This compilation document contains the following articles/excerpts:
1. Vasquez A. Scotland's public health campaigns to improve vitamin D
nutriture occurred within the same timeframe as HPV vaccination
[rapid response]. BMJ.com/content/365/bmj.l1161/rr-8 2019 Apr
2. Vasquez A. Unified Antiviral Strategy published by ICHNFM.
International Journal of Human Nutrition and Functional Medicine
2014 Oct
3. Vasquez A. Translating Microbiome (Microbiota) and Dysbiosis
Research into Clinical Practice: The 20-Year Development of a
Structured Approach that Gives Actionable Form to Intellectual
Concepts. International Journal of Human Nutrition and Functional
Medicine 2015 Jun
4. Vasquez A. Antiviral Strategies and Immune Nutrition [book excerpt,
most recent source Inflammation Mastery 4th Edition
https://www.ichnfm.org/im4]. International College of Human
Nutrition and Functional Medicine, 2014
https://www.amazon.com/dp/B00OPDQG4W
5. Vasquez A, Gilbert Manso, M.D., John Cannell, M.D. The Clinical
Importance of Vitamin D (Cholecalciferol): A Paradigm Shift with
Implications for All Healthcare Providers. Alternative Therapies in
Health and Medicine 2004
6. Antiviral Nutrition Update #1 for 2018: Clinical Trial of Vitamin D3
against HPV/CIN1 [video transcript] https://vimeo.com/251566879
See also:
7. Vasquez A. Scotland's public health programs and trends improving
nutritional status should be considered when discussing HPV trends
[rapid response]. BMJ.com/content/365/bmj.l1375/rr-4 2019 Apr
Scotland's public health campaigns to improve vitamin D nutriture occurred within the
same timeframe as HPV vaccination
In April 2019, Palmer et al [1] published a retrospective population study crediting vaccination against human
papilloma virus (HPV) with reduction in HPV prevalence in Scotland, and the authors attributed a reduction
in HPV prevalence among unvaccinated women with “herd protection.” However the authors did not mention
Scotland’s population-wide public health campaigns to address endemic vitamin D deficiency. The Scottish
Government recognized the high prevalence of vitamin D deficiency in its population and began
recommending vitamin D supplementation not later than 2006. Vitamin D deficiency results in impaired
mucosal and immune defenses and correlates in a dose-dependent manner with increased cervicovaginal HPV
infection [2]. By 2009, coincident with the start of the HPV vaccination campaign in 2008, numerous vitamin D
supplementation (and sun exposure) campaigns were being implemented throughout Scotland to combat the
documented population-wide problem of vitamin D deficiency.
Our views of vitamin D experienced a paradigm shift in the early part of this century with landmark
publications such as Vieth’s authoritative documentation of safety in 1999 [3], Zittermann’s “Vitamin D in
preventive medicine” in British Journal of Nutrition in 2003 [4], and Vasquez’s “Clinical importance of vitamin
Citation: Vasquez A. Scotland's public health campaigns to improve vitamin D nutriture occurred within the
same timeframe as HPV vaccination [rapid response]. BMJ.com/content/365/bmj.l1161/rr-8 2019 Apr
D (cholecalciferol): a paradigm shift with implications for all healthcare providers” in 2004 [5] followed by an
important partial summary of vitamin D usage guidelines in British Medical Journal in 2005 [6]. These and
similarly themed articles have contributed to increased awareness of vitamin D’s safety and roles in preventive
medicine and public health, including reducing the burden of infectious diseases such as viral infections and
various types of cancer. Consistent with this evidence of safety and benefit, along with evidence that the
human daily requirement is an order of magnitude greater than previously believed [7], use of vitamin D
supplementation began to increase slowly and then exponentially in the United States [8] and other countries,
especially English-speaking societies, most notably the United Kingdom. Indeed, according to the Scottish
Health Survey 2003 [9], use of dietary supplements such as vitamins (including vitamin D), fish oils (a source
of vitamin D) and minerals (magnesium supplementation improves vitamin D status and is necessary for
vitamin D activation, binding, transport, metabolism, and gene expression [10]) had already begun to increase
between 1998 and 2003. Certainly not later than 2006, the Scottish Government was already recommending
widespread use of vitamin D supplements to combat the high prevalence of vitamin D deficiency in Scotland
[11].
Widespread vitamin D deficiency in Scotland was followed by widespread recommendations for vitamin D
supplementation starting in 2006 and 2009. In 2006, Burleigh and Potter published in Scottish Medical Journal
[12] stating that, “The prevalence of vitamin D deficiency is high in older outpatients in this geographical area.”
In 2007, Hyppönen and Power [13] showed that among British adults “Prevalence of hypovitaminosis D in the
general population was alarmingly high during the winter and spring, which warrants action at a population
level rather than at a risk group level.” In 2008, Rhein [14] further specified that “Vitamin D deficiency is
widespread in Scotland.” In 2009, the Scottish Government acknowledged the need to educate its population
about the importance of vitamin D3 supplementation [15]. From that time until the present, the Scottish
Government, United Kingdom National Health Services, and various advocacy groups and programs (e.g.,
ScotsNeedVitaminD.com[16], Healthy Start, which provides vitamin D supplements to all children and
pregnant women in Scotland [17]) continue assertive public health campaigns recommending vitamin D
supplementation and increased vitamin D production via sun exposure via the “Shine on Scotland” program
initiated in 2009 [18] for all of its citizens [19-23].
Vitamin D supplementation has been the subject of many clinical trials documenting anti-inflammatory,
antiviral, and anticancer benefits. Correction of vitamin D deficiency has significant anti-inflammatory [24]
and immunomodulatory [25] benefits. Vitamin D and its direct metabolites promote production of
antimicrobial peptides which have antibacterial and antiviral properties, while also reducing viral replication
by inhibiting the NF-kappaB pathway. Consistent with these immunomodulatory and antiviral mechanisms,
data from several placebo-controlled trials shows that vitamin D provides benefit in a variety of infectious
conditions including human immunodeficiency virus (HIV) [26], hepatitis C virus [27-29] and upper
respiratory infections [30-31]. Vitamin D administration displays impressive clinical effectiveness against
dermal HPV as shown in case reports, clinical series, and placebo-controlled trials, with remarkable safety,
high efficacy, and a consistent trend toward complete resolution of lesions [32-36]. In 2014, Schulte-Uebbing et
al [37] published “Chronical cervical infections and dysplasia (cervical intraepithelial neoplasia [CIN] 1-2):
vaginal vitamin D treatment” showing that among 200 women with cervical dysplasia, vitamin D vaginal
suppositories (12,500 IU, 3 nights per week, for 6 weeks) provided “very good anti-inflammatory effects” and
“good antidysplastic effects” in women with CIN 1. In 2017, Vahedpoor and colleagues [38] published a
double-blind placebo-controlled trial of vitamin D in women with HPV, in which they found that vitamin D3
administration for 6 months among women with CIN1 resulted in its regression and had beneficial effects on
markers of insulin metabolism and antioxidant status. In 2018, Vahedpoor and colleagues [39] published a
double-blind placebo-controlled trial of vitamin D in women with HPV, in which they observed, “The
Citation: Vasquez A. Scotland's public health campaigns to improve vitamin D nutriture occurred within the
same timeframe as HPV vaccination [rapid response]. BMJ.com/content/365/bmj.l1161/rr-8 2019 Apr
recurrence rate of CIN1/2/3 was 18.5 and 48.1% in the vitamin D and placebo groups respectively”, thereby
clearly favoring treatment with vitamin D over placebo.
In Scotland, programs advocating HPV vaccination (started in 2008) and vitamin D supplementation (started
not later than 2006 and again in 2009) occurred in close chronologic proximity. Crediting the reduction in HPV-
related disease solely to vaccination via retrospective population study is potentially invalid and misleading,
especially when the authors make no account whatsoever of the national program for vitamin D
supplementation which started in the same timeframe. Numerous studies have shown that vitamin D provides
immunomodulatory, anti-inflammatory, microbiome-modifying, antiviral and anti-HPV benefits with high
safety, good efficacy, low cost, wide availability, and clinically important collateral benefits.
Dr Alex Vasquez
Physician, author, lecturer, editor
Barcelona, Spain
13 April 2019
[1] Palmer T, Wallace L, Pollock KG, Cuschieri K, Robertson C, Kavanagh K, Cruickshank M. Prevalence of
cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland:
retrospective population study. BMJ. 2019 Apr 3;365:l1161. doi: 10.1136/bmj.l1161
[2] Shim J, Pérez A, Symanski E, Nyitray AG. Association Between Serum 25-Hydroxyvitamin D Level and
Human Papillomavirus Cervicovaginal Infection in Women in the United States. J Infect Dis. 2016 Jun
15;213(12):1886-92. doi: 10.1093/infdis/jiw065
[3] Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr.
1999 May;69(5):842-56
[4] Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr. 2003
May;89(5):552-72
[5] 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 Sep-Oct;10(5):28-36
https://www.ncbi.nlm.nih.gov/pubmed/15478784
[6] Vasquez A, Cannell J. Calcium and vitamin D in preventing fractures: data are not sufficient to show
inefficacy. BMJ. 2005 Jul 9;331(7508):108-9 https://doi.org/10.1136/bmj.331.7508.108-b and
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC558659/
[7] 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 Jan;77(1):204-10
[8] Rooney MR, Harnack L, Michos ED, Ogilvie RP, Sempos CT, Lutsey PL. Trends in Use of High-Dose
Vitamin D Supplements Exceeding 1000 or 4000 International Units Daily, 1999-2014. JAMA. 2017 Jun
20;317(23):2448-2450. doi: 10.1001/jama.2017.4392
[9] "The proportion of adults who report taking dietary supplements (such as vitamins, fish oils, minerals etc)
has increased slightly since 1998 (there was no change between 1995 and 1998). In 1998, 15% of men and
16% of women aged 16-64 took some form of dietary supplement, which increased to 20% and 26%,
respectively, in 2003." The Scottish Health Survey 2003. Chapter 3 Fruit and Vegetable Consumption and
Eating Habits.
https://www.webarchive.org.uk/wayback/archive/20180602183443/http://www.gov.scot/Publications/2005/12/
02160336/03491 Accessed April 2019
[10] Reddy P, Edwards LR. Magnesium Supplementation in Vitamin D Deficiency. Am J Ther. 2019
Jan/Feb;26(1):e124-e132. doi: 10.1097/MJT.0000000000000538
[11] "Therefore, routine vitamin D supplementation is recommended for all children over 1 year of age and
should be continued until 5 years unless the diet is diverse and plentiful." Scottish Government. Nutritional
Guidance for Early Years: food choices for children aged 1-5 years in early education and childcare settings.
Published: 23 Jan 2006. https://www.gov.scot/publications/nutritional-guidance-early-years-food-choices-
children-aged-1-5-years-early-education-childcare-settings-2/pages/7/ Accessed April 2019
[12] Burleigh E, Potter J. Vitamin D deficiency in outpatients: a Scottish perspective. Scott Med J. 2006
May;51(2):27-31
Citation: Vasquez A. Scotland's public health campaigns to improve vitamin D nutriture occurred within the
same timeframe as HPV vaccination [rapid response]. BMJ.com/content/365/bmj.l1161/rr-8 2019 Apr
[13] Hyppönen E, Power C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of
dietary and lifestyle predictors. Am J Clin Nutr. 2007 Mar;85(3):860-8
[14] Rhein HM. Vitamin D deficiency is widespread in Scotland. BMJ. 2008 Jun 28;336(7659):1451. doi:
10.1136/bmj.39619.479155.3A
[15] Boy wins NHS backing in vitamin D campaign. The Scotsman 2009 December
https://www.scotsman.com/news/boy-wins-nhs-backing-in-vitamin-d-campaign-1-1363272 Accessed April
2019
[16] “At scotsneedvitamind.com, we believe the people of Scotland would see health improvements by taking
a regular Vitamin D supplement. We think there is enough evidence currently available to make all of us take
action, from health care professionals to parents and teachers.” https://scotsneedvitamind.com/about-us/
Accessed April 2019
[17] "The United Kingdom National Health Services created a program called Healthy Start, which offers
vouchers for free vitamin D supplements to qualifying pregnant women, women with a baby under one year
old and children under the age of five years located in Scotland, Northern Ireland, England and Wales. In
April of 2017, the Scottish government partnered with the Healthy Start program to offer free vitamin D
supplements to all Scottish pregnant women, regardless of whether they qualify for vouchers. This joint effort
was created to decrease the risk of rickets and other health complications caused by vitamin D deficiency.
Scotland offers free vitamin D supplements for all pregnant residents. Posted on: November 28, 2017 by
Missy Sturges and John Cannell, MD. https://www.vitamindcouncil.org/scotland-offers-free-vitamin-d-
supplements-for-all-pregnant-residents/#.XKech1UzaHs. See also: National Health Services Scotland.
Vitamin D. https://www2.gov.scot/resource/0038/00386784.pdf Accessed April 2019
[18] Scottish warning over vitamin D levels. 19 September 2010 https://www.bbc.com/news/uk-scotland-
11355810 Accessed April 2019
[19] "Following recommendations from the Scientific Advisory Committee on Nutrition (SACN), Scottish
Government advice on vitamin D for all age groups has been updated as follows: Everyone age 5 years and
above should consider taking a daily supplement of 10 micrograms vitamin D, particularly during the winter
months (October – March)." Scottish Government. Vitamin D. https://www2.gov.scot/Topics/Health/Healthy-
Living/Food-Health/vitaminD Accessed April 2019
[20] Scottish Government. Vitamin D information for health professionals in Scotland. November 2017
https://www.gov.scot/binaries/content/documents/govscot/publications/publication/2017/11/vitamin-d-
recommendations-infants-information-health-professionals-9781786528506/documents/00527986-
pdf/00527986-pdf/govscot%3Adocument Accessed April 2019
[21] "Scots should consider taking vitamin D supplements all-year round, but particularly in autumn and
winter, according to new health advice." All Scots advised to take vitamin D says new health guidance. 21
July 2016. https://www.bbc.com/news/uk-scotland-36856176 Accessed April 2019
[22] "International experts are calling for food in Scotland to be fortified with vitamin D, in an attempt to cut
the large numbers of people who develop multiple sclerosis at sunshine-deprived northern latitudes." Add
vitamin D to Scotland's food – experts: Dosing whole population would help cut levels of multiple sclerosis,
say scientists. 23 Dec 2011 https://www.theguardian.com/uk/2011/dec/23/vitamin-d-scotland-food-multiple-
sclerosis Accessed April 2019
[23] All Scottish babies should have vitamin D supplement, CMO says. The Pharmaceutical Journal 2017
Nov 30. https://www.pharmaceutical-journal.com/news-and-analysis/news/all-scottish-babies-should-have-
vitamin-d-supplement-cmo-says/20204032.article Accessed April 2019
[24] Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D, Aganna E, Price CP,
Boucher BJ. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype:
mechanisms for inflammatory damage in chronic disorders? QJM. 2002 Dec;95(12):787-96
[25] Sánchez-Armendáriz K, García-Gil A, Romero CA, Contreras-Ruiz J, Karam-Orante M, Balcazar-Antonio
D, Domínguez-Cherit J. Oral vitamin D3 5000 IU/day as an adjuvant in the treatment of atopic dermatitis: a
randomized control trial. Int J Dermatol. 2018 Dec;57(12):1516-1520. doi: 10.1111/ijd.14220
[26] Stallings VA, Schall JI, Hediger ML, Zemel BS, Tuluc F, Dougherty KA, Samuel JL, Rutstein RM. High-
dose vitamin D3 supplementation in children and young adults with HIV: a randomized, placebo-controlled
trial. Pediatr Infect Dis J. 2015 Feb;34(2):e32-40. doi: 10.1097/INF.0000000000000483
[27] Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves
sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients. World J Gastroenterol. 2011
Dec 21;17(47):5184-90. doi: 10.3748/wjg.v17.i47.5184
Citation: Vasquez A. Scotland's public health campaigns to improve vitamin D nutriture occurred within the
same timeframe as HPV vaccination [rapid response]. BMJ.com/content/365/bmj.l1161/rr-8 2019 Apr
[28] Nimer A, Mouch A. Vitamin D improves viral response in hepatitis C genotype 2-3 naïve patients. World
J Gastroenterol. 2012 Feb 28;18(8):800-5. doi: 10.3748/wjg.v18.i8.800
[29] Komolmit P, Kimtrakool S, Suksawatamnuay S, Thanapirom K, Chattrasophon K, Thaimai P,
Chirathaworn C, Poovorawan Y. Vitamin D supplementation improves serum markers associated with
hepatic fibrogenesis in chronic hepatitis C patients: A randomized, double-blind, placebo-controlled study. Sci
Rep. 2017 Aug 21;7(1):8905. doi: 10.1038/s41598-017-09512-7
[30] Jung HC, Seo MW, Lee S, Kim SW, Song JK.Vitamin D3 Supplementation Reduces the Symptoms of
Upper Respiratory Tract Infection during Winter Training in Vitamin D-Insufficient Taekwondo Athletes: A
Randomized Controlled Trial. Int J Environ Res Public Health. 2018 Sep 14;15(9). pii: E2003. doi:
10.3390/ijerph15092003
[31] Lee MT, Kattan M, Fennoy I, Arpadi SM, Miller RL, Cremers S, McMahon DJ, Nieves JW, Brittenham
GM. Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with
sickle cell disease. Blood Adv. 2018 May 8;2(9):969-978. doi: 10.1182/bloodadvances.2017013979
[32] Moscarelli L, Annunziata F, Mjeshtri A, Paudice N, Tsalouchos A, Zanazzi M, Bertoni E. Successful
treatment of refractory wart with a topical activated vitamin d in a renal transplant recipient. Case Rep
Transplant. 2011;2011:368623. doi: 10.1155/2011/368623. Epub 2012 Jan 3.
[33] Aktaş H, Ergin C, Demir B, Ekiz Ö. Intralesional Vitamin D Injection May Be an Effective Treatment
Option for Warts. J Cutan Med Surg. 2016 Mar-Apr;20(2):118-22. doi: 10.1177/1203475415602841. Epub
2015 Aug 20
[34] Raghukumar S, Ravikumar BC, Vinay KN, Suresh MR, Aggarwal A, Yashovardhana DP. Intralesional
Vitamin D3 Injection in the Treatment of Recalcitrant Warts: A Novel Proposition. J Cutan Med Surg. 2017
Jul/Aug;21(4):320-324. doi: 10.1177/1203475417704180. Epub 2017 Apr 6.
[35] Naresh M. A Study of Effectiveness of Intralesional Vitamin D3 in Treatment of Multiple Cutaneous
Warts. IOSR Journal of Dental and Medical Sciences (IOSR -JDMS) 2019:18(3),84-87
[36] Abdel Kareem IM, Ibrahim IM, Fahmy Mohammed SF, Ahmed AA. Effectiveness of intralesional vitamin
D3 injection in the treatment of common warts: single-blinded placebo-controlled study. Dermatol Ther. 2019
Mar 28:e12882. doi: 10.1111/dth.12882
[37] Schulte-Uebbing C, Schlett S, Craiut I, Antal L, Olah H. Chronical cervical infections and dysplasia (CIN
I, CIN II): vaginal vitamin D (high dose) treatment. Dermatoendocrinol 2014 Oct; 6:e27791.
doi:10.4161/derm.27791
[38] Vahedpoor Z, Jamilian M, Bahmani F, Aghadavod E, Karamali M, Kashanian M, Asemi Z. Effects of
Long-Term Vitamin D Supplementation on Regression and Metabolic Status of Cervical Intraepithelial
Neoplasia: a Randomized, Double-Blind, Placebo-Controlled Trial. Horm Cancer. 2017 Feb;8(1):58-67. doi:
10.1007/s12672-016-0278-x. Epub 2017 Jan 3
[39] Vahedpoor Z, Mahmoodi S, Samimi M, Gilasi HR, Bahmani F, Soltani A, Sharifi Esfahani M, Asemi Z.
Long-Term Vitamin D Supplementation and the Effects on Recurrence and Metabolic Status of Cervical
Intraepithelial Neoplasia Grade 2 or 3: A Randomized, Double-Blind, Placebo-Controlled Trial. Ann Nutr
Metab. 2018;72(2):151-160. doi: 10.1159/000487270. Epub 2018 Feb 21
Competing interests: Dr Alex Vasquez is a lecturer and author of numerous articles, letters, and books related
to topics of nutrition, clinical medicine, neuroinflammation, and the human microbiome. Dr Vasquez has served
as a consultant to Biotics Research Corporation.
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Citation: Vasquez A. Scotland's public health campaigns to improve vitamin D nutriture occurred within the
same timeframe as HPV vaccination [rapid response]. BMJ.com/content/365/bmj.l1161/rr-8 2019 Apr
International Journal of Human Nutrition and Functional Medicine www.ICHNFM.org
Photos © by Dr Vasquez, 2013-2015
Mini-Review ● Continuing Education • Microbiome • Dysbiosis • Infectious Disease
Translating Microbiome (Microbiota) and Dysbiosis Research into
Clinical Practice: The 20-Year Development of a Structured
Approach that Gives Actionable Form to Intellectual Concepts
Alex Vasquez DC ND DO FACN
Experience and Perspectives "Dysbiosis" is an important concept, but doctors cannot
Many years ago when I published my first books 1,2 and articles3 treat concepts.
detailing "dysbiosis", the word could hardly be found in the We have to define, describe, and deconstruct the microbes,
Medline index, the topic was controversial at best and ethereal molecules, and mechanisms into their components, then rebuild a
at worst, the term "microbiome" (first published in French in conceptual scaffold and intellectual structure that becomes a useful
1949 and in English in 1988) was virtually unknown, and I spent tool that, with study and experience, can be used in a clinical
most of the time and space in my lectures and articles setting to effective benefit.
substantiating and defending the condition's existence. These practical application is a bit indelicate and cumbersome beyond
days, everyone is talking about microbiome, dysbiosis, "leaky the most commonly repeated advice of advocating probiotics,
gut" (thanks largely to Leo Galland MD), and my 1996 article avoiding antibiotics, perhaps delving into using botanical
on “Silent Infections and Gastrointestinal Dysbiosis" has been antimicrobials and laboratory testing. Breath testing (an
downloaded at least 4,000 times and is one of the top 1% most insensitive test for only one subtype of gastrointestinal
popular articles on Academia.edu.4 In the preparation of my dysbiosis) and microbiologic testing have become popular to the
dysbiosis lecture at a major functional medicine conference in point of overuse as doctors grapple for clinical clues.
2010, I found that only 180 Medline articles indexed the term (Noteworthy in the conversation on functional laboratory testing
“dysbiosis”, and now—slightly less than five years later—more is that one functional medicine laboratory in particular used
than 1,200 articles index that term. Obviously, the dysbiosis inaccurate proprietary microbe-identification methods to extract
concept has become better known to the point of actually being millions of dollars of patient and physician money only to
popular, but this does not mean that clinicians understand what deliver innumerable wasted hours in patient suffering and
to do with it. A recent article from the June 2015 issue of Nature
Medicine perfectly summarized this discrepancy between
microbiota research and clinical action: "In the three years since
the completion of the first phase of the Human Microbiome
Project, the number of scientific papers linking the microbes
that live in our gut to diseases ranging from diabetes and colitis
to anxiety and depression has grown exponentially. Yet, these
tantalizing connections have yielded few benefits from a ICHNFM has many videos on the topics of dysbiosis,
therapeutics standpoint."5 To the extent that this information is persistent infections, and dysbiotic clinical conditions such
being integrated into clinical practice at all, the current level of as fibromyalgia at www.Vimeo.com/ICHNFM
Updates: The most complete version of this article is available at the following location http://intjhumnutrfunctmed.org/
Copyrights: Copyright © 2015 by author(s) and International College of Human Nutrition and Functional Medicine www.ICHNFM.org
Free access: Freely available and distributable with all content, text, and image rights reserved by author(s) and ICHNFM.
Citation: Vasquez A. Translating Microbiome (Microbiota) and Dysbiosis Research into Clinical Practice: The 20-Year Development of a Structured
Approach that Gives Actionable Form to Intellectual Concepts. Int J Hum Nutr Funct Med 2015;v3(q2):p1
physician confusion due to misleading and worthless [e.g., persistently ill—in my case, the situation lasted for seven years
"parasite present: taxonomy unavailable"] laboratory and still occasionally recurs, as discussed later.
information.6) So, despite the bloom in research and the
exponential public awareness of dysbiosis, much progress still Dysbiosis-Triggered Illness: Deconstructing the
needs to be made in order to help clinicians—and ultimately Phenomena and Helping Our Patients
patients—better appreciate, assess, optimize and maintain Dysbiotic illness can ultimately be understood as a
microbiotal health—eubiosis. manifestation of human intolerance of the total microbial load
(TML) and more specifically the total dysbiotic load (TDL)
Clinical Importance which is only one part of the total inflammatory load (TIL),
The priority is to understand the role of dysbiosis in clinical alternately described as the total impairment load—that is, the
disease; patients are suffering day-by-day and hour-by-hour total load of physiologic, biochemical, and psychosocial
because of microbial colonization, bacterial allergy, reactive burdens that promote inflammation or any type of
arthritis, systemic inflammation, fibromyalgia, insulin metabolic/physiologic/mental impairment. As I have said for
resistance, neurocognitive impairments, autoimmunity, and many years, dysbiosis is a disease state best described as a "bad
other manifestations of dysbiosis. The basic science and clinical relationship" wherein neither the host nor the microbe(s) are
research data on these various phenomena is crystal clear and unilaterally "at fault" but rather that they are—for a variety of
intellectually sound but is rarely delivered in a manageable modifiable and nonmodifiable reasons—currently
manner so that time-pressured clinicians can perceive the incompatible. Conceptualizing dysbiotic illnesses as a
information in an interconnected context that expedites clinical relationship rather than as an infection—an extension of the
application in patient assessment and treatment. Personally, I acute infection model wherein the microbe is presumed guilty
have generally approached clinical care with a sense of urgency, gives us three major areas of intervention:
for altruistic reasons and because I know the experience of being immunorestoration, tolerogenic or adaptive, antimicrobial.
Clinical pathophysiology of dysbiosis-induced disease: The total microbial load communicates to the human body in
general and the innate/adaptive immune systems specifically from various locations via specific molecules, which then are
"combinatorially summarized" in conjunction with the patient's physiologic profile—including genetic makeup, nutritional status,
xenobiotic load, sleep and stress status—to produce a pattern of clinical manifestations. Doctors are trained to diagnose and
treat the resulting prototypic pattern rather than the problems contributing to the pattern. Image from cover and text of Vasquez
A. Human Microbiome and Dysbiosis in Clinical Disease. Published, copyrighted ©, trademarked ® by Dr Alex Vasquez and
International College of Human Nutrition and Functional Medicine 2015. [ISBN 1512360295 / 9781512360295]
International Journal of Human Nutrition and Functional Medicine www.IntJHumNutrFunctMed.Org 2015 Final PDF
Personal Experience
I did not become an expert in dysbiosis entirely by choice; I had
to become so in order to literally save my own life and preserve
my own health. The year was 1995, the idea of "leaky gut" was
new and ridiculed (in contrast to its wide acceptance today), and
the entire concept of functional medicine had only been
announced just a few years prior. Thanks to mostly to
Metchnikoff, the naturopathic profession, a handful of
allopathic doctors, and a few scattered and vintage medical
articles, we had some vague ideas about dysbiosis but very few
details with which to understand it better, let alone treat it
effectively. In this case, I am discussing gastrointestinal
dysbiosis, which is the prototype but obviously only one of the
eight location-based subtypes of dysbiosis.
I remember the exact day and moment that it all started. What
began with the typical "brain fog" later progressed to physical Dr Vasquez's test results from ~1996: Everything is obvious
inertia, multiple chemical sensitivity / environmental when you know the answer; sample study guide and CE exam
intolerance (MCS/EI), and progressive immediate-onset food questions are available: http://ow.ly/O15vd
allergies, most of which were frustratingly unidentified except a neurotoxin, thereby explaining the fatigue, and it also
for soy lecithin—of note, 1996 was the first year of genetically chelates cobalamin, thereby explaining the response to
manipulated (GM) soy in the US. I was also progressively vitamin B12, indicative of vitamin B12 deficiency, which
lymphopenic and had remarkable responses to parenteral was also contributing to the fatigue. Constipation was
vitamins, especially vitamin B12 (improved mental clarity) and another problem that was not only miserable, but which also
folic acid (resolution of progressive lymphopenia). At this time, promoted the persistence of the dysbiosis and which was
I was finishing chiropractic college, starting naturopathic caused by the gut-paralyzing effect of H2S.
college, and harvesting gems from every seminar, book, and • The multiple chemical sensitivity / environmental
audiocassette I could find, notably from Bland, Galland, Gaby intolerance (MCS/EI) was due to impaired cytochrome
and Wright. With new access to the internet, I scoured the earlier p450 detoxification secondary to endotoxin in general and
versions of Medline and spent my evenings and weekends in the the O antigen of Klebsiella pneumoniae in particular.
medical libraries at Oregon Health Science University in Additively and synergistically, the elevated fecal beta-
Portland and University of Washington in Seattle. I started glucuronidase was deconjugating whatever little cytochrome
compiling and publishing articles, and my main research p450 detoxification was taking place, leading to the inability
interests at the time—other than studying everything nutrition to clear and thus the accumulation of ambient chemicals and
and trying to find solutions to my own mysterious illnesses— internal toxins that could not be oxidized for conjugation;
were rheumatology and hemochromatosis. 7 notice the dual effect of endotoxin-mediated blockade of
Following graduation and licensure, I opened a clinical cytochrome p450 along with increased enterohepatic
practice in Seattle, and later I was also invited to teach recycling due to the elevated fecal beta-glucuronidase. The
Orthopedics and Rheumatology at Bastyr University. The folate deficiency and resultant lymphopenia are presumed
responsibility of teaching these courses gave me reason to dive due to a combination of malabsorption and increased
even deeper into the research and to begin articulating and utilization; at this time I also had an increased
giving structure to what almost always starts as inklings and lactulose:mannitol ratio and dramatically elevated caffeine
impressions. Slowly, I started to understand dysbiosis, its clearance with horrid benzoate conjugation.
various permutations, and the variances of effect that different
• Immediate-onset food allergies were due to the increased
microbes could have, either in isolation or in combination—
intestinal permeability and immune activation, both of which
what I would later elucidate as combinatorial dysbiosis8 and
can be blamed on elevated gastrointestinal endotoxin.
continue to refine on an almost daily and regular basis. 9
During this time, I gained personal physician heal thyself
With effort and reflection, obscurity morphed into clarity. If
experience with practically innumerable nutrients, botanicals,
all we had to work with is the laboratory result above, this alone
and a few antimicrobial drugs; I also appreciated—and was
would have been sufficient to explain and solve all my health
ultimately cured by—my (in)famous vitamin C purge: first-
problems within hours; I have this level of understanding now,
morning consumption of two cups of coffee (peristalsis
but only after studying the topic—not simply for academic
stimulant) and ~30 grams of vitamin C with the resulting
reasons or in a cursory manner, but with some sense of personal
osmotic laxative and exaggerated migratory motor complex
urgency—for twenty years. The main findings of the results
providing gastrointestinal housecleaning par excellence.
above are the Citrobacter freundii and the Klebsiella
pneumoniae, and additional finding on this same result was that Conclusions
of markedly elevated fecal beta-glucuronidase. With years of With the compilation of personal experiences and ongoing
trial and error and a high degree of certainty based on personal research from thousands of clinicians and basic scientists, we
experience backed by a massive review of the research collectively have the knowledge and tools available to assess
literature, I would interpret the above results as follows: and alleviate dysbiotic illnesses in their various forms. The
• The mental and physical fatigue I experienced were due twilight of the idiopathic era and the dawn of new possibilities
mostly to hydrogen sulfide (H2S) produced by the in health and healthcare continue to be progressively
Citrobacter freundii. H2S is a mitochondrial toxin and thus illuminated.10
International Journal of Human Nutrition and Functional Medicine www.IntJHumNutrFunctMed.Org 2015 Final PDF
Free-access videos related to the topics of this article
https://vimeo.com/117742117 https://vimeo.com/123715277
https://vimeo.com/125074159 https://vimeo.com/129841003
https://vimeo.com/116470021 https://vimeo.com/109318556
International Journal of Human Nutrition and Functional Medicine www.IntJHumNutrFunctMed.Org 2015 Final PDF
History of this publication: This article was written and illustrated by Dr Alex Vasquez; editorial critiques and peer reviews were
provided by a quorum of IJHNFM reviewers. Kind review was also provided by external laboratory specialists. Publication does not
imply endorsement by all members of IJHNFM Editorial Review Board.
1. Vasquez A. Integrative Rheumatology. Integrative and Biological Medicine Research and Consulting, 2006. *
2. Vasquez A. Musculoskeletal Pain: Expanded Clinical Strategies. Institute for Functional Medicine, 2008. * Updated in 2014 as Naturopathic
Rheumatology v3.5 cited below.
3. Vasquez A. Multifocal dysbiosis: Pathophysiology, relevance for inflammatory and autoimmune diseases, and treatment with nutritional and
botanical interventions. Naturopathy Digest 2006 Jun http://www.ichnfm.org/faculty/vasquez/reprints/2006_multifocal_dysbiosis.html
4. Vasquez A. Nutritional and Botanical Treatments Against “Silent Infections” and Gastrointestinal Dysbiosis, Commonly Overlooked Causes of
Neuromusculoskeletal Inflammation and Chronic Health Problems. Nutritional Perspectives 2006 Jan. http://ow.ly/O0Wau
5. de Vrieze J. Microbiome models, on computers and in lab dishes, see progress. Nature Medicine 2015 June; 21: 543–544
www.nature.com/articles/nm0615-543
6. Gingras BA, Duncan SB, Scheuller NJ, Schreckenberger PC. Assessment of diagnostic accuracy of recently introduced DNA stool screening test.
International Journal of Human Nutrition and Functional Medicine 2014;v2(q1);p1 http://ow.ly/O2eRE
7. Vasquez A. Musculoskeletal disorders and iron overload disease: comment on the American College of Rheumatology guidelines for the initial
evaluation of the adult patient with acute musculoskeletal symptoms. Arthritis Rheum. 1996 Oct;39(10):1767-8
http://www.ncbi.nlm.nih.gov/pubmed/8843875
8. Vasquez A. Naturopathic Rheumatology v3.5. International College of Human Nutrition and Functional Medicine, 2014. [ISBN 0990620425 / 978-
0990620426] http://www.amazon.com/dp/0990620425
9. Vasquez A. Human Microbiome and Dysbiosis in Clinical Disease. International College of Human Nutrition and Functional Medicine, 2015. [ISBN
1512360295 / 9781512360295] https://www.createspace.com/5518130
10. Vasquez A. Idiopathic versus Multifactorial: Twilight of the Idiopathic Era and the Dawn of New Possibilities in Health and Healthcare.
Naturopathy Digest 2006 naturopathydigest.com/archives/2006/mar/idiopathic.php with minor edits made in 2010 and 2014 http://ow.ly/O2fW6
Mediterranean Sea: 30 minutes from ICHNFM-Europe
International Journal of Human Nutrition and Functional Medicine www.IntJHumNutrFunctMed.Org 2015 Final PDF
This CME article has been brought to you by an educational grant from Biotics Research Corporation.
6801 Biotics Research Drive
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CME
continuing medical education
THE CLINICAL IMPORTANCE OF VITAMIN D
(CHOLECALCIFEROL): A PARADIGM SHIFT WITH
IMPLICATIONSAlexFOR
Vasquez,
ALL HEALTHCARE PROVIDERS
, Gilbert Manso, , John Cannell, DC, ND MD MD
Alex Vasquez, DC, ND is a licensed naturopathic physician in tice for more than 35 years, he is Board Certified in Family
Washington and Oregon, and licensed chiropractic doctor in Practice and is Associate Professor of Family Medicine at
Texas, where he maintains a private practice and is a mem- University of Texas Medical School in Houston. John
ber of the Research Team at Biotics Research Corporation. Cannell, MD, is a medical physician practicing in
He is a former Adjunct Professor of Orthopedics and Atascadero, California, and is president of the Vitamin D
Rheumatology for the Naturopathic Medicine Program at Council (Cholecalciferol-Council.com), a non-profit, tax-
Bastyr University. Gilbert Manso, MD, is a medical doctor exempt organization working to promote awareness of the
practicing integrative medicine in Houston, Texas. In prac- manifold adverse effects of vitamin D deficiency.
W
hile we are all familiar with the important
InnoVision Communications is accredited by the
role of vitamin D in calcium absorption and
Accreditation Council for Continuing Medical Education to
bone metabolism, many doctors and
provide continuing medical education for physicians. The
patients are not aware of the recent research
learner should study the article and its figures or tables, if
any, then complete the self-evaluation at the end of the activ- on vitamin D and the widening range of
ity. The activity and self-evaluation are expected to take a therapeutic applications available for cholecalciferol, which can be
maximum of 2 hours. classified as both a vitamin and a pro-hormone. Additionally, we
also now realize that the Food and Nutrition Board’s previously
OBJECTIVES defined Upper Limit (UL) for safe intake at 2,000 IU/day was set
Upon completion of this article, participants should be able far too low and that the physiologic requirement for vitamin D in
to do the following: 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
1. Appreciate and identify the manifold clinical presenta- sun exposure.1,2 With the discovery of vitamin D receptors in tis-
tions and consequences of vitamin D deficiency sues other than the gut and bone—especially the brain, breast,
2. Identify patient groups that are predisposed to vitamin D prostate, and lymphocytes—and the recent research suggesting
hypersensitivity that higher vitamin D levels provide protection from diabetes
3. Know how to implement vitamin D supplementation in mellitus, osteoporosis, osteoarthritis, hypertension, cardiovascu-
proper doses and with appropriate laboratory monitoring lar 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 thera-
Reprint requests: InnoVision Communications, 169 Saxony Rd, Suite 103, Encinitas, CA 92024; peutic applications to maintain and improve our patients’ health.3
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
Based on the research reviewed in this article, the current authors
-therapies.com and selecting the Continuing Education option. believe that assessment of vitamin D status and treatment of vita-
28 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 1alpha-hydroxylase (1-OHase).6 Calcitriol is the most biologically
a routine component of clinical practice and preventive medicine. active form of vitamin D and increases calcium and phosphorus
Vitamin D supplementation with doses of 4,000 IU/day for adults absorption in the intestine, induces osteoclast maturation for bone
is clinically safe and physiologically reasonable since such doses remodeling, and promotes calcium deposition in bone and a reduc-
are consistent with physiologic requirements.2 Higher doses up to tion in parathyroid hormone (PTH). While increased calcium
10,000 IU/day appear safe and produce blood levels of vitamin D absorption is obviously important for nutritional reasons, suppres-
that are common in sun-exposed equatorial populations. 1,2 sion of PTH by vitamin D is also clinically important since relative-
Periodic assessment of serum 25-OH-vitamin D [25(OH)D] and ly lower levels of PTH appear to promote and protect health, and
serum calcium will help to ensure that vitamin D levels are suffi- higher levels of PTH correlate with increased risk for myocardial
cient and safe for health maintenance and disease prevention. infarction, stroke, and hypertension.7,8 Relatedly, Fujita9 proposed
Clinical research supporting the use of vitamin D in the manage- the “calcium paradox” wherein vitamin D or calcium deficiency
ment of type 2 diabetes, osteoporosis, osteoarthritis, hyperten- leads to elevations of PTH which increases intracellular calcium
sion, cardiovascular disease, metabolic syndrome, multiple and may thereby promote a cascade of cellular dysfunction that
sclerosis, polycystic ovary syndrome, musculoskeletal pain, can contribute to the development of diabetes mellitus, neurologic
depression, epilepsy, and the prevention of cancer and type 1 dia- diseases, malignancy, and degenerative joint disease.
betes is presented along with our proposals for the interpretation In its autocrine metabolism, circulating 25(OH)D is taken up
of serum 25(OH)D laboratory values, for the design of future by a wide variety of cells that contain both 1-OHase as well as
research studies, and for supplementation in infants, children, nuclear vitamin D receptors (VDR). Therefore, these cells are able
adults, and during pregnancy and lactation. to make their own calcitriol rather than necessarily relying upon
hematogenous supply. Cells and tissues that are known to contain
BASIC PHYSIOLOGY OF VITAMIN D 1-OHase, and which therefore make their own calcitriol, include
Vitamin D is obtained naturally from two sources: sunlight the breast, prostate, lung, skin, lymph nodes, colon, pancreas,
and dietary consumption. Vitamin D3 (cholecalciferol) is the adrenal medulla, and brain (cerebellum and cerebral cortex).3,10
form of vitamin D produced in the skin and consumed in the Cells and tissues with nuclear, cytosolic, or membrane-bound VDR
diet. Vitamin D2 (ergocalciferol), which is produced by irradiat- include islet cells of the pancreas, monocytes, transformed B-cells,
ing fungi, is much less efficient as a precursor to the biologically activated T-cells, neurons, prostate cells, ovarian cells, pituitary
active 1,25-dihydroxyvitamin D (calcitriol). Additionally, since cells, and aortic endothelial cells.11 Indeed, given the wide range of
ergocalciferol shows altered pharmacokinetics compared with cells and tissues that metabolize vitamin D in an autocrine man-
D3 and may become contaminated during its microbial produc- ner, we see that there is biological potential for vitamin D to influ-
tion, it is potentially less effective and more toxic than cholecal- ence function and pathophysiology in a wide range of metabolic
ciferol.4 Although ergocalciferol is occasionally used clinically processes and disease states.
and in research studies, cholecalciferol is the preferred form of Since many cells and tissues of the body have the ability to
supplementation and will be implied in this article when supple- metabolize vitamin D, we should not be surprised that vitamin D
mentation is discussed. plays a role in the function of these cells. Calcitriol is known to
Vitamin D can be described as having two pathways for modulate transcription of several genes, notably those affecting
metabolism: one being “endocrine” and the other “autocrine” differentiation and proliferation such as c-myc, c-fos, and c-sis,6
(within the cell) and perhaps “paracrine” (around the cell). This and this may partially explain the inverse relationship between sun
elucidation, recently reviewed by Heany,5 is vitally important in exposure (eg, vitamin D) and cancer mortality.12,13 Vitamin D
expanding our previously limited conception of vitamin D from appears to modulate neurotransmitter/neurologic function as
only a “bone nutrient with importance only for the prevention of shown by its antidepressant 14 and anticonvulsant 15 benefits.
rickets and osteomalacia” to an extraordinary molecule with far- Vitamin D is obviously immunoregulatory as manifested by its
reaching effects in a variety of cells and tissues. Furthermore, ability to reduce inflammation,16,17 suppress and/or prevent certain
Heany’s distinction of “short-latency deficiency diseases” such as autoimmune diseases,18-20 reduce the risk for cancer,12 and possibly
rickets from “long-latency deficiency diseases” such as cancer reduce the severity and frequency of infectious diseases, such as
provides a conceptual handle that helps us grasp an understand- acute pneumonia in children.21
ing of the differences between the acute manifestations of severe
nutritional deficiencies and the delayed manifestations of chron- CLINICAL APPLICATIONS AND THERAPEUTIC BENEFITS
ic subclinical nutritional deficiencies.5 OF VITAMIN D
In its endocrine metabolism, vitamin D (cholecalciferol) is Support for a broad range of clinical applications for vita-
formed in the skin following exposure to sunlight and then travels min D supplementation comes from laboratory experiments,
in the blood to the liver where it is converted to 25-hydroxyvitamin clinical trials, and epidemiologic surveys. Despite the imperfec-
D (calcidiol, 25(OH)D) by the enzyme vitamin D-25-hydroxylase. tions of current data, we can still see significant benefits from vit-
25(OH)D then circulates to the kidney for its final transformation amin D supplementation in a variety of human diseases, as
to 1,25-dihydroxyvitamin D (calcitriol) by 25-hydroxyvitamin D3- briefly reviewed below.
CME: The Clinical Importance of Vitamin D ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 29
Cardiovascular Disease scribed daily supplementation with approximately 1,000 mg
Deaths from cardiovascular disease are more common in calcium, 600 mg magnesium, and 5,000 IU vitamin D (from 20
the winter, more common at higher latitudes and more com- g cod liver oil) for up to two years and found a reduction in the
mon at lower altitudes, observations that are consistent with number of exacerbations and an absence of adverse effects.
vitamin D insufficiency.22 The risk of heart attack is twice as This is one of very few studies in humans that employed suffi-
high for those with 25(OH)D levels less than 34 ng/ml (85 cient daily doses of vitamin D (5,000 IU) and had sufficient
nmol/L) than for those with vitamin D status above this level.23 duration (2 years). More recently, Mahon et al37 gave 800 mg
Patients with congestive heart failure were recently found to calcium and 1,000 IU vitamin D per day for six months to 39
have markedly lower levels of vitamin D than controls,24 and patients with MS and noted a modest anti-inflammatory effect.
vitamin D deficiency as a cause of heart failure has been docu-
mented in numerous case reports.25-29 Prevention of Type 1 Diabetes
Type 1 diabetes is generally caused by autoimmune/inflam-
Hypertension matory destruction of the pancreatic beta-cells. Vitamin D sup-
It has long been known that blood pressure is higher in the plementation shows significant preventive and ameliorative
winter than the summer, increases at greater distances from the benefits in animal models of type 1 diabetes. In a study with
equator and is affected by skin pigmentation—all observations more than 10,000 participants, Hypponen et al18 showed that
consistent with a role for vitamin D in regulating blood pres- supplementation in infants (less than one year of age) and chil-
sure. 30 When patients with hypertension were treated with dren with 2,000 IU of vitamin D per day reduced the incidence of
ultraviolet light three times a week for six weeks their vitamin D type 1 diabetes by approximately 80%. Relatedly, several studies
levels increased by 162%, and their blood pressure fell signifi- using cod liver oil as a rich source of vitamin D have also docu-
cantly.31 Even small amounts of oral cholecalciferol (800 IU) for mented significant reductions in the incidence of type 1 diabetes.
eight weeks lowered both blood pressure and heart rate.32
Depression
Type 2 Diabetes Seasonal affective disorder (SAD) is a particular subtype
Hypovitaminosis D is associated with insulin resistance of depression characterized by the onset or exacerbation of
and beta-cell dysfunction in diabetics and young adults who melancholia during winter months when bright light, sun
are apparently healthy. Healthy adults with higher serum exposure, and serum 25(OH)D levels are reduced. Recently, a
25(OH)D levels had significantly lower 60 min, 90 min and 129 dose of 100,000 IU of vitamin D was found superior to light
min postprandial glucose levels and significantly better insulin therapy in the treatment of SAD after one month.38 Similarly,
sensitivity than those who were vitamin D deficient. 33 The in a study involving 44 subjects, supplementation with 400 or
authors noted that, compared with metformin, which improves 800 IU per day was found to significantly improve mood within
insulin sensitivity by 13%, higher vitamin D status correlated five days of supplementation.14
with a 60% improvement in insulin sensitivity. In a recent clini-
cal trial using 1,332 IU/day for only 30 days in 10 women with Epilepsy
type 2 diabetes, vitamin D supplementation was shown to Seizures can be the presenting manifestation of vitamin D
improve insulin sensitivity by 21%.34 deficiency.39 Hypovitaminosis D decreases the threshold for
and increases the incidence of seizures, and several “anticon-
Osteoarthritis vulsant” drugs interfere with the formation of calcitriol in the
Many practitioners know that vitamin D helps prevent kidney and further reduce calcitriol levels via induction of
and treat osteoporosis, but few know that the progression of hepatic clearance. Therefore, antiepileptic drugs may lead to
osteoarthritis, the most common arthritis, is lessened by ade- iatrogenic seizures by causing iatrogenic hypovitaminosis D.40
quate blood levels of vitamin D. Framingham data showed Conversely, supplementation with 4,000–16,000 IU per day of
osteoarthritis of the knee progressed more rapidly in those vitamin D2 was shown to significantly reduce seizure frequen-
with 25(OH)D levels lower than 36 ng/ml (90 nmol/L). 3 5 cy in a placebo controlled pilot study by Christiansen et al.15
Another study found that osteoarthritis of the hip progressed
more rapidly in those with 25(OH)D levels lower than 30 Migraine Headaches
ng/ml (75 nmol/L).36 Calcium clearly plays a role in the maintenance of vascular
tone and coagulation, both of which are altered in patients
Multiple Sclerosis with migraine. Thys-Jacobs 41 reported two cases showing a
The autoimmune/inflammatory disease multiple sclerosis reduction in frequency, duration, and severity of menstrual
(MS) is notably rare in sunny equatorial regions and becomes migraine attacks following daily supplementation with 1,200
increasingly prevalent among people who live farther from the mg of calcium and 1,200–1,600 IU of vitamin D in women with
equator and/or who lack adequate sun exposure. In a clinical vitamin D deficiency.
trial with 10 MS patients, Goldberg, Fleming, and Picard19 pre-
30 ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 CME: The Clinical Importance of Vitamin D
Polycystic Ovary Syndrome inadequate exposure to sunlight, and hence hypovitaminosis D,
Polycystic ovary syndrome (PCOS) is a disease seen only in is associated with an increased risk of cancer mortality for sever-
humans and is classically characterized by polycystic ovaries, al malignancies, namely those of the breast, colon, ovary,
amenorrhea, hirsuitism, insulin resistance, and obesity. prostate, bladder, esophagus, kidney, lung, pancreas, rectum,
Animal studies have shown that calcium is essential for oocyte stomach, uterus, and non-Hodgkin lymphoma. He proposes that
activation and maturation. Vitamin D deficiency was highly adequate exposure to ultraviolet light and/or supplementation
prevalent among 13 women with PCOS, and supplementation with vitamin D could save more than 23,000 American lives per
with 1,500 mg of calcium per day and 50,000 IU of vitamin D2 year from a reduction in cancer mortality alone.
on a weekly basis normalized menstruation and/or fertility in The aforementioned clinical trials using vitamin D in a
nine of nine women with PCOS-related menstrual irregularities wide range of health conditions have helped to expand our con-
within three months of treatment.42 cept of vitamin D and to appreciate its manifold benefits.
However, in light of new research showing that the physiologic
Musculoskeletal Pain requirement is 3,000–5,000 IU/day for adults and that serum
Patients with non-traumatic, persistent musculoskeletal levels plateau only after 3-4 months of daily supplementation,2
pain show an impressively high prevalence of overt vitamin D we must conclude that studies using lower doses and/or short-
deficiency. Plotnikoff and Quigley43 recently showed that 93% of er durations have underestimated the clinical efficacy of vita-
their 150 patients with persistent, nonspecific musculoskeletal min D. Guidelines for the critique and design of clinical trials
pain were overtly deficient in vitamin D. Masood et al44 found a are proposed later in this article to aid clinicians and
high prevalence of vitamin D deficiency in children with limb researchers in evaluating and designing clinical studies for the
pain, and vitamin D supplementation ameliorated pain within determination of the therapeutic efficacy of vitamin D.
three months. Al Faraj and Al Mutairi45 found vitamin D defi-
ciency in 83% of their 299 patients with low-back pain, and sup- ASSESSMENT OF VITAMIN D STATUS WITH
plementation with 5,000–10,000 IU of vitamin D per day lead to MEASUREMENT OF SERUM 25-OH-VITAMIN D
pain reduction in nearly 100% of patients after three months. Current laboratory reference ranges for 25(OH)D were
erroneously based on average serum levels for the “apparently
Critical Illness and Autoimmune/Inflammatory Conditions healthy” nonrachitic, nonosteomalacic American population, a
Deficiency of vitamin D is common among patients with large proportion of which is vitamin D deficient. Currently, lab-
inflammatory and autoimmune disorders and those with pro- oratories do not report optimal levels so they will mislead the
longed critical illness. In addition to the previously mentioned practitioner unless he or she is aware of current research. For
epidemic of vitamin D insufficiency in patients with MS, we the majority of labs, the bottom of the reference range is set too
also see evidence of vitamin D insufficiency in a large percent- low due to the previous underappreciation of the clinical bene-
age of patients with Grave’s disease,46 ankylosing spondylitis,47 fits of and physiologic requirement for higher vitamin D levels,
systemic lupus erythematosus,48 and rheumatoid arthritis.20 and the top of the range is too low due to previous misinterpre-
Clinical trials with proper dosing and duration need to be per- tations of the research resulting in an overestimation of vita-
formed in these patient groups. C-reactive protein was reduced min D toxicity.1,2,51,52 Therefore, new reference ranges need to be
by 23% and matrix metalloproteinase-9 was reduced by 68% in determined based on the current research, and we present our
healthy adults following bolus injections of vitamin D that proposals in Figure 1 and in the following outline:
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 pro- • Vitamin D Deficiency: less than 20 ng/mL (50 nmol/L).
longed critical illness showed a significant and dose-dependent Serum 25(OH)D levels below 20 ng/mL (50 nmol/L) are
“anti-inflammatory effect” evidenced by reductions in IL-6 and clearly indicative of vitamin D deficiency. However, several
CRP.16 However, the insufficient dose of only 400 IU per day authorities note that this level appears to be too low; Heaney5
(administered intravenously) for only ten days precluded more and Holick51 both state that 25(OH)D levels should always be
meaningful and beneficial results, and we present guidelines greater than 30 ng/mL (75 nmol/L).
for future studies later in this paper.
• Vitamin D Insufficiency: less than 40 ng/mL (100 nmol/L).
Cancer Prevention and Treatment According to Zittermann,11 hypovitaminosis D, wherein tis-
The inverse relationship between sunlight exposure and sue levels are depleted and PTH is slightly elevated, correlates
cancer mortality was documented by Apperly in 1941.13 Vitamin with serum levels of 30–40 ng/mL (75–100 nmol/L).
D has anti-cancer effects mediated by anti-proliferative and Independently, Dawson-Hughes et al53 showed that serum levels
proapoptotic mechanisms3 which are augmented by modulation of PTH begin to elevate when 25(OH)D levels fall below 45
of nuclear receptor function and enzyme action,49 and limited ng/mL (110 nmol/L) in elderly men and women, and these find-
research shows that synthetic vitamin D analogs may have a role ings were supported by Kinyamu et al54 who found that optimal
in the treatment of human cancers.50 Grant12 has shown that PTH status deteriorates when 25(OH)D levels fall below 49
CME: The Clinical Importance of Vitamin D ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 31
ng/mL (122 nmol/L) in elderly women. Therefore, in order to interventional clinical trials comparing different serum levels of
maintain physiologic suppression of PTH, serum levels of 25(OH)D with clinical outcomes are necessary to elucidate the
25(OH)D need to be greater than 40 ng/mL (100 nmol/L). exact optimal range in various clinical conditions. While no acute
or subacute risks are associated with the 25(OH)D levels suggest-
• Optimal Vitamin D Status: 40–65 ng/mL (100–160 nmol/L) ed here, research shows clear evidence of long-term danger associ-
Based on our review of the literature, we propose that the ated with vitamin D levels that are insufficient.
optimal—“sufficient and safe”—range for 25(OH)D correlates
with serum levels of 40–65 ng/mL (100–160 nmol/L).55 This pro- • Vitamin D Excess: Serum Levels Greater than 80 ng/mL
posed optimal range is compatible with other published recom- (200 nmol/L) with Accompanying Hypercalcemia
mendations: Zittermann 11 states that serum levels of 40–80 Serum levels of 25(OH)D can exceed 80 ng/mL (200 nmol/L)
ng/mL (100–200 nmol/L) are “adequate,” and Mahon et al37 with ultraviolet light exposure in the absence of oral vitamin D
recently advocated an optimal range of 40–100 ng/mL (100–250 supplementation1,6 and with oral supplementation with 10,000 IU
nmol/L) for patients with multiple sclerosis. The lower end of our per day as previously mentioned2—in neither scenario is toxicity
proposed range is consistent with suggestions by Mercola56,57 who observed. 25(OH)D greater than 80 ng/mL (200 nmol/L) are not
advocates an optimal range of 45–50 ng/mL (115–128 nmol/L) indicative of toxicity unless accompanied by clinical manifesta-
and by Holick51 who states that levels should be 30–50 ng/mL tions and hypercalcemia. Vieth1 notes that hypercalcemia due to
(75–125 nmol/L). The upper end of our proposed optimal range hypervitaminosis D is always associated with serum 25(OH)D con-
is modified from the previously mentioned ranges offered by centrations greater than 88 ng/mL (220 nmol/L), and Holick6 pre-
Zittermann11 (up to 80 ng/mL [200 nmol/L]) and Mahon et al37 viously stated, “Vitamin D intoxication does not occur until the
(up to 100 ng/mL [250 nmol/L]). According to the authoritative circulating levels of 25(OH)D are over 125 ng/mL [312 nmol/L].”
monograph by Vieth,1 there is no consistent, credible evidence of Assessment for hypervitaminosis D is performed by measurement
vitamin D toxicity associated with levels below 80–88 ng/mL (200 of serum 25(OH)D and serum calcium.
–220 nmol/L). Vieth1 states, “Although not strictly within the ‘nor-
mal’ range for a clothed, sun-avoiding population, serum MONITORING FOR VITAMIN D TOXICITY WITH 25(OH)D
25(OH)D concentrations of 220 nmol/L (88 ng/mL) are consis- AND SERUM CALCIUM
tent with certain environments, are not unusual in the absence of Hypercalcemia can occur with vitamin D supplementation by
vitamin D supplements, and should be regarded as being within either directly causing direct toxicity (rare) or by being associated
the physiologic range for humans.” Similarly, in his very thorough with a vitamin D hypersensitivity syndrome (more common). If
review of the literature, Zittermann 11 concludes that serum serum calcium becomes abnormally high, then vitamin D supple-
25(OH)D concentrations up to 100 ng/mL (250 nmol/L) are mentation must be discontinued until the cause of the hypercal-
subtoxic. Additional support for the safety of this upper limit cemia is identified; however, direct vitamin D toxicity will rarely be
comes from documentation that sun exposure alone can raise lev- the sole cause of the hypercalcemia.
els of 25(OH)D to more than 80 ng/mL (200 nmol/L)1 and that
oral supplementation with 10,000 IU/day (mimicking endoge-
Excess vitamin D > 80ng/ml (200 nmol/L)
nous production from sun exposure) in healthy men resulted in
serum levels greater than 80 ng/mL (200 nmol/L) with no evi-
dence 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
Proposed optimal range 40 - 65 ng/mL (100 - 160 nmol/L)
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 Insufficiency range < 20 - 40 ng/mL (50 - 100 nmol/ L)
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 Deficiency < 20 ng/mL (50 nmol/L)
adverse effects associated with a 25(OH)D level of 65 ng/mL (160 * Modified from: Vasquez A. Integrative Orthopedics: Concepts, Algorithms,
nmol/L), and we found that this level is considered normal by and Therapeutics. Houston; Natural Health Consulting Corporation. 2004:
some medical laboratories6 and that it can be approximated and 417-419 with permission.
safely exceeded with frequent full-body exposure to ultraviolet
FIGURE 1. Proposed normal and optimal ranges for serum
light1 or oral administration of physiologic doses of 5,000–10,000 25(OH)D levels based on current research*
IU cholecalciferol per day for 20 weeks.2 Prospective studies and
32 ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 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 Past and Future Vitamin D Studies: Critique and Design
than 90 ng/ml (225 nmol/L). Elevated 1,25(OH)D levels are com- Nearly all published clinical trials have suffered from
monly—though not always—seen with vitamin D toxicity. Severe flawed design, including inadequate dosing, inadequate
vitamin D intoxication is rare and usually seen only with industrial duration, wrong type of vitamin D (ie, ergocalciferol, D2),
accidents, such as overdosing the fortification of milk, or with failure to test serum vitamin D levels, and/or failure to
long-term administration of more than 40,000 IU of vitamin D per ensure that serum vitamin D levels entered into the optimal
day. Severe hypercalcemia may require urinary acidification and range. The following guidelines are provided for clinicians
corticosteroids to expedite the reduction in serum calcium.58 and researchers using vitamin D in clinical practice and
Induction of vitamin D toxicity generally requires 1–4 research to improve the quality of research and patient care.
months of 40,000 IU per day in infants.58 In adults, toxicity gen-
erally requires several months of supplementation of at least 1. Dosages of vitamin D must reflect physiologic require-
100,000 IU per day. Hypercalcemia appears to be the mechanism ments and natural endogenous production and should
of vitamin D toxicity (rather than a direct toxic effect of the vita- therefore be in the range of 3,000–10,000 IU per day
min), and 25-OH-vitamin D levels may be normal in patients The physiologic requirement for vitamin D appears to
who are vitamin D toxic and hypercalcemic, particularly with vit- be 3,000–5,000 IU per day in adult males.2 Full-body expo-
amin D hypersensitivity syndrome. It has therefore been suggest- sure to ultraviolet light (eg, sunshine) can produce the
ed that serum calcium be measured on a weekly and then equivalent of 10,000–25,000 IU of vitamin D3 per day.1
monthly basis in patients receiving high-dose vitamin D. Therefore, intervention trials with supplemental vitamin
Manifestations attributable to hypervitaminosis D and hypercal- D should use between 4,000 IU/day, which is presumably
cemia include anorexia, nausea, and vomiting followed by weak- sufficient to meet physiologic demands, and 10,000
ness, nervousness, pruritus, polyuria, polydipsia, renal IU/day, which is the physiologic dose attained naturally
impairment, and soft-tissue calcifications. via full-body sun exposure. Based on these physiologic cri-
As a cause of hypercalcemia, vitamin D hypersensitivity syn- teria, we see that the majority of intervention studies in
dromes are more common than vitamin D toxicity, and they gener- adults have used inadequate, subphysiologic doses of vita-
ally arise when aberrant tissue uncontrollably produces the most min D. Therefore, studies that failed to identify therapeu-
active form of the vitamin—calcitriol. Primary hyperparathy- tic benefits from vitamin D supplementation were flawed
roidism, granulomatous disease (such as sarcoidosis, Crohn’s dis- due to insufficient therapeutic intervention—the dose of
ease, and tuberculosis) and various forms of cancer may cause the vitamin D was too low.
syndrome. 25(OH)D levels are normal or even low in vitamin D
hypersensitivity while serum calcium and 1,25(OH)D levels are 2. Vitamin D supplementation must be continued for at
elevated. Additional causes include adrenal insufficiency, hyper- least 5-9 months for maximum benefit
thyroidism, hypothyroidism, and adverse drug effects, particularly Since serum 25(OH)D levels do not plateau until after 3-
with thiazide diuretics. Whatever the cause, patients with persis- 4 months of supplementation,2 and we would expect clinical
tent hypercalcemia should discontinue vitamin D supplementa- and biochemical changes to become optimally apparent some
tion and receive a thorough diagnostic evaluation to determine the time after the attainment of peak serum levels, any interven-
cause of the problem. tion study of less than 5-9 months is of insufficient duration
to determine either maximum benefit or that vitamin D sup-
Interventional Strategies to Treat Vitamin D Deficiency by plementation is ineffective for the condition being investigat-
Increasing Serum Vitamin D Levels ed. Conversely, since vitamin D supplementation can alter
Human physiology adapted to and was shaped by a natural intracellular metabolism within minutes of administration,11
environment with ample exposure to sunlight.5, 61 Full-body expo- benefits seen in short-term studies should not be inaccurately
sure to ultraviolet light on clear days in equatorial latitudes can eas- attributed to statistical error or placebo effect.
ily provide the equivalent of 4,000–20,000 IU of vitamin D.1,61
Slightly longer durations of full-body sun exposure of approximate- 3. Supplementation should be performed with D3 rather than D2
ly 30 minutes (3x the minimal erythemal dose) will produce 50,000 Although cholecalciferol (vitamin D3) and ergocalcif-
IU of vitamin D in lightly pigmented persons, while 5x longer dura- erol (vitamin D2) are both used as sources of vitamin D,
tions are required for more darkly pigmented people to attain the D3 is the human nutrient and is much more efficient in
same vitamin D production.61 The oral dose of vitamin D required raising and sustaining serum 25[OH]D levels. Vitamin D2
to obtain adequate blood levels depends on latitude, sun exposure, is a fungal metabolite and has been associated with
body weight, skin pigmentation, dietary sources, efficiency of adverse effects due to contamination and altered pharma-
absorption, presence of intestinal disease (eg, intestinal resection cokinetics.4 The type of vitamin D must always be clearly
or malabsorption), and medication use, for example with the vita- stated in published research reports.
min D-depleting actions of common anticonvulsant drugs.40
CME: The Clinical Importance of Vitamin D ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 33
Vitamin D Supplementation in Adults
4. Supplements should be tested for potency When 28 men and women were administered 4,000 IU per
Some products do not contain their claimed amount. day for up to five months, in the absence of UVB from the sun,
This problem was illustrated in the study by Heaney et al2 serum 25(OH)D levels reached approximately 40 ng/mL (100
who found that the vitamin D supplement they used in their nmol/L), and no toxicity was observed.4 When 67 men were admin-
study, although produced by a well-known company, con- istered 5,000 and 10,000 IU of cholecalciferol per day for twenty
tained only 83% of its stated value. To ensure accuracy and weeks, again in the absence of UVB from the sun, serum levels of
consistency of clinical trials, actual dosages must be known. 25(OH)D increased to approximately 60 ng/mL (150 nmol/L) and
90 ng/mL (225 nmol/L), respectively, and no toxicity was
5. Effectiveness of supplementation must include evaluation observed.2 Therefore, given that endogenous vitamin D production
of serum vitamin D levels following full-body sun exposure at lower latitudes can produce
Supplementation does not maximize therapeutic efficacy >10,000 IU1 and that 4,000 IU per day is a safe level of supplementa-
unless it raises serum 25(OH)D levels into the optimal range. tion4 that meets physiologic needs in adults,2 we recommend at
To assess absorption, compliance, and safety, serum 25(OH)D least 4,000 IU per day for adults, with efficacy and safety ensured by
levels must be monitored in clinical trials involving vitamin D periodic measurement of 25(OH)D and serum calcium.
supplementation. Assessment of serum levels is important
also to determine the relative dose-effectiveness of different Vitamin D Supplementation in Pregnant Women
preparations of vitamin D, as some evidence suggests that In 1966, two case reports and a brief review of the literature
micro-emulsification facilitates absorption of fat-soluble nutri- showed no adverse effects of 100,000 IU per day of vitamin D in
ents.56,59,60 Measurement of 1,25-dihydroxyvitamin (calcitriol) hypoparathyroid pregnant women. 62 In 1971, a study of 15
is potentially misleading and is not recommended for the eval- hypoparathyroid pregnant women was reported wherein the
uation of vitamin D status. 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
6. Serum vitamin D levels must enter the optimal range conclude that there was “no risk from vitamin D in pregnancy.”63
The majority of clinical intervention studies using vita- Doses of vitamin D for pregnant women were extensively reviewed
min D have failed to use supplementation of sufficient dosage by Hollis and Wagner61 immediately prior to the completion of this
and duration to attain optimal serum levels of vitamin D. Our article, and the authors concluded that doses of 100,000 IU per day
proposed optimal range for 25(OH)D is 40–65 ng/mL were safe for pregnant women. The authors write, “Thus, there is
(100–160 nmol/L) and is presented in Figure 1. no evidence in humans that even a 100,000 IU/day dose of vitamin
The above-mentioned criteria will aid future researchers D for extended periods during pregnancy results in any harmful
in designing interventional studies that can accurately evalu- effects.” Data from several placebo-controlled clinical trials with
ate the relationship between vitamin D status and human ill- pregnant women show that vitamin D supplementation results in
ness. Clinicians, who are not conducting research but rather superior health status for the mother and infant. The current daily
are interested in attaining clinical improvement in their reference intake (DRI) for vitamin D of 200–400 IU per day is there-
patients, should follow these guidelines as well when using fore “grossly inadequate,” and administration of less than 1,000 IU
vitamin D supplementation in patients, while remembering vitamin D per day to pregnant women is scientifically unjustifiable
to monitor for toxicity with the triad of clinical assessments, and ethically questionable. Hollis and Wagner61 conclude that up to
serum 25(OH)D, and serum calcium. Clinicians and 4,000 IU per day is necessary for pregnant women, and this conclu-
researchers need to remember, however, that optimal clinical sion is consistent with previously cited research on physiologic
effectiveness often depends on synergism of diet, lifestyle, requirements2 and endogenous vitamin D production.1 In order to
exercise, emotional health, and other factors. Single interven- ensure safety and efficacy in individual patients, we encourage peri-
tion studies are a reasonable research tool only for evaluating odic measurement of serum calcium and 25(OH)D levels.
cause-and-effect relationships based on the presumption of a
simplistic, linear model that is generally inconsistent with the Vitamin D Supplementation in Infants and Children
complexity and multiplicity of synergistic and interconnected In Finland from the mid-1950s until 1964, the recommended
factors that determine health and disease. Thus, single inter- daily intake of vitamin D for infants was 4,000–5,000 IU, a dose
vention studies with vitamin D supplementation will be use- that was proven safe and was associated with significant protection
ful from an intellectual standpoint insofar as they will help us from type 1 diabetes.61 More recently, in a study involving more
to further define the role of vitamin D in human physiology than 10,000 infants and children, daily administration of 2,000 IU
and pathophysiology. However, optimal clinical results with per day was safe and effective for reducing the incidence of type 1
individual patients are more easily attained with the use of diabetes by 80%.18 Thus, for infants and children, doses of 1,000 IU
multicomponent treatment plans that address many facets of per day are certainly safe, and higher doses should be monitored
the patient’s health.55 by serum calcium and 25(OH)D levels.
34 ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 CME: The Clinical Importance of Vitamin D
Options for Raising Vitamin D Blood Levels plementation has been shown to safely help prevent or alleviate all
We have two practical options for increasing vitamin D lev- of the aforementioned conditions.
els in the body: oral supplementation and/or exposure to ultravi- Vitamin D deficiency/insufficiency is an epidemic in the
olet radiation. Sunlight is commonly unavailable on rainy or developed world that has heretofore received insufficient attention
cloudy days, during the winter months, and in particular geo- from clinicians despite documentation of its prevalence, conse-
graphic locations. Topical sunscreens block vitamin D production quences, and the imperative for daily supplementation at levels
by 97%-100%. Furthermore, since many people work indoors above the current inadequate recommendations of 200–600 IU.65
where sunshine is inaccessible, or they are partially or fully For example, at least 57% of 290 medical inpatients in
clothed when outside, reliance on sunshine to provide optimal Massachusetts, USA were found to be vitamin D deficient,66 and
levels of vitamin D is generally destined to provide unsatisfactory overt vitamin D deficiency was recently found in 93% of 150
and inconsistent biochemical and clinical results. The use of UVB patients with chronic musculoskeletal pain in Minnesota, USA.43
tanning beds can increase vitamin D levels; but this option is Other studies in Americans have shown vitamin D deficiency in
more expensive and time-consuming than oral supplementation, 48% of patients with multiple sclerosis,37 50% of patients with
and excess ultraviolet radiation exposure expedites skin aging and fibromyalgia and systemic lupus erythematosus,48 42% of healthy
encourages the development of skin cancer. Given the impracti- adolescents67 and African American women,68 and at least 62% of
calities and disadvantages associated with relying on sun expo- the morbidly obese.69 International studies are consistent with the
sure to provide optimal levels of vitamin D year-round, for the worldwide prevalence of vitamin D deficiency in various patient
majority of patients, oral vitamin D supplementation is the better groups, showing vitamin D deficiency in 83% of 360 patients with
option for ensuring that biochemical needs are consistently met. chronic low-back pain in Saudi Arabia,45 73% of Austrian patients
Vitamin D is either absent or present in non-therapeutic with ankylosing spondylitis,47 up to 58% of Japanese women with
amounts in dietary sources. One of the only major dietary Grave’s disease,46 more than 40% of Chinese adolescent girls,70 and
sources of vitamin D is cod-liver oil, but the amount required to 40%-70% of Finnish medical patients.71 As a medically valid diagno-
obtain a target dose of 4,000 IU per day would require patients to sis (ICD-9 code: 268.9 Unspecified vitamin D deficiency) with a
consume at least three tablespoons of cod-liver oil, or the amount high prevalence and clinically significant morbidity, vitamin D
contained in >18 capsules of most commercial preparations.55 deficiency deserves equal attention and status with other diagnoses
Clearly this would be unpalatable and prohibitively expensive for encountered in clinical practice. Given the depth and breadth of
most patients, and it would result in very low compliance. the peer-reviewed research documenting the frequency and conse-
Additionally, such a high dose of cod-liver oil may produce quences of hypovitaminosis D, failure to diagnose and treat this
adverse effects with long-term use, particularly with regard to disorder is ethically questionable (particularly in pregnant
excess vitamin A, and perhaps an increased tendency for bleeding women61) and is inconsistent with the delivery of quality, science-
and reduced biological activity of gamma-linolenic acid due to the based healthcare. Failure to act prudently based on the research
high content of eicosapentaenoic acid.55,64 Oral supplementation now available in favor of vitamin D supplementation appears likely
with “pure” vitamin D supplements allows the dose to be tailored to invite repetition analogous to the previous failure to act on the
to the individual needs of the patient. research supporting the use of folic acid to prevent cardiovascular
disease and neural tube defects—a blunder that appears to have
DISCUSSION AND CONCLUSIONS resulted in hundreds of thousands of unnecessary cardiovascular
Vitamin D is not a drug, nor should it be restricted to pre- deaths72 and which has contributed to incalculable human suffer-
scription availability. Vitamin D is not a new or unproven “treat- ing related to otherwise unnecessary neural tube defects, cervical
ment.” Vitamin D is an endogenous, naturally occurring, dysplasia, cancer, osteoporosis, and mental depression. Currently,
photochemically-produced steroidal molecule with essential func- Grant12 estimates that at least 23,000 and perhaps as many as
tions in systemic homeostasis and physiology, including modula- 47,000 cancer deaths73 might be prevented each year in America if
tion of calcium metabolism, cell proliferation, cardiovascular we employed simple interventions (ie, sunshine or supplementa-
dynamics, immune/inflammatory balance, neurologic function, tion) to raise vitamin D levels. Of course, additional lives may be
and genetic expression. Insufficient endogenous production due to saved and suffering reduced by alleviating the morbidity and mor-
lack of sufficient sun exposure necessitates oral supplementation tality associated with hypertension, autoimmune disease, depres-
to meet physiologic needs. Failure to meet physiologic needs cre- sion, epilepsy, migraine, diabetes, polycystic ovary syndrome,
ates insufficiency/deficiency and results in subtle yet widespread musculoskeletal pain, osteoporosis, and cardiovascular disease.
disturbances in cellular function which appear to promote the Until proven otherwise, the balance of the research clearly indi-
manifestation of subacute long-latency deficiency diseases such as cates that oral supplementation in the range of 1,000 IU/day for
osteoporosis, cardiovascular disease, hypertension, cancer, depres- infants, 2,000 IU/day for children, and 4,000 IU/day for adults is
sion, epilepsy, type 1 diabetes, insulin resistance, autoimmune dis- safe and reasonable to meet physiologic requirements, to promote
ease, migraine, polycystic ovary syndrome, and musculoskeletal optimal health, and to reduce the risk of several serious diseases.
pain. In case reports, clinical trials, animal studies, and/or epi- Safety and effectiveness of supplementation are assured by period-
demiologic surveys, the provision of vitamin D via sunlight or sup- ic monitoring of serum 25(OH)D and serum calcium.
CME: The Clinical Importance of Vitamin D ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 35
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32. Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C. Effects of a short-term vitamin cy among healthy adolescents. Arch Pediatr Adolesc Med. 2004;158(6):531-7.
D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in 68. Nesby-O'Dell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW, Looker AC, Allen C,
elderly women. J Clin Endocrinol Metab. 2001;86(4):1633-7. Doughertly C, Gunter EW, Bowman BA. Hypovitaminosis D prevalence and determi-
33. Chiu KC, Chu A, Vay LWG, Saad MF. Hypovitaminosis D is associated with insulin resistance nants among African American and white women of reproductive age: third National
and beta cell dysfunction. Am J Clin Nutr. 2004; 79:820-5. Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr. 2002;76:187-92.
34. Borissova AM, Tankova T, Kirilov G, Dakovska L, Kovacheva R. The effect of vitamin D3 69. Buffington C, Walker B, Cowan GS Jr, Scruggs D. Vitamin D Deficiency in the Morbidly
on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Obese. Obes Surg. 1993;3:421-424.
Clin Pract. 2003;57(4):258-61. 70. Fraser DR. Vitamin D-deficiency in Asia. J Steroid Biochem Mol Biol. 2004;89-90:491-5
35. McAlindon TE, Felson DT, Zhang Y, Hannan MT, Aliabadi P, Weissman B, Rush D, Wilson PW, 71. Kauppinen-Makelin R, Tahtela R, Loyttyniemi E, Karkkainen J, Valimaki MJ. A high prevalence of
Jacques P. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis hypovitaminosis D in Finnish medical in- and outpatients. J Intern Med. 2001;249(6):559-63.
of the knee among participants in the Framingham Study. Ann Intern Med.1996;125(5):353-9. 72. Ellis A. Inertia on folic acid has caused thousands of unnecessary deaths. BMJ.
36. Lane NE, Gore LR, Cummings SR, Hochberg MC, Scott JC, Williams EN, Nevitt MC. Serum 2003;326(7398):1054.
vitamin D levels and incident changes of radiographic hip osteoarthritis: a longitudinal study. 73. Grant WB. Personal communication by email, “My current estimate is 47,000 premature
Study of Osteoporotic Fractures Research Group. Arthritis Rheum. 1999;42(5):854-60. cancer deaths/year.” June 3, 2004.
36 ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 CME: The Clinical Importance of Vitamin D
CME
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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. 5. If a patient has hypovitaminosis D and a vitamin
D-responsive condition such as depression, hypertension,
1. In clinical trials, augmentation of vitamin D levels with insulin resistance, or multiple sclerosis, which of the
ultraviolet light exposure or oral supplementation has been following is appropriate first-line treatment?
shown to benefit which of the following conditions: A. Drugs only
A. Osteoporosis; Hypertension B. Vitamin D only
B. Depression; Multiple sclerosis C. Correction of the vitamin D deficiency, and
C. Back pain; Insulin resistance co-administration of medications if necessary
D. All of the above D. Use of synthetic vitamin D analogs
2. In the absence of vitamin D supplementation, ultraviolet 6. Since vitamin D is highly effective for the prevention and
light exposure (ie, sunshine) can produce 25(OH)D levels alleviation of several health problems, and because it has a
that exceed current laboratory reference ranges: wide range of safety, physiologic doses should be regulated as
A. True a prescription drug and prohibited from public access:
B. False A. True
B. False
3. Which of the following can cause hypercalcemia?
A. Sarcoidosis and Crohn’s disease 7. Given the prevalence and consequences of vitamin D
B. Adrenal insufficiency and hypothyroidism deficiency, failure to test for and treat vitamin D insufficiency
C. Coadministration of vitamin D and thiazide diuretics is ethical:
D. All of the above A. True
B. False
4. According to the current research literature reviewed in this
article, which of the following may be considered 8. Since vitamin D has a wide margin of safety, patients should
long-latency deficiency diseases associated with insufficiency be administered vitamin D routinely and receive which of the
of vitamin D? following types of monitoring:
A. Metabolic syndrome A. Periodic measurement of serum 1,25-dihydroxyvitamin D
B. Autoimmune disease such as multiple sclerosis and (calcitriol) and urinary creatinine
type 1 diabetes B. Periodic measurement of serum 25-hydroxyvitamin D
C. Depression and cancer (calcidiol) and serum calcium
D. All of the above 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
Antiviral Nutrition Update #1 for 2018:
Clinical Trial of Vitamin D3 against HPV/CIN1
The video of this presentation is archived at ichnfm.org/hpv1, and the transcript in PDF format—which is considered the final
and citable version—is archived at academia.edu/35808436; any corrections or updates will be made to the PDF file. Observe
that this video presentation is truly an *update* subsequent to previous publications and that therefore not all sources are cited;
for citations, see the video, and for complete citations regarding the protocol in its entirety, see the book Antiviral Strategies and
Immune Nutrition or the ebook version titled Antiviral Nutrition.
“Hello everyone, Dr Alex Vasquez here with our next video which is going to discuss antiviral nutrition. This will
be the first update for 2018.
If I'm providing an update, then obviously that information will be founded upon and predicated upon
some previous information. So let's take a look at those sources right now. This series of updates builds upon
previously published books, articles, videos and blogs. In 2014, I published a small book called Antiviral Strategies
and Immune Nutrition; it's also available as an ebook through the Amazon Kindle platform, that was published
under the name of Antiviral Nutrition. I also published kind of an editorial journal article called “Unified Antiviral
Strategy” in 2014, you can get that online for free. And I also did a presentation in 2016 at the International Congress
on Naturopathic Medicine in Barcelona, you can see that on the internet for free as well and I've provided you the
website address. Also in 2014, I published a series of videos which you can find online for free if you're interested
in looking at those.
1. Book: Antiviral Strategies and Immune Nutrition (2014) https://www.amazon.com/dp/1502894890/
2. eBook: Antiviral Nutrition (Kindle ebook, 2014) https://www.amazon.com/dp/B00OPDQG4W
3. Journal: Unified Antiviral Strategy published by ICHNFM. International Journal of Human Nutrition and
Functional Medicine 2014:v2(q4);p1 ichnfm.org/antiviral5
© Vasquez A. Antiviral Nutrition Update #1 for 2018. Video presentation (ichnfm.org/hpv1) and official transcript (academia.edu/35808436) 2018 January.
Conference: Vaccines—The Truth: International Congress on Naturopathic Medicine in Barcelona 2016
4.
ichnfm.org/antiviral4
5. Tutorials: AntiViral Strategies and Immune Nutrition: Antiviral Nutrition (video, 2014)
https://vimeo.com/109318556
If you want an independent view of some of these topics, the best article that I could recommend for you would be
this one from British Journal of Nutrition 2007, “Selected vitamins and trace elements support immune function by
strengthening epithelial barriers and cellular and humoral immune responses.” So if you want kind of an
independent view of some of the things we're going to talk about today, then you might look at that article, British
Journal of Nutrition, 2007 October.
So when we talk about viral infections which is mostly what we're talking about, we're going to talk about viral
infections—a particular viral infection called HPV: human papilloma virus—and its relationship to vitamin D status
and response to vitamin D supplementation.
So again, kind of laying the foundation and putting all of this in a reasonable context, when we talk about
the treatment of viral infections, we have to have a comprehensive way of looking at that, not just talking about
virus here and virus there. As you can imagine, with the book, I've developed not simply an antiviral strategy but
also a more cohesive and comprehensive way of looking at viral infections and their clinical complications.
So as I said, in 2014, I'll state it again here, if you don't have a structured understanding of a good,
comprehensive antiviral strategy, then you really don't have either an understanding or a strategy. And I can say
that, after having gone through three different doctoral programs: we never learned an antiviral strategy, we never
learned how to understand viral infections in a comprehensive way that would really leverage the clinical tools
that we have for optimal effectiveness. And when you look at my strategy, you get to see some ways that you can
intervene and understand how these viral infections progress and how the body responds and that provides you
some insight into ways that you could treat these virus-infection-related diseases, whether those are acute infections
or persistent infections that go on to have other complications. So at the very least, let's touch upon these major four
categories.
1. Antiviral: Starting with antiviral interventions, we can target the virus itself.
2. Antireplication: We can use antireplication intervention, so that is targeting the machinery of viral
replication, we can attack that process as well.
3. Immunonutrition: We can use immunomodulation and immunonutrition because obviously, the immune
system does usually a very competent job, protecting us from these viral infections. So let's optimize
immune function and that usually means nutritional supplementation.
4. Cell and systemic support: We can also use cell and systemic support to mitigate some of the consequences
of viral infections and of course, I'm talking about inflammation, oxidative stress and of course,
mitochondrial dysfunction which accompanies many viral infections.
So when we start to deconstruct this phenomenon of viral infections and we look at each of these components, we
can intervene at each of these levels/layers and provide better treatment, whether we're treating ourselves or
whether we're treating our clients. So today, we're going to talk about vitamin D in the treatment of a very common
type of viral infection and most of that work is going to put us here in this third category of immunonutrition, but
also, you'll see some implications for this antireplication category as well. (See book and video for explanatory
diagrams: http://www.ichnfm.org/hpv1)
So let us go ahead and start taking a look at this article that we're going to focus on today which is “Effects
of Long-Term Vitamin D Supplementation on Regression and Metabolic Status…” associated with cervical
intraepithelial neoplasia. This article comes from Hormones and Cancer, February of 2017. You've got the digital
object identifier here as well. This is a randomized double-blind placebo-controlled trial with 58 women with
cervical intraepithelial neoplasia grade one (CIN1). The intervention was 50,000 international units (IU) of vitamin
D3 each two weeks, so that averages out to a bit over 3,500 IU per day for six months. And overall, I consider that
intervention to be reasonable; the dose is reasonable but certainly not heroic, nor assertive.1
1
Vasquez A. How to Understand, Refute, and Plan Studies Using Vitamin D. International Journal of Human Nutrition and Functional Medicine 2017 http://www.ichnfm.org/d
© Vasquez A. Antiviral Nutrition Update #1 for 2018. Video presentation (ichnfm.org/hpv1) and official transcript (academia.edu/35808436) 2018 January.
Vitamin D3 dosed at 4,000 IU per day is considered to be the minimum for replacing vitamin D in patients
who are deficient. We might use higher doses closer to 10,000 IU; I think that would have been a bit more robust
and not necessarily heroic; six months of duration is certainly the minimum. We wouldn't want to see a study for
example for two months or three months or four months but six months is acceptable, and the dose is acceptable.
So we can evaluate this study, thinking that this might actually be a reasonable representation of competent clinical
practice.
And that's an important place for us to start because a lot of these studies using vitamin D have used
inadequate dosing and inadequate duration and they reached the false conclusion that vitamin D is inefficacious
for whatever it is that they're investigating. And really, vitamin D is not at fault. The fault lies with the researchers
for poorly designing their studies. I have published guidelines on the use of vitamin D in clinical practice as well
as guidelines for designing clinical trials in Alternative Therapies in Health and Medicine2, British Medical Journal,3 and
International Journal of Human Nutrition and Functional Medicine. You can download those articles from the internet
for free at http://www.ichnfm.org/d. Results of the study show the following:
1. After six months of vitamin D administration, a greater percentage of women in the vitamin D group had
regressed their cervical intraepithelial neoplasia grade one, 84% success versus 33% in the placebo group.
2. They had improved vitamin D status, that's another thing that we always want to look for in studies; they
always need to actually measure vitamin D levels, not simply give people vitamin D and assume it was a
properly manufactured supplement with good absorption, et cetera. We actually have to measure vitamin
D response by looking at 25 hydroxyvitamin D in the serum.
3. These patients also benefited from showing reduced serum insulin levels and improved insulin sensitivity.
4. They had improved antioxidant defenses, they had elevated glutathione levels, relative to the placebo
group and they had reduced oxidative stress as well.
5. Excellent safety.
6. The authors barely mentioned modulation of the vaginal microbiome, and I think that this beneficial
microbiome-specific effect is likely of major importance. This is probably where a lot of the power of this
intervention is coming from against HPV/CIN1. Not necessarily the systemic administration of vitamin D
but the effect that that vitamin D has on systemic inflammation but also immune function and the
modification of the vaginal microbiome via improved immune function, via vitamin D supplementation. I
think that's probably where the action is here in terms of mechanisms of effect of this intervention.
Let's look at some more details and how we might understand this study a bit more; here I will review several of
the Biological effects of vitamin D3: When we're talking about optimizing serum levels and therefore body
reserves. Vitamin D improves gut absorption of calcium—we are quite sure about that, magnesium probably and
also we see some new data showing that vitamin D might also improve selenium absorption. If vitamin D3 indeed
increases selenium absorption, this would greatly explain the reported benefits in antioxidant status, reductions in
mortality and the antiviral benefits that are apparently being reported here. So selenium has antiviral effects,
number one, by blocking viral replication and number two, by blocking viral mutagenesis; those are very important
when the body is trying to combat these persisting viral infections. Reductions in physiologic elevations of
parathyroid hormone which reduces intracellular calcium—this is referred to as the “calcium paradox.” I've also
published an article detailing “intracellular hypercalcinosis”4 (reprinted online http://www.ichnfm.org/ichc), and
it's also republished in my book Inflammation Mastery, 4th Edition as well as in Textbook of Clinical Nutrition and
Functional Medicine, Volume 1. This reduction of parathyroid hormone reduces intracellular calcium which promotes
a reduction in excess inflammation and cell proliferation. Inhibiting excess cellular proliferation is one of the
physiologic and clinical benefits of vitamin D. Also, inducing differentiation and apoptosis—obviously effects have
anticancer benefits. Vitamin D also reduces systemic inflammation, this has been very well documented. One very
nice study back in December of 2002 published in the Quarterly Journal of Medicine showed this very conclusively.
Vitamin D metabolites inhibit the NFkB pathway. This is very important because the NFkB pathway drives viral
replication. So anything that's going to block that NFkB pathway, whether it's vitamin D, selenium, zinc, et
2
Vasquez et al. The clinical importance of vitamin D (cholecalciferol): a paradigm shift with implications for all healthcare providers. Altern Ther Health Med. 2004
3
Vasquez et al. Calcium and vitamin D in preventing fractures: Data are not sufficient to show inefficacy. BMJ: British Medical Journal 2005
4
Vasquez A. Intracellular Hypercalcinosis. Naturopathy Digest 2006 September. See reprint online: http://www.ichnfm.org/ichc
© Vasquez A. Antiviral Nutrition Update #1 for 2018. Video presentation (ichnfm.org/hpv1) and official transcript (academia.edu/35808436) 2018 January.
cetera, is going to probably provide some antiviral benefit by reducing viral replication. Vitamin D also improves
immune efficiency, increased resistance to infections and dysbiosis with improved immunotolerance. People
commonly have a simplistic “bipolar” view of the immune system, whether it's “overactive”—resulting in allergies
and autoimmunity, or “underactive”—resulting in an increased susceptibility to infections. But what we see with
vitamin D is actually improved resistance against infections and dysbiosis and also improved tolerance at the same
time. The expected result would be a reduction in allergy and autoimmunity; certainly a reduction in autoimmunity
has been documented and also some increased resistance to infections. Now in this context, when we're talking
about cervical intraepithelial neoplasia (CIN), we have to talk about not simply the HPV virus, the human
papillomavirus but also the bacterial microbiome within the vagina which obviously affects the cervix. So what I
suspect is happening in this study is that the administration of vitamin D is improving immune function,
modulating the bacterial microbiome within the vagina—obviously that's directly adjacent to the cervix. When
the immune system of the vaginal mucosa is improved, that favorably modulates the bacterial microbiome
within the vagina to reduce inflammation and the reduced inflammation leads to a reduction in viral
mutagenesis and viral replication. I suspect that this is the mechanism of action here. As I mentioned before,
these patients also showed improved glucose insulin sensitivity; that same result has been shown in several other
studies, so I think we can believe quite strongly in that. Several studies have shown reductions in elevated blood
pressure as well. We consistently see with vitamin D supplementation improved mood, reduced
neuroinflammation and reduced pain and—well documented by William Grant's work—reductions in all-cause
mortality and disease-specific mortality.
© Vasquez A. Antiviral Nutrition Update #1 for 2018. Video presentation (ichnfm.org/hpv1) and official transcript (academia.edu/35808436) 2018 January.
I will conclude with a brief summary and clinical contextualization. This study—
“Effects of Long-Term Vitamin D Supplementation on Regression and Metabolic
Status of Cervical Intraepithelial Neoplasia” published in February of 2017 in the
journal Hormones and Cancer—is a small trial but it is placebo-controlled and does
provide encouraging data consistent with known benefits of vitamin D
supplementation, whether that's provided systemically (for an endocrine effect)
or directly vaginally (for endocrine [systemic absorption], and local paracrine and
autocrine effects)—specifically the effects that that vitamin D has on the vaginal
microbiome via its antiinflammatory and eubiosis-promoting effects.
Enhancement of self-resolution I think is one of the major keys here.
Given the well-established fact that most people clear various human
papillomavirus infections without consequence, research (such as this) should be
emphasizing those natural and endogenous factors that promote viral clearance.
Medical interventions related to HPV disease include PAP smears and
these should be continued every one to three years. The controversial anti-HPV vaccination is expensive and has
produced many biologically-proven adverse effects, including autoimmunity (e.g., acute disseminated
encephalomyelitis5), neuroinflammation6, infertility7, and death8. And of
course, that vaccine provides zero collateral benefits.
In contrast, nutritional interventions such as vitamin D and
methylfolate or calcium folinate safely provide numerous disease specific
and general collateral benefits. What we need in the future are well-
performed clinical trials using a complete antiviral nutrition protocol such
as the one that I published back in 2014.
So thank you for your attention during this short video. What
we're going to talk about in one of the upcoming videos is again, the role
of vitamin D in modulating the vaginal microbiome, reducing
inflammation and reducing the clinical consequences of various diseases.
Citation: Vasquez A. Antiviral Nutrition Update # 1 for 2018. Video
presentation (ichnfm.org/hpv1) and official transcript
(academia.edu/35808436) 2018 January
Primary reference—same information in different formats and contexts:
• Antiviral Strategies and Immune Nutrition https://www.amazon.com/dp/1502894890/
• also published in digital ebook format as Antiviral Nutrition (Kindle ebook)
https://www.amazon.com/dp/B00OPDQG4W.
• Also published in Inflammation Mastery, 4th Edition https://www.amazon.com/dp/B01KMZZLAQ/ and
• Textbook of Clinical Nutrition and Functional Medicine, vol. 1: Essential Knowledge for Safe Action and Effective
Treatment https://www.amazon.com/dp/B01JDIOHR6/
Introductory videos:
• Video introduction to books: http://www.ichnfm.org/im4
• Conference presentation—introducing the clinical protocol:
http://www.ichnfm.org/video-funct-inflam-1
5
Sekiguchi et al. Two Cases of Acute Disseminated Encephalomyelitis Following Vaccination against Human Papilloma Virus. Intern Med. 2016;55(21):3181-3184
6
Takahashi et al. Immunological studies of cerebrospinal fluid from patients with CNS symptoms after human papillomavirus vaccination. J Neuroimmunol. 2016 Sep 15;71-8
7
Martínez-Lavín M, Amezcua-Guerra L. Serious adverse events after HPV vaccination: a critical review of randomized trials and post-marketing case series. Clin Rheumatol.
2017 Oct;36(10):2169-2178
8
"The adverse reaction reports detail 26 new deaths reported between September 1, 2010 and September 15, 2011 as well as incidents of seizures, paralysis, blindness, pancreatitis,
speech problems, short term memory loss and Guillain-Barré Syndrome. The documents come from the FDA’s Vaccine Adverse Event Reporting System (VAERS) which is used
by the FDA to monitor the safety of vaccines." Lind P. U.S. court pays $6 million to Gardasil victims. The Washington Times December 31, 2014
https://www.washingtontimes.com/news/2014/dec/31/us-court-pays-6-million-gardasil-victims/
© Vasquez A. Antiviral Nutrition Update #1 for 2018. Video presentation (ichnfm.org/hpv1) and official transcript (academia.edu/35808436) 2018 January.
