This disease, so frequently attending all long voyages, and so particularly destructive to us, is surely the most singular and unaccountable of any that affects the human body. For its symptoms are inconstant and innumerable, and its progress and effects extremely irregular: for scarcely two persons have the same complaints, and where there is found some conformity in symptoms, the order of their appearance has been totally different. However, though it frequently puts on the form of many other diseases, and is therefore not to be described by any exclusive and infallible criterions.

Chaplain Richard Walter
Anson's Voyages Around the World in the Years 1740-1744

The link between nutrient deficiency and the "inconstant and innumerable symptoms" was not understood when the above observation of scurvy was penned. Two centuries later, Roger Williams, the discoverer of pantothenic acid (vitamin B5), described biochemical individuality and the genetotrophic theory of disease. Nutritional deficiencies, he observed, are expressed differently among individuals, both in symptoms and in the order they appear, based upon the impact of environmental inputs on individual biochemistry and genetics.

Science has advanced appreciably since that well-controlled but unintentional experiment that place groups of individuals on boats and systematically deprived them of a particular nutrient over an extended period of time. We know a lot about how nutrients function, the roles they play in the health of different organ systems, and the symptoms and diseases of nutrient deficiency. This knowledge has virtually eradicated nutrient deficiency diseases from countries with adequate food supply and fortification. As a result, the convention in medicine is that, so long as we get the Recommended Daily Allowance (RDA) levels in our diets (and there is a basic assumption that most of us do), nutrition is not a significant factor in most diseases we see today. Doctors diagnose the diverse symptoms that patients bring to the doctor's office as disparate diseases, often using diagnostic laboratory test results to identify a marker for organ malfunction or failure. Therapy often involves pharmaceutical and surgical intervention to reduce symptoms.

The Integrative and Functional Medicine Approach
Patients come to Integrative and Functional Medicine (IFM) clinicians with a variety of complex, chronic symptoms and diseases. Drugs or surgery may not have worked for them or may even have made them worse. They may be part of a growing number of individuals with an aversion to covering up symptoms with medications or cutting out a misbehaving organ. They may want a truly integrative treatment that combines the best of conventional and IFM treatments. The IFM clinician looks for suboptimal nutrient status that can adversely affect function, or nutrient insufficiency, that underlies many complex, chronic diseases. Initial conditions of insufficiency are seen at a biochemical level without symptoms. As the duration of the insufficiency increases, additional changes appear in cellular function that can be seen as subclinical manifestations, such as behavioral and mental/emotional instabilities and other symptoms. As the insufficiency progresses into later stages, morphological and functional changes occur that can be defined as the early stage of disease. Finally, diagnosed pathology is expressed with end organ failure and ultimately death. (Figure 1).

Because essential nutrients play fundamental roles in cellular metabolism, as insufficiencies develop, the effects can be system-wide. Variation in disease expression is exponentially compounded when multiple nutrient deficiencies are involved, which is often the case in complex, chronic diseases. Any and every aspect of body function can potentially become compromised, making it difficult to determine the type and quantity of a needed nutrient by studying symptoms alone.

The IFM clinician does not treat fibromyalgia, chronic fatigue, and inflammatory bowel; rather, the clinician treats the individual nutritional insufficiencies, metabolic imbalances, and toxicities that prevent normal function and are expressed in each person as a different set of symptoms. Once corrected, symptoms are mitigated, just as the various expressions of vitamin C deficiency in scurvy are reversed once the patient is replete in the vitamin. Similarly, B-vitamin insufficiencies can be seen in many different symptoms related to energy metabolism and mitochondrial efficiency. Supplementation of these nutrients to ameliorate metabolic disorders has been well documented.¹ Another example is toxic lead exposure, which may be expressed in some individuals as inflammatory disorders, in others as immune disorders, and still others as neurological disorders.^2,3

Many factors influence nutrient status in the individual (Figure 2), such as diet, digestion, absorption, disease states, age, medications, stress, toxic exposures, activity levels, genetics, and biological differences. The IFM practitioner takes into consideration this full range of factors that can be affecting patient symptoms and uses laboratory assessments to fine-tune treatment.

Targeting Therapy with Laboratory Tests
Protocol-driven nutritional regimens based upon symptoms have been the major approach in IFM for decades. Supplement companies continue to develop products to treat specific symptoms. This approach is limited, since two individuals can present with the same symptoms but resulting from two different causes, and the same underlying mechanisms in two patients can result in different symptoms in each patient. Clinicians relying on protocols recommend supplements and dosages that may not address underlying issues. The clinical laboratory provides valuable information for targeted therapy based upon the biochemical individuality of the patient.

Many IFM laboratory tests are not used to diagnose disease since patients with different symptoms may have very similar metabolic profiles. Familiar diagnostic tests (fasting blood glucose, elevated serum PSA, and elevated white blood cells, etc.) help to put labels on diseases. But is there a metabolic, nutritional, or toxicity pattern to fibromyalgia that would distinguish it from chronic fatigue or autistic spectrum disorders – or even cardiovascular disease? Decades of experience with nutritional and metabolic profiling call into question the value of attempting to diagnose many complex chronic diseases by laboratory test results. However, they can be extremely useful in targeting underlying mechanisms and guiding therapy.

What tests provide the most useful information for treating the types of patients that come to the IFM practitioner? Obviously, the "serum chemistry" of conventional care is not the answer. That test was developed as a tool to screen for a variety of conditions involving serious biochemical or physiological imbalances associated with end-stage pathology. More often than not, patients come to their IFM doctor with test results in hand that indicate they are perfectly "normal" and wonder why they feel so bad. Doctors look to the laboratory for more relevant tests to help guide the types of therapies in the IFM arsenal. Should I modify the diet and, if so, how? Does the patient need nutrient supplementation and, if so, how much and what type? Is detoxification in order and, if so, what regimen?

Organic Acid Profiling – The "Basic Chemistry" for IFM
Of all the tests currently offered by IFM laboratories, the quantitative organic acid profile is emerging as the basic chemistry profile for IFM. Qualitative screening for organic acids has been used for decades to detect neonatal inborn errors of metabolism – metabolic defects that respond to specific cofactor supplementation. Quantitation of these metabolites at lower levels was first offered to IFM practitioners by Metametrix Clinical Laboratory in 1992 to detect more subtle inefficiencies in enzyme function. Using an overnight urine collection, the organic acid profile assesses a broad variety of nutritional and metabolic issues that can directly affect patient care, including the following:

· Carnitine insufficiency
· Need for B-complex vitamins, including specific markers for biotin, folate, B12, B6, and lipoic acid
· Methylation status
· Mitochondrial function and need for coenzyme Q10
· Neurotransmitter metabolism
· Detoxification status
· Oxidant stress status
· Glutathione sufficiency
· Microbial compounds whose presence indicates potential dysbiotic conditions

No other single test profile provides such a broad array of information that can be used to identify and treat nutritional insufficiencies, metabolic imbalances, and toxicities. This is why many IFM practitioners are more commonly using this test profile to help decipher the complex maze of symptoms they see every day. As a result, more IFM laboratories have recognized the profile's value and added it to their testing menus.

Case Illustration
A 73-year-old woman who had been relatively healthy her entire life recently developed a raised, hot and itchy rash on parts of her body. She had been to several doctors with no relief. She sought the advice of an IFM practitioner, who ordered the organic acid comprehensive profile as a "basic chemistry." The test results indicated she had an excessive amount of ammonia production. Bacterial overgrowth in the intestines can produce large amounts of ammonia that is absorbed into the system and can cause systemic reactions. There were a number of elevated dysbiosis markers in the profile, indicating this may be a causative factor. In addition, there was an up-regulation of glutathione production and a significant depletion of sulfate, which is critical for detoxification. These findings indicated her detoxification systems were under severe stress. The functional markers for B-complex vitamins, including lipoic acid, were elevated, indicating insufficiency. Co-enzyme Q10 markers indicated insufficiency of this critical nutrient. Treatment included N-acetylcysteine, lipoic acid, and silymarin for liver support; B-complex and co-enzyme Q10 to improve mitochondrial function; and a bowel detoxification program to normalize bowel flora. Her rash completely resolved in one month and had not recurred by her four-month, follow-up visit.

It is understandable that the conventional approach to diagnosis and treatment would not have resolved her symptoms. Even an IFM protocol-driven approach might have failed to uncover the complex mechanisms underlying her rash. The organic acid profile provided targeted information for this non-intuitive, comprehensive treatment plan that resulted in positive patient outcome.

Conclusion
The use of laboratory assessments can significantly assist the IFM practitioner in improving patient outcome. Organic Acid Profiling is proving to be a popular and useful clinical tool for routine screening of the IFM patient, providing a wide array of information in one test. Combination profiles for assessing not only organic acids but amino and fatty acids and other nutrients are also available. Supplement companies are also beginning to develop personalized supplements based on test results rather than protocols. This "Test, Don't Guess" approach replaces the older, protocol-driven, "shotgun" approach with targeted, personalized therapies based upon biochemical individuality. Because nutrient deficiencies, metabolic disturbances, and toxicities can express differently in individuals, based on their unique environmental, biochemical, and genetic make-up, a strategy that targets the underlying disturbances can improve patient outcome in a wide variety of diseases.

J. Alexander Bralley, PhD
3425 Corporate Way
Duluth, Georgia 30096
800-221-4640 / 770-446-5483
Fax 770-441-2237

Notes
1. Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K[m]): Relevance to genetic disease and polymorphisms. Am J Clin Nutr. 2002;75(4):616-58.

2. Milanov I, Kolev P. Clinical and electromyographic examinations of patients with tremor after chronic occupational lead exposure. Occup Med (Lond). 2001;51(3):157-162.

3. Hwang YF, et al. Chronic industrial exposure to lead in 63 subjects: Clinical and erythrokinetic findings. Southeast Asian J Trop Med Public Health. 1976;7(4):559-68.