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Functional Laboratory Testing for Naturopathic Physicians

By John Hahn, ND, DPM

The modern naturopathic physician is faced with many challenges when it comes to patient selection for minor surgical procedures. The high-risk diabetic patient presents with challenges that can lead to postoperative complications and potential lawsuits. There are groups of patients that experience delayed wound healing, with no obvious preoperative disease elucidated in the preoperative history, physical or laboratory studies.
Faced with these challenges, the astute naturopathic physician now has the ability to order functional laboratory testing that will help ascertain a patient's ability to heal postoperatively and reduce the incidence of postoperative infections. The purpose of this article is to elucidate the use of functional and predictive tests that can help assess patients preoperatively and avoid postoperative complications.
Cortisol Testing
In our fast-paced society, many Americans are subjected to chronic stress that influences their body's ability to produce a normal circadian rhythm of cortisol production from the adrenal glands. Cortisol is a very powerful intrinsic hormone produced by the adrenal glands and is essential for life. However, excess cortisol has many detrimental effects on health.
Cortisol can function as a catabolic hormone in the body. As an example, when blood sugar is low, cortisol stimulates the breakdown of protein and fat to reduce glucose, in order to counteract the low blood sugar. Cortisol also is important in moderating inflammation. Inflammation can result in greater damage to tissues than the original trauma that caused the inflammation. Therefore, in response to inflammation, the adrenal glands increase cortisol production to control the inflammatory response. Cortisol takes part in the regulation of blood volume and blood pressure by reducing the loss of sodium in the urine. Cortisol also helps to maintain emotional stability. All of these cortisol-related effects assist the body in dealing with physical and emotional trauma and stress. Increased adrenal stress also is found in patients undergoing operative procedures. There is the emotional stress of the contemplated surgical procedure, and there is the physical stress of the anesthetic and the surgical stress of tissue insult to both soft tissue and bone.
Chronically elevated cortisol, however, has many detrimental effects on the body. Hypercortisolemia causes increased protein breakdown and decreased protein synthesis. This effect can result in the loss of muscle mass. A decrease in protein synthesis also will result in accelerated aging of the skin. Protein synthesis is essential for adequate soft-tissue and bone healing postoperatively.
Excess cortisol promotes osteoporosis by enhancing the breakdown of the protein matrix within the bone, which holds minerals in the bone and reduces the synthesis of the protein matrix for the formation of new bone. Thus, we can see that hypercortisolemia will result in a delay in bone healing for procedures involving osteotomies. Hypercortisolemia causing delayed bone healing also holds true for fracture repair. Additionally, hypercortisolemia will reduce the uptake and utilization of intracellular glucose. This reduction has a significant effect on brain function, since intracellular glucose is the optimum fuel for the cells of the brain and the nervous system.
Hypercortisolemia has a profound effect on the body's immune system. Natural killer cell function is reduced in the presence of hypercortisolemia, which increases the body's susceptibility to cancer cell growth. The increased protein breakdown secondary to hypercortisolemia and the decreased protein synthesis results in a decrease in lymph tissue, with corresponding reductions in T cells and antibodies. Secretory IGA, produced by mucocytes lining the mucous membranes of the body, would show a dramatic reduction in production in the presence of hypercortisolemia. This reduction would increase the chances of bacterial and viral infections involving the respiratory, gastrointestinal, urinary and reproductive tracts. A low preoperative level of secretory IGA could increase the risk of a postoperative infection. Infectious agents disseminated from a site distant to the operative site could result in a postoperative infection.
Hypercortisolemia causes a reduction in the detoxification function of the liver, as well as a reduction in the body's ability to chelate or remove heavy metals such as mercury. Patients undergoing surgery need to have optimal liver detoxification pathways available postoperatively. There needs to be detoxification in the liver from anesthetics, analgesics and cellular debris created during the perioperative period.
Hypercortisolemia has a significant effect on the thyroid hormones. Hypercortisolemia will result in a decrease in the active hormone T3 and increase the level of the inactive thyroid hormone rT3. As we know, adults don't utilize rT3 in governing cell metabolism. Hypercortisolemia downregulates the production of 5-deiodinase. This enzyme is responsible for the conversion of T4 to T3 by the removal of any iodine molecule. Standard thyroid blood tests don't distinguish between active and inactive hormones. Thyroid hormone production is regulated by the pituitary hormone TSH (thyroid stimulating hormone). Persistent hypercortisolemia also reduces TSH production, thereby reducing the production of thyroid hormone at a time when active thyroid hormone is already reduced. This overall reduction in thyroid production and the conversion of T4 to the active T3 form has a negative impact on wound healing, since it downregulates cellular metabolism. This reduction in cellular metabolism also affects the basal metabolic rate and impacts tissues that have been operated on, delaying and/or reducing the rate of healing of both soft tissue and bone. The activities of the immunocytes also are directly affected by a decrease in thyroid hormone production, thus reducing the amount of antibody agents available to fight infection.
Cortisol production by the adrenal glands follows a circadian rhythm. Levels of cortisol vary depending upon the time of day. Therefore, a dexamethasone suppression test would not give valid information to the clinician regarding the status of the cortisol output over a 12-hour period, but only a window of time in the morning.
Cortisol levels reach a peak at 7 a.m. to 8 a.m. and then gradually decrease to a low level around midnight. High cortisol levels at night, when production should be low, can result in insomnia and poor sleep quality. A nighttime peaking of growth hormone is required to initiate quality REM sleep. When cortisol is high, there is a reduction in growth hormone and REM sleep is not achieved. Conversely, low cortisol in the morning, when cortisol levels should be at their peak, can result in a feeling of being tired and groggy upon waking. Patients who need a caffeine boost in the morning to get them going might have low morning cortisol output and secondary functional hypothyroidism caused by the abnormal circadian rhythm of the adrenal-pituitary-thyroid axis.
There are many stressors that can lead to increased cortisol production. These stressors, as mentioned previously, might be physical, such as a surgical procedure; or mental and emotional. Patients contemplating a surgical procedure need to have a detailed assessment of their life stressors taken in their preoperative history, in order to determine if a laboratory study of their cortisol output should be done preoperatively. The most common stressor that causes elevations of cortisol levels is low blood sugar. The most common causes of low blood sugar are:

going too long between meals;
meals with insufficient carbohydrates available in the food;
meals and snacks with excess carbohydrates, resulting in a hyperinsulinemia response.

Chronic production of excess cortisol also is noted in response to the physical stress caused by chronic pain and inflammation, as well as that introduced by excessive exercise and physical training. To minimize hypercortisolemia production, training schedules should be designed to give the body rest and healing time between workouts. Another stimulus of excess cortisol and abnormal cortisol rhythms is working the night or graveyard shift several days per week and then trying to be a "day person" on days off.
Women who use topical progesterone cream for even one month can have an elevation in active cortisol levels. The progesterone hormone absorbed from the cream, in excess of what the body can break down each day (approximately 25 mg per day), kicks cortisol off the binding protein. Cortisol in the free form is then able to perform its varied functions as noted above. Stimulation of excess cortisol also can be caused by the ingestion of stimulants such as caffeine, guarine, ephedra and gotu kola. Decongestants such as Sudafed and adrenal gland extracts also will increase cortisol production.
The best functional laboratory test a naturopathic physician can order for the measurement of cortisol output is a saliva test. The World Health Organization has determined that these noninvasive saliva tests on certain hormones are much more accurate than serum levels. Salivary cortisol is measured at two or four different times during the day to evaluate the amount of free cortisol secreted by the adrenals and to assess the rhythm of cortisol secretion. Cortisol also can be measured in the blood and urine. Whereas a saliva test measures only the active hormone, a blood level measures the total hormone, both bound and unbound. Therefore, blood testing does not distinguish between active and inactive cortisol. Urine testing of cortisol measures only the active cortisol; however, cortisol is measured on all of the urine collected during a 24-hour period. This test cannot tell if there are highs or lows in the cortisol levels at various times throughout the day. The time of day when active cortisol levels are high or low will indicate the cause and assist the practitioner in the correction of the abnormal high or low levels.
Many laboratories offering salivary testing for cortisol levels also include levels of dehydroepiandrosterone (DHEA), another hormone secreted by the adrenal glands and a building block for 17 other hormones.
Adrenal stress testing and saliva tests also can measure secretory IGA levels, allowing the practitioner to know the level of resistance to disease the patient's immune system will offer if exposed to pathogens. This is a very valuable piece of laboratory information for naturopathic physicians operating on patients who have questionable immune function from a history of postoperative infections or infections in general. A low secretory IGA level can identify patients susceptible to both viral as well as bacterial infections.
There are several laboratories in the U.S. that supply practitioners with adrenal stress testing kits, with return mailers, at no charge to the physician. The patient takes this test kit home and provides the four required salivary samples at specific times during the day, as specified in the laboratory instructions to the patient. The patient then sends the completed sample back to the laboratory for analysis. A printed report is either faxed or sent to the practitioner. The report usually presents several scenarios as to why the cortisol levels might be high or low. Recommendations for further functional testing also might be made, such as a glucose tolerance test if hypoglycemia or hyperinsulinemia is suspected.
A new, unique functional test to determine if the patient's abnormal cortisol levels are a result of abnormal sugar metabolism is the fasting insulin blood spot test. This is a minimally invasive finger prick test; a few drops of blood are all that is needed to quantify fasting insulin levels. This test offers particular insight into imbalances in patients with symptoms, despite a normal blood glucose test, or in individual patients with known or suspected hypoglycemia, insulin resistance, diabetes, pre-diabetes or a family history of diabetes. Hyperinsulinemia also is found in individuals with long-standing obesity.
Low cortisol output also is of concern to the naturopathic physician, because low adrenal function can cause other symptoms such as pain and fatigue, recurrent infections, crashing during stress, hypoglycemia, low blood pressure and dizziness upon first standing.
The standard blood tests for cortisol functions might give faulty results as to the actual function of the adrenal gland during the day. The normal range for morning cortisol is 6-24 µg per deciliter. This range actually was based on an assessment of when cortisol deficiency should be considered a problem, and officially, low cortisol probably is found in fewer than one out of 100,000 people. Most healthy people have a morning cortisol level between 18 and 24 µg per deciliter. Nonetheless, a level of 12, 8 or even 6 is considered by most endocrinologists as totally normal and healthy. A level of 5.9, however, is considered life-threatening (5.9 is life-threatening, while a level of 6.1 is totally healthy). What makes this concept scary is that the analyzing machine used to analyze the serum cortisol is only accurate within two points. Patients don't go from totally healthy to near-death based on a .1 µg per deciliter difference in cortisol levels. Yet, this is how almost all endocrinologists in the U.S. practice reading these levels, so it's not so surprising that they can miss most cases of inadequate/suboptimal adrenal function that is not technically life-threatening.
Three-Hour Glucose Tolerance Test With Corresponding Insulin Levels
I have found in my clinical practice that a three-hour glucose tolerance test (75g load of glucose after a 12-hour fast) with a corresponding insulin level is very helpful in elucidating whether a patient might be a surgical risk because of hyperglycemia, hyperinsulinemia and insulin resistance. Patients with a history of hypoglycemia, which they might have described in their history as becoming shaky and nervous, then dizzy, and then irritable and fatigued when they get hungry, might be hypoglycemic with hyperinsulinemia. Many patients would have a normal fasting or two-hour postprandial blood glucose. However, when challenged with a 75g load of glucose after a 12-hour fast, there might be a normal blood sugar curve over the three-hour, four-draw blood test. However, if the insulin levels are doubled to triple their normal range during the three-hour test, this might indicate insulin resistance and a possible pre-diabetic state. Patients scheduled for afternoon surgery might become hypoglycemic if they are NPO midnight and scheduled for a general anesthetic, if their three-hour glucose tolerance test demonstrates high levels, insulin or low blood sugar. These results will alert the naturopathic physician to plan accordingly.
Additional Functional Laboratory Tests to Evaluate Immune Competencies
There are functional tests available to the naturopathic physician that will help evaluate the patient's immune defense and repair system in a way that allows for diagnostically predictive as well as therapeutic outcome monitoring.
Laboratory tests that lead to specific clinical actions or that monitor specific outcomes during treatment qualify as functional tests. Conventional laboratory testing is mechanistic and reductionist, and has been well-reviewed in the literature, but has its limits as far as uncovering disease processes that are better elucidated by a functional test.
In the human body, the immune competence cells are divided between dendritic and lymphocytic cells. Dendritic cells include macrophages and monocytes, granulocytes and fibroblasts, endothelial cells and Kupfer cells in the liver, and glial cells and sinusoidal cells in the spleen. The dendritic cells are the engulfers and recyclers in the body. Dendritic cells prevent us from developing an infection when they are robust and functional. Defense and repair cells originally come from our bone marrow and mature in the thymus, spleen and lymph glands, particularly along the intestinal lining's Peyer's patches.
The different cell lineages that develop all share one common objective: to identify and destroy all substances, living or inert, recognized as not being part of what our body knows as "itself," and which are therefore tolerant and nonreactive toward the body and give these cell lineages life.
In good health, we are tolerant of self and homeostasis is active within our bodies. This means our bodies can neutralize any foreign invaders while keeping up the daily repair needs our body requires. These repair needs are based upon wear and tear from normal daily activities and surgical interventions. This also means we can return to equilibrium at the end of the day, during our time of REM sleep. The role of a healthy immune system is to repair and keep the body resilient, flexible and resistant to disease.
Functional laboratory tests that measure different aspects of homeostasis and immune competency include the following:

sedimentation rate and C-reactive protein (Hs CRP);
ascorbate calibration (measures antioxidant need and turnover in the body);
homocysteine levels (measure methylation, a key to detoxification and to repairs; this correlates with hypersegmentation of polymorphonuclear cells);
mercapturate and glucarate (measure detoxification pathways through metabolites in urine);
isoprostane (measures antioxidant sufficiency);
fasting glucose/insulin ratio to assess cell energetics, hypoglycemia and hyperinsulinemia.
creatine kinase with isoenzymes to distinguish skeletal muscle from cardiac muscle, if the values are above the normal reference ranges in a screening blood test;
blood urea nitrogen/creatinine ratio.

Functional Testing for Nutritional Status
Health, nutrition and diet are a major topic, with many tabloids and self-help books available in the U.S. The CDC, in a 2004 government publication, stated that the major causes of death at that time in the U.S. were from chronic diseases such as cardio- and cerebrovascular diseases, cancer, diabetes, infections and immune system failures, making up more than two-thirds of all the deaths in this country. Obesity and malnutrition both play an important role in these mortality statistics. Within the past five years, more than 17,000 articles have been published in medical journals relating vitamins, minerals and/or antioxidant deficiencies to hypertension and cardiovascular disease, cancer, diabetes and immune system disorders, providing strong evidence that many of these illnesses possess a nutritional component and that correcting the nutritional issues might help ameliorate the severity of these often lethal illnesses. As pointed out in JAMA (June 19, 2002; volume 287, number 23), vitamins are necessary for the treatment and prevention of chronic diseases in adults. How do we know if our patients are getting adequate vitamin and mineral intake from their standard American diet?
A new functional test has been developed by Dr. William Shive, at the University of Texas at Austin's Biochemical Institute. Dr. Shive realized that effective utilization of nutrition in medical practice is dependent upon the development of methods for assessing the nutritional status in each individual and identifying the factors that limit the nutritional responses of each individual patient. Dr. Shive wanted to develop a comprehensive assay that took into account all the factors affecting nutritional status: genetic and individual biochemistry, diet, and the effect of environmental and physical stressors, looking at the cumulative effect of diet over a larger period of time. Current nutritional assays measure serum levels of a given nutrient, only representing a snapshot of the past few days and nutritional intake. Serum measurements also failed to take into account individual differences between the abilities of a person's cells to take in nutrients and to convert them into an active form to be utilized properly by the body. Dr. Shive developed a method of functional intercellular nutrient analysis that has been performed commercially for approximately 11 years.
The idea of the functional intercellular analysis, at its most basic, is that by growing individual cells in a solution lacking a specific nutrient, the cells are forced to rely upon their own store supplies of that nutrient to grow and divide. By measuring the nutrient-deprived cell growth in comparison to cells growing in a complete solution containing all of the nutrients required for growth, the nutritional status of a person can be functionally determined. If a person's cells can't mobilize a particular nutrient, whether for genetic, biochemical, dietary or other reasons, this test will identify that deficiency. Intracellular stores of nutrients accumulate over a period of months and might represent a more complete picture of overall nutritional status than other assays. Nutrients analyzed by this method are essential for cell growth and for the production of antibodies crucial for prevention of infection. This test is important to practitioners concerned about the nutritional status of patients who might have concomitant diseases such as diabetes or ulcerative colitis, and who might have a subclinical nutrient deficiency that would affect their surgical outcome.
References

Fletcher, RH, Fairfield, KM. Vitamins for chronic disease prevention in adults: clinical applications. Journal of the American Medical Association, June 19, 2002;287(23):3127-29.
www.cdc.gov/nccdphp/burdenbook2004/section01/tables.htm.
Shive W, Pinkerton, Humphries, J, Johnson M, Hamilton W., Matthews K. Development of a chemically defined serum and protein-free medium for growth of human peripheral lymphocytes. Proceedings From the National Academy of Sciences, January 1986;83:9-13.
Russell Jaffee, M.D., Ph.D. Immuno Laboratories. Client services, 800-553-5472.
Jonathan Stein, Ph.D., Spectracell Laboratories, 800-227-5227.
Tietz, N. Clinical Guide to Laboratory Tests, 2^nd edition, 1990.
"Alternative Laboratory Testing." Townsend Letter for Doctors and Patients, January 2006;270.
Tuan CY, et al. Usefulness of plasma glucose and insulin concentrations in identifying patients with insulin resistance. American Journal of Cardiology 2003;92:606-10.
Allard, P, Delvin, E, et al. Distribution of fasting plasma insulin, free fatty acids, glucose concentrations in the homeostasis model assessment of insulin resistance. Clinical Chemistry 2003;49(4): 644-9.
McLaughlin, T, Abbasi F, Reaven, G, et al. Differentiation between obesity and insulin resistance in the association with c-reactive protein. Circulation 2002;106:2908-12.

About the Author: Dr. John Hahn is a graduate of the Sacramento State University, California College of Podiatric Medicine and National College of Naturopathic Medicine. He has operated a private practice in Oregon since 1972, with special interest in podiatric surgery and podiatric sports biomechanics. He added naturopathic medicine to his practice in 1993. He has lectured at various naturopathic and podiatric conventions, and has been published in numerous journals. Dr. Hahn can be reached at jmhahn2@verizon.net.