Vitamin D3 Pharmacology Infographic: Physiologic Dosing versus Bolus Roulette

International Journal of Human Nutrition and Functional Medicine ® ISSN 2378-4881 ICHNFM.ORG/journal Pharmacology Infographic • Science Education • Clinical Nutrition • Primary Care • Policy • Medicine Vitamin D3 Pharmacology Infographic: Physiologic Dosing versus Bolus Roulette Alex Vasquez D.O., D.C., N.D. (USA), F.A.C.N. Infographics: D3 dose size determines clinical effect: Modest physiologic doses (demonstrated above) follow first-order pharmacokinetics characterized by a dose-response relationship that is predictable and also which does not result in significant accumulation of D3 relative to 25(OH)D; in contrast, unnatural bolus dosing of D3 follows unpredictable zero-order kinetics resulting in >500x non-physiologic elevations of D3 relative to deficient 25(OH)D with antagonistic biochemical/physiological effects leading to negative clinical consequences (Heaney Am J Clin Nutr 2008 Jun; Vieth, "Chapter 57: Pharmacology of Vitamin D" in Vitamin D, 3rd Ed., Academic, 2011). Citation: © Vasquez A. Vitamin D3 Pharmacology Infographic: Physiologic Dosing versus Bolus Roulette. Int J Hum Nutr Funct Med ® 2021 Feb;9:3 ichnfm.org/journal. Externally archived at ichnfm.academia.edu/AlexVasquez and InflammationMastery.com/d; article updated 24-Feb-21 Infographic: Interpretation of serum 25-hydroxy-cholecalciferol levels in adults: Interpretation of any laboratory variable requires clinical contextualization; assessing renal function and measuring 1,25-dihydroxycholecalciferol prior to the initiation of vitamin D3 supplementation is reasonable, especially in patients with higher probability of renal insufficiency or granulomatous/malignant disease, respectively. Coadministration of calcium-sparing drugs (e.g., thiazides) warrants caution; periodic measurement of serum calcium is advised, especially during the first year of higher-dose vitamin D supplementation. Supplementation with cholecalciferol should generally be accompanied by adequate magnesium intake and/or supplementation with magnesium 600 mg/d for adults; vitamins K1 and K2 should also be utilized to optimize calcium metabolism. Dietary optimization, moderation of sodium intake, broad-spectrum nutritional supplementation, and avoidance of dietinduced metabolic acidosis are likewise important; see citations listed below for proper implementation. Treatment should be supervised by a nutrition-knowledgeable clinician. Infographic citations included in images; see also: 1. Vasquez et al. Clinical importance of vitamin D: a paradigm shift for all healthcare providers. Altern Thera Health Med 2004 Sep 2. Vasquez A. Textbook of Clinical Nutrition and Functional Medicine. ICHNFM.ORG, 2016 3. Vasquez A. How to Plan Studies Using Vitamin D. Int J Hum Nutr Funct Med 2017 academia.edu/31412957 4. Vasquez A. Revisiting the Supplemented Paleo-Mediterranean Diet. Nutr Perspect 2011 Jan academia.edu/39751813 5. Videos/excerpts 2020, articles and correspondence compilation 2004-2019. InflammationMastery.com/d 6. Heaney et al. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003 Jan;77(1):204-10. doi: 10.1093/ajcn/77.1.204 7. Heaney et al. 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin Nutr. 2008 Jun;87(6):1738-42. doi: 10.1093/ajcn/87.6.1738 Citation: © Vasquez A. Vitamin D3 Pharmacology Infographic: Physiologic Dosing versus Bolus Roulette. Int J Hum Nutr Funct Med ® 2021 Feb;9:3 ichnfm.org/journal. Externally archived at ichnfm.academia.edu/AlexVasquez and InflammationMastery.com/d; article updated 24-Feb-21 About the author and presenter: Alex Kennerly Vasquez DO ND DC (USA), Fellow of the American College of Nutrition (FACN), Overseas Fellow of the Royal Society of Medicine: An award-winning clinician-scholar and founding Program Director of the world's first fully-accredited university-based graduate program in Human Nutrition and Functional Medicine, Dr Alex Vasquez is recognized internationally for his high intellectual and academic standards and for his expertise spanning and interconnecting many topics in medicine and nutrition. Dr Vasquez holds three doctoral degrees as a graduate of University of Western States (Doctor of Chiropractic, 1996), Bastyr University (Doctor of Naturopathic Medicine, 1999), and University of North Texas Health Science Center, Texas College of Osteopathic Medicine (Doctor of Osteopathic Medicine, 2010). Dr Vasquez has completed hundreds of hours of post-graduate and continuing education in subjects including Obstetrics, Pediatrics, Basic and Advanced Disaster Life Support, Nutrition and Functional Medicine; while in the final year of medical school, Dr Vasquez completed a Pre-Doctoral Research Fellowship in Complementary and Alternative Medicine Research hosted by the US National Institutes of Health (NIH). Dr Vasquez is the author of many textbooks, including Integrative Orthopedics (2004, 2007 2012), Functional Medicine Rheumatology (Third Edition, 2014), Musculoskeletal Pain: Expanded Clinical Strategies (commissioned and published by Institute for Functional Medicine, 2008), Chiropractic and Naturopathic Mastery of Common Clinical Disorders (2009), Integrative Medicine and Functional Medicine for Chronic Hypertension (2011), Brain Inflammation in Migraine and Fibromyalgia (2016), Mitochondrial Nutrition and Endoplasmic Reticulum Stress in Primary Care, 2nd Edition (2014), Antiviral Strategies and Immune Nutrition (2014), Mastering mTOR (2015), Autism, Dysbiosis, and the Gut-Brain Axis (2017) and the 1200-page Inflammation Mastery 4th Edition (2016) also published as the two-volume set Textbook of Clinical Nutrition and Functional Medicine. "DrV" has also written approximately 100 letters and articles for professional magazines and medical journals such as TheLancet.com, British Medical Journal (BMJ), Annals of Pharmacotherapy, Nutritional Perspectives, Journal of Manipulative and Physiological Therapeutics (JMPT), Journal of the American Medical Association (JAMA), Original Internist, Integrative Medicine, Holistic Primary Care, Alternative Therapies in Health and Medicine, Journal of the American Osteopathic Association (JAOA), Dynamic Chiropractic, Journal of Clinical Endocrinology and Metabolism, Current Asthma and Allergy Reports, Complementary Therapies in Clinical Practice, Nature Reviews Rheumatology, Annals of the New York Academy of Sciences, and Arthritis & Rheumatism, the Official Journal of the American College of Rheumatology. Dr Vasquez lectures internationally to healthcare professionals and has a consulting practice and service for doctors and patients. DrV has served as a consultant, product designer, writer and lecturer for Biotics Research Corporation since 2004. Having served on the Review Boards for Journal of Pain Research, Autoimmune Diseases, PLOS One, Alternative Therapies in Health and Medicine, Neuropeptides, International Journal of Clinical Medicine, Journal of Inflammation Research, BMC Complementary and Alternative Medicine (all PubMed/Medline indexed), and Journal of Naturopathic Medicine and as the founding Editor of Naturopathy Digest, Dr Vasquez is currently the Editor (2013-) of International Journal of Human Nutrition and Functional Medicine and Former Editor (2018-2019) of Journal of Orthomolecular Medicine, published for more than 50 consecutive years by the International Society for Orthomolecular Medicine. Citation: © Vasquez A. Vitamin D3 Pharmacology Infographic: Physiologic Dosing versus Bolus Roulette. Int J Hum Nutr Funct Med ® 2021 Feb;9:3 ichnfm.org/journal. Externally archived at ichnfm.academia.edu/AlexVasquez and InflammationMastery.com/d; article updated 24-Feb-21 Download your personal copies from inflammationmastery-com-ichnfm-org.dpdcart.com 1. VIDEO: Integrating Functional and Naturopathic Medicine Concepts and Therapeutics into Medical Practice for Primary Care and Specialty Conditions o View for free https://www.InflammationMastery.com/medical 2. PDF eBOOK: Antiviral Nutrition 2014-2020 3. VIDEO: Re-Introduction to DrV's Antiviral Strategies and Immune Nutrition (1hour) 4. VIDEO: Antiviral Use of the Amino Acid NAC, N-acetyl-L-cysteine (1hour42minutes) 5. VIDEO: Antiviral Nutrition against C-V-1-9 (1hour) 6. VIDEO: Antiviral Nutrition 2020 Risk Management, Laboratory Assessment of Common Interventions FREE PDF eBOOK: Integrating Functional and Naturopathic Medicine Concepts and Therapeutics into Medical Practice for Common Conditions: lnkd.in/gP_9DMN Calcium and vitamin D in preventing fractures Data are not sufficient to show inefficacy EDITOR—The study by Porthouse et al had two major design flaws.1 Firstly, the dose of vitamin D (800 IU per day) is subphysiological and therefore subtherapeutic. Secondly, their use of "self report" as a measure of compliance is unreliable. The dose of vitamin D at 800 IU daily was not determined scientifically but determined arbitrarily before sufficient scientific methodology was available.2-4 Heaney et al determined the physiological requirement of vitamin D by showing that healthy men use 4000 IU cholecalciferol daily,2 an amount that is safely attainable with supplementation3 and often exceeded with exposure of the total body to equatorial sun.4 We provided six guidelines for interventional studies with vitamin D.5 Dosages of vitamin D must reflect physiological requirements and natural endogenous production and should therefore be in the range of 3000-10 000 IU daily. Vitamin D supplementation must be continued for at least five to nine months. The form of vitamin D should be D3 rather than D2. Supplements should be assayed for potency. Effectiveness of supplementation must include measurement of serum 25hydroxyvitamin D. Serum 25(OH)D concentrations must enter the optimal range, which is 40-65 ng/ml (100-160 nmol/l). Since the study by Porthouse et al met only the second and third of these six criteria, their data cannot be viewed as reliable for documenting the inefficacy of vitamin D supplementation. Alex Vasquez, researcher Biotics Research Corporation, 6801 Biotics Research Drive, Rosenberg, TX 77471, USA avasquez@bioticsresearch.com John Cannell, president Vitamin D Council, 9100 San Gregorio Road, Atascadero, CA 93422, USA Competing interests: AV is a researcher at Biotics Research Corporation, a drug manufacturing facility in the United States that has approval from the Food and Drug Administration. References 1. 2. 3. 4. 5. Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 2005;330: 1003. (30 April.)[Abstract/Free Full Text] Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77: 204-10.[Abstract/Free Full Text] Vieth R, Chan PC, MacFarlane GD. Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. Am J Clin Nutr 2001;73: 288-94.[Abstract/Free Full Text] Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999;69: 842-56.[Abstract/Free Full Text] Vasquez A, Manso G, Cannell J. The clinical importance of vitamin D (cholecalciferol): a paradigm shift with implications for all healthcare providers. Altern Ther Health Med 2004;10: 28-36.[ISI][Medline] Related Article Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care Jill Porthouse, Sarah Cockayne, Christine King, Lucy Saxon, Elizabeth Steele, Terry Aspray, Mike Baverstock, Yvonne Birks, Jo Dumville, Roger Francis, Cynthia Iglesias, Suezann Puffer, Anne Sutcliffe, Ian Watt, and David J Torgerson BMJ 2005 330: 1003. [Abstract] [Full Text] This CME article has been brought to you by an educational grant from Biotics Research Corporation. 6801 Biotics Research Drive Rosenberg, TX 77471 Toll Free: 1-800-231-5777 www.bioticsresearch.com CME continuing medical education THE CLINICAL IMPORTANCE OF VITAMIN D (CHOLECALCIFEROL): A PARADIGM SHIFT WITH IMPLICATIONSAlexFOR ALL HEALTHCARE PROVIDERS Vasquez, , Gilbert Manso, , John Cannell, DC, ND Alex Vasquez, DC, ND is a licensed naturopathic physician in Washington and Oregon, and licensed chiropractic doctor in Texas, where he maintains a private practice and is a member of the Research Team at Biotics Research Corporation. He is a former Adjunct Professor of Orthopedics and Rheumatology for the Naturopathic Medicine Program at Bastyr University. Gilbert Manso, MD, is a medical doctor practicing integrative medicine in Houston, Texas. In prac- InnoVision Communications is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The learner should study the article and its figures or tables, if any, then complete the self-evaluation at the end of the activity. The activity and self-evaluation are expected to take a maximum of 2 hours. OBJECTIVES Upon completion of this article, participants should be able to do the following: 1. 2. 3. Appreciate and identify the manifold clinical presentations and consequences of vitamin D deficiency Identify patient groups that are predisposed to vitamin D hypersensitivity Know how to implement vitamin D supplementation in proper doses and with appropriate laboratory monitoring Reprint requests: InnoVision Communications, 169 Saxony Rd, Suite 103, Encinitas, CA 92024; phone, (760) 633-3910 or (866) 828-2962; fax, (760) 633-3918; e-mail, alternative.therapies@ innerdoorway.com. Or visit our online CME Web site by going to http://www.alternative -therapies.com and selecting the Continuing Education option. 28 MD MD tice for more than 35 years, he is Board Certified in Family Practice and is Associate Professor of Family Medicine at University of Texas Medical School in Houston. John Cannell, MD, is a medical physician practicing in Atascadero, California, and is president of the Vitamin D Council (Cholecalciferol-Council.com), a non-profit, taxexempt organization working to promote awareness of the manifold adverse effects of vitamin D deficiency. W hile we are all familiar with the important role of vitamin D in calcium absorption and bone metabolism, many doctors and patients are not aware of the recent research on vitamin D and the widening range of therapeutic applications available for cholecalciferol, which can be classified as both a vitamin and a pro-hormone. Additionally, we also now realize that the Food and Nutrition Board’s previously defined Upper Limit (UL) for safe intake at 2,000 IU/day was set far too low and that the physiologic requirement for vitamin D in adults may be as high as 5,000 IU/day, which is less than half of the >10,000 IU that can be produced endogenously with full-body sun exposure.1,2 With the discovery of vitamin D receptors in tissues other than the gut and bone—especially the brain, breast, prostate, and lymphocytes—and the recent research suggesting that higher vitamin D levels provide protection from diabetes mellitus, osteoporosis, osteoarthritis, hypertension, cardiovascular disease, metabolic syndrome, depression, several autoimmune diseases, and cancers of the breast, prostate, and colon, we can now utilize vitamin D for a wider range of preventive and therapeutic applications to maintain and improve our patients’ health.3 Based on the research reviewed in this article, the current authors believe that assessment of vitamin D status and treatment of vita- ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 CME: The Clinical Importance of Vitamin D min D deficiency with oral vitamin D supplements should become a routine component of clinical practice and preventive medicine. Vitamin D supplementation with doses of 4,000 IU/day for adults is clinically safe and physiologically reasonable since such doses are consistent with physiologic requirements.2 Higher doses up to 10,000 IU/day appear safe and produce blood levels of vitamin D that are common in sun-exposed equatorial populations. 1,2 Periodic assessment of serum 25-OH-vitamin D [25(OH)D] and serum calcium will help to ensure that vitamin D levels are sufficient and safe for health maintenance and disease prevention. Clinical research supporting the use of vitamin D in the management of type 2 diabetes, osteoporosis, osteoarthritis, hypertension, cardiovascular disease, metabolic syndrome, multiple sclerosis, polycystic ovary syndrome, musculoskeletal pain, depression, epilepsy, and the prevention of cancer and type 1 diabetes is presented along with our proposals for the interpretation of serum 25(OH)D laboratory values, for the design of future research studies, and for supplementation in infants, children, adults, and during pregnancy and lactation. BASIC PHYSIOLOGY OF VITAMIN D Vitamin D is obtained naturally from two sources: sunlight and dietary consumption. Vitamin D3 (cholecalciferol) is the form of vitamin D produced in the skin and consumed in the diet. Vitamin D2 (ergocalciferol), which is produced by irradiating fungi, is much less efficient as a precursor to the biologically active 1,25-dihydroxyvitamin D (calcitriol). Additionally, since ergocalciferol shows altered pharmacokinetics compared with D3 and may become contaminated during its microbial production, it is potentially less effective and more toxic than cholecalciferol.4 Although ergocalciferol is occasionally used clinically and in research studies, cholecalciferol is the preferred form of supplementation and will be implied in this article when supplementation is discussed. Vitamin D can be described as having two pathways for metabolism: one being “endocrine” and the other “autocrine” (within the cell) and perhaps “paracrine” (around the cell). This elucidation, recently reviewed by Heany,5 is vitally important in expanding our previously limited conception of vitamin D from only a “bone nutrient with importance only for the prevention of rickets and osteomalacia” to an extraordinary molecule with farreaching effects in a variety of cells and tissues. Furthermore, Heany’s distinction of “short-latency deficiency diseases” such as rickets from “long-latency deficiency diseases” such as cancer provides a conceptual handle that helps us grasp an understanding of the differences between the acute manifestations of severe nutritional deficiencies and the delayed manifestations of chronic subclinical nutritional deficiencies.5 In its endocrine metabolism, vitamin D (cholecalciferol) is formed in the skin following exposure to sunlight and then travels in the blood to the liver where it is converted to 25-hydroxyvitamin D (calcidiol, 25(OH)D) by the enzyme vitamin D-25-hydroxylase. 25(OH)D then circulates to the kidney for its final transformation to 1,25-dihydroxyvitamin D (calcitriol) by 25-hydroxyvitamin D3- CME: The Clinical Importance of Vitamin D 1alpha-hydroxylase (1-OHase).6 Calcitriol is the most biologically active form of vitamin D and increases calcium and phosphorus absorption in the intestine, induces osteoclast maturation for bone remodeling, and promotes calcium deposition in bone and a reduction in parathyroid hormone (PTH). While increased calcium absorption is obviously important for nutritional reasons, suppression of PTH by vitamin D is also clinically important since relatively lower levels of PTH appear to promote and protect health, and higher levels of PTH correlate with increased risk for myocardial infarction, stroke, and hypertension.7,8 Relatedly, Fujita9 proposed the “calcium paradox” wherein vitamin D or calcium deficiency leads to elevations of PTH which increases intracellular calcium and may thereby promote a cascade of cellular dysfunction that can contribute to the development of diabetes mellitus, neurologic diseases, malignancy, and degenerative joint disease. In its autocrine metabolism, circulating 25(OH)D is taken up by a wide variety of cells that contain both 1-OHase as well as nuclear vitamin D receptors (VDR). Therefore, these cells are able to make their own calcitriol rather than necessarily relying upon hematogenous supply. Cells and tissues that are known to contain 1-OHase, and which therefore make their own calcitriol, include the breast, prostate, lung, skin, lymph nodes, colon, pancreas, adrenal medulla, and brain (cerebellum and cerebral cortex).3,10 Cells and tissues with nuclear, cytosolic, or membrane-bound VDR include islet cells of the pancreas, monocytes, transformed B-cells, activated T-cells, neurons, prostate cells, ovarian cells, pituitary cells, and aortic endothelial cells.11 Indeed, given the wide range of cells and tissues that metabolize vitamin D in an autocrine manner, we see that there is biological potential for vitamin D to influence function and pathophysiology in a wide range of metabolic processes and disease states. Since many cells and tissues of the body have the ability to metabolize vitamin D, we should not be surprised that vitamin D plays a role in the function of these cells. Calcitriol is known to modulate transcription of several genes, notably those affecting differentiation and proliferation such as c-myc, c-fos, and c-sis,6 and this may partially explain the inverse relationship between sun exposure (eg, vitamin D) and cancer mortality.12,13 Vitamin D appears to modulate neurotransmitter/neurologic function as shown by its antidepressant 14 and anticonvulsant 15 benefits. Vitamin D is obviously immunoregulatory as manifested by its ability to reduce inflammation,16,17 suppress and/or prevent certain autoimmune diseases,18-20 reduce the risk for cancer,12 and possibly reduce the severity and frequency of infectious diseases, such as acute pneumonia in children.21 CLINICAL APPLICATIONS AND THERAPEUTIC BENEFITS OF VITAMIN D Support for a broad range of clinical applications for vitamin D supplementation comes from laboratory experiments, clinical trials, and epidemiologic surveys. Despite the imperfections of current data, we can still see significant benefits from vitamin D supplementation in a variety of human diseases, as briefly reviewed below. ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 29 Cardiovascular Disease Deaths from cardiovascular disease are more common in the winter, more common at higher latitudes and more common at lower altitudes, observations that are consistent with vitamin D insufficiency.22 The risk of heart attack is twice as high for those with 25(OH)D levels less than 34 ng/ml (85 nmol/L) than for those with vitamin D status above this level.23 Patients with congestive heart failure were recently found to have markedly lower levels of vitamin D than controls,24 and vitamin D deficiency as a cause of heart failure has been documented in numerous case reports.25-29 Hypertension It has long been known that blood pressure is higher in the winter than the summer, increases at greater distances from the equator and is affected by skin pigmentation—all observations consistent with a role for vitamin D in regulating blood pressure. 30 When patients with hypertension were treated with ultraviolet light three times a week for six weeks their vitamin D levels increased by 162%, and their blood pressure fell significantly.31 Even small amounts of oral cholecalciferol (800 IU) for eight weeks lowered both blood pressure and heart rate.32 Type 2 Diabetes Hypovitaminosis D is associated with insulin resistance and beta-cell dysfunction in diabetics and young adults who are apparently healthy. Healthy adults with higher serum 25(OH)D levels had significantly lower 60 min, 90 min and 129 min postprandial glucose levels and significantly better insulin sensitivity than those who were vitamin D deficient. 33 The authors noted that, compared with metformin, which improves insulin sensitivity by 13%, higher vitamin D status correlated with a 60% improvement in insulin sensitivity. In a recent clinical trial using 1,332 IU/day for only 30 days in 10 women with type 2 diabetes, vitamin D supplementation was shown to improve insulin sensitivity by 21%.34 Osteoarthritis Many practitioners know that vitamin D helps prevent and treat osteoporosis, but few know that the progression of osteoarthritis, the most common arthritis, is lessened by adequate blood levels of vitamin D. Framingham data showed osteoarthritis of the knee progressed more rapidly in those with 25(OH)D levels lower than 36 ng/ml (90 nmol/L). 3 5 Another study found that osteoarthritis of the hip progressed more rapidly in those with 25(OH)D levels lower than 30 ng/ml (75 nmol/L).36 Multiple Sclerosis The autoimmune/inflammatory disease multiple sclerosis (MS) is notably rare in sunny equatorial regions and becomes increasingly prevalent among people who live farther from the equator and/or who lack adequate sun exposure. In a clinical trial with 10 MS patients, Goldberg, Fleming, and Picard19 pre- 30 scribed daily supplementation with approximately 1,000 mg calcium, 600 mg magnesium, and 5,000 IU vitamin D (from 20 g cod liver oil) for up to two years and found a reduction in the number of exacerbations and an absence of adverse effects. This is one of very few studies in humans that employed sufficient daily doses of vitamin D (5,000 IU) and had sufficient duration (2 years). More recently, Mahon et al37 gave 800 mg calcium and 1,000 IU vitamin D per day for six months to 39 patients with MS and noted a modest anti-inflammatory effect. Prevention of Type 1 Diabetes Type 1 diabetes is generally caused by autoimmune/inflammatory destruction of the pancreatic beta-cells. Vitamin D supplementation shows significant preventive and ameliorative benefits in animal models of type 1 diabetes. In a study with more than 10,000 participants, Hypponen et al18 showed that supplementation in infants (less than one year of age) and children with 2,000 IU of vitamin D per day reduced the incidence of type 1 diabetes by approximately 80%. Relatedly, several studies using cod liver oil as a rich source of vitamin D have also documented significant reductions in the incidence of type 1 diabetes. Depression Seasonal affective disorder (SAD) is a particular subtype of depression characterized by the onset or exacerbation of melancholia during winter months when bright light, sun exposure, and serum 25(OH)D levels are reduced. Recently, a dose of 100,000 IU of vitamin D was found superior to light therapy in the treatment of SAD after one month.38 Similarly, in a study involving 44 subjects, supplementation with 400 or 800 IU per day was found to significantly improve mood within five days of supplementation.14 Epilepsy Seizures can be the presenting manifestation of vitamin D deficiency.39 Hypovitaminosis D decreases the threshold for and increases the incidence of seizures, and several “anticonvulsant” drugs interfere with the formation of calcitriol in the kidney and further reduce calcitriol levels via induction of hepatic clearance. Therefore, antiepileptic drugs may lead to iatrogenic seizures by causing iatrogenic hypovitaminosis D.40 Conversely, supplementation with 4,000–16,000 IU per day of vitamin D2 was shown to significantly reduce seizure frequency in a placebo controlled pilot study by Christiansen et al.15 Migraine Headaches Calcium clearly plays a role in the maintenance of vascular tone and coagulation, both of which are altered in patients with migraine. Thys-Jacobs 41 reported two cases showing a reduction in frequency, duration, and severity of menstrual migraine attacks following daily supplementation with 1,200 mg of calcium and 1,200–1,600 IU of vitamin D in women with vitamin D deficiency. ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 CME: The Clinical Importance of Vitamin D Polycystic Ovary Syndrome Polycystic ovary syndrome (PCOS) is a disease seen only in humans and is classically characterized by polycystic ovaries, amenorrhea, hirsuitism, insulin resistance, and obesity. Animal studies have shown that calcium is essential for oocyte activation and maturation. Vitamin D deficiency was highly prevalent among 13 women with PCOS, and supplementation with 1,500 mg of calcium per day and 50,000 IU of vitamin D2 on a weekly basis normalized menstruation and/or fertility in nine of nine women with PCOS-related menstrual irregularities within three months of treatment.42 Musculoskeletal Pain Patients with non-traumatic, persistent musculoskeletal pain show an impressively high prevalence of overt vitamin D deficiency. Plotnikoff and Quigley43 recently showed that 93% of their 150 patients with persistent, nonspecific musculoskeletal pain were overtly deficient in vitamin D. Masood et al44 found a high prevalence of vitamin D deficiency in children with limb pain, and vitamin D supplementation ameliorated pain within three months. Al Faraj and Al Mutairi45 found vitamin D deficiency in 83% of their 299 patients with low-back pain, and supplementation with 5,000–10,000 IU of vitamin D per day lead to pain reduction in nearly 100% of patients after three months. Critical Illness and Autoimmune/Inflammatory Conditions Deficiency of vitamin D is common among patients with inflammatory and autoimmune disorders and those with prolonged critical illness. In addition to the previously mentioned epidemic of vitamin D insufficiency in patients with MS, we also see evidence of vitamin D insufficiency in a large percentage of patients with Grave’s disease,46 ankylosing spondylitis,47 systemic lupus erythematosus,48 and rheumatoid arthritis.20 Clinical trials with proper dosing and duration need to be performed in these patient groups. C-reactive protein was reduced by 23% and matrix metalloproteinase-9 was reduced by 68% in healthy adults following bolus injections of vitamin D that resulted in an average dose of 547 IU per day for 2.5 years.17 A recent trial of vitamin D supplementation in patients with prolonged critical illness showed a significant and dose-dependent “anti-inflammatory effect” evidenced by reductions in IL-6 and CRP.16 However, the insufficient dose of only 400 IU per day (administered intravenously) for only ten days precluded more meaningful and beneficial results, and we present guidelines for future studies later in this paper. Cancer Prevention and Treatment The inverse relationship between sunlight exposure and cancer mortality was documented by Apperly in 1941.13 Vitamin D has anti-cancer effects mediated by anti-proliferative and proapoptotic mechanisms3 which are augmented by modulation of nuclear receptor function and enzyme action,49 and limited research shows that synthetic vitamin D analogs may have a role in the treatment of human cancers.50 Grant12 has shown that CME: The Clinical Importance of Vitamin D inadequate exposure to sunlight, and hence hypovitaminosis D, is associated with an increased risk of cancer mortality for several malignancies, namely those of the breast, colon, ovary, prostate, bladder, esophagus, kidney, lung, pancreas, rectum, stomach, uterus, and non-Hodgkin lymphoma. He proposes that adequate exposure to ultraviolet light and/or supplementation with vitamin D could save more than 23,000 American lives per year from a reduction in cancer mortality alone. The aforementioned clinical trials using vitamin D in a wide range of health conditions have helped to expand our concept of vitamin D and to appreciate its manifold benefits. However, in light of new research showing that the physiologic requirement is 3,000–5,000 IU/day for adults and that serum levels plateau only after 3-4 months of daily supplementation,2 we must conclude that studies using lower doses and/or shorter durations have underestimated the clinical efficacy of vitamin D. Guidelines for the critique and design of clinical trials are proposed later in this article to aid clinicians and researchers in evaluating and designing clinical studies for the determination of the therapeutic efficacy of vitamin D. ASSESSMENT OF VITAMIN D STATUS WITH MEASUREMENT OF SERUM 25-OH-VITAMIN D Current laboratory reference ranges for 25(OH)D were erroneously based on average serum levels for the “apparently healthy” nonrachitic, nonosteomalacic American population, a large proportion of which is vitamin D deficient. Currently, laboratories do not report optimal levels so they will mislead the practitioner unless he or she is aware of current research. For the majority of labs, the bottom of the reference range is set too low due to the previous underappreciation of the clinical benefits of and physiologic requirement for higher vitamin D levels, and the top of the range is too low due to previous misinterpretations of the research resulting in an overestimation of vitamin D toxicity.1,2,51,52 Therefore, new reference ranges need to be determined based on the current research, and we present our proposals in Figure 1 and in the following outline: • Vitamin D Deficiency: less than 20 ng/mL (50 nmol/L). Serum 25(OH)D levels below 20 ng/mL (50 nmol/L) are clearly indicative of vitamin D deficiency. However, several authorities note that this level appears to be too low; Heaney5 and Holick51 both state that 25(OH)D levels should always be greater than 30 ng/mL (75 nmol/L). • Vitamin D Insufficiency: less than 40 ng/mL (100 nmol/L). According to Zittermann,11 hypovitaminosis D, wherein tissue levels are depleted and PTH is slightly elevated, correlates with serum levels of 30–40 ng/mL (75–100 nmol/L). Independently, Dawson-Hughes et al53 showed that serum levels of PTH begin to elevate when 25(OH)D levels fall below 45 ng/mL (110 nmol/L) in elderly men and women, and these findings were supported by Kinyamu et al54 who found that optimal PTH status deteriorates when 25(OH)D levels fall below 49 ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 31 ng/mL (122 nmol/L) in elderly women. Therefore, in order to maintain physiologic suppression of PTH, serum levels of 25(OH)D need to be greater than 40 ng/mL (100 nmol/L). • Optimal Vitamin D Status: 40–65 ng/mL (100–160 nmol/L) Based on our review of the literature, we propose that the optimal—“sufficient and safe”—range for 25(OH)D correlates with serum levels of 40–65 ng/mL (100–160 nmol/L).55 This proposed optimal range is compatible with other published recommendations: Zittermann 11 states that serum levels of 40–80 ng/mL (100–200 nmol/L) are “adequate,” and Mahon et al37 recently advocated an optimal range of 40–100 ng/mL (100–250 nmol/L) for patients with multiple sclerosis. The lower end of our proposed range is consistent with suggestions by Mercola56,57 who advocates an optimal range of 45–50 ng/mL (115–128 nmol/L) and by Holick51 who states that levels should be 30–50 ng/mL (75–125 nmol/L). The upper end of our proposed optimal range is modified from the previously mentioned ranges offered by Zittermann11 (up to 80 ng/mL [200 nmol/L]) and Mahon et al37 (up to 100 ng/mL [250 nmol/L]). According to the authoritative monograph by Vieth,1 there is no consistent, credible evidence of vitamin D toxicity associated with levels below 80–88 ng/mL (200 –220 nmol/L). Vieth1 states, “Although not strictly within the ‘normal’ range for a clothed, sun-avoiding population, serum 25(OH)D concentrations of 220 nmol/L (88 ng/mL) are consistent with certain environments, are not unusual in the absence of vitamin D supplements, and should be regarded as being within the physiologic range for humans.” Similarly, in his very thorough review of the literature, Zittermann 11 concludes that serum 25(OH)D concentrations up to 100 ng/mL (250 nmol/L) are subtoxic. Additional support for the safety of this upper limit comes from documentation that sun exposure alone can raise levels of 25(OH)D to more than 80 ng/mL (200 nmol/L)1 and that oral supplementation with 10,000 IU/day (mimicking endogenous production from sun exposure) in healthy men resulted in serum levels greater than 80 ng/mL (200 nmol/L) with no evidence of toxicity.2 Until more data becomes available, we have chosen 65 ng/mL (160 nmol/L) rather than 80 ng/mL (200 nmol/L) as the upper end of the optimal range to provide a safety zone between the optimal level and the level which may possibly be associated with toxicity, and to allow for other factors which may promote hypercalcemia, as discussed below. Long-term prospective interventional studies with large groups and clinical trials involving patients with vitamin D-associated illnesses (listed above) will be needed in order to accurately define the optimal range—the serum level of vitamin D that affords protection from illness but which does not cause iatrogenic complications. In reviewing much of the current literature, we found no evidence of adverse effects associated with a 25(OH)D level of 65 ng/mL (160 nmol/L), and we found that this level is considered normal by some medical laboratories6 and that it can be approximated and safely exceeded with frequent full-body exposure to ultraviolet light1 or oral administration of physiologic doses of 5,000–10,000 IU cholecalciferol per day for 20 weeks.2 Prospective studies and 32 interventional clinical trials comparing different serum levels of 25(OH)D with clinical outcomes are necessary to elucidate the exact optimal range in various clinical conditions. While no acute or subacute risks are associated with the 25(OH)D levels suggested here, research shows clear evidence of long-term danger associated with vitamin D levels that are insufficient. • Vitamin D Excess: Serum Levels Greater than 80 ng/mL (200 nmol/L) with Accompanying Hypercalcemia Serum levels of 25(OH)D can exceed 80 ng/mL (200 nmol/L) with ultraviolet light exposure in the absence of oral vitamin D supplementation1,6 and with oral supplementation with 10,000 IU per day as previously mentioned2—in neither scenario is toxicity observed. 25(OH)D greater than 80 ng/mL (200 nmol/L) are not indicative of toxicity unless accompanied by clinical manifestations and hypercalcemia. Vieth1 notes that hypercalcemia due to hypervitaminosis D is always associated with serum 25(OH)D concentrations greater than 88 ng/mL (220 nmol/L), and Holick6 previously stated, “Vitamin D intoxication does not occur until the circulating levels of 25(OH)D are over 125 ng/mL [312 nmol/L].” Assessment for hypervitaminosis D is performed by measurement of serum 25(OH)D and serum calcium. MONITORING FOR VITAMIN D TOXICITY WITH 25(OH)D AND SERUM CALCIUM Hypercalcemia can occur with vitamin D supplementation by either directly causing direct toxicity (rare) or by being associated with a vitamin D hypersensitivity syndrome (more common). If serum calcium becomes abnormally high, then vitamin D supplementation must be discontinued until the cause of the hypercalcemia is identified; however, direct vitamin D toxicity will rarely be the sole cause of the hypercalcemia. Excess vitamin D > 80ng/ml (200 nmol/L) Proposed optimal range 40 - 65 ng/mL (100 - 160 nmol/L) Insufficiency range < 20 - 40 ng/mL (50 - 100 nmol/ L) Deficiency < 20 ng/mL (50 nmol/L) * Modified from: Vasquez A. Integrative Orthopedics: Concepts, Algorithms, and Therapeutics. Houston; Natural Health Consulting Corporation. 2004: 417-419 with permission. ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 FIGURE 1. Proposed normal and optimal ranges for serum 25(OH)D levels based on current research* CME: The Clinical Importance of Vitamin D The most important indicator of direct vitamin D toxicity is elevated serum calcium associated with a 25(OH)D level greater than 90 ng/ml (225 nmol/L). Elevated 1,25(OH)D levels are commonly—though not always—seen with vitamin D toxicity. Severe vitamin D intoxication is rare and usually seen only with industrial accidents, such as overdosing the fortification of milk, or with long-term administration of more than 40,000 IU of vitamin D per day. Severe hypercalcemia may require urinary acidification and corticosteroids to expedite the reduction in serum calcium.58 Induction of vitamin D toxicity generally requires 1–4 months of 40,000 IU per day in infants.58 In adults, toxicity generally requires several months of supplementation of at least 100,000 IU per day. Hypercalcemia appears to be the mechanism of vitamin D toxicity (rather than a direct toxic effect of the vitamin), and 25-OH-vitamin D levels may be normal in patients who are vitamin D toxic and hypercalcemic, particularly with vitamin D hypersensitivity syndrome. It has therefore been suggested that serum calcium be measured on a weekly and then monthly basis in patients receiving high-dose vitamin D. Manifestations attributable to hypervitaminosis D and hypercalcemia include anorexia, nausea, and vomiting followed by weakness, nervousness, pruritus, polyuria, polydipsia, renal impairment, and soft-tissue calcifications. As a cause of hypercalcemia, vitamin D hypersensitivity syndromes are more common than vitamin D toxicity, and they generally arise when aberrant tissue uncontrollably produces the most active form of the vitamin—calcitriol. Primary hyperparathyroidism, granulomatous disease (such as sarcoidosis, Crohn’s disease, and tuberculosis) and various forms of cancer may cause the syndrome. 25(OH)D levels are normal or even low in vitamin D hypersensitivity while serum calcium and 1,25(OH)D levels are elevated. Additional causes include adrenal insufficiency, hyperthyroidism, hypothyroidism, and adverse drug effects, particularly with thiazide diuretics. Whatever the cause, patients with persistent hypercalcemia should discontinue vitamin D supplementation and receive a thorough diagnostic evaluation to determine the cause of the problem. Interventional Strategies to Treat Vitamin D Deficiency by Increasing Serum Vitamin D Levels Human physiology adapted to and was shaped by a natural environment with ample exposure to sunlight.5, 61 Full-body exposure to ultraviolet light on clear days in equatorial latitudes can easily provide the equivalent of 4,000–20,000 IU of vitamin D.1,61 Slightly longer durations of full-body sun exposure of approximately 30 minutes (3x the minimal erythemal dose) will produce 50,000 IU of vitamin D in lightly pigmented persons, while 5x longer durations are required for more darkly pigmented people to attain the same vitamin D production.61 The oral dose of vitamin D required to obtain adequate blood levels depends on latitude, sun exposure, body weight, skin pigmentation, dietary sources, efficiency of absorption, presence of intestinal disease (eg, intestinal resection or malabsorption), and medication use, for example with the vitamin D-depleting actions of common anticonvulsant drugs.40 CME: The Clinical Importance of Vitamin D Past and Future Vitamin D Studies: Critique and Design Nearly all published clinical trials have suffered from flawed design, including inadequate dosing, inadequate duration, wrong type of vitamin D (ie, ergocalciferol, D2), failure to test serum vitamin D levels, and/or failure to ensure that serum vitamin D levels entered into the optimal range. The following guidelines are provided for clinicians and researchers using vitamin D in clinical practice and research to improve the quality of research and patient care. 1. Dosages of vitamin D must reflect physiologic requirements and natural endogenous production and should therefore be in the range of 3,000–10,000 IU per day The physiologic requirement for vitamin D appears to be 3,000–5,000 IU per day in adult males.2 Full-body exposure to ultraviolet light (eg, sunshine) can produce the equivalent of 10,000–25,000 IU of vitamin D3 per day.1 Therefore, intervention trials with supplemental vitamin D should use between 4,000 IU/day, which is presumably sufficient to meet physiologic demands, and 10,000 IU/day, which is the physiologic dose attained naturally via full-body sun exposure. Based on these physiologic criteria, we see that the majority of intervention studies in adults have used inadequate, subphysiologic doses of vitamin D. Therefore, studies that failed to identify therapeutic benefits from vitamin D supplementation were flawed due to insufficient therapeutic intervention—the dose of vitamin D was too low. 2. Vitamin D supplementation must be continued for at least 5-9 months for maximum benefit Since serum 25(OH)D levels do not plateau until after 34 months of supplementation,2 and we would expect clinical and biochemical changes to become optimally apparent some time after the attainment of peak serum levels, any intervention study of less than 5-9 months is of insufficient duration to determine either maximum benefit or that vitamin D supplementation is ineffective for the condition being investigated. Conversely, since vitamin D supplementation can alter intracellular metabolism within minutes of administration,11 benefits seen in short-term studies should not be inaccurately attributed to statistical error or placebo effect. 3. Supplementation should be performed with D3 rather than D2 Although cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) are both used as sources of vitamin D, D3 is the human nutrient and is much more efficient in raising and sustaining serum 25[OH]D levels. Vitamin D2 is a fungal metabolite and has been associated with adverse effects due to contamination and altered pharmacokinetics.4 The type of vitamin D must always be clearly stated in published research reports. ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 33 4. Supplements should be tested for potency Some products do not contain their claimed amount. This problem was illustrated in the study by Heaney et al2 who found that the vitamin D supplement they used in their study, although produced by a well-known company, contained only 83% of its stated value. To ensure accuracy and consistency of clinical trials, actual dosages must be known. 5. Effectiveness of supplementation must include evaluation of serum vitamin D levels Supplementation does not maximize therapeutic efficacy unless it raises serum 25(OH)D levels into the optimal range. To assess absorption, compliance, and safety, serum 25(OH)D levels must be monitored in clinical trials involving vitamin D supplementation. Assessment of serum levels is important also to determine the relative dose-effectiveness of different preparations of vitamin D, as some evidence suggests that micro-emulsification facilitates absorption of fat-soluble nutrients.56,59,60 Measurement of 1,25-dihydroxyvitamin (calcitriol) is potentially misleading and is not recommended for the evaluation of vitamin D status. 6. Serum vitamin D levels must enter the optimal range The majority of clinical intervention studies using vitamin D have failed to use supplementation of sufficient dosage and duration to attain optimal serum levels of vitamin D. Our proposed optimal range for 25(OH)D is 40–65 ng/mL (100–160 nmol/L) and is presented in Figure 1. The above-mentioned criteria will aid future researchers in designing interventional studies that can accurately evaluate the relationship between vitamin D status and human illness. Clinicians, who are not conducting research but rather are interested in attaining clinical improvement in their patients, should follow these guidelines as well when using vitamin D supplementation in patients, while remembering to monitor for toxicity with the triad of clinical assessments, serum 25(OH)D, and serum calcium. Clinicians and researchers need to remember, however, that optimal clinical effectiveness often depends on synergism of diet, lifestyle, exercise, emotional health, and other factors. Single intervention studies are a reasonable research tool only for evaluating cause-and-effect relationships based on the presumption of a simplistic, linear model that is generally inconsistent with the complexity and multiplicity of synergistic and interconnected factors that determine health and disease. Thus, single intervention studies with vitamin D supplementation will be useful from an intellectual standpoint insofar as they will help us to further define the role of vitamin D in human physiology and pathophysiology. However, optimal clinical results with individual patients are more easily attained with the use of multicomponent treatment plans that address many facets of the patient’s health.55 34 Vitamin D Supplementation in Adults When 28 men and women were administered 4,000 IU per day for up to five months, in the absence of UVB from the sun, serum 25(OH)D levels reached approximately 40 ng/mL (100 nmol/L), and no toxicity was observed.4 When 67 men were administered 5,000 and 10,000 IU of cholecalciferol per day for twenty weeks, again in the absence of UVB from the sun, serum levels of 25(OH)D increased to approximately 60 ng/mL (150 nmol/L) and 90 ng/mL (225 nmol/L), respectively, and no toxicity was observed.2 Therefore, given that endogenous vitamin D production following full-body sun exposure at lower latitudes can produce >10,000 IU1 and that 4,000 IU per day is a safe level of supplementation4 that meets physiologic needs in adults,2 we recommend at least 4,000 IU per day for adults, with efficacy and safety ensured by periodic measurement of 25(OH)D and serum calcium. Vitamin D Supplementation in Pregnant Women In 1966, two case reports and a brief review of the literature showed no adverse effects of 100,000 IU per day of vitamin D in hypoparathyroid pregnant women. 62 In 1971, a study of 15 hypoparathyroid pregnant women was reported wherein the women received more than 100,000 IU per day of vitamin D with no adverse effects to the mother or child, leading the authors to conclude that there was “no risk from vitamin D in pregnancy.”63 Doses of vitamin D for pregnant women were extensively reviewed by Hollis and Wagner61 immediately prior to the completion of this article, and the authors concluded that doses of 100,000 IU per day were safe for pregnant women. The authors write, “Thus, there is no evidence in humans that even a 100,000 IU/day dose of vitamin D for extended periods during pregnancy results in any harmful effects.” Data from several placebo-controlled clinical trials with pregnant women show that vitamin D supplementation results in superior health status for the mother and infant. The current daily reference intake (DRI) for vitamin D of 200–400 IU per day is therefore “grossly inadequate,” and administration of less than 1,000 IU vitamin D per day to pregnant women is scientifically unjustifiable and ethically questionable. Hollis and Wagner61 conclude that up to 4,000 IU per day is necessary for pregnant women, and this conclusion is consistent with previously cited research on physiologic requirements2 and endogenous vitamin D production.1 In order to ensure safety and efficacy in individual patients, we encourage periodic measurement of serum calcium and 25(OH)D levels. Vitamin D Supplementation in Infants and Children In Finland from the mid-1950s until 1964, the recommended daily intake of vitamin D for infants was 4,000–5,000 IU, a dose that was proven safe and was associated with significant protection from type 1 diabetes.61 More recently, in a study involving more than 10,000 infants and children, daily administration of 2,000 IU per day was safe and effective for reducing the incidence of type 1 diabetes by 80%.18 Thus, for infants and children, doses of 1,000 IU per day are certainly safe, and higher doses should be monitored by serum calcium and 25(OH)D levels. ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 CME: The Clinical Importance of Vitamin D Options for Raising Vitamin D Blood Levels We have two practical options for increasing vitamin D levels in the body: oral supplementation and/or exposure to ultraviolet radiation. Sunlight is commonly unavailable on rainy or cloudy days, during the winter months, and in particular geographic locations. Topical sunscreens block vitamin D production by 97%-100%. Furthermore, since many people work indoors where sunshine is inaccessible, or they are partially or fully clothed when outside, reliance on sunshine to provide optimal levels of vitamin D is generally destined to provide unsatisfactory and inconsistent biochemical and clinical results. The use of UVB tanning beds can increase vitamin D levels; but this option is more expensive and time-consuming than oral supplementation, and excess ultraviolet radiation exposure expedites skin aging and encourages the development of skin cancer. Given the impracticalities and disadvantages associated with relying on sun exposure to provide optimal levels of vitamin D year-round, for the majority of patients, oral vitamin D supplementation is the better option for ensuring that biochemical needs are consistently met. Vitamin D is either absent or present in non-therapeutic amounts in dietary sources. One of the only major dietary sources of vitamin D is cod-liver oil, but the amount required to obtain a target dose of 4,000 IU per day would require patients to consume at least three tablespoons of cod-liver oil, or the amount contained in >18 capsules of most commercial preparations.55 Clearly this would be unpalatable and prohibitively expensive for most patients, and it would result in very low compliance. Additionally, such a high dose of cod-liver oil may produce adverse effects with long-term use, particularly with regard to excess vitamin A, and perhaps an increased tendency for bleeding and reduced biological activity of gamma-linolenic acid due to the high content of eicosapentaenoic acid.55,64 Oral supplementation with “pure” vitamin D supplements allows the dose to be tailored to the individual needs of the patient. DISCUSSION AND CONCLUSIONS Vitamin D is not a drug, nor should it be restricted to prescription availability. Vitamin D is not a new or unproven “treatment.” Vitamin D is an endogenous, naturally occurring, photochemically-produced steroidal molecule with essential functions in systemic homeostasis and physiology, including modulation of calcium metabolism, cell proliferation, cardiovascular dynamics, immune/inflammatory balance, neurologic function, and genetic expression. Insufficient endogenous production due to lack of sufficient sun exposure necessitates oral supplementation to meet physiologic needs. Failure to meet physiologic needs creates insufficiency/deficiency and results in subtle yet widespread disturbances in cellular function which appear to promote the manifestation of subacute long-latency deficiency diseases such as osteoporosis, cardiovascular disease, hypertension, cancer, depression, epilepsy, type 1 diabetes, insulin resistance, autoimmune disease, migraine, polycystic ovary syndrome, and musculoskeletal pain. In case reports, clinical trials, animal studies, and/or epidemiologic surveys, the provision of vitamin D via sunlight or sup- CME: The Clinical Importance of Vitamin D plementation has been shown to safely help prevent or alleviate all of the aforementioned conditions. Vitamin D deficiency/insufficiency is an epidemic in the developed world that has heretofore received insufficient attention from clinicians despite documentation of its prevalence, consequences, and the imperative for daily supplementation at levels above the current inadequate recommendations of 200–600 IU.65 For example, at least 57% of 290 medical inpatients in Massachusetts, USA were found to be vitamin D deficient,66 and overt vitamin D deficiency was recently found in 93% of 150 patients with chronic musculoskeletal pain in Minnesota, USA.43 Other studies in Americans have shown vitamin D deficiency in 48% of patients with multiple sclerosis,37 50% of patients with fibromyalgia and systemic lupus erythematosus,48 42% of healthy adolescents67 and African American women,68 and at least 62% of the morbidly obese.69 International studies are consistent with the worldwide prevalence of vitamin D deficiency in various patient groups, showing vitamin D deficiency in 83% of 360 patients with chronic low-back pain in Saudi Arabia,45 73% of Austrian patients with ankylosing spondylitis,47 up to 58% of Japanese women with Grave’s disease,46 more than 40% of Chinese adolescent girls,70 and 40%-70% of Finnish medical patients.71 As a medically valid diagnosis (ICD-9 code: 268.9 Unspecified vitamin D deficiency) with a high prevalence and clinically significant morbidity, vitamin D deficiency deserves equal attention and status with other diagnoses encountered in clinical practice. Given the depth and breadth of the peer-reviewed research documenting the frequency and consequences of hypovitaminosis D, failure to diagnose and treat this disorder is ethically questionable (particularly in pregnant women61) and is inconsistent with the delivery of quality, sciencebased healthcare. Failure to act prudently based on the research now available in favor of vitamin D supplementation appears likely to invite repetition analogous to the previous failure to act on the research supporting the use of folic acid to prevent cardiovascular disease and neural tube defects—a blunder that appears to have resulted in hundreds of thousands of unnecessary cardiovascular deaths72 and which has contributed to incalculable human suffering related to otherwise unnecessary neural tube defects, cervical dysplasia, cancer, osteoporosis, and mental depression. Currently, Grant12 estimates that at least 23,000 and perhaps as many as 47,000 cancer deaths73 might be prevented each year in America if we employed simple interventions (ie, sunshine or supplementation) to raise vitamin D levels. Of course, additional lives may be saved and suffering reduced by alleviating the morbidity and mortality associated with hypertension, autoimmune disease, depression, epilepsy, migraine, diabetes, polycystic ovary syndrome, musculoskeletal pain, osteoporosis, and cardiovascular disease. Until proven otherwise, the balance of the research clearly indicates that oral supplementation in the range of 1,000 IU/day for infants, 2,000 IU/day for children, and 4,000 IU/day for adults is safe and reasonable to meet physiologic requirements, to promote optimal health, and to reduce the risk of several serious diseases. Safety and effectiveness of supplementation are assured by periodic monitoring of serum 25(OH)D and serum calcium. 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Falkenbach A, Tripathi R, Sedlmeyer A, Staudinger M, Herold M. Serum 25-hydroxyvitamin D and parathyroid hormone in patients with ankylosing spondylitis before and after a three-week rehabilitation treatment at high altitude during winter and spring. Wien Klin Wochenschr. 2001;113(9):328-32. 48. Huisman AM, White KP, Algra A, Harth M, Vieth R, Jacobs JW, Bijlsma JW, Bell DA. Vitamin D levels in women with systemic lupus erythematosus and fibromyalgia. J Rheumatol. 2001;28(11):2535-9. 49. Banerjee P, Chatterjee M. Antiproliferative role of vitamin D and its analogs--a brief overview. Mol Cell Biochem. 2003;253(1-2):247-54. 50. Trouillas P, Honnorat J, Bret P, Jouvet A, Gerard JP. Redifferentiation therapy in brain tumors: long-lasting complete regression of glioblastomas and an anaplastic astrocytoma under long term 1-alpha-hydroxycholecalciferol. J Neurooncol. 2001;51(1):57-66 51. Holick MF. Vitamin D deficiency: what a pain it is. Mayo Clin Proc. 2003;78(12):1457-9 52. Wright JV. Vitamin D: Its Role in Autoimmune Disease and Hypertension. Townsend Letter for Doctors and Patients. 2004; May #250: 75-78. 53. Dawson-Hughes B, Harris SS, Dallal GE. Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women. Am J Clin Nutr. 1997;65(1):67-71. 54. Kinyamu HK, Gallagher JC, Rafferty KA, Balhorn KE. Dietary calcium and vitamin D intake in elderly women: effect on serum parathyroid hormone and vitamin D metabolites. Am J Clin Nutr. 1998;67(2):342-8. 55. Vasquez A. Integrative Orthopedics: Concepts, Algorithms, and Therapeutics. Houston; Natural Health Consulting Corporation (www.OptimalHealthResearch.com): 2004. Pages 417-419 and website updates. 56. Mercola J. Available at: http://www.mercola.com/forms/vitamind.htm. Accessed July 23, 2004. 57. Mercola J. Test Values and Treatment for Vitamin D Deficiency. Available at: http://www.mercola.com/2002/feb/23/vitamin_d_deficiency.htm. Accessed July 23, 2004. 58. Berkow R, Fletcher AJ. The Merck Manual of Diagnosis and Therapy. Fifteenth Edition. Rathway; Merck Sharp and Dohme Research Laboratories. 1987: 928, 974-5. 59. Bucci LR, Pillors M, Medlin R, Henderson R, Stiles JC, Robol HJ, Sparks WS. Enhanced uptake in humans of coenzyme Q10 from an emulsified form. Third International Congress of Biomedical Gerontology; Acapulco, Mexico: June 1989. 60. Bucci LR, Pillors M, Medlin R, Klenda B, Robol H, Stiles JC, Sparks WS. Enhanced blood levels of coenzyme Q-10 from an emulsified oral form. In Faruqui SR and Ansari MS (editors). Second Symposium on Nutrition and Chiropractic Proceedings. April 15-16, 1989 in Davenport, Iowa 61. Hollis BW, Wagner CL. Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr. 2004;79(5):717-26. 62. O’Leary JA, Klainer LM, Neuwirth RS. The management of hypoparathyroidism in pregnancy. Am J Obstet Gynecol. 1966;94(8):1103-7. 63. Goodenday LS, Gordon GS. No risk from vitamin D in pregnancy. Ann Intern Med. 1971;75(5):807-8. 64 Horrobin DF. Interactions between n-3 and n-6 essential fatty acids (EFAs) in the regulation of cardiovascular disorders and inflammation. Prostaglandins Leukot Essent Fatty Acids.1991;44(2):127-31. 65. Utiger RD. The need for more vitamin D. N Engl J Med. 1998;338:828-9 66. Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, Prince RL, Finkelstein JS. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338(12):777-83. 67. Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med. 2004;158(6):531-7. 68. Nesby-O'Dell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW, Looker AC, Allen C, Doughertly C, Gunter EW, Bowman BA. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr. 2002;76:187-92. 69. Buffington C, Walker B, Cowan GS Jr, Scruggs D. Vitamin D Deficiency in the Morbidly Obese. Obes Surg. 1993;3:421-424. 70. Fraser DR. Vitamin D-deficiency in Asia. J Steroid Biochem Mol Biol. 2004;89-90:491-5 71. Kauppinen-Makelin R, Tahtela R, Loyttyniemi E, Karkkainen J, Valimaki MJ. A high prevalence of hypovitaminosis D in Finnish medical in- and outpatients. J Intern Med. 2001;249(6):559-63. 72. Ellis A. Inertia on folic acid has caused thousands of unnecessary deaths. BMJ. 2003;326(7398):1054. 73. Grant WB. Personal communication by email, “My current estimate is 47,000 premature cancer deaths/year.” June 3, 2004. ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 CME: The Clinical Importance of Vitamin D CME continuing medical education CME Test Instructions To receive 2.0 hours of CME credit for this article, visit www.cecmeonline.com, log in, purchase the CME course for $10 and take the online test. This test is valid for 1 year from the date of publication. Within 3 to 4 weeks of InnoVision Communications receiving your completed online test, you will receive a CME certificate. InnoVision Communications is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. InnoVision Communications designates these educational activities on an hour-for-hour basis toward category 1 credit of the AMA Physician’s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. CME Test Questions* The Clinical Importance of Vitamin D (Cholecalciferol): A Paradigm Shift with Implications for All Healthcare Providers In the following questions, only one answer is correct. 1. In clinical trials, augmentation of vitamin D levels with ultraviolet light exposure or oral supplementation has been shown to benefit which of the following conditions: A. Osteoporosis; Hypertension B. Depression; Multiple sclerosis C. Back pain; Insulin resistance D. All of the above 2. In the absence of vitamin D supplementation, ultraviolet light exposure (ie, sunshine) can produce 25(OH)D levels that exceed current laboratory reference ranges: A. True B. False 3. Which of the following can cause hypercalcemia? A. Sarcoidosis and Crohn’s disease B. Adrenal insufficiency and hypothyroidism C. Coadministration of vitamin D and thiazide diuretics D. All of the above 5. If a patient has hypovitaminosis D and a vitamin D-responsive condition such as depression, hypertension, insulin resistance, or multiple sclerosis, which of the following is appropriate first-line treatment? A. Drugs only B. Vitamin D only C. Correction of the vitamin D deficiency, and co-administration of medications if necessary D. Use of synthetic vitamin D analogs 6. Since vitamin D is highly effective for the prevention and alleviation of several health problems, and because it has a wide range of safety, physiologic doses should be regulated as a prescription drug and prohibited from public access: A. True B. False 7. Given the prevalence and consequences of vitamin D deficiency, failure to test for and treat vitamin D insufficiency is ethical: A. True B. False 4. According to the current research literature reviewed in this article, which of the following may be considered long-latency deficiency diseases associated with insufficiency of vitamin D? A. Metabolic syndrome B. Autoimmune disease such as multiple sclerosis and type 1 diabetes C. Depression and cancer D. All of the above 8. Since vitamin D has a wide margin of safety, patients should be administered vitamin D routinely and receive which of the following types of monitoring: A. Periodic measurement of serum 1,25-dihydroxyvitamin D (calcitriol) and urinary creatinine B. Periodic measurement of serum 25-hydroxyvitamin D (calcidiol) and serum calcium C. Clinical assessments only D. Liver function tests and electrocardiography * See page 94 for Self-Assessment answers CME: The Clinical Importance of Vitamin D ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 37 Preface & Introduction Chapter and Introduction Page Preamble 1. Patient Assessments, Laboratory Interpretation, Clinical Concepts, Patient Management, Practice Management and Risk Reduction: This chapter i 1 introduces/reviews/updates patient assessments, laboratory interpretation, musculoskeletal emergencies, healthcare paradigms; the common and important conditions hemochromatosis and hypothyroidism are also included in this chapter since these need to be considered on a frequent basis in clinical practice 2. Wellness Promotion & Re-Establishing the Foundation for Health: Reviewed here are diet, 187 lifestyle, psychosocial health, and—given the pervasiveness of persistent organic pollutants and their increasingly recognized clinical importance—an introduction to environmental medicine 3. Basic Concepts and Therapeutics in (Nondrug) Musculoskeletal Care and Integrative Pain Management: Nonpharmacologic management of musculoskeletal problems is preferred over 243 pharmacologic (e.g., NSAID, Coxib, steroid, opioid) management because of the collateral benefits, safety, and cost-effectiveness associated with manual, dietary, botanical, and nutritional treatments. A brief discussion of the current crisis in musculoskeletal medicine is provided for contextualization and emphasis of the importance of expanding clinicians' knowledge of effective nondrug treatments 4. The Major Modifiable Factors in Sustained Inflammation: Major components of the 303 “Functional Inflammology Protocol” are reviewed here, from concepts and molecular biology to an emphasis on practical clinical applications 1) Food & Basic Nutrition 307 2) Infections: Dysbiosis / Viral 3) Nutritional Immunomodulation 609 4) Dysmetabolism, Mitochondrial Dysfunction, ERS/UPR, mTOR 622 5) Special Considerations: Sleep, Sociopsychology, Stress, Surgery 674 6) Endocrine Imbalances 688 7) Xenobiotic Immunotoxicity 699 396 / 540 5. Clinical Applications 713 1) Hypertension 727 2) Diabetes Mellitus 819 3) Migraine & Headaches 863 4) Fibromyalgia 901 5) Allergic Inflammation 984 6) Rheumatoid Arthritis 1019 7) Psoriasis and Psoriatic Arthritis 1038 8) Systemic Lupus Erythematosus 1053 9) Scleroderma & Systemic Sclerosis 1074 10) Vasculitic Diseases 1094 11) Spondyloarthropathies & Reactive Arthritis 1108 12) Sjögren Syndrome/Disease 1119 13) Raynaud's Syndrome/Phenomenon/Disorder 1127 14) Clinical Notes on Additional Conditions: Behçet's Disease, Sarcoidosis, Dermatomyositis and Polymyositis 1131 Index & Appendix ICHNFM.ORG 1154 Inflammation Mastery & Functional Inflammology iii Inflammation Mastery 4th Edition: The Colorful and Definitive Guide toward Health and Vitality and away from the Boredom, Risks, Costs, and Inefficacy of Endless Analgesia, Immunosuppression, and Polypharmacy A Three-Part Learning System of Text, Images, and Video Alex Vasquez D.C. N.D. D.O. F.A.C.N. Doctor of Osteopathic Medicine, graduate of University of North Texas Health Science Center, Texas College of Osteopathic Medicine (2010) Doctor of Naturopathic Medicine, graduate of Bastyr University (1999) Doctor of Chiropractic, graduate of University of Western States (1996) Fellow of the American College of Nutrition (2013-present) Former Overseas Fellow of the Royal Society of Medicine Editor, International Journal of Human Nutrition and Functional Medicine IntJHumNutrFunctMed.org. Former Editor, Naturopathy Digest; Former/Recent Reviewer for Journal of Naturopathic Medicine, Alternative Therapies in Health and Medicine, Autoimmune Diseases, International Journal of Clinical Medicine, and PLOS One Private practice of integrative and functional medicine in Seattle, Washington (2000-2001), Houston, Texas (2001-2006), Portland, Oregon (2011-2013), consulting practice (present) Consultant Researcher and Lecturer (2004-present), Biotics Research Corporation Teaching and Academics: o Director of Programs, International College/Conference on Human Nutrition and Functional Medicine ICHNFM.org o Founder and Former Program Director of the world’s first accredited university-affiliated graduate-level program in Functional Medicine o Adjunct Professor, Integrative and Functional Nutrition in Immune Health, Doctor of Clinical Nutrition program o Former Adjunct Professor (2009-2013) of Laboratory Medicine, Master of Science in Advanced Clinical Practice o Former Faculty (2004-2005, 2010-2013) and Forum Consultant (2003-2007), The Institute for Functional Medicine o Former Adjunct Professor (2011-2013) of Pharmacology, Evidence-Based Nutrition, Immune and Inflammatory Imbalances, Principles of Functional Medicine, Psychology of Wellness o Former Adjunct Professor of Orthopedics (2000), Radiographic Interpretation (2000), and Rheumatology (2001), Naturopathic Medicine Program, Bastyr University Author of more than 100 articles and letters published in JAMA—Journal of the American Medical Association, BMJ—British Medical Journal, TheLancet.com, JAOA—Journal of the American Osteopathic Association, Annals of Pharmacotherapy, Journal of Clinical Endocrinology and Metabolism, Alternative Therapies in Health and Medicine, Nutritional Perspectives, Journal of Manipulative and Physiological Therapeutics, Integrative Medicine, Current Allergy and Asthma Reports, Nutritional Wellness, Evidencebased Complementary and Alternative Medicine, Nature Reviews Rheumatology and Arthritis & Rheumatism: Official Journal of the American College of Rheumatology International College of Human Nutrition & Functional Medicine ICHNFM.ORG Copyrights:  2004-present by Dr Alex Vasquez. All rights reserved by the author and enforced to the full extent of legal and financial consequences internationally. No part of this book may be reproduced, stored in a retrieval system, used for the creation of derivative works, or transmitted by any means (electronic, mechanical, photocopying, recording, or otherwise) without written permission from the author. Trademarks: ® 2013-present by Dr Alex Vasquez and International College of Human Nutrition and Functional Medicine. The functional immunology/inflammology protocol discussed in this series of videos/notes/books/audios is recalled by the F.I.N.D.S.E.X. acronym trademarked™ in association with Dr Vasquez’s books and videos including but not limited to Functional Immunology and Nutritional Immunomodulation (2012), F.I.N.D. S.E.X. The Easily Remembered Acronym for the Functional Inflammology Protocol (2013), Integrative Rheumatology and Inflammation Mastery, 3rd Edition (2014). Portland, Oregon; Integrative and Biological Medicine Research and Consulting, LLC. All rights reserved and enforced. For additional information and resources, see InflammationMastery.com and/or FunctionalInflammology.com. Additional trademarks referenced/cited in this work include International College of Human Nutrition and Functional Medicine®, International Conference on Human Nutrition and Functional Medicine®, and International Journal of Human Nutrition and Functional Medicine®. Intellectual property: This book contains the creative work and intellectual property of Dr Alex Vasquez, owned and protected internationally by Dr Alex Vasquez, Integrative and Biological Medicine Research and Consulting (“IBMRC”) LLC, and International College of Human Nutrition and Functional Medicine (“ICHNFM” and “ICHNFM.ORG”), based in North America and Europe. Except for quotes and excerpts from other sources, all of the information and images are protected by copyright ©; phrases and terms such as the FINDSEX ® acronym are additionally protected by registered trademark. The book is the means of licensed transmittal of this intellectual property; ownership of the book as an instance of licensed private transmittal and access does not equate to ownership of the property. The book also provides individual, private access to proprietary video archives. This work is supported and made possible by revenue from book sales, and readers/purchasers are asked and expected to respect the author’s ownership of the work—specifically to not inappropriately copy or distribute—so that this work can continue. Violations of intellectual property rights, copyrights, and trademarks will be pursued to the highest extent possible internationally. For use permissions and to report violations, please contact admin@ichnfm.org. Notices: The intended audiences for this book are health science students and doctorate-level licensed medical clinicians. This book has been written with every intention to make it as accurate as possible, and each section has undergone peer-review by an interdisciplinary group of clinicians. In view of the possibility of human error and as well as ongoing discoveries in the biomedical sciences, neither the author nor any party associated in any way with this text warrants that this text is perfect, accurate, or complete in every way, and all disclaim responsibility for harm or loss associated with the application of the material herein. Information and treatments applicable to a specific condition may not be appropriate for or applicable to a specific patient; this is especially true for patients with multiple comorbidities and those taking pharmaceutical medications, which are generally associated with multiple adverse effects and drug/nutrient/herb interactions. Given that this book is available on an open market, lay persons who read this material should discuss the information with a licensed medical provider before implementing any treatments and interventions described herein. ii Inflammation Mastery & Functional Inflammology ICHNFM.ORG Index: 11-beta hydroxysteroid dehydrogenase, 737 12-hydroperoxyeicosatetraenoic acid, 370 12-R-HETE, 370 12-R-lipoxygenase, 375 12-S-HETE, 370 12-S-lipoxygenase, 375 13-S-HODE, 369 15-hydroperoxyeicosatetraenoic acid, 370 15-hydroxy-eicosatrienoic acid, 368 15-lipoxygenase-1, 375 15-lipoxygenase-2, 375 15-S-HETE, 370 2,4-dichlorophenol, 237 2,5-dichlorophenol, 236 2010 ACR guidelines for the diagnosis and assessment of FM, 910 25(OH) vitamin D, 59, 745 2-hydroxyestrone, 693 3-3-hydroxyphenyl-3hydroxypropionic acid, 442, 935 5-HETE, 370 5-hydroperoxyeicosatetraenoic acid, 369 5-hydroxytryptophan, 960 5-lipoxygenase, 374 5pSPMD, 717 8-lipoxygenase, 375 8-S-HETE, 370 Abducens, 23 Acacia catechu, 535 ACEi, 807 Acetaminophen, 913 Acetyl-L-carnitine, 789 Acetyl-L-carnitine, 970 Acinetobacter spp, 94 Acupuncture, 791, 973 Acute nontraumatic monoarthritis, 122 Acute red eye, 119 Acute-onset HTN, 752 Adenosine monophosphate (AMP), 571 Adipokines, 205, 822 Adipose, 205, 822 ADP, dosing and clinical use, 493, 720 Adrenic acid, 367 Adverse food reactions, 379, 984 African American, 807 ALA, 359 Alcohol, 413, 460, 929 Aldolase, 1146 Aldosterone:renin ratio, 748 Aldosterone-to-renin ratio, 748 Algal chlorovirus ATCV-1, 441, 935 Alginate, 1093 Alkalinization, 267, 770 Allergy diagnosis, 391 Allium sativum, 779 Alpha-2 agonists, 813 Alpha-adrenergic receptor class-2 agonist, 813 1154 Alpha-adrenergic receptor type-1 antagonist, 812 Alpha-linolenic acid, 359 Alveolar hemorrhage, 1062 Alzheimer’s disease, 92 Amitriptyline, 912 Amlodipine, 810 Amoxicillin, 496 ANA - interpretation, 78 ANA - overview, 26 Analgesia (natural), 266, 267 ANCA, 1103 ANCA-associated vasculitis (also called "granulomatosis with polyangiitis", formerly Wegener’s granulomatosis, 428 Andrographis paniculata, 537 Anesthetics, 298 Anethum graveolens, 535 Aneurysm (intracranial), 875 Angiotensin-2 converting enzyme inhibitors, 807 Anise, 534 Ankylosing spondylitis, 1110 Anti-autoantibody interventions, 1071 Antibiotic/antifungal drugs, 495 Anticardiolipin antibodies, 1064 Anti-CCP antibodies, 81, 1024 Anticitrullinated protein antibodies, 81 Anticyclic citrullinated peptide, 1024 Anti-double stranded (DS, native) DNA antibodies, 1064 Antidysbiotic lifestyle, 489 Antifibrillarin antibodies, 1092 Anti-histone antibodies, 1064 Antihistorical, 196 Anti-inflammatory & analgesic treatments, 255 Anti-Jo-1, 1146 Antimetabolites, 413, 415, 928 Antimicrobial treatment of SIBO, 963 Antimutagenesis as a direct antiviral strategy, 573, 582 Anti-nuclear antibodies, 1064 Antinuclear antibody - interpretation, 78, 79 Antioxidant capacity of fruits and vegetables, 209 Antiphospholipid and Anticardiolipin antibodies, 1064 Antiphospholipid syndrome, 427 Antiphospholipid/ anticardiolipin/ Hughes syndrome, 85 Anti-Ro antibodies, 1064 Anti-Sm (anti-Smith) antibodies, 1064 Antiviral (phyto)nutrition, 723 Aortic coarctation, 735 Arachidonate avoidance, 769 Arachidonic acid metabolites formed by cyclooxygenase, 368 Arachidonic acid, 366 Arginine, 775, 776 Arginine, omega-3 fatty acids and nucleotide-supplemented enteral support, 585 Armour thyroid, 697 Inflammation Mastery & Functional Inflammology Aromatase, 693 Aromatase, 828 Artemisia annua, 494, 533, 722 Artificial sweeteners, colors and other additives, 212 Ascorbic acid, 587, 770 Aspartame, 212 Asthma & Reactive Airway Disease, 1001 Atlantoaxial instability in AS and RA, 1111 Atlantoaxial instability, 120, 121 Atlas vertebra realignment, 795 Augmentin, 496, 964 Authentic living, 221 Autism, 414, 415, 483, 484, 485, 530 Auto-brewery syndrome, 459 Autoimmune hepatitis, 85 Autoimmune thyroid disease, 85 Autointoxication, 459 Autonomization, 224 Avascular necrosis of the femoral head, osteonecrosis, 123 Azithromycin for psoriasis, 1048 Azithromycin, 496 Babesia, 93 Bacterial allergy, 434 Bacterial DNA, 409 Bacterial overgrowth, 473 Bacteriophage therapy, 497 Bacteriophages, 556, 1059 Balance shoes, 294 Barrett’s esophagus, 1078 Bed rest, 254 Beets, 537 Behcet's Disease, 1133 Behcet's Syndrome, 1133 Berberine, 533, 781 Berberine: dosing and clinical use, 720 Beta-adrenergic receptor blockers, “beta blockers”, 809 Beta-glucuronidase, 104, 488 Betaine, 576 Betulina, 534 Bile flow, 706 Biochemical Individuality - overview, 216 Biochemical individuality, 195 Biofilms, 439 Bioflavonoids in the treatment of allergy, 388, 994 Biotin, 611 Bismuth, 494, 534, 722 Blastocystis hominis, 493, 525, 720 Bleach bath, 515 Blood Dysbiosis, 511 Blood pressure measurement, 743 Body mass index (BMI) for predicting amount and duration of weight loss, 744 Body Mass Index, 204, 822 Boerhaavia diffusa, 537 Bone necrosis caused by NSAIDs, 250 Borrelia burgdorferi, 93 ICHNFM.ORG Index & Appendix Boswellia serrata, 259 Bowel-associated dermatitis-arthritis syndrome (BADAS), 434 Bradycardia, 807 Breath testing, 487 Bromocriptine, 691, 692 Brucea javanica, 535 Buchu/betulina, 534 Butyrate, 415 BVG-LOC profile, 753 Bystander activation, 428 Cabergoline, 691 Caffeine, 212 Calcium channel blockers (dihydropyridine class), 810 Calcium pyrophosphate dihydrate deposition disease, 124, 125 Campylobacter, 93 Canadian Hypertension Education Program recommendations, 761 C-ANCA, 1103 Candida albicans, 526 Candida hypersensitivity, 434 Cannabis sativa and related variants, 261 Caprylic acid, 535 Capsicum annuum, Capsicum frutescens, 260, 1049 Carbohydrate loading for supercompensation, 211 Carboxy-methyl-lysine, 904 Cardiopulmonary examination, 743 Carica papaya ("papaya"), 567 Carnitine Insufficiency Caused by Aging and Overnutrition, 789 Carnitine, antiinflammatory effects, 1049 Carpal bones myofascial release, 290 Carpal tunnel syndrome - clinical management, 286 Carpal tunnel syndrome manipulative treatment, 292 Carrageenan, 212 Cartilage destruction caused by NSAIDs, 250 Casokinins, 773 Catecholamine-O-methyltransferase, 737 Cat's claw, 259 Cauda equina syndrome, 2, 120 Cayenne pepper - monograph, 1049 Cayenne pepper, 260 CBC – overview, 25 CCB, 810 CCP, 81, 1024 Celiac disease and autoimmunity, 492 Celiac disease and autoimmunity, 719 Celiac disease, 85, 429 Cell wall-deficient bacteria, 408 Centella asiatica, 1088 Central neurogenic hypertension, 738 Cephalexin, 497, 516 Cervical spine dysfunction, 742 Cervical Spine: Rotation Emphasis, 280 CH50, 1064 Chemistry panel – overview, 25 Chemistry/metabolic panel, 745 Chiropractic model of illness and healing, 152 Chiropractic spinal manipulative therapy, 792, 794 Chiropractic, 973 Chiropractic-supervised water-only fasting in the treatment of borderline hypertension, 668, 669, 763 Chlamydia trachomatis, 93 Chlamydia/Chlamydophila pneumoniae, 93, 517, 918 Chlorella pyrenoidosa, 673, 725 Chlorella, 673, 725, 979 Chlorovirus ATCV-1, 441, 935 Chlorpyrifos, 236 Chocolate, 771 Chondroitin, 270 Chronic fatigue syndrome, 94 Chronic inflammatory disease, sustained inflammatory response, 398 Churg-Strauss syndrome, 1099 CIC (circulating immune complexes), 1141 Ciprofloxacin, 497 Citrate synthase, 890 Citrobacter freundii, 526 Citrobacter rodentium, 526 Clinical Assessments for HTN, 742 Clinical Case: 45yo HLA-B27+ woman with recurrent UTIs and a 7-year history of ankylosing spondylitis, 501 Clinical Case: Abnormal lactulosemannitol ratio in a patient with idiopathic peripheral neuropathy, 499 Clinical Case: Elevated hsCRP (highsensitivity C-reactive protein) in a male patient with metabolic syndrome and rheumatoid arthritis, 500 Clinical Case: Elevated plasma ammonia in the absence of liver disease, 461 Clinical Case: Exemplary case of clinical and laboratory evidence of reversal of “severe, aggressive, drug-resistant” rheumatoid arthritis, 402 Clinical Management, 752 Clinical practice involves much more than “diagnosis and treatment”, 114 Clonidine, 813 Clostridium, especially in autism, 485 Clove, 534 Cluster headache - differential diagnosis of head pain, 875 Cluster headache, 874 ICHNFM.ORG Inflammation Mastery & Functional Inflammology Cluster headaches, treatment with melatonin, 899 Cocaine, 735 Cockcroft-Gault formula, 740 Cocoa, 771 Cod liver oil, 588 Coenzyme Q10 (CoQ10) in cardiac disease, 788 Coenzyme Q-10, 787, 966 Coffee as a gastrointestinal stimulant, 495 Cold and stretch treatment for MFTP, 277 Colonization, 399 Combination of streptococcal antigen with bacterial DNA, 410 Combinatorial inflammology, 478 Combinatorial multifocal polydysbiosis, 398 Commiphora molmol, 533 Complement, 84 Complements C3 and C4, 54 Composite seropositivity, 1024 Composite seropositivity, 81 Comprehensive parasitology, 102 Comprehensive parasitology, 102, 501, 529 Compression - use in injury management, 255 Conn’s syndrome, 739 Conscious living, 196 Consciousness-raising, 224 Consent to treatment, 110 Contemplation, 194 Contraceptives, 735 Controlled breathing, 791 CoQ-10 in the treatment of allergy, 388, 994 CoQ-10 treatment for migraine, 890 CoQ10, 420, 787, 969 Corrective experience, 224 Cortef, 695 Cortical spreading depression, 866 Cortisol, 694 Cosmetics, 979 Cough headache - differential diagnosis of head pain, 875 Counterthrust, 279 CPDD, 125 CPPD, 124, 125 Cranberry, 534 Cranial nerve V, pain sensation in migraine, 863 Cranial nerves, 22, 23 C-reactive protein - interpretation, 27 Creatine kinase, 1146 Creatine monohydrate, 970 CREST syndrome, 1074 Cross-reactivity, 423 CRP - interpretation, 52 Cryoglobulinemia, 1098 Curcumin requires piperine for absorption, 308, 377, 389, 996 Curcumin, 537 Cushing’s disease/syndrome, 735 1155 Cutaneous dysbiosis/colonization— introduction to assessment, 90 Cyclic citrullinated protein antibodies, 81, 1024 Cyclobenzaprine, 913 Cyclooxygenase (COX), 373 Cymbalta, 912 Cytochrome-c-oxidase, 890 Cytomegalovirus (CMV), 1054 Cytomegalovirus (CMV), 548 Cytomegalovirus (CMV), 92 Cytomegalovirus—Induction of vasculopathy, 1084 Cytomegalovirus—Induction of vasculopathy, 549 Cytomel, 697 Daily living, 190 DAMP, 417 Danazol, 1066 Danger/damage-associated molecular patterns—DAMP—receptors, 417 Dark Chocolate, 771 DASH: Dietary Approaches to Stop Hypertension, 758 DDE, 235 DDT, 235 Deep tendon reflexes, 24 Definition of dysbiosis, 396 Deglycyrrhizinated licorice, 1122 Delta-4-desaturase, 373 Delta-5-desaturase, 373 Delta-6-desaturase, 372 Dengue virus, 567 Dental care, 505 Depuration, 238, 239 Dermatomyositis sine myositis, 1142 Dermatomyositis, 1142 Dermatopolymyositis, 1142 Detoxification defects caused by leaky gut, 486 Detoxification programs are a necessity, 235 Detoxification, 239, 921 Detoxification, problems and solutions, 704 Detoxification: An Ultracondensed Clinical Review, 699 Devil’s claw, 259 DGLA metabolites formed by 15lipoxygenase, 368 DGLA metabolites formed by cyclooxygenase, 367 DGLA, 365 DHA, 257 DHA, 361 DHEA, 1108 DHEA, 695 Diabetes mellitus type 1.5, 85 Diabetes, 512 Dientamoeba fragilis, 526 Diet optimization, 957 Dietary haptenization, 382, 988 Dietary molecular mimicry, 383 Dietary molecular mimicry, 988 Differential Diagnoses of HTN, 734 Diffuse idiopathic skeletal hyperostosis, 1114 1156 Diffuse systemic sclerosis, 1074 Diflucan, 965 Dihomo-gamma-linolenic acid, 365 Diindolylmethane, 693 Dill (antimicrobial actions), 535 DIM, 693 Dimercaptosuccinic acid, 709, 920 DISH, 1114 D-lactic acid intestinal bacteria in chronic fatigue syndrome, 413, 929 D-lactic acid, 924 D-lactic acidosis, 414 D-lactic acidosis, 929 DMSA, 709 DMSA, 920 DNA methylation and "folic acid"*, 577 DNA methylation and histone acetylation, 449 DNA methylation as an antiviral antireplication strategy, 576 DNA methylation, 1058, 582 Docere, 131 Docosahexaenoic acid, 361 Docosapentaenoic acid, 361, 367 Docosatrienes, 308, 362 Dostinex, 691 Double hit model of microbe synergism for autoimmunity induction, 427 DPA, 361 D-ribose, 970 Drop thrust, 283, 607 Drug treatments for chronic HTN, 805 Drug-induced lupus, 428 Drugs for intestinal bacterial overgrowth, 495 Dry needling or injection of local anesthetic or saline Duloxetine, 912 Dysbiosis can be distinguished based on the location(s) of the dysbiotic foci/focus, 396 Dysbiosis in scleroderma, 553 Dysbiosis treatments, 532 Dysbiosis—introduction to concepts and testing, 86 Ear lobe crease, 743 Ebola virus infection, 544, 572 ECG, 749 Eicosanoid modulation, 267 Eicosapentaenoic acid, 360 Eicosatetraenoic acid, 360, 366 Eicosatrienoic acid, 365 EKG, 749, 750 Electrocardiography, 749 Elimination and challenge technique, 391, 999 Elongase, 373 Emergencies, 119 Emotional literacy, 224 Emotional, mental, and social health, 221 Endocrinologic activity of adipose tissue, 205 Endolimax nana, 493, 527, 720 Inflammation Mastery & Functional Inflammology Endoplasmic reticulum (ER) and ER stress (ERS), 651 Endotoxins (lipopolysaccharide) from gram-negative bacteria, 404 Enemas, 537 Enhanced processing of autoantigens, 425, 441, 934 Entamoeba hartmanni, 493, 720 Entamoeba histolytica, 471, 479, 527 Enterococcus, 527 Enteropathic spondylo-arthropathy, enteropathic arthritis, 1110 Enterovirus D68, 544 Enthesopathies, 1111 Environmental dysbiosis, 517 Environmental dysbiosis/colonization— introduction to assessment, 90 Enzyme therapy, 594 Enzymes in fatty acid metabolism, 372 EPA - review, 360 EPA, 257 Epicatechin, 772 Epigenetic dysbiosis/eubiosis, 448 Epigenetic dysfunction, 448 Epigenetic silencing of viral sequences, 543 Epinephrine and norepinephrine, 749 Epstein-Bar virus (EBV), 92, 548, 1054, 1085 Erythromycin, 496, 722 Esophageal dysfunction and GERD in scleroderma, 1092 ESR - interpretation, 54 Essay: Common Oversights and Shortcomings in the Study and Implementation of Nutritional Supplementation, 315 Essay: Five-Part Nutritional Wellness Protocol That Produces Consistently Positive Results, 310 Essay: Implementing the Five-Part Nutritional Wellness Protocol for the Treatment of Various Health Problems, 312 Essay: Twilight of the Idiopathic Era and The Dawn of New Possibilities in Health and Healthcare, 814, 858 Essential fatty acid, 358, 365 Estrogen, 692, 735 Ethanol, 460, 736 Eucalyptus oil, 521 Exceptional living, 195 Exercise, 201, 791 Eye and fundoscopic examination, 743 Facial nerve, 23 Faecalibacterium, 472 Family health history, 13 Fasting (short-term water-only), 762 Fatty Acid Modulation of Eicosanoid Production and Genetic Expression, 309 Fatty acid supplementation, 769 Fatty acids, 588 Fecal transplant, 497 ICHNFM.ORG Index & Appendix Homologs, 423, 427 Hormones in the treatment of allergy, 390, 998 Hospital/physician errors, 253 HPHPA, 442, 935 HPV, 1054 HPV, 548, 561, 1054 HTLV (human T-lymphotropic virus) in SLE, 549, 1055 HTN prevalence, 732 HTN, CVD, 730 Hughes syndrome, 85 Human endogenous retroviruses (HERVs) play a role in autoimmune diseases, 554 Human herpes virus type-6 (HHV-6), 92, 560 Human immunodeficiency virus (HIV), 92, 558 Human papilloma virus (HPV), 548, 561, 1054 HVLA, 279 Hydralazine, 813 Hydrochlorothiazide (HCTZ), 811 Hydrogen sulfide, 413, 474, 924, 929 Hydrosoluble coenzyme Q10, 789 Hydroxocobalamin, 883 Hyperaldosteronism, 739 Hypercalcemia, 736 Hyperglycemia adversely impacts the innate immune system, 599 Hypericum perforatum shows impressive antibacterial action, 494, 533, 722 Hyperinsulinemia, 211, 736 Hyperprolactinemia, 689 Hypersensitivity/allergic dysbiosis, 474 Hypertension, see also HTN, 728 Hypertensive emergency, 752, 752 Hyperthyroidism, 742 Hypochlorite, 516 Hypoglossal nerve, 23 Hypomethylation, 577 Hypothyroidism, 742, 801, 917 I3C, 693 Iatrogenic neurosis, 265 Ice/heat, 254 Idiopathicization, 1143 IgE and IgG assays, 999 Immune complex formation and deposition, 430, 1053 Immune complexes, 1141 Immunodysregulatory dysbiosis, 479 Immunonutrition (against dysbiosis), 536 Immunonutrition, 585 Immunophenotype determination, 610 Immunostimulation by bacterial DNA, 409 Immunosuppression via gliotoxins, 438 Immunosuppressive dysbiosis, 474 Immunotoxicity, 699 Ferritin - interpretation, 54 Ferritin - overview, 26 Feverfew, 897 Fibromyalgia clinical criteria: description and contrast of the 1990 criteria and the 2010 criteria, 909 Fibromyalgia disease, 902 Fibromyalgia initiated by dysbiosis, 463 Fibromyalgia, 901 Fibrosis of the skin and internal organs, 1074 Fish oil, 769 Fish oil, EPA with DHA - rationale for use in basic conservative care, 257 Flax seed oil, 359 Flossing, including use of "floss picks", 505 Fluconazole, 965 Folate deficiency and cervical dysplasia, 576 Food allergen avoidance, 763 Food allergens, 213 Food allergy diagnosis, 391, 999 Food allergy in the induction and perpetuation of autoimmunity, 986 Food allergy, 379, 985 Food challenges, 391, 999 Formula SF722, 493, 720 Fructose avoidance, 767 Fumaderm, 1141 Fumaric acid esters, 1141 Functional assessment, 19 Functional Medicine (FxMed) perspectives, 916 Fundoscopic examination, 743 Furosemide, 811 Gamma delta T cells, 610 Gamma strep, 527 Gamma-linolenic acid, 257, 365 Garlic, 534, 779 Gastric ulceration and gastrointestinal bleeding caused by NSAIDs, 250 Gastrointestinal dysbiosis, 471 Gastrointestinal dysbiosis/colonization— introduction to assessment, 88 Gene products - amplification by NFkappaB, 376 Genital mucosal lesions, 1135 Genitourinary dysbiosis/colonization— introduction to assessment, 89 GERD in scleroderma, 1092 Gestational hypertension, 736 Giant Cell (Temporal) Arteritis, 1097 Giant Cell Arteritis (previously Temporal Arteritis), 1100 Giant cell arteritis, 119 Giardia lamblia, 527, 528 Ginger, 258, 537 GLA - review, 365 Glial activation, 441, 935 Gliotoxin, 438 Glossopharyngeal, 23 Glucosamine, 270 Glutamate and the NMDA receptor in headache, 870, 872 Glutamate/NMDA receptor, 442, 935 Glutamine, 589 Gluten avoidance, SLE treatment, 1066 Glycolytic pathways, 894 Glycyrrhiza glabra, 565, 737 Goldhamer, 762 Gottron’s sign, 1144 Gotu cola, 1088 Gout, 124 Granulomatosis with polyangiitis, formerly Wegener’s granulomatosis, 429 Granulomatous disease (sarcoidosis), 1138 Granulomatous uveitis, 1138 Grape seed extract (GSE), 308, 377, 389, 571, 996 Green tea, 308, 377, 389, 618, 996 Group A streptococci, 531 Gulf War Illness, 94 H2S—hydrogen sulfide, 924, 929 Haemophilus influenzae, 427 Haptenization, 428 Harpagophytum procumbens, 259 HCTZ, 811 Helicobacter pylori, 94, 528, 1085 Heliotrope/purple facial/cheek rash, 1144 Hematocolpos, 1113 Hemochromatosis, 160 Hemochromatosis, 919 Hemoglobin A1c, 747 Henoch-Schonlein purpura, 1099 Hepatic and renal injury and failure caused by NSAIDs, 250 Hepatic encephalopathy in the absence of liver disease, 459 Hepatitis B virus (HepB, HBV), 92 Hepatitis C virus (HepC, HCV), 92 Hepatobiliary stimulation for IgAcomplex removal, 536 Herpes simplex virus type-2 (HSV-2), 560 Herpes simplex virus types 1 and 2 (HSV1, HSV2), 92 Herpes zoster. The treatment and prevention of neuralgia with adenosine monophosphate, 571 HERV, 554, 1055 HFE mutation, 167 Hgb-A1c, 747 Hierarchy of Therapeutics, 131 High glycemic foods, 255 High-dose mannose-binding lectin therapy for Ebola virus infection, 572 High-fructose corn syrup, 737 High-risk pain patients, 109 History taking, 8 HLA-B27, 425 ICHNFM.ORG Inflammation Mastery & Functional Inflammology 1157 Inadequacies in musculoskeletal education and training among physicians, 247 Inclusion body myositis, 1145 Increased intestinal permeability caused by NSAIDs, 250 Individualize treatment - importance, 255 Individuation, 196 Indole, 413, 929 Indole-3-carbinol, 693 Inflammation promotes more inflammation, 376 Inflammatory bowel disease-laboratory testing, 85 Inflammatory dysbiosis, 475 Informed consent, 110 Inhibition of detoxification by dysbiosis, 434 Insufficiency dysbiosis, 432 Insulin resistance and gut dysbiosis, 481 Insulin resistance, 211, 512, 736 Insulin, 747 Internal locus of control, 226 Intestinal/mesenteric vasculitis, 1062 Intracranial aneurysm, 875 Intracranial mass lesion, 876 Intradependence, 224 Introduction to Injection Therapies, 298 Iodine, 697 Iodine/iodide—oral administration of pharmacologic doses, 569 Iron overload as a cause of headaches, 877 Iron Overload, 160, 876, 919 Juvenile spondylo-arthropathy, 1111 Kawasaki disease, 552, 1099 Keflex, 497 Keratoconjunctivitis sicca, 1120 Klebsiella pneumoniae, 471, 528 Koch’s Postulates, 399 LA, 365 Labile support surface, 294 Laboratory assessments: general considerations, 25 Lactoferrin, 104, 488 Lactokinins, 773 Lactulose-mannitol assay evaluates paracellular/pathologic and transcellular/physiologic absorption, 487 Lactulose-mannitol assay, 26, 487 LADA, 85 Lambert-Eaton myasthenic syndrome, 1145 L-Arginine, 775 Lasix, 811 Latent autoimmune diabetes in adults, 85 Laxatives promote eradication of intestinal microbes, 495 L-carnitine, 789 Lead accumulation, 748 Lead and HTN, 77, 748 Lead, 920 1158 Leaky gut diagram, 486 Leaky gut, 101, 416 Lemon balm (Melissa officinalis), 568 Leukotriene B4, 370 Leukotriene B-5, 362 Levothyroxine, 696 L-form, 408 Licorice, 565, 737 Lifestyle habits, 191 Limited cutaneous scleroderma, 1074 Linoleic acid metabolites formed by lipoxygenases, 369 Linoleic acid, 365 Linolenic acid, 359 Liothyronine, 697 Liotrix, 697 Lipoic acid, 308, 377, 389, 578, 996 Lipoxygenases (LOX), 374 Lisinopril, 808 Liver biopsy in iron overload, 167 Low starch diet, 492, 719 Low-back pain: differential diagnostic considerations, 1113 Low-carbohydrate (low fermentation) supplemented PaleoMediterranean diet, 491 Low-carbohydrate (low fermentation) supplemented PaleoMediterranean diet, 718 LOX, 374 LPS triggers TRL4 to activate mitochondrial hyperpolarization, 421 LT-C4, 370 LT-D4, 370 LT-E4, 370 L-tryptophan, 949 L-tyrosine and iodine, 697 Lugol’s solution against influenza, 569 Lumbar Roll, 284 Lupus and Epstein-Barr, 549 Lupus, 1053 Lyme disease, 93 Lyrica, 912 Lysine, 570 Madecassol, 1088 Magnesium, 767, 961 Malignant HTN, 752 Manipulation of the Costovertebral Junction, 282 Manipulation, mobilization, and massage, 266 ManKind Project, 224 Manual Medicine, 278 Marshall protocol, 452 Mask-like face, 1075 Massage, 263 Mechanisms of autoimmune disease induction by microorganisms, 403 Mechanistic dysbiosis, 479 Mechanistic Target of Rapamycin, 656 Medical history, 13 Meditation, 791 Melatonin, 200, 592, 802, 969 Melissa officinalis, 568 Melzack and Wall, 908 Inflammation Mastery & Functional Inflammology Meningitis, 876 Mentha piperita, 494, 534, 722 Mercurial myopathy, 920 Mercury impairs catecholamine degradation, 737 Mercury toxicity, 237, 702, 737, 920 Metabolic dysbiosis, 479 Metabolism of omega-3 fatty acids and related eicosanoids illustration, 364 Metabolism of omega-6 fatty acids and related eicosanoids illustration, 371 Methylation of DNA, 582, 1058 Metoprolol, 810 Metronidazole, 495 Metronidazole, 722 MFTP - clinical management, 274 Microbial colonization, 86 Microbial dysepigenetics, 448 Microbial hypersensitivity, bacterial allergy, 434 Microbial Induction of Noninfectious Systemic Disease, 403 Microglial activation, 441, 935 Migraine - differential diagnosis of head pain, 876 Migraine with aura, 874 Milk protein-derived peptide inhibitors of angiotensin-I-converting enzyme, 775 Milk thistle, 537 Milnacipran, 913 Mimotopes, 423, 427 Mind-Body Approaches, 791 Minimize factors that promote disease, 241 Minocycline, 496 Mitochondrial DAMPs, 417 Mitochondrial dysfunction and mTOR activation, 420 Mitochondrial dysfunction promotes central sensitization, 928 Mitochondrial dysfunction, 904, 905 Mitochondrial impairment is the origin of migraine and cluster headache, 864 Mitochondrial myopathy, 905 Mitophagy, 906, 925, 949, 951, 965, 966 Mixed connective tissue disease, 1074 Mobilization, 266 Molecular mimicry, 423 Monoarthritis, 122 Mononeuritis multiplex, 1101 Mononucleosis, 92 Motivation, 193 Motivation: moving from theory to practice, 194 mTOR, 420, 656 Mucuna pruriens, 690 Multifocal Dysbiosis, 396, 1152 Multifocal polydysbiosis, 86 Multiple chemical sensitivity, 436 Multiple sclerosis (MS), 93, 94, 514 ICHNFM.ORG Index & Appendix Peppermint, 494, 534 Peppermint, 722 Peptidoglycans and exotoxins from gram-positive bacteria, 406 Peripheral neurogenic hypertension, 738 Pesticide exposure, 237 Phenolic content, 209 Pheochromocytoma, 739 Phlogenzym, 595 Phospholipase-A2, 373 Physical examination, 19, 743 Physical exertion, 201 Physical medicine: spinal manipulation, mobilization, 605 Physician errors, 253 Phytochelatins, 711 Phytochemicals, 208 PI3K/Akt/mTOR pathway, 422 Picrorhiza, 537 Plasminogen activator inhibitor, 362 Pleomorphic, "cell wall-deficient" bacteria, 408 Political and social action, 238 Polyarteritis nodosa, 1098 Polymicrobial dysbiosis in scleroderma, 553 Polymyalgia Rheumatica, 1100 Polymyositis, 1142 Polyphenolics and phytonutrients, 581 Porphyria cutanea tarda, 162 Post-isometric stretching treatment for MFTP, 276 Potaba, 1088 Potassium supplementation, 764 Potassium-sparing diuretic: spironolatone, 812 Povidone iodine, 515 Prazosin, 813 Pre-contemplation, 194 Preeclampsia, 736 Pregabalin, 912 Preparation, 194 Primary biliary cirrhosis, 85 Primary sclerosing cholangitis, 85 Primary/Genetic Hemochromatosis, 160 Primum Non Nocere, 130 Probiotic supplementation, 535 Probiotics, 490, 603, 782, 962 Progressive Systemic Sclerosis, 1074 Proinflammatory and endocrinologic activity of adipose tissue, 205 Pro-inflammatory foods, 255 Prolactin, 689 Prolotherapy, 298 Propionic acid, 414 Propolis, 308, 377, 389, 996 Proprioceptive rehabilitation and retraining, 293, 300 Proprioceptive retraining, 266 Prostacyclin, 368 Prostaglandin D2, 368 Prostaglandin E-1, 367 Prostaglandin E2, 308, 368 Multivitamin/multimineral supplementation, 600 Muscle strength – grading scale, 24 Musculoskeletal emergencies, 119 Musculoskeletal Manipulation, 278 Mycoplasma species including pneumoniae, fermentans, hominis, penetrans, genitalium, 94 Mycoplasma species, 918 Myelopathy, 2, 120 Myofascial trigger points - clinical management, 274 Myrrh, 533 NAC, 580 N-acetyl-cysteine (NAC), 580 NADH-cytochrome-c-reductase, 890 NADH-dehydrogenase, 890 Nail pitting, 1039 National Heart, Lung, and Blood Institute (NHLBI), 818 Nattokinase, 781 Naturopathic model of illness and healing, 129, 130 Neisseria gonorrhoeae, 427 Neoantigens/neoautoantigens, 428 Neomycin, 964 Neurogenic hypertension, 738 Neurologic deficit in the evaluation of head pain - clinical management, 877 Neurologic examination, 19, 744 Neuronal autoimmunity, 94 Neuropsychiatric lupus is a medical emergency, 1061 Neuropsychiatric lupus, 119 Neurotoxic dysbiosis, 483 NF-kappaB, 417, 418, 419 NFkB and its phytonutritional modulation, 376 NFkB inhibition as an antiviral antireplication strategy, 578 Niacinamide, 270 NLRP3 inflammasome is activated in fibromyalgia, 419 NLRP3 inflammasome is activated in fibromyalgia, 969 NMDA receptor, 442, 935 NMDA-type glutamate receptor (NMDAr), 871 NOD-like receptors (NLR), 419 Nonsteroidal anti-inflammatory drugs, 739 Nuclear transcription factor kappa beta, 376, 419 Nucleotide-binding oligomerization domain, 419 Nucleotides, 590 Nutrigenomics, 217 Nutrition and Physical Degeneration, textbook by Weston Price,, 206 Nutritional Genomics, 217 Nutritional immunomodulation, 307, 609 Nystatin, 496, 723 O’Keefe and Cordain in Mayo Clinic Proceedings, 206 Obesity, 204, 822 Objective means for the identification of allergens, 999 Occult infections, 918 Octreotide, 1083 Oculomotor, 23 Oil pulling/swishing, 505 Olfactory, 23 Omega-3 fatty acids - review, 359 Ophthalmic, 23 Opioid epidemic, 245 Oral contraceptives, 735 Oregano oil, 533, 720 Organic foods rather than industriallyproduced foods, 212 Orodental dysbiosis, 88, 503 Orthoendocrinology, 688 Orthomolecular Immunomodulation, 386, 993 Orthomolecular Medicine - overview, 216 Orthopedic/musculoskeletal examination: concepts and goals, 20 Orwellian newspeak, 249 Osteochondritis dissecans, 123 Osteomyelitis, 2, 121 Osteopathic manipulation, 798, 973 Osteopathic manipulative treatment for adult pneumonia, 606 Osteopathic Medicine, 149 Overlap syndromes, 1074 Oxygen, for cluster headaches, 892, 970, 973 PABA, 1088 Pain/fatigue syndromes and SIBO, 480 Paleo-, 758 Paleo-Mediterranean Diet, 219, 492, 597, 756 Pancreatic and proteolytic enzymes, 273, 594 Papaya, 567 PAR, 110 Paradigms, and their reasonable alternatives, 197 Parasitelogy, 102 Parasiteology, 501, 529 Parasites, 525 Parenchymal dysbiosis/colonization— introduction to assessment, 91 Parenchymal/Blood Dysbiosis, 511 Parvovirus B-19 (PvB19), 548, 561, 1054, 1085 Pasteurian paradigm, 399 Pathophysiologic responses, 416 Patient (mis)education in standard medicine, 914 Pattern recognition receptors—PRRs, 417 P-cresol, 415 Penicillin treatment of psoriasis, 1048 Pentosedine, 904 ICHNFM.ORG Inflammation Mastery & Functional Inflammology 1159 Prostaglandin E-3, 362 Prostaglandin F2-alpha, 369 Prostaglandin G2, 369 Prostaglandin G-3, 362 Prostaglandin H2, 369 Prostaglandin H-3, 362 Prostaglandin I2, 368 Prostaglandin I-3, 362 Prostaglandin synthase complex, 373 Protect & prevent re-injury, 254 Protein - calculation of daily intake, 206, 268, 328 Proteolytic enzymes (used in the treatment of dysbiosis), 535 Proteolytic enzymes, 273, 594 Proteus mirabilis, 471 PRRs, 417 Pseudomonas aeruginosa, 94, 471 Psoriasis, main chapter, 1038 Psoriatic rheumatism, 1038 Putrescine, 413, 929 Pyridoxine lowers serum/blood glutamate levels, 886 Pyridoxine, 288, 689, 885 Pyruvate dehydrogenase complex, 894 Qigong, 791, 973 Quorum sensing, 439 Raynaud’s phenomenon in scleroderma, 1094, 1129 Raynaud's phenomenon, 94, 1129, 1133 Reactive arthritis, 93, 466, 1110 Reasons to avoid the use of nonsteroidal anti-inflammatory drugs (NSAIDs), 247, 249 Referred pain with compression, 274 REFLEXES – grading scale, 24 Relative rest - definition and application in basic holistic care, 254 Renal artery (renovascular) stenosis, 740 Renal disease survey, 743 Renal failure, cause of death in patients with SLE, 1061 Renal injury and failure caused by NSAIDs, 250 Resolvins, 363 Restless leg syndrome, 949 Retinal vasculitis, 1062 Review of systems, 12 Rheumatic psoriasis, 1038 Rheumatoid Factor - interpretation, 80 Rib manipulation, 282 Riboflavin, 290 Rifaxamin, 496 Rifaximin as treatment for SIBO and IBS, 954 Rifaximin, 954, 964 ROS: review of systems, 12 Rosacea, 482 Rose Bengal staining, 1121 Roseburia intestinalis, 427 Rosemary, 308, 377, 389, 996 Saccharomyces boulardii, 492, 719 SAD: Standard American Diet, 757 1160 S-adenosyl-methionine, 576, 962 Safe patient + safe treatment = safe outcome, 110 Salivary gland biopsy, 1121 Salmonella, 93 SAMe, 576 Sarcoidosis, 1138 Savella, 913 Schirmer test, 1121 Schober test, 1114 Scleraderma, 741 Scleroderma secondary to xenobiotic immunotoxicity, 1074 Scleroderma, 1074 Screening laboratory tests in the evaluation of patients with musculoskeletal complaints, 25 Secondary Hemochromatosis, 160 Secretory IgA, 103, 488 SEID, 479 Selective estrogen receptor modulators inhibit Ebola virus infection, 572 Selenium, 573 Septic arthritis, 121, 125, 126 Septic arthritis, in rheumatoid arthritis, 1023 Seropositivity, 81, 1024 Serotonin synthesis, 211 Serum IgE and IgG assays, 391 Shigella, 93 Short-chain fatty acids, 104, 488 SIBO, 922 Sicca syndrome, 1120 Sick role, 265 Silibinin/silybin from Silymarin marianum, 593 Silymarin, 168 Sinorespiratory dysbiosis, 508 Sjögren Syndrome/Disease, 550, 1120 Skatole, 413, 929 Skin taping to increase afferent stimuli, 296 Skin-prick testing, 391, 999 SLE, 1053 Sleep apnea, 741 Sleep, 199 Slipped capital femoral epiphysis, 124 Small intestinal bacterial/microbial overgrowth, 473 Small intestine bacterial overgrowth in fibromyalgia, 923 Social history, 13 Sodium avoidance, 613 Sodium benzoate, 212 Sodium chloride, 763 Sodium hypochlorite, 516 Somatic dysfunction, 149 Somatostatin analog, 1083 Special considerations in the evaluation of children, 112 Spinal accessory nerve, 23 Spinal cord compression, 2, 120 Spinal manipulation, 605 Spironolatone, 812 SPMD, 717 Inflammation Mastery & Functional Inflammology Sporothrix schenckii, 570 St. John’s Wort, 533 Standard Medical Treatment for Fibromyalgia, 912 Staphylococcus aureus, 531 Stearidonic acid, 360 Stool analysis and comprehensive parasitology, 487 Stool analysis, 103 Streptococcal infections, 94 Streptococcus pyogenes, 531 Stress is a “whole body” phenomenon, 222 Stress management and authentic living, 221 Subluxation, 742 Superantigens, 411 Supercompensation (carbohydrates), 211 Supplemented Paleo-Mediterranean Diet, 219, 256 Syndemic obesity, inflammation, cardiometabolic syndrome, and brain dysfunction, 652 Synthroid, 696 Systemic exertion intolerance disease, 479 Systemic Lupus Erythematosus, main chapter, 1053 Systemic Sclerosis, 741, 1074 Systolic hypertension, 788 Syzygium species, 534 Takayasu arteritis, 1098 Tanacetum parthenium, 897 Tartaric acid, 413, 929 Tartrazine, 212 Television, 191 Temporal arteritis, 119, 1100 Testing for Occult Infections and Dysbiosis, 86 Testosterone, 694 Tetanus toxoid, 427 Tetracycline, 497 Th17 cells, 609 Therapeutic dependency - defined, 265 Therapeutic exercise, 266 Therapeutic Interventions, 956 Therapeutic passivity - defined, 265 Thrombocytopenia, 719 Thromboxane A-2, 368 Thromboxane A-3, 362 Thromboxane B2, 368 Thrust vectors, 279 Thyme, 534 Thymus vulgaris, 534 Thyroid (insufficiency or autoimmunity), 696, 697 Thyroid disease, 742 Thyroid glandular—nonprescription T3, 697 Thyroid hormone, 689 Thyroid stimulating hormone interpretation, 64 Thyroid testing, 745 Thyrolar, 697 Tinidazole, 495 ICHNFM.ORG Index & Appendix Tissue/Parenchymal/Blood Dysbiosis, 511 Tolle Causam, 130 Toll-like receptors (TLR), 417 Toll-like receptors (TLR, e.g., TLR2 and TLR4), 651 Toll-like receptors, 418 Total inflammatory load (TIL), 479 Total microbial load (TML), 479, 1054 Toxic oil syndrome, 1076 Toxicant Exposure and Detoxification/Depuration, 705 Toxoplasma gondii, 1086 Tramadol, 913 Transcendental meditation, 791 Transgenic food avoidance, 613 Transient synovitis, irritable hip, 123 Treatment for MFTP, 277 Treatment-resistant hypertension, 731 T-regulatory cells, 609 Tricycline, dosing and clinical use, 494, 720 Trigeminal nerve, pain sensation in migraine, 863 Trigeminal, 23 Tripterygium wilfordii Hook F, 690 Triptolide, 690 Trochlear, 23 Truncated self, 226 Tryptamine, 413, 929 Tryptophan, 960 TSH: thyroid stimulating hormone interpretation, 64 Turmeric, 537 Twitch response, 274 Tyramine, 413, 483, 929 Una de gato, 259 Uncaria guianensis and Uncaria tomentosa, 259 Undecenoic acid, 493, 720 Undecylenic acid, 535 Undecylenic acid, dosing and clinical use, 493, 720 Unfolded protein response (UPR), 650 Unhistorical, 196 Uric acid reduction, 767 Uric acid, 746 Urinalysis (UA), 745 Urinary alkalinization, 770 Urine pH, 746 Urine sodium and potassium, 746 Uva Ursi, 534 Vagal stimulation, 443, 923 Vancomycin, 964, 496 Varicella zoster virus (VZV), 561 Varicella zoster virus in giant cell arteritis, 552 Varicocele, 693 Vasculitic Diseases, 1095 Vasculitis, 464, 508 Vasodilators, 813 Vegetarian diet for fibromyalgia, 958 Vegetarian diet, 758 Vestibulocochlear, 23 Vinyl chloride disease, 1076 Viruses, part 1—Known/popular "epigenomic" viruses, 1054 Viruses, part 2—Human endogenous retroviruses (endoretroviruses, HERVs or ERVs), 1055 Viruses, part 3—Bacteriophages of the gastrointestinal bacteria, 1059 Viruses, part 4—Bacterial synergism via NFkB activation and immunosuppression, 1060 Vis Medicatrix Naturae, 130 Viscous Agents, 298 Visual analog scale, 23 Vitamin A for all patients with measles, 587 Vitamin A, 587 Vitamin A, retinoic acid, RA, 615 Vitamin B-12 in the treatment of allergy, 388 Vitamin B-12 in the treatment of allergy, 995 Vitamin B-6, 288 Vitamin C (ascorbic acid), 587 Vitamin C in the treatment of allergy, 388, 994 Vitamin C purge, 494, 720 ICHNFM.ORG Inflammation Mastery & Functional Inflammology Vitamin C, 273, 770 Vitamin D - antiinflammatory benefits, 378, 450 Vitamin D deficiency - assessment in patients with musculoskeletal pain, 26, 916 Vitamin D status testing, 59 Vitamin D, 728, 742, 746, 769, 770, 801, 815, 816 Vitamin D, 982, 983 Vitamin D3 (cholecalciferol, not ergocalciferol), 586 Vitamin E in the treatment of allergy, 388, 994 Vitamin E, 612 Vitex astus-cagnus, 690 Wall, neurophysiology researcher, 908 Wall-less bacteria, 408 Waterhouse, 456 Wegener’s granulomatosis, 428, 1097, 1102 Weight optimization, 265, 791 Wellness, 4 Whey peptides, 773 Whey protein isolate, 591 Williams, Roger J, 195 Willow bark, 258 Wobble board, 294 Wobenzym, 595 WomanWithin, 224 Work ethic, 198 Xenobiotic Immunotoxicity, 699 Xenobioticcs, 920 Xerostomia, 1120 Xifaxan, 496, 964 Yellow dye #5, 212 Yersinia, 93 Yoga, 290 Zeff, Jared N.D., 189 Zingiber officinale, 258 Zonulin, 404 Zygomycosis, 570 1161