory foods, which is the usual complement of the standard American diet. The trigger for this clinical condition occurred years before the presentation. It was potentiated and mediated through diet, obesity, and genetic predisposition. Understanding these interconnections gives us additional tools to evaluate and treat our patients in a more comprehensive manner.

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Conclusion

The quest of people is to live a long, healthy, and fulfilling life. Since the mid-19th century, the average American lifespan has increased by approximately 2.5 years per decade. Healthy lifestyle activities are associated with decreased disability, illness, and a more functional status. The lifestyle factors that have the highest correlation to health are smoking, body mass index, and exercise. The greatest focus of prevention by allopathic and integrative medicine practitioners should be geared toward smoking cessation, consuming a healthy diet, achieving a healthy body weight, and regular exercise. As our knowledge in molecular medicine advances, we can now demon strate that these activities have associated biologic markers that show improvement in cellular function, decreased inflammatory mediators, and a reduction in oxidative stress. Thus, we can now look for a molecular basis for what we have shown to be either a beneficial or detrimental lifestyle. Before disease becomes apparent, considerable dysfunction has occurred. If it is possible to intervene in this state of dysfunction and supply the needed nutrients or achieve lifestyle changes, then disease could be prevented.

The sobering reality is that our youngest generation is predicted to have a shorter lifespan than their parents due to obesity and the development of type 2 diabetes. The prevalence of type 2 diabetes is expected to reach 50% in some minorities. The Pima Indians have a rate of diabetes that reaches 90%. Traditionally they survived in a hostile environment where the next meal was not necessarily around the corner. To survive in this environment, they needed to develop thrifty genes so that in times when food was available they could store it efficiently. When their environment changed and highly processed, nutrient-poor, calorie-dense food became immediately available in the convenience store or at the fast-food establishment, their genotype continued in its thrifty mode and resulted in the development of obesity and type 2 diabetes with its myriad of complications, human suffering, and health care costs.

As health care providers we need to be mindful and vocal to pro-mote positive lifestyle changes through education for our own families, patients, employees, school systems, and other institutions. There are many different starting points to accomplish this in our patients, including stress reduction, healthy whole-food diets, and exercise. We may be that ripple in a pond and touch many lives in the future through our work. We have the opportunity to affect the children, grandchildren, and future generations of the patients we serve.

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Summary

• Many patients take supplements or nutraceuticals.
• The clinician must understand the scientific rationale for the use of particular herbs and supplements and must have resources to help guide patients and to prevent drug interactions.
• The science supporting the use of supplements is robust, although clinical outcome studies are lacking for various reasons.

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Suggested Readings

• Alternative Medicine Review Monographs. vol 1: 2002; ;Dover, Idaho.
• Probiotics in pediatric gastrointestinal disorders. Curr Opin Pediatr. 12: 2000; 477-481.
• Textbook of Functional Medicine. 2005; ;Gig Harbor, Wash.
• Antibiotics increase functional abdominal symptoms. Am J Gastroenterol. 97: 2002; 104-108.
• Lycopene as a chemopreventive agent in the treatment of high-grade prostate intraepithelial neoplasia. Urol Oncol. 23: 2005; 383-385.
• Relative imbalances in the expression of estrogen-metabolizing enzymes in the breast tissue of women with breast car-cinoma. Oncol Rep. 14: 2005; 1091-1096.