Clinical and Health Affairs
Interventional Nutrition and Cancer Survivorship: A Case Study
By Gregory A. Plotnikoff, M.D., M.T.S., FACP
Abstract
Interventional nutrition is an emerging field in medicine that utilizes advanced laboratory technologies to identify a patient’s clinically relevant biochemical uniqueness in order to treat the metabolic contributors to multifactorial symptoms such as fatigue, insomnia, and pain. This article presents a complex case in which a breast cancer patient’s severe symptoms fit no clear disease pattern and prevented her from undergoing chemotherapy and radiation treatment. Specialized testing for metabolic, gastrointestinal, and immunologic function uncovered important nutritional deficiencies that could not be identified through isolated tests or addressed by supplementation with a daily multivitamin. Nutritional intervention based on specific measurements, rather than a one-size-fits-all approach to supplementation, resolved this patient’s debilitating symptoms and restored her capacity to benefit from chemotherapy and radiation.
For all patients, including those with cancer, nutritional and metabolic function are critical to well-being. For many patients, simply eating a balanced diet supplemented with vitamin D may be enough for optimal metabolic function. For patients with a clear deficiency, supplementation with a single nutrient may be the right approach such as vitamin C for scurvy or niacin for pellagra. But as we now know from clinical experience with vitamins B12 and D, even single-nutrient deficiencies can have different clinical appearances because of the web-like interconnectedness of human metabolism. For the most challenging patients, those with multiple symptoms that do not fit a clear, definitive pattern, consideration of how wide variations in nutritional and metabolic status may complicate disease processes may be required. Today, bundled advanced laboratory technologies make it possible to look at metabolic status as a system.
Physicians can now test urine and blood for beta-oxidation and Krebs cycle function, neurotransmitter production, essential fatty acid profiles, and other indicators that can cause clinical symptoms and use the results of those tests to determine the need for specialized supplementation (Table 1). This approach is consistent with physician training and practice, as many physicians already can and do measure the functionality of nutrients in their biological context. For example, neurologists routinely note that a serum level of vitamin B12 may be “normal” according to the standard bell-curve definition but that the patient may have a functional deficiency if the B12-dependent biomarker methylmalonic acid is elevated.1
The intentional use of vitamins, minerals, or other dietary supplements for optimal metabolic function based on biomarker measurements is sometimes termed “functional medicine.” As that term refers specifically to the approach of the Institute for Functional Medicine, many physicians prefer to use the term “interventional nutrition” to describe their applications of peer-reviewed biochemistry and nutrition studies to the treatment of complex illness. The approach requires clinical expertise in topics primarily studied during the first two years of medical school and that are not emphasized during residency or fellowship training.
Interventional nutrition is particularly helpful to cancer patients with refractory multifactorial symptoms such as fatigue that limit their ability participate in therapy and enjoy a satisfactory quality of life. This article presents a case in which specialized testing of urine, blood, and stool for metabolic, gastrointestinal, and immunologic function identified interconnected factors that resulted in debilitating clinical symptoms. Because the testing is not standard of care but did lead to remarkably positive clinical results that were not obtainable by other means, the case is presented to illustrate and generate constructive dialogue on how considering metabolic function and specialized testing may enhance medical efficacy.
Case Presentation
In August of 2009, a 60-year-old woman, S.W., presented to the Penny George Institute for Health and Healing at Abbott Northwestern Hospital after referral from her surgeon for evaluation and treatment of severe emotional and physical depletion. She had been diagnosed in June of 2009 with metastatic breast cancer and underwent a mastectomy that was complicated by persistent cellulitis despite appropriate long-term antibiotic treatment. She reported extreme physical and emotional fatigue, insomnia, migraine headaches, nonspecific musculoskeletal pain and weakness, and lifelong GI symptoms including marked constipation and intermittent dyspepsia. She noted significant emotional stress as a result of her diagnosis, her delayed recovery from surgery, and the severity of her constitutional symptoms, especially her fatigue. She wanted to review supportive options and begin implementing a plan of action as quickly as possible.
S.W. had been healthy until one year prior to her diagnosis, when she underwent spinal surgery and was treated with prednisone for a prolonged period. After completing the prednisone, she suffered from falls with injuries, marked bilateral onychomycosis, and extreme muscle fatigue and aches. She was vegetarian and described poor gastrointestinal function that resulted in insufficient vegetable and protein intake. She expressed despair and appeared frail but did not meet the criteria for depression.
The severity of her symptoms and the length of her surgical recovery despite intensive care by multiple physicians and the fact that her thyroid, hematologic, liver, and renal function—the usual suspects associated with fatigue—proved to be normal, affirmed the need to do a more extensive nutritional and metabolic assessment. Issues specific to vegetarians include deficiencies of vitamin B12, methionine/key amino acids, and the omega-3 essential fatty acid docohexaeonic acid (DHA). Each of these could be tested for in isolation. However, her history and symptoms implied a much broader differential diagnosis, so we decided to proceed with bundled testing to assess her metabolic function. Those results led to further testing of her gastrointestinal and immunologic function.
Doing bundled testing of the metabolic system, as opposed to doing isolated specific testing, has diagnostic advantages when determining the cause of a multifactorial issue such as fatigue. From a systems perspective, bundled testing makes visible the interconnectedness of human metabolism.
■ Metabolic Assessment
Mitchondrial/Krebs Cycle Function. Bundled assessment of mitochondrial function diagnosed sources of compromised energy metabolism, which helped us understand S.W.’s severe fatigue (Figure). Fasting morning urine analysis demonstrated significant elevations of adipic and suberic acids, normal pyruvate, and marked abnormalities of citric acid cycle intermediates. This broad systems assessment became the basis for a much more focused differential diagnosis and intervention. Adipic and suberic acids are both products of omega oxidation and only elevate when normal beta-oxidation cannot occur. This indicates significant carnitine deficiency.2,3 Carnitine transports long-chain acyl groups from fatty acids into the mitochondria, where they are broken down through beta-oxidation to produce acetyl-Co-A for energy extraction through the Krebs cycle.4 Symptoms of carnitine deficiency include lethargy and fatigue refractory to conventional interventions.5 Carnitine deficiency can follow persistent renal or gastrointestinal loss.6
Low acetyl-Co-A can mean reduced downstream production of co-enzyme Q10 (ubiquinone), the electron shuttle for oxidative phosphorylation in the mitochondrial inner membrane. In this case, the patient’s serum CoQ10 level was far below normal, indicating significant metabolic dysfunction that can cause significant-but-reversible fatigue.7
In addition, her levels of citric, isocitric, and cis-aconitic acids were all quite low. Her pyruvate level was normal, however, which ruled out pyruvate dehydrogenase or pyruvate carboxylase dysfunction. This meant that the differential diagnosis for her severe fatigue included not only low acetyl Co-A and CoQ10 production that resulted from carnitine deficiency but also low citrate production caused by gastrointestinal dysfunction. Citrate is formed inside mitochondria from acetyl-coenzyme A via the enzyme citrate synthase. Intraluminal bacterial transamination of glutamine, which can occur in overgrowth or other ecological imbalances in the intestinal flora, can result in succinate excess and secondary inhibition of the citrate synthase.8 This consideration was also supported by the patient’s gastrointestinal symptoms, her multiple courses of antibiotics, and her use of prednisone. She received supplementation with both L-carnitine 500 mg by mouth three times a day and CoQ10 200 mg by mouth once a day.
Essential Fatty Acid Status. The total omega-3 fatty acid concentration in S.W.’s red blood cells was low at 5.9% (ideal being >10%) with total omega-6 concentration high at 37.3% (ideal <35.5%). This imbalance of essential fatty acids was reflected in her low omega-3 index of 3.9 (ideal 8 to 10) and elevated inflammation index of 4. Confirmation of her relative insufficiency of omega-3s came from the elevated concentration of the omega-7 fatty acid palmitoleic acid. Increased endogenous production of omega-7 fatty acids is the result of omega-3 functional insufficiency.9 Testing also revealed a clinically relevant excess of arachidonic acid.
These findings are consistent with augmented pain and fatigue caused by increased pro-inflammatory prostaglandin, leukotriene, and thromboxane production from high levels of arachidonic acid (AA, 20:4 n6) and low levels of eicosapentaenoic acid (EPA, 20:5 n3).10 These essential fatty acids are crucial for the optimal functioning of nearly every organ system including the central nervous system.11 Additionally, increasing evidence supports the importance of omega-3 essential fatty acids for augmentation of anticancer chemotherapeutics because of their anti-inflammatory, anti-apoptotic, anti-proliferative, and anti-angiogenic effects.12 S.W. was prescribed omega-3 fatty acid supplementation of eicosapentaenoic acid and docosahexaenoic acid at 1,000 mg a day.
Functional Status of Key Vitamins and Minerals. Many metabolites of amino acid catabolic pathways are functions of coenzyme vitamin status or mineral enzyme activators. A common example is methylmalonic acid as a marker for functional B12 deficiency. Methylmalonic acid is converted into succinic acid by the vitamin B12-dependent enzyme methylmalonly-CoA-mutase. Low B12 means impaired conversion and elevated methylmalonic acid.
In S.W.’s case, urine analysis demonstrated exceptionally high levels of formiminoglutamic acid. This derivative of the amino acid histidine requires tetrahydrofolate for conversion into metabolically useful forms. The differential diagnosis included deficiency of folic acid (the source of tetrahydrofolate) as well as deficiency of vitamin B12 (for folic acid uptake and cell retention), or deficiency of vitamin B6 as pyridoxal 5 phosphate (for coenzyme function in formiminoglutamic acid transformation).13 The normal methylmalonic acid supported supplementation with vitamins B6 and B9 at 25 mg and 1,200 mcg per day, amounts above the recommended daily intake level. It is important to note that because of biochemical individuality, some people require significantly higher vitamin doses to achieve the same level of enzyme functionality.
As with vitamin B12 assessment, enzyme activation assessment can provide rational guidance for mineral supplementation when serum measurements cannot. In this case, testing demonstrated a very high ethanolamine-to-phosphoethanolamine ratio. Measurement of these two obscure metabolic intermediaries indicate a patient’s magnesium status, as the transformation from ethanolamine to phosphoethanolamine requires magnesium as a co-factor. The high ratio demonstrates blocked transformation and, thus, a relative insufficiency of the mineral.
The results both justify and guide magnesium dosing and illustrate the importance of a systems biology approach rather than measurement in isolation. In this case, S.W. was supplemented with 800 mg of magnesium glycinate per day.
Oxidant Stress. Reactive oxygen species such as oxygen ions and peroxides can attack lipids, protein, and nucleic acids simultaneously in vivo. Evidence suggests that reactive oxygen species act as second messengers in intracellular signaling cascades that both induce and maintain the oncogenic phenotype of cancer cells. Measurements of generalized, cellular oxidative stress include urinary lipid peroxides and 8-hydroxydeoxyguanosine (8-OHdG), an oxidized nucleoside of DNA. The latter is the most frequently detected and was found to be extremely high in the DNA of the lesion in this patient at 23 mcg/g Cr (< 16). This finding can be seen with invasive breast cancer but would not be expected in a patient two months after mastectomy.14 Thus, the impaired beta-oxidation of fats and the low CoQ10 level represented strong evidence of impaired oxidant/antioxidant balance and supported additional supplementation with vitamins A, C, and E at levels above the recommended daily allowance prior to chemo- and radiation therapies. Changes in diet often can support adequate serum levels. For S.W., recommendations included increased consumption of colored vegetables that could provide 10,000 to 15,000 IUs per day of vitamin A; daily intake of citrus fruits that could provide 250 to 500 mg of vitamin C; additional intake of nuts and whole grains to provide Vitamin E as d-alpha, beta, delta and gamma-tocopherol; and supplementation of natural (mixed RRR) vitamin E at 200 IUs per day.
■ Gastrointestinal Testing
Ecological and metabolic imbalances in the gastrointestinal tract can be assessed through multiple testing methods. The metabolic profile of this patient documented very low citrate in the Krebs cycle as well as elevated dihydroxyphenylproprionic acid (DHPPA). The need for a comprehensive stool analysis was supported by an elevated DHPPA level of 8.6 (ideal <2.2). This is a byproduct of the intraluminal metabolism of the aromatic amino acids phenylalanine, tryptophan, and/or tyrosine by overgrowth of Clostridia or Pseudomonas species.15 These findings, along with S.W.’s history of gastrointestinal problems, strongly suggested the need for further testing to assess digestive and metabolic functions.
Further testing of gastrointestinal metabolic functioning, including intraluminal vitamin production, deconjugation of steroid hormones and bile acids, as well as metabolism of small-chain fatty acids, can be done through stool analysis. In this case, stool analysis demonstrated the surprising finding that the secondary bile acids lithocholic acid and deoxycholic acid, which are normally measureable, were unmeasurable.15 Under normal conditions, excreted bile acids are metabolized in a variety of ways by intestinal bacteria yielding deoxycholic acid and lithocholic acid. Their unusual absence required culturing the stool to understand the status of the patient’s intestinal microbiota. These surprising findings, including the complete absence of culturable Escherichia coli noted in Table 2, are highly unusual and represent significant ecological imbalance. Rebalancing required use of both antibiotics and pre- and probiotics to eliminate and then restore the intestinal ecology.17,18 Based on antibiotic sensitivity results, S.W. was prescribed ciprofloxacin at 250 mg by mouth twice a day for seven days plus a multispecies probiotic at 20 billion CFUs per day for at least three months in addition to increased soluble fiber in her diet.
Because the patient had marked elevation of eosinophil protein X at >35 (ideal <7) and a high normal calprotectin, further testing to understand gut immunology appeared warranted. These two stool immune markers reflect activation of eosinophils and neutrophils, respectively. Laboratory tests for these markers are widely used in Europe, and their use is likely to become routine in the United States in the near future. Calprotectin is inflammation-specific, and levels can help differentiate inflammatory bowel disease from irritable bowel syndrome.19 Food allergies can cause the level to be elevated. Eosinophil protein X is elevated in patients with food allergies, celiac disease, colon cancer, inflammatory bowel disease, and helminthic infections.20 In addition to having elevated eosinophil protein X and calprotectin levels, S.W. had a total serum IgE level of 199.0 IU/mL (ideal <80). These findings strongly supported the need for further evaluation for food allergies/reactivities.
■ Immunologic Assessment
A simple blood test for food allergies (IgE) and food reactivities (IgG) has proved to be quite helpful in identifying triggers of nonspecific symptoms such as pain, fatigue, and memory and concentration difficulties as well as mood swings. A recent randomized controlled crossover trial of IgG food testing and elimination demonstrated causality in migraine headaches.21 In this case, despite the patient’s elevated IgE levels, a screen of common foods demonstrated no IgE reactivity. In contrast, IgG screening of more than 100 foods demonstrated markedly high activity against many frequently consumed foods including wheat, oats, pecans, garlic, lettuce, and grapes. Strong reactivity was also seen with chocolate, peanuts, sesame seeds and oil, peas, and string beans. These results indicated a need for further testing with elimination and rotation diets. The strongly positive results for so many foods in the setting of gastrointestinal signs and symptoms and markedly abnormal stool testing indicated the need for glutamine support for n-butyrate production and intestinal wall integrity.22 S.W. was prescribed glutamine at 3,500 mg twice a day as a powdered supplement in addition to the anti- and probiotics previously noted.
Discussion
Nutritional status is too often overlooked during recovery from surgery and treatment for cancer. In the case presented here, the patient at first reported overwhelmingly severe fatigue plus pain, headaches, and secondary insomnia. She was not responding to curative therapies for her postsurgical infections and did not have the physical capacity to participate in chemotherapy and radiation.
The results of bundled metabolic evaluation supported the need for significant dietary supplementation above and beyond what is available in a multivitamin. They also documented the need for important gastrointestinal and immunologic testing. The combination led to an intense, customized nutritional intervention (Table 3) that resulted in the patient experiencing a marked increase in energy and improved mood, sleep, and quality of life. Additionally, the patient’s cellulitis resolved, and, after several months, she was able to fully participate in chemotherapy and radiation. Both the patient and her physicians attribute her clinical success to functional normalization of multiple metabolic, gastrointestinal, and immunologic parameters through interventional nutrition.
Nutritional testing has frequently been limited to iron, vitamin B12, and folate in isolation. Most often, a physician’s idea of nutritional intervention is a nonspecific recommendation for multivitamins. Consequently, many patients may be underdiagnosed for vitamin and mineral deficiencies. And, as we have seen with treatment of vitamin D deficiency, the one-size-fits-all recommendation doctors often give for multivitamins may mean that patients are undertreated. In complicated cases, bundled assessment that provides a systems biology perspective can be attained through several national Medicare- and CLIA-certified reference laboratories. In the case described, the total cost to the patient for these three tests was $427. The patient’s insurance covered the remaining cost associated with the testing.
Conclusion
Interventional nutrition represents a new way of thinking about the fundamental determinants of health and illness. Bundled metabolic assessments enable identification of factors contributing to poor health and may lead to improved clinical outcomes in some patients with cancer and other chronic illnesses. Improved research methodologies are needed to define which patients are most likely to benefit from this approach. For the most complex patients, however, it appears to be both cost-efficient and effective in relieving suffering. MM
Gregory Plotnikoff is a senior consultant for the Allina Center for Health Care Innovation.
References
1. Matteini AM, Walston JD, Bandeen-Roche K, et al. Transcobalamin-II variants, decreased vitamin B12 availability and increased risk of frailty. J Nutr Health Aging. 2010;14(1):73-7.
2. Matsumoto M, Matsumoto I, Shinka T, et al. Organic acid and acylcarnitine profiles of glutaric aciduria type I. Acta Paediatr Jpn. 1990;32(1):76-82.
3. Shimizu N, Yamaguchi S, Orii T. A study of urinary metabolites in patients with dicarboxylic aciduria for differential diagnosis. Acta Paediatr Jpn. 1994;36(2):139-45.
4. Feller AG, Rudman D. Role of carnitine in human nutrition. J Nutr. 1988;118(5):541-7.
5. Crentsil V. Mechanistic contribution of carnitine deficiency to geriatric frailty. Ageing Res Rev. 2010;9(3):265-8.
6. Rebouche CJ. Carnitine. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease. 10th ed. Philadelphia: Lippincott, Williams & Wilkins; 2006:537-44.
7. Quinzii CM, López LC, Gilkerson RW, et al. Reactive oxygen species, oxidative stress, and cell death correlate with level of CoQ10 deficiency. FASEB J. 2010 May 21 (epub ahead of print)
8. Kovacevic Z, Mc Givan JD, Chappell JB. Conditions for activity of glutaminase in kidney mitochondria. Biocem J. 1970:118(2);265-74.
9. Siguel EN, Chee KM, Gong JX, Schaefer EJ. Criteria for essential fatty acid deficiency in plasma as assessed by capillary column gas-liquid chromatography. Clin Chem. 1987;33(10):1869-73.
10. Calder PC. The 2008 ESPEN Sir David Cuthbertson Lecture: Fatty acids and inflammation—from the membrane to the nucleus and from the laboratory bench to the clinic. Clin Nutr. 2010;29(1):5-12.
11. Shaikh IA, Brown I, Wahle KW, Heys SD. Enhancing cytotoxic therapies for breast and prostate cancers with polyunsaturated fatty acids. Nutr Cancer. 2010;62(3):284-96.
12. Spencer L, Mann C, Metcalfe M, et al. The effect of omega-3 FAs on tumour angiogenesis and their therapeutic potential. Eur J Cancer. 2009;45(12):2077-86.
13. Matthews JH. Cobalamin and folate deficiency in the elderly. Ballieres Clin Haematol. 1995;8(3): 679-97.
14. Himmetoglu S, Dincer Y, Ersoy YE, et al. DNA oxidation and antioxidant status in breast cancer. J Investig Med. 2009;57(6):720-3.
15. Elsden SR, Hilton MG, Waller JM. The end products of the metabolism of aromatic amino acids by Clostridia. Arch Microbiol. 1976;107(3):283-8.
16. Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47(2):241–59.
17. Andoh A, Fujiyama Y. Therapeutic approaches targeting intestinal microflora in inflammatory bowel disease. World J Gastroenterol. 2006;12(28):4452-60.
18. Tlaskalova-Hogenova H, Stepankova R, Hudcovic T, et al. Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunol Lett. 2004;93 (2-3):97-108.
19. Van Rheenen PF, Van de Vijver E, Fidler V. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis. BMJ. 2010;341:c3369.
20. Blanchard C, Rothenberg ME. Biology of the eosinophil. Adv Immunol. 2009; 101:81-121.
21. Alpay K, Ertas M, Orhan EK, et al. Diet restriction in migraine based on IgG against foods: a clinical double-blind, randomized, cross-over trial. Cephalalgia. 2010;30(7): 829-37.
22. Dos Santos RG, Viana ML, Generoso SV, et al. Glutamine supplementation decreases intestinal permeability and preserves gut mucosa integrity in an experimental mouse model. JPEN J Parenter Enteral Nutr. 2010;34(4):408-13.