Category Archives: osteoporosis

4 August 2015 VITAMIN D: FOR INDOOR TYPES, HOW MUCH eg 50 000iu/d IS ENOUGH, AND SAFE? & 2million iu loading dose is not toxic for adults. Especially for infants, acute illness- ICU, INFECTIONS:

 VITAMIN D REVIEW: WHAT DOSE IS ENOUGH ?   INSUFFICIENCY vs DEFICIENCY, VIT D RESISTANCE?    COMBINATION OF ANABOLICS?     ACUTE LOADING DOSE eg FOR INFECTION, ICU, BURNS, BRONCHIOLITIS?     SAFE vs OVERDOSE-TOXICITY DOSE & LEVELS?  VIT D ALLERGY?

neil.burman@gmail.com

see previous vit D updates:  at  23 Mar 2015 womens’ day: the crucial role of vitamin D as HRT in reducing all major diseases . Salute Dr Walter Stumpf

and    https://healthspanlife.wordpress.com/2009/10/29/is-there-a-vitamin-d3-conspiracy-of-suppression/

and 17 JUNE 2015 VITAMIN D DEFICIENCY VIRUS EPIDEMICS.

PREFACE WARNING: nb black italics are abbreviated quotes; for the link click on blue italics  eg McKenna ea.            NB conclusions depend, are based on, apparently reliable formal  randomized controlled RCTs trials  and team experiences, (but RCTs, metaanalysis, reviews and case reports   are also notoriously  vulnerable to vested interests of authors and sponsors, statistical errors, omission of inconvenient results, even subtle blatant fraud and fabrication;  to small numbers, heuristics and bias   – confusing causality, type 2 statistical errors ie sheer random chance; per  eg per Nobel prizewinner – the American  Daniel Kahneman : Thinking, Fast and Slow: New York 2011; the Briton   Oliver  Gillie 2014; Vit D, Sunlight, mortality, causality  and The Scots   Paradox, the Swiss Paradox;  the Flu, MERS, AIDs-TB-ebola epidemics: Can Sun Exposure, or  Lack of it, Explain Major Paradoxes in Epidemiology; https://www.linkedin.com/in/olivergillie;biography); the Semmelweis Paradox;  the current epidemics in Central and South Africa, Saudi Arabia, South Korea, cities & refugee camp  ghettos, 1918-19 et seq;  the German Gerd Gigenzer  http://www.gocognitive.net/interviews/gerd-gigerenzer-decision-making.

4 August 2015 update: why do new trials/ reviews keep referring to mediocre dose vitamin D3 as high dose?    Karen Hansen’s  Univ Wisconsin  trial compared placebo, with baseline  vit D3  24000iu /month and as high dose 5 fold more ie  124000iu/month- finding no significant benefits. BUT  124000iu/month is still only about 4000iu/day, which on average increases 25OH Vit D3 only by about 40ng/ml. This is hardly high dose when vigorous levels are at least double this ie close to 100ng/ml; and vigorous safe dose long term is around 50 000iu/day ; with up to 150 000iu/day, up to above 250ng/ml blood level,  having been taken for decades, or single dose of 2million units,  without toxicity... Of course safety depends on adequate water, magnesium and vit K2 intake, and not adding  calcium supplements since average city diet is low in magnesium, iodine  and vit K2, not calcium or toxic fluoride or bromine. 

                      2015 Aug 3  JAMA Intern Med. . Treatment of Vitamin D Insufficiency in Postmenopausal Women: A Randomized Clinical Trial. Hansen, Marvdashti ea http://www.ncbi.nlm.nih.gov/pubmed/26237520 . Experts debate optimal 25-hydroxyvitamin D (25[OH]D) levels for musculoskeletal health. Objective  randomized, double-blind, placebo-controlled clinical trial was conducted at a single center in Univ Wisconsin   from  2010, completed 2014. A total of 230 postmenopausal women 75 years or younger with baseline 25(OH)D levels of 14 through 27 ng/mL and no osteoporosis were studied.  Interventions: Three arms included daily white and twice monthly yellow placebo (n=76), daily 800 IU vitamin D3 and twice monthly yellow placebo (n=75), and daily white placebo and twice monthly 50,000 IU vitamin D3 (n=79). The high-dose vitamin D regimen achieved and maintained 25(OH)D levels ≥30 ng/mL. Main  Results:  After baseline absorption was controlled for, calcium absorption increased 1% (10 mg/d) in the high-dose arm but decreased 2% in the low-dose arm (P = .005 vs high-dose arm) and 1.3% in the placebo arm (P = .03 vs high-dose arm). We found no between-arm changes in bone mineral density, trabecular bone score, muscle mass, and Timed Up and Go or five sit-to-stand test scores.  High-dose cholecalciferol therapy increased calcium absorption, but the effect was small and did not translate into beneficial effects on bone mineral density, muscle function, muscle mass, or falls. We found no data to support experts’ recommendations to maintain serum 25(OH)D levels of 30 ng/mL or higher in postmenopausal women. Instead, we found that low- and high-dose cholecalciferol were equivalent to placebo in their effects on bone and muscle outcomes in this cohort of postmenopausal women with 25(OH)D levels less than 30 ng/mL.
26 JULY 2015 UPDATE:
1,   Calcium supplements are no longer recommended for adults:  they promote vascular calcification and worse.

J Intern Med. 2015 Jul 14. Calcium supplements: benefits and risks. Reid , Bristow , Bolland .University of Auckland, New Zealand. Calcium is an essential element in the diet, but Calcium Study demonstrates no relationship between dietary calcium intake and rate of bone loss over 5 years in healthy older women with intakes varying from <400 to >1500 mg day. Thus, supplements are not needed within this range of intakes to compensate for a demonstrable dietary deficiency, but might be acting as weak anti-resorptive agents via effects on parathyroid hormone and calcitonin.  As a result, anti-fracture efficacy remains unproven, with no evidence to support hip fracture prevention (other than in a cohort with severe vitamin D deficiency) and total fracture numbers are reduced by 0-10%, depending on which meta-analysis is considered. Five recent large studies have failed to demonstrate fracture prevention in their primary analyses. This must be balanced against an increase in gastrointestinal side effects (including a doubling of hospital admissions for these problems), a 17% increase in renal calculi and a 20-40% increase in risk of myocardial infarction. Each of these adverse events alone neutralizes any possible benefit in fracture prevention. Thus, calcium supplements appear to have a negative risk-benefit effect, and so should not be used routinely in the prevention or treatment of osteoporosis.
        Rather it is vits D3, C,  K2 ;  and magnesia supps that are recommended for multisystem benefits-  magnesia especially for prevention of common renal stones- since the classic paper from Harvard  Am J Clin Nutr. 1967;20:393-9. Effect of daily 200mg MgO   and 10mg vitamin B6   administration to patients with recurring calcium oxalate kidney stones. Gershoff & Prien.
2. for preventing eg calcium stones and mortality etc, vit D3 in high enough dose to switch off hyperparathyroidism. eg Clin Nutr. 2015 Mar 24.    Vitamin D3 supplementation and body composition in persons with obesity and type 2 diabetes in the UAE Sadiya , Abusnana ea The study was executed in 3 phases in two arms vitamin D arm (n = 45) and placebo arm (n = 42); in Phase 1 the vitamin D arm received 6000 IU vitamin D3/day (3 months) followed by Phase 2 with 3000 IU vitamin D3/day. During follow up (phase 3) both the arms were un-blinded and supplemented with 2200 IU vitamin D3/day for another 6 months . On supplementation no significant changes in anthropometric dimensions was observed. S-25(OH) D peaked in phase 1 (77.2 ± 30.1 vs 28.5 ± 9.2, p = 0.003) followed by a decrease in phase 2 (62.3 ± 20.8, p = 0.006) paralleled by a decrease in parathyroid hormone in phase 2 (5.9 ± 2.4 vs 4.5 ± 1.8, p < 0.01) compared to baseline in vitamin D group. Supplementation was safe, improved s- 25 (OH)D also reducing the incidence of eucalcemic parathyroid hormone elevation.
      Crit Care Med. 2015 Jul 16.   A Randomized Study of a Single Dose of Intramuscular Cholecalciferol in Critically Ill Adults.  Nair, Center ea   Univ Sydney & Brisbane, Australia.  LMU, Munich, Germany.    To determine the effect of two doses of intramuscular cholecalciferol on serial serum 25-hydroxy-vitamin-D levels and on pharmacodynamics endpoints.Prospective randomized interventional study.
Fifty critically ill adults with the systemic inflammatory response syndrome.Patients were randomly allocated to receive a single intramuscular dose of either 150,000 IU (0.15 mU) or 300,000 IU (0.3 mU). Secondary hyperparathyroidism was manifested in 28% of patients at baseline. Parathyroid hormone levels decreased over the study period with patients achieving vitamin D sufficiency at day 7 having significantly lower parathyroid hormone levels (p < 0.01).  Although in-hospital mortality rate did not differ between the groups, patients who did not mount a parathyroid hormone response to vitamin D deficiency had a higher mortality (35% vs 12%; p = 0.05). No significant adverse effects were observed.
     3  universal vitamin D3 deficiency:   our local population, as in virtually all populations worldwide who no longer work and live bare in the sun and eat plenty of raw fish(eg unfiltered cod liver) (oil) have average blood 25 OH vit D levels at or below 20ng/ml, whereas it is  incontestable that all diseases decline steadily as this marker vit D3 level is elevated by sunshine to the probable maximum natural achievable level around 40ng/ml- and with vigorous supplements eg 50 000iu/wk  up to around 80ng/ml, but in sickness to around >100ng/ml.
 4.    But the vit D overdose literature shows that while the highest adult vit D3 doses that have been prescribed are about 640 000iu as monthly dose (Salhuddin N ea , Karachi Pakistan 2013- with 40% improvement in TB recovery after only 2 months compared to TB pts given antiTB Rx alone), and 40 000iu/day in South America for months  for serious pemphigus and albinism. The Pakistan Endocrine Society is a pioneer professional group in endorsing vigorous vit D3 dosing.
But the threshold for toxicity- hypervitaminosis D– seems to be above 2million units single dose in nonagenarians (Netherlands 2 pts) or 88 000iu/day longterm (Canada); and blood 25OHvit D above 250 – 500ng/ml. one 70yr old women was reported to present with Hypervit D only after 10 years  taking 100 000ium/d ie over ~300million iu.. Another women was reportedly  unharmed after 5  times that ie @ 150 000iu/day ,  1.5 billion vit D2 iu over 28yrs –Stephenson & Peiris 2009.
small Subcontinent people–  Pakistanis, Indians etc may be more prone to overdose with vit D, often from massive doses given by injection weekly ie no chance of reducing absorption plateauing as oral overdose increases, as normally happens.
 
VIT D2 VS D3:  note that as one of the most backward Govts in the world, RSA   STATE  authorities- at least in W Cape eg state hospitals and  day hospitals- still distribute and promote vit D2 for osteoporosis, altho these tabs falsely labelled Strong Calciferol are in fact fraudulently labelled,  only their manufacturer website Lennons-Aspen reveals that they are in fact ergocalciferol vit D2, which experts have long condemned as only about 1/4 the strength of vit D3, and which D2 in two studies actually worsens not improves rheumatoid arthritis. This in contrast to the all-disease beneficial  anabolic steroid vit D3 which wholesales in bulk at around R200/kg.a different independent website eg http://www.ndrugs.com/?s=lennon-strong%20calciferol does reveal that Strong calciferol is in fact D2, but not that it is a xenohormone manufactured only by yeasts, not animals; and that it elevates 25OH vit D2– not D3- in our blood, thus blocking both our D3 receptors and formation.   Wiki does detail that it is made only by lichen, mushrooms and alphalpha- but not by any animals.
Already in 2006 Houghton and Veith (Univ Toronto Canada) published The Case Against vitamin D2.. Vitamin D2, or ergocalciferol, should not be regarded as a nutrient suitable for supplementation or fortification… no successful clinical trials to date have shown that vitamin D2 prevents fractures..The poorer stability of and greater impurities in vitamin D2 powders may also lead to a higher risk of toxicity than that associated with the vitamin D3 metabolites. However, it is more likely that the weaker affinity of vitamin D2 metabolites to DBP produces higher and more biologically available proportions of free 25(OH)D2 and 1,25-(OH)2D2 and may thus be responsible for the greater risk of D2 toxicity .  Taken together, the most plausible explanations for the greater bioefficacy of vitamin D3 are conceivably due to the higher affinities of vitamin D3 and its metabolites than vitamin D2 for hepatic 25-hydroxylase, DBP, and VDR and because vitamin D3 is not directly metabolized to 24(OH)D as is vitamin D2.”D2may be safe in mega-overdose, but this  2009 abstract from a Tennessee Veterans’ Admin unit  begs the question of whether the D2 tablets were indeed genuine vitamin D, of any benefit to the patient? who apparently consumed over a billion iu of vit D2 in  half a lifetime – at least 20 times the aggressive dose of 50 000iu/week. :

South Med J. 2009 Jul;102:765-8..  The lack of vitamin D toxicity with megadose of daily ergocalciferol (D2) therapy: a case report and literature review.   Stephenson & Peiris .The maximum daily dose of vitamin D currently recommended is 2000 IU. Ergocalciferol (D2) 50,000 IU orally weekly for 8-12 weeks is often used to treat vitamin D deficient patients (25(OH) vitamin D <20 ng/mL). The lack of vitamin D toxicity after massive doses of ergocalciferol has yet to be reported in the literature. We report a case of a 56-year-old woman who received supratherapeutic doses of ergocalciferol (150,000 IU orally daily) for 28 years without toxicity. We discuss the possible mechanisms which may account for a lack of toxicity despite intake of massive daily doses of ergocalciferol in this patient.
                    1 July 2015 update:  The  2008  report from Kimball & Veith, Toronto concludes:  The lowest observed adverse effect level for vitamin D, said to cause hypercalcaemia in normal adults, is officially 95 mg/day ie 4 000iu/d. But collective  reports  indicate that serum 25(OH)D concentrations need   to exceed 700 nmol/L ie 280 ng/ml chronically   before vitamin D3 toxicity becomes  evident ie from at least ~40 000iu D3 /day or perhaps a million iu monthly. .

update 30 June 2015: The Univ Toronto team  in the previous decade published more evidence of safety and benefit  of vit D3 up to 40 000iu a day 280 000iu/week; but   not 88 000iu/day: the warning is that calcium supplement should be avoided in such high vit D3 dosage. They were not yet advising supplement vit K2 and magnesium.                       Neurology . A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis.   Burton JM1, Kimball S, Vieth R   ea  St  Michael’s Hospital, Toronto, Canada.     Low vitamin D status has been associated with multiple sclerosis (MS) prevalence and risk; .  to assess the tolerability of highdose oral vitamin D prospectively, an open-label randomized prospective controlled 52-week trial matched patients with MS to treatment or control groups. Treatment patients received escalating vitamin D doses up to 40,000 IU/day (280 000iu/wk) over 28 weeks to raise serum 25-hydroxyvitamin D [25(OH)D] rapidly and assess tolerability, followed by 10,000 IU/day (12 weeks).. Calcium (1,200 mg/day) was given throughout the trial. Endpoints were mean change in  biochemical measures,  biomarkers, relapse events, and Expanded Disability Status Scale (EDSS) score.    RESULTS:   Forty-nine patients (25 treatment, 24 control) were enrolled [mean age 40.5 years, EDSS 1.34, and 25(OH)D 78 nmol/L]. All calcium-related measures within and between groups were normal. Despite a mean peak 25(OH)D of 413 nmol/L 164ng/ml, no significant adverse events occurred. Although there may have been confounding variables in clinical outcomes, treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell proliferation compared to controls.   Highdose vitamin D (approximately 10,000 IU/day) in multiple sclerosis is safe, with evidence of immunomodulatory effects.    This trial provides Class II evidence that highdose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on highdose supplementation. The trial, however, lacked statistical precision. , providing only Class level IV evidence for these outcomes.

          Ann Clin Biochem. 2008;.   Self-prescribed highdose vitamin D3: effects on biochemical parameters in two men.     Kimball S1, Vieth R.   , University of Toronto, Toronto, Canada. ..  The lowest observed adverse effect level for vitamin D, said to cause hypercalcaemia in normal adults, is officially 95 microg/day 4000iu/d. Serum 25-hydroxyvitamin D (25[OH]D) concentrations associated with hypervitaminosis D remain undefined. Reported 25(OH)D concentrations resulting from prolonged excessive vitamin D3 intakes have exceeded 700 nmol/L 280ng/ml. We report self-prescribed high dose of vitamin D3 over 5-6 years by two men.               Subject 1 had been taking 100 microg/4000iu day for 3 years followed by 3 years of 200 microg/8000iu/day. Serum 25(OH)D concentrations averaged 130 nmol/L 52ng/ml while taking 100 microg/4000iu day of vitamin D3. While taking 200 microg/8000iu/day of vitamin D3, mean serum 25(OH)D concentrations were 260 nmol/L 102ng/ml with no hypercalcaemia or hypercalcuria over the 6 years of vitamin D3 intake.                                                  Subject 2 was a 39-year-old man diagnosed with multiple sclerosis.  his own dose-escalation schedule  increased from 200ugm 8000iu  to 2200 microg/ 88000iu/day over 4 years. The  evidence of a potential adverse effect was that urinary calcium:creatinine ratios showed an increasing trend, which preceded serum calcium concentrations above the reference range (2.2-2.6 mmol/L). His serum 25(OH)D concentration was 1126 nmol/L 450ng/ml  when total serum calcium reached 2.63 mmol/L. He stopped vitamin D3 supplementation at this point. Two months later, all biochemistry values were within reference ranges; serum 25(OH)D concentrations fell by about one-half, to 656 nmol/L 260ng/ml . These results help to clarify the human response to higher intakes of vitamin D3. Close monitoring of biochemical responses confirmed that an increase in urinary calcium:creatinine ratio precedes hypercalcaemia as serum 25(OH)D concentrations rise.

update 28 June : a landmark trial in Brazil 2 years ago finally shows what a really high dose of Vit D3 – 35000iu/d  can do safely over 6 months, a cumulative safe dose of 6million iu A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis:  Dermatoendocrinol. 2013  Finamor,  Coimbra ea    University São Paulo, Brazil     Autoimmunity has been associated with vitamin D deficiency and resistance, and vitamin D metabolism gene polymorphisms   frequently described. May high dose vitamin D3  compensate for inherited resistance to its biological effects?.  To assess the efficacy and safety of prolonged high-dose vitamin D3 treatment of patients with psoriasis and vitiligo, 25 patients with psoriasis or  vitiligo received vitamin D3 35,000 IU once daily for six months ie >1million iu/mo,  >6 million iu over 6mo  in association with a low-calcium diet (avoiding dairy products and calcium-enriched foods like oat, rice or soya “milk”) and hydration (minimum 2.5 L daily). Psoriasis patients were scored according to “Psoriasis Area and Severity Index” (PASI) . All patients presented low vitamin D status (serum 25(OH)D3 ≤ 30 ng/mL) at baseline. After treatment 25(OH)D3 levels significantly increased (from~16 to ~120ng/mL)  ie increase of +- 100ng/ml by 35000iu dly – a flattened highdose response curve, only 10ng/ml rise per 3500iu/d;    and PTH levels significantly decreased (from ~57 to 27 pg/mL. PTH and 25(OH)D3 serum concentrations correlated inversely. The PASI score significantly improved in all nine patients with psoriasis. 14 of 16 patients with vitiligo had 25–75% repigmentation. Serum urea, creatinine and calcium (total and ionized) did not change and urinary calcium excretion increased within the normal range. High-dose vitamin D3 therapy may be effective and safe for vitiligo and psoriasis patients. WHAT WAS THEIR BMI? my 25OHvit D level runs at ~90ng/ml on ~9000iu vit D3 a day; and my  patient’s level runs at ~150ng/ml on ~15000iu/d… so perhaps the Brazilians with these skin disorders (unlike us) have  resistance genes that block higher levels of 25OHvit D. So without doing costly genotyping, we in practice need to check vit D level response early where very high dose is indicated in severe disease. .

Mediocre chronic dose vit D3 supp  eg 2000iu/d , 25OHvitD well > 30ng/ml-   is not enough– it needs high loading eg >400 000- 600 000iu  for acute illness, and good maintenance dose eg >5o 000- 75 000iu/wk  for blood level >60ng/ml, for chronic prevention, to maintain good vit D level and thus real protection:    BMJ Open Respir Res. 2015 Jun   Association between prehospital vitamin D status and incident acute respiratory failure in critically ill patients:  retrospective cohort study.  Thickett , Christopher ea:      Boston, Massachusetts , USA     Intensive care units of Boston teaching hospitals.  1985 critically ill adults admitted between 1998 and 2011    Exposure of interest was prehospital serum 25(OH)D categorised as ≤10 ng/mL, 11-19.9 ng/mL, 20-29.9 ng/mL and ≥30 ng/mL.  In the cohort, the mean age was 63 years,     25(OH)D was ≤10 ng/mL in 8% of patients, 11-19.9 ng/mL in 24%, 20-29.9 ng/mL in 24% and ≥30 ng/mL in 44% of patients. Eighteen per cent (n=351) were diagnosed with acute respiratory failure.  Prehospital 25(OH)D  30ng/ml  in our critically ill patient cohort.  

Thorax. 2015 Jun 10.Double-blind randomised controlled trial of vitamin D3 suppl for the prevention of acute respiratory infection ARI  in older adults and their carers (ViDiFlu).    Martineau , Griffiths ea.Univ London.  clinical trial of high-dose versus low-dose vitamin D3 supplementation for ARI prevention in residents of sheltered-accommodation housing schemes and their carers in London, UK.    137 individuals were allocated to the active intervention (vitamin D3 2.4 mg = 100 000iu once every 2months +10 μg =400iu daily for residents= 62 000iu/mo; carers 3 mg once every 2 months =60 000iu/mo);  and 103 participants to placebo once every 2 months +vitamin D3 10 μg daily = 12000iu/mo for residents, placebo once every 2 months for carers) for 1 year. RESULTS:Inadequate vitamin D status was common at baseline:  92% of 240  participants had serum 25(OH)D concentration < 30ng/ml. The active intervention did not influence time to first ARI (adjusted HR (aHR) 1.18, 95% CI 0.80 to 1.74, p=0.42). When URI and LRI were analysed separately, allocation to the active intervention was associated with 50% higher  risk of URI (aHR 1.48, 95% CI 1.02 to 2.16, p=0.039) and increased duration of URI symptoms (median 7.0 vs 5.0 days for active vs control, adjusted ratio of geometric means 1.34, 95% CI 1.09 to 1.65, p=0.005), but not with altered risk or duration of LRI.   CONCLUSIONS: Addition of intermittent bolus-dose vitamin D3 supplementation to a daily low-dose regimen to average  ~2000iu/d did not influence risk of ARI in older adults and their carers, but was associated with increased risk and duration of URI  over 400iu dly ie 12000iu spread over the month.

Thorax. 2015 May.   Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs).  Martineau ,Griffiths ea    London  University UK. Asthma exacerbations are commonly precipitated by viral upper respiratory infections (URIs). Vitamin D insufficiency associates with susceptibility to URI in patients with asthma.  randomised controlled trial of vitamin D3 supplementation for  prevention of asthma exacerbation and URI. 250 adults with asthma in London, UK were allocated to receive six 2-monthly oral doses of 120 000iu 3 mg vitamin D3 (n=125) or placebo (n=125) over 1 year.   206/250 participants (82%) were vitamin D insufficient at baseline. Vitamin D3 did not influence time to first severe exacerbation (adjusted HR 1.02, 95% CI 0.69 to 1.53, p=0.91) or first URI (adjusted HR 0.87, 95% CI 0.64 to 1.16, p=0.34). No clinically important effect of vitamin D3 was seen on any of the secondary outcomes listed above. The influence of vitamin D3 on coprimary outcomes was not modified by baseline vitamin D status or genotype. Bolus-dose vitamin D3 supplementation – 60 000iu/mo = average 2000iu/d – did not influence time to exacerbation or URI in a population of adults with asthma with a high prevalence of baseline vitamin D insufficiency.

update 27 June 2015  another review Safety of vitamin D3 in adults in multiple sclerosis  Kimball ,Vieth ea  2007 University  Toronto, Canada confirms that  up to at least 40 000iu daily for 28 weeks  is safe. Patients’ serum 25(OH)D concentrations reached twice the top of the physiologic range without eliciting hypercalcemia or hypercalciuria. The data provide objective evidence that vitamin D intake beyond the current upper limit is safe by a large margin.

      update  20 June 2015 : the  10th  HIGHDOSE VIT D STUDY  (100 000 to  600 000iu stat, or up to 55 000iu/day):       Quraishi,  Bhan ea 2009 Harvard Univ Boston: Effect of  Highdose VIT D Supplement on Vitamin D Status and Cathelicidin Levels in Sepsis: Crit Care Med. 2015 Jun 17: RCT  to compare changes in vitamin D status and cathelicidin (LL-37) levels in 30  adult ICU patients given  Placebo (n = 10) vs 200,000 IU cholecalciferol (n = 10) vs 400,000 IU cholecalciferol (n = 10), within 24 hours of new-onset severe sepsis or septic shock in a single Boston, MA teaching hospital.  Blood samples  at baseline (day 1) and on days 3, 5, and 7. At baseline, median (interquartile range) plasma 25-OHvitD  was 17 ng/ml,  peaked by day 5 in  intervention groups.  On day 5, median change in biomarkers for placebo, 200,000 IU vit D3 cholecalciferol , and 400,000 IU vit  D3 groups, respectively, were as follows: 1) total 25OHvitD, 3% (-3% to 8%), 49% (30-82%), and 69% (55-106%) (p < 0.001); 2) bioavailable 25OHvitD, 4% (-8% to 7%), 45% (40-70%), and 96% (58-136%) (p < 0.01); and 3) LL-37 : -17% (-9% to -23%), 4% (-10% to 14%), and 30% (23-48%) (p = 0.04). Change in high-sensitivity CRP levels did not differ between groups. A positive correlation was observed between bioavailable 25OHvit D and LL-37 (Spearman ρ = 0.44; p = 0.03) but not for total 25OHvitD and LL-37. CONCLUSIONS:High-dose vitD3 supplement rapidly and safely improves total  and bioavailable 25OHvitD  levels in patients with severe sepsis or septic shock. Changes in bioavailable 25OHvitD are associated with concomitant increases in circulating LL-37 levels.

Clin Nutr. 2015 Apr 14.    Increases in pre-hospitalization serum 25(OH)D concentrations are associated with improved 30-day mortality after hospital admission: A cohort study in Boston, Mass.. Amrein , Christopher ea   in two Boston univ. hospitals .Pre-hospital vitamin D status may be a modifiable risk factor for all-cause mortality among hospitalized patients.  4344 adults hospitalized between 1993 and 2011..  INTERVENTION(S):  None.  The main outcome was 30-day all-cause mortality.  In an adjusted logistic regression model, absolute changes of ≥10 ng/mL in patients with initial 25(OH)D  < 20 ng/mL (n = 1944) decreased the odds of 30-day all-cause mortality by 48% (adjusted OR 0.52, P = 0.026).  A causal relation may not be inferred from this observational study.
      Conversely, another new study this month confirms the hazard of gross overdose of anything:   Kaur, Mithal ea .India Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency  Clin Endocrinol (Oxf). 2015 Jun “Vitamin D toxicity, wrongly  considered rare, can be life-threatening,  with substantial morbidity, if not identified promptly. In 16 patients with vitamin D toxicity seen between January 2011 and January 2013  Clinical manifestations included nausea, vomiting, altered sensorium, constipation, pancreatitis, acute kidney injury and weight loss. Median (range) age was 64.5 (42-86) years. Median  serum 25(OH)D level  371 (175-1161) ng/ml, serum total serum calcium level  13.0 (11.1-15.7) mg/dl . Irrational Overdose of vitamin D caused by prescription of mega doses of vitamin D was the cause of vitamin D toxicity in all cases. Median (range) cumulative vitamin D dose was 3,600,000 (2,220,000-6,360,000)”– but the abstract doesnt mention the timespan . Generally, after loading dose for urgent risk,  maintenance dose  need  not exceed about 80 iu/kg/d eg 7000iu/day ie ~50 000iu/wk or 2500 000 iu/yr, ideally with ideally occasional blood vit D, calcium & creatinine tests. .

           UPDATE FOR KIDS: Pediatr Rheumatol Online J. 2015 May .  Vitamin D-update for the pediatric rheumatologists.    Vojinovic J1, Cimaz R2. University of Nis, Serbia.   ” So in accordance with new vitamin D recommendations, we recommend that a child with rheumatic disease, especially if treated with steroids, needs at least 2-3 time higher doses of vitamin D than the dose recommended for age (approximately 2000 UI/day). Vitamin D supplementation has become an appealing and important adjunct treatment option in PRD

      17 June update : Proc Natl Acad Sci U S A. 2015 Jun 15. pii: 201500909.           High-dose vitamin D3 reduces deficiency caused by low UVB exposure and limits HIV-1 replication in urban Southern Africans.  .Cape Town, South Africa, has a seasonal pattern of UVB radiation and a predominantly dark-skinned urban population who suffer high HIV-1 prevalence. This coexistent environmental and phenotypic scenario puts residents at risk for vitamin D deficiency, which may potentiate HIV-1 disease progression. Coussens ,  Jablonski   ea  from Univ. Cape Town & Stellenbosch conducted a longitudinal study in two  Cape Town ethnically distinct groups of healthy young adults, supplemented with 50 000iu weekly  vitamin D3  for 6 weeks  in winter, to determine whether vitamin D status modifies the response to HIV-1 infection and to identify the major determinants of vitamin D status (UVB exposure, diet, pigmentation, and genetics). Vitamin D deficiency was observed in the majority of subjects in winter and in a proportion of individuals in summer, was highly correlated with UVB exposure, and was associated with greater HIV-1 replication in peripheral blood cells. High-dosage oral vitamin D3 supplementation attenuated HIV-1 replication, increased circulating leukocytes, and reversed winter-associated anemia. Vitamin D3 therefore presents as a low-cost supplementation to improve HIV-associated immunity.
    16 June 2015  REVIEW: ADULTS: WHAT VIT D DOSE IS ENOUGH? Because of our increasingly government-encouraged soporific  TV lifestyle and western processed- food-factory low-fat high-carbs HCLF diet, vitamin D has turned out to be as important as >vitamin C as the seriously deficient primary major nutrients in far higher than scurvy/rickets prevention doses.
Just as we ‘only’ need vitamin C 10mg/d to prevent scurvy, the historical DAILY recommended allowance RDA dose of vitamin D for rickets is ‘only’ ~10mcg 400iu/d.
But current expert opinions advocate  effective multisystem chronic prevention against infections, cancer, neurological, cardiovascular and bone disease in adults  vit C between 1gm  and 30gm/day; and

       vit D between 100mcg 4000iu and 250mcg 10 000iu/d (ie 80-100iu/kg/d); or about 25000 to 70 000iu/week or equivalent spacing;
to a blood 25hydroxyvit D 25OHvitD level of ~60 (40 to 80ng)/ml for global prevention; but around ~100ng/ml depending on severity of illness being targeted.

     DONT REJECT A SUPPLEMENT AS OF NO VALUE JUST BECAUSE IT TESTED INEFFECTIVE  IN  LOW DOSE:   eg Martineau , Griffiths ea.Univ London Thorax. 2015 Jun   Double-blind randomised controlled trial of vitamin D3 supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu). CONCLUSION: Addition of intermittent bolus-dose vitamin D3 supplementation to a daily low-dose regimen did not influence risk of ARI in older adults and their carers, but was associated with increased risk and duration of URI.   BUT like so many trials,this trial in  240 London Seniors and carers is not about high dose, but mediocre dose, in small numbers: it  confirms that 100 000iu vit D3 every 2 mo ie average ~extra  1666iu/d is no better protection than just 400iu dly ie 12000iu spread over the month.

Since like all steroids the many vitamin Ds are vitamin C-cholesterol-derived oils stored and carried in fat, the fatter the patient the higher the maintenance dose vit D3 (eg 100 iu/kg/d) to maintain a good steady optimal bloodlevel.                                Fortunately, unlike the other essential physiological human anabolic steroids (eg androgens, progesterone and estrogens that are poorly absorbed , and trans-hepatically dangerous if swallowed), vitamin D3 is well absorbed either by mouth, by injection; or transdermally / intranasally; and apparently not degraded to risky byproducts in the liver as are the “sex” steroids. .

And of course for best absorption, fat-soluble essentials like vits A, D, E , K; CoQ10 & alphalipoic acid ALA are best eaten with fat not carbs eg veggies, cereals or on empty.
To minimize risk of stones and vascular calcification from imbalance, it is important to take vit D3 with                                                                                      *liberal water, magnesia and vitamin K2; perhaps                                                 *~30gms fresh marine oil /wk eg a tsp of cod liver oil 3 x a week; and                       * a few tsp/d of virgin coconut oil (and for cooking/frying in);
*at least half of daily non-protein energy as FATS- animal, dairy and avocado &
*while minimizing moderate omega6 as nuts and raw olive/ oil; and avoiding/minimizing diabesogenic insulin-resistance-causing refined carbs, and synthetic junk fats like margarine, and other seed oils- eg sunflower and canola – certainly not for frying.

A new university study from Ireland ( Endocr Connect. 2015 June. McKenna ea) confirms that average vitamin D levels there are still well below sufficiency let alone good levels, although it finds Rising trend in vitamin D status from 1993 to 2013: “The Institute of Medicine 2011 Dietary Report specified higher Vitamin D intakes for all age groups compared to 1997, but also cautioned against spurious claims about epidemic vitamin D deficiency and against advocates of higher intake requirements. 40 years have seen marked improvement in vitamin D status, but we are concerned about hypervitaminosis D. Time series sequence chart demonstrated a steady upward trend with seasonality. The average 25OHD increased by ~50% from ~15ng/ml in 1993 to ~23ng/ml in 2013. CONCLUSIONS: Vitamin D status improved over the past 40 years, but there is a dual problem:                             *groups at-risk of vitamin D deficiency, who need public health preventative measures; and                                                                                                     *random members of the public  taking unnecessarily high vitamin D intakes for unsubstantiated claims. “

       Last year Autier, Mullie ea from Lyon France and Bolland, Reid ea from Auckland NZ published major reviews concluding that “In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.  And “vitamin D supplementation with or without calcium does not reduce skeletal or non-skeletal outcomes in unselected community-dwelling individuals by more than 15%. Future trials with similar designs are unlikely to alter these conclusions
But Gillie from Health Research Forum, London 2014 in Controlled trials of vitamin D, causality and type 2 statistical error  rebuts Autier ea, Bolland ea:    “In Lancet Diabetes Endocrinol, Autier, Mullie ea. (2013) , and Bolland, Reid ea. (2014) , concluded that low levels of vitamin D are not a cause but a consequence of ill health brought about by reduced exposure to the sun, an association known as ‘reverse causality’ Denial of the possible benefits of vitamin D, as suggested by insistent interpretation of studies with reverse causation, may lead to serious harms, some of which are listed.” So Gillie affirms the focus of this June 2015 review on vigorous dose vit D without chronic toxic overdose, that Autier ea and Bolland ea overlook, that their conclusions were based on lowdose vitamin D, not vigorous dose eg loading dose 600 000iu  monthly with or without ~50 000iu weekly that has been increasingly validated.

         COMBINED BALANCE ALWAYS BEST:
While  human sex hormones in good youthful balance are all essential physiological anabolic ie growth-promoting steroids, Atif ea at Emory University, Atlanta, 2009  and 2015   showed that in rats, Vitamin D with progesterone P4 supplement affords significantly better brain protection against excitotoxicity in cultured cortical neurons  and in traumatic brain injury in vivo than progesterone or vit D alone. In their 2009 braincell culture experiment, the optimal ratio of the hormones given was Prog:Vit D 1000:1 (Prog 20 umol/L: vitD 20nmol/L); whereas in their 2015 in life study the ratio was 8000:1– the rats were injected intraperitoneally  Prog 16mg/kg and VitD 1ug  one and 6 hours after the brain injury, and at 24 hours after brain injury they were killed and the brain damage compared. The optimal ratio, balance of the two steroid  hormones  for rat brain protection (1000:1 in a bench cellculture  and 8000:1 in an acute living rat model) is noteworthy for human dosing although the absolute doses cannot be extrapolated to living humans.   In humans this review below shows that the optimal acute dosing thus far reported seems to be  about 1000mg progesterone injection ie ~13mg/kg (some disputed trial evidence for protecting human brain injury after 50 years of research), and vit D for acute global protection about  600 000iu = 10 000iu/kg= 250 ug /kg ie P:vitD ratio about 50:1.

But vit D3, & androgens, and progesterone (eg Roeder 1986 & Starkov 1997), are the classic muscle-bone anabolic (ie growth- protein-water-salt-retaining) steroids. So we should always combine them in appropriate dose if needed for men, and even women. Estrogen is essential for reproduction, bone strength and femininity, but is muscle-anabolic only for the female reproductive tract; and for fat and glandular tissue ie breasts: estrogenic  dominance doubles cancer; adiposity;  sarcopenia;  and urinary incontinence ie weakens the pelvic floor; so should never be given unopposed by progesterone/androgen and vigorous vit D3 .

          ACUTE LOADING DOSE OF VIT D?: Like antibiotics, for acute (antimicrobial or ICU metabolic eg vascular, brain, cancer ) disease, adult vitamin D3 LOADING dose 540 000 to 600 000iu monthly – but not much lower loading dosing – has been recommended and proven major benefit, eg

1. New Zealand 2009 Osteoporos Int. ;20:1407-15.. Bacon ea :              High-dose 500 000iu oral vitamin D3 supplementation in the elderly were concerned that: vitamin D doses are frequently inadequate; compliance with daily medication is likely to be suboptimal; large loading doses of vitamin D(3) rapidly and safely normalize 25OHD levels; and monthly dosing is similarly effective only after 3-5 months. With baseline 25OHD > 20ng/ml, vitamin D supplement does not reduce parathyroid hormone PTH levels. This randomized double-blind trial RCT compares “high-dose” vitamin D3 regimens and estimates optimal 25OHD levels, from changes in PTH & procollagen type I propeptide (P1NP) in relation to baseline vit D . Sixtythree elderly participants were randomized to three regimens of vitamin D supplementation: a 500,000-IU loading dose; the loading dose plus 50,000 IU/month; or 50,000 IU/month. the Loading and Loading + Monthly groups showed increases in 25OHD of 23+/- 11ng/ml from baseline to 1 month. Thereafter, levels gradually declined to plateaus of 27 +/- 2 ng/mlL and 36 +/- 2 nmol/l, respectively. In the Monthly group, 25OHD reached a plateau of ~32 +/- 8 ng/dl at 3-5 months. There were no changes in serum calcium concentrations. PTH and P1NP were only suppressed by vitamin D treatment in those with low baseline 25OHD level.. CONCLUSIONS: Large loading doses of vitamin D(3) rapidly and safely normalize 25OHD levels in the frail elderly. Monthly dosing is similarly effective and safe, but takes 3-5 months for plateau 25OHD levels to be reached.

2, Pakistan 2013 Salahuddin N ea:  600 000IU Vitamin D monthly for 2 doses improves clinical recovery from tuberculosis. 259 patients with pulmonary TB were randomized to receive either 600,000 IU of Intramuscular vitamin D3 ie ~20 000iu/day, or placebo for 2 doses. After just 12 weeks, the vitamin D supplemented arm demonstrated significantly greater ~40% improvement: mean weight gain (kg)+3.75, (3.16-4.34) versus+2.61 (95% CI 1.99-3.23) p 0.009 and lesser residual disease by chest radiograph; number of zones involved 1.35 v/s 1.82 p 0.004 (95% CI 0.15, 0.79) and 50% or greater reduction in cavity size 106 (89.8%) v/s 111 (94.8%), p 0.035.

3. Austria 2014  Amrein ea, 540 000iu loading dose in 475 ICU pts significantly reduced morbidity and mortality by 40% in 492 vit D deficient pts,  ie is anabolic ie reverses muscle wasting – sarcopenia. as also found by Aganostis 2015 metanalysis

4. Canada/USA universities 2014 Ekwaru, Holick ea: “in a survey, 17,614 Healthy volunteers reported vitamin D supplement ranging from     0 to    55000iu/day= ~1.65million iu/mo; and had serum 25(OH)D levels ranging from 4 to 160ng/ml. The dose response relationship between vitamin D supplementation and serum 25(OH)D followed an exponential curve. On average, serum 25(OH)D increased by 5ng/ml per 1,000 IU in the supplementation interval of 0 to 1,000 IU /day; and by 92% less eg 0.4ng/ml per 1,000 IU in the supplementation interval of 15,000 to 20,000 IU per day. BMI, relative to absolute body weight, was found to be the better determinant of 25(OH)D. Relative to normal weight subjects, obese and overweight participants had serum 25(OH)D that were on average 8 and 3 ng/ml lower, respectively (P<0.001). We observed no increase in the risk for hypercalcemia with increasing vitamin D supplement.”

5. Pakistan 2015 April 22nd Endocrine Society seminar RCT : Vit D3 up to 600 000iu loading dose : Prof Muhammad Masood, Consultant Endocrinologist of Aga Khan University : “ How Much Vitamin D We Need?” vit D deficiency VDD has resurfaced as significant health problem in recent years. In Pakistan region, VDD is very prevalent despite adequate sunshine throughout the year. A huge number of studies associate Vitamin D deficiency with almost any disease. Recently, concerns about the safe upper level of vitamin D have been raised and a reverse J or U shaped relation has been described with 25-OHD level and mortality. Increasing number of patients are being reported with vitamin D toxicity because of excessive intake of vitamin D resulting from misinterpretation of prescription, manufacturing errors, inappropriate prescription of excessive vitamin D doses for vague musculoskeletal complaints without monitoring 25-OHD concentrations. A study conducted at our center revealed important implications, first a dose of VD3 ranging from 200,000-600,000 IU given orally or IM will correct the deficiency in more than 70% of individual at 2 months. A dose of vitamin D 600,000 IU given IM will correct the deficiency in more than 90% of individuals and maintained levels > 20ng/ml in 84% of individuals at 6 months. Multiple mega doses may pose the risk of toxicity.”
6 Belgium 2014.:Vitamin D status after a 100 000iu highdose cholecalciferol in healthy and burn subjects. Rousseau ea Burns patients are at risk of vitamin D (VDD) deficiency and may benefit from its pleiotropic effects in acute phase. Two groups received an oral dose of 100,000IU VD3 RESULTS:A total of 49 subjects were included: 29 in GHealth and 20 in GBurns. At D0, prevalence of VDD was higher in GB: 25OH-D was 21.5 (10.1-46.3) ng/ml in GH vs 11 (1.8-31.4) ng/ml in GB. DBP and ALB were lower in GB. At D7 In GB, changes in 25OH-D extended from -36.7% to 333.3% with a median increase of 33.1%. This study highlighted the differences in VD status and in response to a high dose VD3 in burn patients when compared to healthy patients. 25OH-D measurement needs cautious interpretation, should not prevent burn patients to receive VD supplements during acute care. Higher doses than general should probably be considered

7 Canada 2015 Jan; up to 300 000iu vit D3 loading: McNally Univ Ontario ea Rapid normalization of vitamin D levels: a meta-analysis.. systematic review of pediatric clinical trials of high-dose vitamin D with 25[OH]D.., selected 88 Uncontrolled and controlled trials reporting 25(OH)D levels after high-dose (≥1000 IU) calciferol. Two of 6 studies that administered daily doses approximating the Institute of Medicine’s Tolerable Upper Intake Level (1000-4000 IU) to vitamin D-deficient populations achieved group 25(OH)D levels >30ng/dl within 1 month. Nine of 10 studies evaluating loading therapy (>50 000 IU) achieved group 25(OH)D levels >30ng/dlL. Adverse event analysis identified increased hypercalcemia risk with doses >400 000 IU, but no increased hypercalcemia or hypercalciuria with loading doses 300 000 IU. . CONCLUSIONS: Rapid normalization of vitamin D levels is best achieved by using loading therapy that considers disease status, baseline 25(OH)D, and age (or weight). Loading doses >300 000 IU should be avoided until trials are conducted to better evaluate risk and benefit.
Australia: some Australians are fearful in claimed cautious ignorance: Sanders ea University of Melbourne 2013 ask Is high dose vitamin D harmful? With potential to minimize risk of many chronic diseases, and apparent biochemical safety of ingesting doses of oral vitamin D several-fold higher than current recommended intakes, recent research has focused on supplementing intermittent, high-dose vitamin D. However, two recent randomized controlled trials (RCTs) both using annual high-dose vitamin D reported an increase, rather than a decrease, in the primary outcome of fractures.” So annual megadose doesnt help in prevention?.
but they are planning bold highdose trial:                                                                                    8. BMC Cancer. 2014 Saw ea Melanoma Institute, SydneyAdjuvant therapy with 500,000 IU high dose vitamin D following primary treatment of melanoma; Patients with primary cutaneous melanomas that are ulcerated and >2 mm in thickness, or nodal micrometastases, have few options for adjuvant treatment. Recent studies suggest a role for vitamin D to delay and improve overall prognosis. This pilot placebo-controlled randomised phase II trial will assess feasibility, safety and toxicity of an oral loading dose of Vitamin D (500,000 IU) followed by an oral dose of 50,000 IU of Vitamin D monthly for 2 years in patients treated by wide excision…”

        9 INDIAN PEDIATR 2014 :   300,000 IU or 600,000 IU RCT. Mittal ea Delhi. 76 children (median age 12 mo) with rickets. Oral vitamin D3 as 300,000 IU (Group 1; n=38) or 600,000 IU (Group 2; n=38) in a single day. 25(OH)D levels increased from baseline to 12 weeks after therapy :[Group 1: 7.58 to 16.06 (12.71– 20.29) ng/mL, P<0.001]; Group 2: 6.57 (4.66–9.25) to 17.60 . ie 25(OH)D levels were deficient (

But while all the data above are too heterogenous to do a metaanalysis, we now know as well as the South Africans, Pakistanis, Indians, Americans, Canadians, ANZIOs and Austrians do from this literature analysis and collective experience that a level of 25OHvit D of 20 or 40ng/ml is not adequate protection; conversely a bloodlevel of ~>200ng/ml has to be exceeded long term to incur risk. And a loading adult dose orally in adults of at least 600 000iu vit D3 – more likely >1 million iu- (that’s 6gm of 100cwt vit D concentrate powder, costing perhaps $0.25 in South Africa) taken with fat -may be needed to achieve safe high enough bloodlevel to have acute protective effect- and the vit D bloodlevel will drop below vigorous levels within weeks without maintenance doses, as the Austrian study used after their loading dose 540 000iu..

so even 50 000iu every week – my standard chronic illness adult maintenance dose that I take- is ineffective initially for acute protection in eg TB adults (Daley ea India 2015) or ICU . It seems such adults (pneumonia, TB, acute AIDS, ICU) need ? 600 000iu (or ? a ~ million iu orally) to start, then eg 100 000iu/wk till better, then drop to maintenance. .

            VIT D & INFANTILE BRONCHIOLITIS
Infantile bronchiolitis is a severe and common occurrence and killer under a year of age in South Africa as in the northern hemisphere; especially in tiny premmies; in the majority due to RSV respiratory syncytial virus rather than coronavirus, ‘flu etc; with no conventional therapy except support- leaving the doctor actively doing nothing except comfort, while the nurse nurses…
BUT eight papers since 2011 on Bronchiolitis strongly support vit D: that vitamin D deficiency/ polymorphism plays a major role from pregnancy on:
Three studies from 2011-2014 show that such bronchiolitis infants have low vitamin D or vitamin D polymorphisms that make them vulnerable; Two studies in 2014, from Harvard (Randolph ea ) and Ottawa (McNally ea) Universities in RSV bronchiolitis infants show vit D-binding haplotype, or Vitamin D receptor (VDR) polymorphisms;      And a 2011 study from Belderbos ea Utrech Univ Netherlands 2011 that Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis- Neonates born with 25-OHD concentrations <20ng/ml had a sixfold (95% confidence interval: 1.6-24.9; P = .01) increased risk of RSV LRTI in the first year of life compared with those with 25-OHD concentrations ≥ 30ng/dl. These studies thus point to brisk vitamin D supplement as likely major benefit against both RSV and subsequent asthma./COPD.

and Five recent team reviews 2011 to 2014 of RSV bronchiolitis from Italy—Baraldi ea ;   Canada- Poon ea ; Ireland – Clancy ea; and USA: Herzog ea-Cornell Univ NY, and Massachusetts-Maxwell ea – thus encourage the use of vigorous vitamin D and A and omega3 supplements in pregnancy or infancy to prevent  our  high RSA risk of bronchiolitis and future asthma/COPD.  eg
Curr Drug Targets. 2011.Herzog ea Cornell Univ. Immunologic impact of nutrient depletion in chronic obstructive pulmonary disease. Maternal smoking may diminish interferon response secondary to micronutrient deficiency, particularly of Vits A & D, and support persistence of RSV into adult life , Muscle wasting and cachexia systemic features of COPD. Nutritional depletion is related to poor survival and is a rational target for therapeutic intervention also in advanced and critically ill patients. Preliminary studies and suggest that supplementation with omega-3 and Vitamin A, Vitamin D3, and zinc may have beneficial effects in COPD.

now    2015  Salimi ea in Iran show in  Association between vitamin D receptor polymorphisms and haplotypes with pulmonary tuberculosis  in  Biomed Rep.   “The vitamin D receptor (VDR) is an important factor in activating immune response in different infectious diseases. Case control study on 120 PTB patients and 131 healthy controls with  Genetic analysis  by polymerase chain reaction.. The VDR Fok1 Ff genotype was associated with TB and the risk of PTB was two times higher in individuals with the Ff genotype. A higher frequency of f allele was observed in PTB patients and therefore, the f allele may be a risk factor for PTB susceptibility. In addition, haplotype analysis showed that the f-T-B and f-t-b haplotypes (Fok1, Taq1 and Bsm1) may have the potential to increase PTB susceptibility. In conclusion, the Ff genotype and f allele of the VDR Fok1 polymorphism were associated with PTB susceptibility. In addition, the f-T-B and f-t-b haplotypes may be the susceptible haplotypes for PTB.”

     THE RSA HOLOCAUST ESPECIALLY FOR WOMEN AND KIDS:  This new cumulative data above  is crucial given that while men fight ruthlessly for power, sex, money- even wars- the high birthrate in poor malnourished teenage girls in RSA, (especially with prevalent violence, alcohol, smoking and other drug abuses, AIDS and pulmonary and abdominal/ meningeal TB), who are thus ill-equipped both to breastfeed and parent with the myriad burdens of illiteracy and joblessness poverty, single parenting, starvation, male violence, refugee squatter survival, and then having to take ARVs, antiTB drugs or at least INH, cotrimoxazole and frequent other antimicrobials.

It is controversial, but Marks DF1.Br J Health Psychol. 2007 Department of Psychology, City University, UK argues that Literacy not intelligence moderates the relationships between economic development, income inequality and health: ” Kanazawa (2006) presented data allegedly supporting a racist version of evolutionary psychology that claims that the populations of wealthier and more egalitarian societies live longer and stay healthier, not because they are wealthier and more egalitarian, but because they are more intelligent. The objectives of this study are: (i) to determine the relationship between IQ and literacy in Kanazawa’s sample of countries and (ii) to reanalyse Kanazawa’s dataset using measures of literacy in lieu of national IQ test scores. RESULTS:National literacy scores across the countries in the sample are highly skewed. In spite of this, the literacy measures are highly correlated with alleged differences in national IQ (r = .83-.86). The measure of literacy together with economic development (GDPpc) and income inequality (Gini coefficient) control at least 59-64% of the variance in national life expectancy at birth.CONCLUSIONS:There is no scientific justification for believing that alleged intelligence differences play any role in explaining international differences in health status. Measures of alleged national IQ scores are highly confounded with differences in literacy. Literacy is a key factor in the health of any community and policies designed to enhance the literacy of a population are expected to lead to significant improvements in health status.
For these intellectually challenged illiterate women from remote rural villages  – many of whom cannot even write their initials let alone a signature, or understand English or Afrikaans-   anything but their tribal dialect-  pregnancy and AIDS/TB are the only relative escape from starvation and manual ie servile labour- which marginally paid drudgery is disappearing with the government-caused collapsed SA economy, power supply and industry. But the disability grant of ~R1500 ($125pm ie <$1/work hour) ) pm, and child welfare grant of perhaps R300 ($25)pm, is a drop in their ocean of despair. And given the mushrooming STD rates and costs thereof from male recklessness , from worsening corrupt central-government- led illiteracy and effective mass unemployment – state HIV-TB clinics and hospitals seldom have a little B6 or C to give these women, let alone regular supplies of ARVs or essential healing nutritionals eg vits A, Bco, minerals D, iodine, zinc, and biologicals eg  cod liver oil etc.

In the private sector, medical aid schemes also dont pay for supplements, only synthetic designer drugs that ignore underlying causal immunodeficiencies – since Only Disease Pays.
OVERDOSE? Between the two topic headings Hypervitaminosis D and Vitamin D toxicity, there are already 1798 refs on Pubmed alone. Hypervitaminosis D  428 reports on Pubmed since the first, from Harris & Moore, The Nutrition Lab, Cambridge 1929; Hypervitaminosis and vitamin balance: ..        and there are 1436 entries under Vitamin D toxicity since the first Vitamin D Toxicity by Leake 1936 at  UCLA .
ADULTS: But experts and numerous overdose reports ( only a few of which are noted below) reveal the truth,  that at least oral DAILY, well over 50 000iu to 1 MILLION iu/d of vitamin D for months, LONGTERM to up to 100 000IU/D for months to 365 million iu over 10 years has to be taken to cause illness ie symptomatic hypercalcemia .
Conversely, Chakraborty ea at Roy Research Center, Kolkata, India, report (Lab Med. 2015) A nontoxic case of vitamin d toxicity, a woman who developed very high serum Vitamin D levels (746 ng/mL, RI: 20 to 50) as a result of medication error. In spite of such high serum concentrations the patient was without any clinical symptoms and had normal serum calcium. The evidence base regarding the safety profile of Vitamin D supplementation in humans has been build through case reports, not dose titration RCTs to astronomical levels- which would be unethical.

So while routine maintenance dose eg 600 000iu/month, or 4000- to 10 000iu/d, or 100 000iu/wk in adults has never been reported to cause overdose toxicity,
on vigorous chronic vitamin D3 (not calcium or D2) dosing for disease, obviously ideally baseline (or at least after say 2-3 months of trial of conservative vitamin D replacement) calcium, vitamin D and kidney function levels should be measured since very rarely, unexpected silent hypercalcemia may already be present. .
But numerous reports eg from Netherlands 2014 show that a single overdose of even 2million iu vit D (=~100 000iu/d over 30days given the T 1/2 of vit D of 2 wks to 2 months), while kicking the bloodlevel up a few hundred ng/ml, does no harm even in two Dutch nonagenarians.

Relative hypovitaminosis D (bloodlevel below 30ng/ml) is prevalent locally and internationally in an indoor-working sunburn-fearing over-dressed city population not taking supplements more than the usual 400iu vit D in a daily multivite – especially in alcoholics, and the undernourished poor, and those following the government -recommended disease- promoting diabesogenic high- carbs low- fat diet marketed by commercial interests and bad science the past 50 years..

Already in 1999 Vieth at Univ Toronto wrote in Am J Clin Nutr. “Vitamin D supplementation, 25-OH vit D concentrations, and safety. . for adults, the 5-microg (200 IU) vitamin D RDA may prevent osteomalacia in the absence of sunlight, but more is needed to help prevent osteoporosis and secondary hyperparathyroidism, and prevention of some cancers, osteoarthritis progression, multiple sclerosis, and hypertension. Total-body sun exposure easily provides the equivalent of 250 microg (10000 IU) vitamin D/d, suggesting that this is a physiologic limit. The assembled data from many vitamin D supp. studies reveal a curve for vitamin D dose versus serum 25(OH)D response that is surprisingly flat up to 250 mcg (10000 IU) vitamin D/d. To ensure that serum 25(OH)D concentrations exceed 40ng/ml, a total vitamin D supply of >100 microg (4000 IU)/d is required. Except with conditions causing hypersensitivity, there is no evidence of adverse effects with serum 25(OH)D concentrations <55ng/ml, which require a total vitamin D supply of 250 microg (10 000 IU)/d to attain. Published cases of vitamin D toxicity with hypercalcemia, for which the 25(OH)D concentration and vitamin D dose are known, all involve intake of >/= 1000 mcg (40 000 IU)/d. Because vitamin D is potentially toxic, intake of >1000 IU/d has been avoided – even though the weight of evidence shows that the currently accepted, no observed adverse effect limit of 2000 Iu)/d is too low by at least 5-fold ie >10 000iu/d long term.”
O/Dose INFANTS: to avoid vitamin D poisoning and permanent damage to infants, of course dose needs to be scaled down accordingly on the 100iu/kg/d basis; but infants have a much bigger body surface area and thus meds requirement & tolerance. Human breast milk vit D is usually inadequate especially for swaddled darker-skinned babies and mothers; so conventionally at least 1000iu/d supplement vit D is for babies up to 6 months, 2500iu/d above 1year, and 4000iu/d from 9 years; or a pro rata loading dose, is advised eg Canada http://www.cps.ca/documents/position/vitamin-d and USA Heaney ea http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/. Conversely, serum 25(OH)D concentration consistently >200 ng/mL is considered to be potentially toxic [5].” Without a fingerprick vit D and calcium assay (lab cost here is ~R300 ie $25), monitoring here is tedious and costly…
ALLERGY TO VITAMIN D3? That vigorous vitamin D3 replacement can improve immunodeficiency and even relieve dermatitis is common cause.
But since Vit D’s discovery in 1914 (USA McCollum and Davis) and soon commercial production and marketing the past 90 years, not a single documented verified ALLERGY case (not overdose) can be found on Pubmed or Google?.Such true allergy cannot be anything but very very rare, since with vit D3, like all other bioidentical human hormones, and vitamins, allergy (unlike overdose) is almost inconceivable- although receptor loss or blockade may create resistance to eg thyroid, testosterone, vit D etc. . Allergy could conceivably occur to some carrier/ additive to the vitamin D3- but not even in the lungs from inhalation of old high-vit D oil droplets in fish factory workers
VitaminDwiki puts it in perspective. Designer ie prescription synthetic meds, and common foods, and tap water, are more likely to cause problem.

None of the 14 refs on Pubmed reports allergy to vitamin D. Google merely notes some anecdotes from users.

The last and urgent word today  -on medical and parental responsibilities- is by Wolfgang Högler ,Birmingham Children’s Hospital, UK ,Clin.Endoc. 2015: Complications of vitamin D deficiency from the foetus to the infant: One cause, one prevention, but who’s responsibility? The supplier of bone Calcium and phosphorus is the hormone calcitriol, which originates from vitamin D, itself made by sunshine in human skin. Requirement for bone minerals is highest during phases of rapid growth, and no one grows faster than the foetus and the infant, making them particularly vulnerable. Deprivation of calcium, whether through low calcium intake or low vitamin D, leads to serious health consequences throughout life, such as hypocalcaemic seizures, dilated cardiomyopathy, skeletal myopathy, congenital and infantile rickets, and osteomalacia.                                                                                                                    These 5 conditions are often summarised as ‘symptomatic vitamin D deficiency’, are fully reversible but also fully preventable. However, the increasing prevalence of rickets and osteomalacia, and the deaths from hypocalcaemic cardiomyopathy, demand action from global health care providers. Clarification of medical and parental responsibilities is a prerequisite to deliver successful prevention programmes.     The foetus and infant have the human right to be protected against harm, and vitamin D supplementation has the same public health priority as vaccinations.

And Dr John Cannell of The Vitamin D Council comments today : Dr. Hogler does not discuss the growing evidence that maternal and infantile vitamin D deficiencies may lead to neurodevelopmental disorders such as autism. I have always thought that the only way obstetricians and pediatricians will prescribe adequate doses of vitamin D is if they are charged for malpractice from failing to identify and treat vitamin D deficiency. If it is established that vitamin D deficiency causes autism, the malpractice attorneys will swarm like sharks to blood. Given increasing evident harms from numerous vaccinations, and often lack of real longterm supporting evidence of good eg the (swine and seasonal) flu and cervix HPV vaccines, we must consider vitamin D supplementation as far more proven benefit and safety than intensive multiple vaccinations.
-And on sepsis and brain salvage:  Dr Cannell promotes   –  vitamin D is a viable treatment for sepsis?, the landmark work of Drs William Grant and Ray Matthews.

The evidence is strong that vigorous natural supplements (vits, minerals, human hormones and some natural biological like marine oil and chondroglucosamine) are priorities especially in both acute emergencies, chronic diseases and prevention, from conception at all ages, over vaccinations and antibiotics and all synthetic designer drugs. .

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REFS:
BMC Cancer. 2014 ;14:780 Adjuvant therapy with high dose vitamin D following primary treatment of melanoma at high risk of recurrence: a placebo controlled randomised phase II trial Saw RP1, Thompson JF. ea Melanoma Institute Australia,North Sydney , Australia. .

  Indian Pediatr. 2014 ;51:265-72. 300,000 IU or 600,000 IU of oral vitamin D3 for treatment of nutritional rickets: a randomized controlled trial. Mittal , Gupta ea University College Medical Sci,, New Delhi.
Calcif Tissue Int. 2013 ;92(2):191-206. Is high dose vitamin D harmful? Sanders KM1, Nicholson GC, Ebeling PR., University of Melbourne

Med J Aust. 2005 Jul 4;183(1):10-2. Annual intramuscular injection of a megadose of cholecalciferol for treatment of vitamin D deficiency: efficacy and safety data. Diamond TH1, Ho KW, Rohl PG, Meerkin M.University of New South Wales, Australia.

Geriatr Orthop Surg Rehabil. 2011 May;2(3):94-9. . Improving mobility and reducing disability in older people through early high-dose vitamin d replacement following hip fracture: a protocol for a randomized controlled trial and economic evaluation. Mak JC1,  Cameron ID ea. , University of Sydney, Australia .Hypovitaminosis D is particularly common among older people with a proximal femoral (hip) fracture and has been linked with poorer lower extremity functioning, falls, and fractures.

     J Nutr. 2014;144:2002-8. Vitamin D deficiency is associated with progression of knee osteoarthritis. Zhang FF1, McAlindon TE EA2.usa uNIVERSITIES

    Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2014 ;28(14):1031-3. [Effect of nasal instillation of vitamin D3 on patient with allergic rhinitis symptoms]. [Article in Chinese] Gong, Jiang Y EA

      Nutrients. 2014 ;6(9):3403-30. doi: 10.3390/nu6093403. Does sufficient evidence exist to support a causal association between vitamin D status and cardiovascular disease risk? An assessment using Hill’s criteria for causality.Weyland PG1, Grant WB2, Howie-Esquivel J3., University of California,
Eur J Clin Nutr. 2014 ;68(5):632-4..Pharmacokinetics of daily versus monthly vitamin D3 supplementation in non-lactating women.Meekins ME1,, Thacher TD2Mayo Clinic, Rochester,& University of Witwatersrand, Johannesburg,
Mol Med. 2009 ;15(9-10):328-36. Vitamin D affords better neuroprotection against excitotoxicity in cultured cortical neurons than progesterone alone. Atif F1, Sayeed I, Ishrat T, Stein Emory University, Atlanta, Georgia, USA
.
Am J Clin Nutr. 2008 ;87(6):1952-8. Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Aloia, Yeh ea Winthrop University Hospital, NY.
Am J Clin Nutr. 2008:87(3):688-91.Pharmacokinetics of a single, large dose of cholecalciferol.  Ilahi M1, Armas LA, Heaney Creighton University Omaha, .
Curr Opin Lipidol. 2007 ;18(1):41-6. Vitamin D and vascular calcification.Zittermann Schleithoff Koerfer Ruhr University Bochum, Germany.
J Am Coll Nutr. 2003 Apr;22(2):142-6. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. Heaney RP1, Dowell MS, Hale CA, Bendich A.Creighton University, USA.

         Diabetes Care. 2015 May. pii: dc150323. Effect of LOWDOSE Vitamin D Supplementation on Glycemic Control in Patients With Type 2 Diabetes (SUNNY Trial): A Randomized Placebo-Controlled Trial. Krul-Poel YH1, Simsek S7 eu .

          Horm Metab Res. 2015 May 4 Effects of High-Dose Vitamin D Supplementation on Metabolic Status and Pregnancy Outcomes in Pregnant Women at Risk for Pre-Eclampsia. Karamali M1, Asemi Z ea.
J Am Geriatr Soc. 2014 ;62(8):1546-50..Effectiveness and safety of a high-dose weekly vitamin D (20,000 IU) protocol in older adults living in residential care. Feldman F1, Green TJ.ea. Simon Fraser University, Burnaby, BC, Canada.

    Maturitas. 2015 Mar 27. Sarcopenia in post-menopausal women: Is there any role for vitamin D? Anagnostis P1, Goulis DG ea Greek Universities http://www.ncbi.nlm.nih.gov/pubmed/?term=aganostis+Sarcopenia
J Adolesc Health. 2015 Apr 11. Vitamin D =<2000iu/d Fail to Increase 25-Hydroxyvitamin D Levels or to Alter Cardiovascular Risk Factors in Obese Adolescents: A Pilot Study.
Shah S1, Wilson DM2, Bachrach LK2.

     Lancet Infect Dis. 2015 May;15(5):528-34.Adjunctive vitamin D 400 000iu in 6 weeks for treatment of active tuberculosis in India no benefit : a randomised, double-blind, placebo-controlled trial. Daley P1, Vieth R4, , Mathai D ea .
Thorax. 2015 May;70(5):451-7. doi: 10.1136/thoraxjnl-2014-206449. Epub 2015 Feb 27.
PLoS One. 2015 Feb 23;10(2):e0117123. doi: 10.1371/journal.pone.0117123. eCollection 2015. Vitamin D₃ supplementation in Batswana children and adults with HIV: a pilot double blind randomized controlled trial. Steenhoff AP1, Stallings ea .
Eur J Endocrinol. 2015 Mar;172(3):235-41. doi: 10.1530/EJE-14-0870.Vitamin D3 increases in abdominal subcutaneous fat tissue after supplementation with vitamin D3. Didriksen , Jorde R3 ea

44-9987.12279. Epub 2015 Feb 6. Effects of a single, high oral dose of 25-hydroxycholecalciferol on the mineral metabolism markers in hemodialysis patients. Merino , 2, Quereda ea, .
Pediatr Neurol. 2015 ;52:160-4.Vitamin D supplementation in children with epilepsy and intellectual disability. Snoeijen-Schouwenaars , Majoie MH ea .:.
J Acad Nutr Diet. 2015 Feb;115(2):225-30. .Dietary fat increases vitamin D-3 absorption.Dawson-Hughes B, Rasmussen H.
Eur J Clin Nutr. 2015 ;69(2):193-7 The effect of a single, large bolus of vitamin D 250,000 IU in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial.Kearns MD1, Tangpricha V3

.
Sleep Breath. 2015 May;19(2):579-83. doi: 10.1007/s11325-014-1049-y. Epub 2014 Aug 23. The effect of vitamin D supplements on the severity of restless legs syndrome. Wali S1, Krayem A.

Endocr Pract. 2014 ;20(12):1258-64..The vitamin d dose response in obesity.Dhaliwal R1, Aloia JF1.

BMC Infect Dis. 2013;13:22. Vitamin D accelerates clinical recovery from tuberculosis: Salahuddin N ea.
VIT D & INFANTILE BRONCHIOLITIS
Curr Drug Targets. 2011;12(4):489-500. Immunologic impact of nutrient depletion in chronic obstructive pulmonary disease. Herzog R1, Cunningham-Rundles , Cornell University, NY.

    Ital J Pediatr. 2014 Oct 24;40:65. Inter-society consensus document on treatment and prevention of bronchiolitis in newborns and infants. Baraldi , Corsello EA -Società Italiana per le Malattie Respiratorie Infantili, Italy. http://www.ncbi.nlm.nih.gov/pubmed/25344148
Pharmacol Ther. 2013;140(2):148-55.Vitamin D deficiency and severe asthma. Poon AH1, Mahboub B, Hamid Q. McGill University, http://www.ncbi.nlm.nih.gov/pubmed/?term=Vitamin+D+deficiency+and+severe+asthma.+++Poon+AH
Clin Exp Allergy. 2014 Feb;44(2):231-7. doi: 10.1111/cea.12247.Vitamin D-binding protein haplotype is associated with hospitalization for RSV bronchiolitis. Randolph, Bont EA Harvard Medical School.
Pediatr Pulmonol. 2014;49(8):790-9. Vitamin D receptor (VDR) polymorphisms and severe RSV bronchiolitis: a systematic review and meta-analysis. McNally1, Little ea. Univ Ottawa, Canada.
Pediatrics. 2011;127):e1513-20. Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis. Belderbos, Bont ea, University Utrecht,Ndl. http://www.ncbi.nlm.nih.gov/pubmed/?term=Cord+blood+vitamin+D+deficiency+is+associated+with+respiratory+syncytial+virus+bronchiolitis.+Belderbos

     J Matern Fetal Neonatal Med. 2013;26;639-46.Vitamin D and neonatal immune function. Clancy ea Ireland http://www.ncbi.nlm.nih.gov/pubmed/?term=Vitamin+D+and+neonatal+immune+function.
Nutr Rev. 2012;70:548-52. Better newborn vitamin D status lowers RSV-associated bronchiolitis in infants.Maxwell CS1, Carbone ET, Wood RJ. University of Massachusetts, Amherst, USA. http://www.ncbi.nlm.nih.gov/pubmed/?term=.+Better+newborn+vitamin+D+status+lowers+RSV-associated+bronchiolitis+in+infant
OVERDOSE
Am J Clin Nutr. 1999 ;69:842-56.Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Vieth.   University of Toronto, Canada.

     Clin Endocrinol (Oxf). 2015 Jun . doi: 10.1111/cen.12836. Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency. Kaur, Mithal ea Delhi.

     J Steroid Biochem Mol Biol. 2015 Apr;148:14-8. Iatrogenic vitamin D toxicity in an infant–a case report and review of literature. Ketha, Singh EA

    Einstein (Sao Paulo). 2014;12(2):242-4. Vitamin D intoxication: case report.
[Article in English, Portuguese] Marins TA1, Korkes H1.ea Hospital Israelita Albert Einstein, São Paulo, Brazil.
J Clin Endocrinol Metab. 2011;96(12):3603-8. .Vitamin D intoxication with severe hypercalcemia due to manufacturing and labeling errors of two dietary supplements made in the United States.Araki T1, Holick MF, Newman LG.ea

Ann Pharmacother. 2011 ;45(10):e52. Hypervitaminosis D associated with a vitamin D dispensing error. 4.5million iu over 3 mo. Jacobsen , Schilling ea.

Am J Public Health. 1995 ;85(10):1418-22.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1615632/pdf/amjph00448-0092.pdf Subclinical health effects in a population exposed to excess vitamin D in milk. Scanlon, Falk H.ea
N Engl J Med. 1992 ;326(18):1173-7. Hypervitaminosis D associated with drinking milk. Jacobus CH1, Holick MF, Seely EW.:ea .

Q J Med. 1986 Oct;61(234):911-9. The osteodystrophy of hypervitaminosis D 365million iu over 10 years: a metabolic study. Davies M, Mawer EB, Freemont AJ. A patient received 2.5 mg vitamin D2 ie 100 000iu/d daily for 10 years ie 365 million iu total, presented with increasing skeletal pain and hypercalcaemia. The limbs were painful to touch especially at the insertions of ligaments and tendons, and radiographs showed osteosclerosis with calcification in the periosteum, blood vessels, tendoachilles and plantar fascia. A negative external calcium balance was documented in the presence of enhanced intestinal calcium absorption and an increase in urinary hydroxyproline excretion. Cortisone improved calcium balance and corrected the hypercalcaemia by reducing serum 1,25-dihydroxyvitamin D levels and urinary hydroxyproline excretion.

Nouv Presse Med. 1981;10(36):2965-7.[Vitamin D metabolites in a new case of drug-induced hypercalcemia (author’s transl)]. [ French] Ulmann A, Bourdeau A, Lair M, Bader C. the authors report on a new case of severe hypercalcaemia induced by prolonged oral treatment with high doses of vitamin D2. (6 mg ie 240 000iu/day ie for 9 months ie 23million iu).

     Lancet. 1978 ;2(8090):621-3. The continuing risk of vitamin-D intoxication.
Davies, Adams . Eight cases of vitamin-D poisoning are described.
.
Arch Intern Med. 1975 Jul;135(7):986-8. Protracted vitamin D intoxication.
Shetty , Hagen ea   A 56-year-old woman underwent subtotal thyroidectomy for Graves disease in 1963. After the operation, hypoparathyroidism developed and therapy was begun with vitamin D2 (ergocalciferol), 100,000 units daily.  Four months later, ie 12 million iu vit D, after hypercalcemia (14 mg/100 ml) had been noted, vitamin D therapy was discontinued

    Dtsch Med Wochenschr. 1975 ;100(9):415-6, 419-23. [Observations in vitamin D and dihydrotachysterol poisoning]. [German] Ziegler R, Delling ea. In three women intoxication with vitamin D or dihydrotachysterol occurred. Two patients died from complications despite successful lowering of the serum calcium, the third died after a pulmonary embolus during hypercalcaemia 5 months after cessation of vitamin D. .

    Br Med J. 1972 ;3(5820):205-7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785685/pdf/brmedj02214-0027.pdf Vitamin D intoxication treated with porcine calcitonin. Buckle RM, Gamlen TR, Pullen IM.Southampton UK Porcine calcitonin was used to treat three Southampton women in their sixties with hypercalcaemia due to accidental chronic vitamin D intoxication with 30 000 to 500 000iu/d for 4 to 13 weeks (vit D 9 million iu over 4wks; 4.5million iu over 13 week; and 29 million iu over 2 months). Normocalcaemia was achieved in 3 to seven days, with rapid full recovery.

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23 MARCH 2015: THE CRUCIAL ROLE OF ANABOLIC PROHORMONES – MELATONIN, VITAMIN C AND steroids- PROGESTERONE, SUNSHINE and SOLTRIOL=D3 – AS HRT IN REDUCING ALL MAJOR DISEASE. Salute Dr Walter Stumpf.

 REVERSE THE POST-WW2  GLOBAL SHIFT FROM  HEALTHY ANABOLIC  OUTDOOR (VIT D AND ANDROGEN ie DIET CHOLESTEROL– FAT  DOMINANCE) EXERCISE ABUNDANCE TO THE RECENT LETHAL CARBOHYDRATE-SUGAR- ESTROGENICS- CORTISOL INDOOR TV DOMINANCE AND FAMINE.

update 22 MARCH 2015: VIGOROUS DOSE VITAMIN D UPDATE

NEW STUDIES:

More Canadian and USA studies confirm that vigorous vitamin D  need  applies especially to those living in far northern USA-Canada  and  EurAsia etc;    but also to all of us  globally who spend little time well exposed to the sun- especially the more driven  who both live/work indoors and cover even our limbs and heads outdoors as eg more ‘observant’ adults of many faiths do. As a new Creighton Univ study shows, we are at minimal risk of kidney stones on vigorous supplement vit D3 provided we balance it with enough water and magnesium supplement,

This is why in this age of increasing stress, longevity, epidemics, and pollution of both environment and the food and medicine chains, we have for a couple of years now   been advocating   and taking  vitamin D3  – on a  century of voluminous evidence (62500 papers on Pubmed alone) since 1914  from top nutritional scientists like Drs Jack Drummond, Linus Pauling, Walter Stumpf, Chris Nordin, Chris Gallagher, Rob Heaney, John Cannell, Bill Grant,  Mike Holick, Cedric Garland,  ea  – at least  vit D3  50 000iu a week (~7000iu/d)  ie a million units every 20 weeks;   retail costing  R30 ie R6pm  for us aging frailer types (half that dose ie 50 000iu twice a month @R3/month for the poor/ well or small kids).. at R12/US$, that costs all of $3 to $6 a year.

On about 9000iu vit D3 average supplement/day, my total 25OH vit D bloodlevel runs about 90-100 ng/ml ie 220-250 nmol/l.  so only 400- 1000iu vit D /day will boost the vit D  bloodlevel and benefits little if not  trivially.

But  vigorous D3 dose must be buffered by vit K2  about >100mcg/day , magnesium about 400mg/d, and the usual basket of other ~50 vits, minerals and other natural supplements, to protect us from kidney and arterial calcification etc. We have previously  highlighted trials eg from Pakistan showing that even 600 000iu vit D3 a month ie ~20 000iu/day safely and greatly improves recovery and healing from severe PTB+- AIDS in eg frail Pakistatin patients; whereas overdose of 90year old patients with a  2million iu  vit D3 dose (in Netherlands)  produced no toxicity. Hence we load sick patients with (an antibiotic-like )  200 000 to 400 000iu dose before continuing weekly or fortnightly maintenance- with the sickest fattest getting the highest dose, and infants scaled down accordingly (after a loading dose of eg 25 000iu)   to eg 1000-2000iu/d,  or 50000iu 1/2 scoop ie 25000iu every 2 weeks- the older extrapolation (as for adults)  of ~100iu/kg/day.

For the concerned vegan, vitamin D is vegetarian:  supplement of vit D2 is extracted from yeast or mushrooms;  vit D3 by UV irradiation of cholesterol from lanolin. Like all life, since vitamin D soltriol  is a sun-induced sterol oil product (in this case of cholesterol which in turn is built via  vitamin C ascorbic acid from plant glucose-sugar),   vitamin D does not contain or be made from animal flesh ie animal protein nitrogen  any more than does fish oil.

          Vitamin D may keep low-grade  cancer from becoming aggressive:
http://www.sciencedaily.com/releases/2015/03/150322080155.htm    Taking vitamin D supplements could slow or even reverse the progression of less aggressive, or low-grade, prostate tumors without the need for surgery or radiation, scientists say. Taking vigorous vits C & D does this for all cancers, all disease.

 

               VITAMIN D DEFICIENCY IS ASSOCIATED WITH INSULIN RESISTANCE INDEPENDENT OF INTRACELLULAR CALCIUM, DIETARY CALCIUM AND SERUM LEVELS OF PARATHORMONE, CALCITRIOL AND CALCIUM IN PREMENOPAUSAL WOMEN.   Da Silva Ferreira T,  Sanjuliani AF ea .   Nutr Hosp. 2015 Apr 1;31(n04):1491-1498.

25-Hydroxyvitamin D in the range of 20 to 100 ng/mL doesnt increase  kidney stones.    Am J Public Health. 2014 Sep;104(9):1783-7  Garland, Heaney ea Creighton Univ, USA   Increasing 25-hydroxyvitamin D serum levels can prevent a wide range of diseases. There is a concern about increasing kidney stone risk with vitamin D supplementation. The study included 2012 participants followed prospectively for a median of 19 months. Thirteen individuals self-reported kidney stones during the study period. Multivariate logistic regression was applied to assess the association between vitamin D status and kidney stones.We found no statistically significant association between serum 25-hydroxyvitamin D and kidney stones (P = .42). Body mass index was significantly associated with kidney stone risk (odds ratio = 3.5; 95% confidence interval = 1.1, 11.3).           We concluded that a serum 25-hydroxyvitamin D level of 20 to 100 nanograms per milliliter has no significant association with kidney stone incidence.       

A Statistical Error in the Estimation of the Recommended Dietary Allowance for Vitamin D. Letter to Veugelers, P.J. and Ekwaru, J.P.,           Nutrients. 2015 Mar 10;7(3):1688-90. doi: 10.3390/nu7031688.  Nutrients 2014, 6, 4472-4475; doi:10.3390/nu6104472.   Heaney , Garland ea.    1Creighton University & University of California, San Diego,   GrassrootsHealth, Encinitas, CA .   Recently Veugelers and Ekwaru published data indicating that, in its dietary reference intakes for calcium and vitamin D, the Institute of Medicine (IOM) had made a serious calculation underestimation  [2]. Using the same data set as had the IOM panel, these investigators showed that the Recommended Dietary Allowance (RDA) for vitamin D had been underestimated by an order of magnitude. Veugelers and Ekwaru, using the IOM’s data, calculated an RDA of 8895 IU per day. They noted that there was some uncertainty in that estimate, inasmuch as this value required an extrapolation from the available data, which did not include individuals receiving daily vitamin D inputs above 2400 IU/day.[…].

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210929/        Nutrients. 2014 Oct; 6(10): 4472–4475.Statistical Error in the Estimation of  Recommended Dietary Allowance for VitaminD     Paul J. Veugelers* and John Paul Ekwaru   University of Alberta, Canada

The Institute of Medicine (IOM) issues dietary recommendations on the request of the U.S. and Canadian governments. One of these recommendations is the Recommended Dietary Allowance (RDA). The RDA is the nutrient intake considered to be sufficient to meet the requirements of 97.5% of healthy individuals [1]. The RDA for vitamin D is 600 IU per day for individuals 1 to 70 years of age and is assumed to achieve serum 25-hydroxyvitamin D (25(OH)D) levels of 50 nmol/L or more in 97.5% of healthy individuals [1]. Serum 25(OH)D is the established proxy for vitamin D status and levels of 50 nmol/L or more have been shown to benefit bone health and to prevent disease and injury [1].

The IOM based their RDA for vitamin D on an aggregation of 10 supplementation studies that were carried out during winter months and at locations with latitudes above the 50th parallel north to minimize the influence of cutaneous vitamin D synthesis [2,3,4,5,6,7,8,9,10,11]. As several of these 10 studies examined more than one supplementation dose, collectively they provided 32 study averages of serum 25(OH)D levels. These are replicated as the green diamonds in Figure 1. The IOM regressed the 32 study averages against vitamin D intake to yield the dose response relationship of vitamin D intake and serum 25(OH)D (green solid line in Figure 1). The IOM further calculated the lower and upper 95% confidence prediction interval based on the 32 study averages and the standard deviation of these 32 study averages (green dashed lines in Figure 1). On the basis of this, the IOM estimated that 600 IU of vitamin D would achieve an average 25(OH)D level of 63 nmol/L and a lower 95% confidence prediction limit (2.5 percentile) of 56 nmol/L. The latter value was rounded downwards to 50 nmol/L to accommodate uncertainty in the estimation [1]. This data point (600 IU vitamin D, 50 nmol/L) is the basis for the current RDA and for the IOM’s conclusion that an intake of 600 IU of vitamin D per day will achieve serum 25(OH)D levels of 50 nmol/L or more in 97.5% of individuals.

The correct interpretation of the lower prediction limit is that 97.5% of study averages are predicted to have values exceeding this limit. This is essentially different from the IOM’s conclusion that 97.5% of individuals will have values exceeding the lower prediction limit. To illustrate the difference between the former and latter interpretation, we estimated how much vitamin D is needed to achieve that 97.5% of individuals achieve serum 25(OH)D values of 50 nmol/L or more. For this purpose we reviewed each of the 10 studies used by the IOM. Eight studies reported both the average and standard deviation [2,5,6,7,8,9,10,11]. These eight studies had examined a total of 23 supplementation doses [2,5,6,7,8,9,10,11]. For each of these 23 study averages we calculated the 2.5th percentile by subtracting 2 standard deviations from the average (depicted by yellow dots in Figure 2). Next, we regressed these 23 values against vitamin D intake to yield the lower prediction limit (red line in Figure 2). This regression line revealed that 600 IU of vitamin D per day achieves that 97.5% of individuals will have serum 25(OH)D values above 26.8 nmol/L rather than above 50 nmol/L which is currently assumed. It also estimated that 8895 IU of vitamin D per day may be needed to accomplish that 97.5% of individuals achieve serum 25(OH)D values of 50 nmol/L or more. As this dose is far beyond the range of studied doses, caution is warranted when interpreting this estimate. Regardless, the very high estimate illustrates that the dose is well in excess of the current RDA of 600 IU per day and the tolerable upper intake of 4000 IU per day [1].

The public health and clinical implications of the miscalculated RDA for vitamin D are serious. With the current recommendation of 600 IU, bone health objectives and disease and injury prevention targets will not be met. This became apparent in two studies conducted in Canada where, because of the Northern latitude, cutaneous vitamin D synthesis is limited and where diets contribute an estimated 232 IU of vitamin D per day [12]. One study estimated that despite Vitamin D supplementation with 400 IU or more (including dietary intake that is a total intake of 632 IU or more) 10% of participants had values of less than 50 nmol/L [13]. The second study reported serum 25(OH)D levels of less than 50 nmol/L for 15% of participants who reported supplementation with vitamin D [14]. If the RDA had been adequate, these percentages should not have exceeded 2.5%. Herewith these studies show that the current public health target is not being met.              We recommend that the RDA for vitamin D be reconsidered to allow for appropriate public health and clinical decision-making.

update 1 March 2015Screening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion? 

                   Since its founding, the  USPSTF has sought to provide a firm evidential base for early detection strategies, evaluating such screening methods as mammography and prostate-specific antigen testing. Although it has also evaluated a few interventions, its predominant focus has been testing for markers that identify persons at risk who are likely to benefit from preventive action. Only recently has the USPSTF ventured into the field—or perhaps the minefield—of nutrition, a territory distant from screening tests and risk assessment, with different and unfamiliar landmarks.

The USPSTF presents its conclusions on testing for vitamin D deficiency (1), reporting that it was unable to find evidence for or against such testing. It noted that one of the likely reasons was the absence of a scientific consensus on both the level of vitamin D status that should be judged “deficient” and what the measurable manifestations of deficiency might be. These are also issues for many other nutrients, such as folate, ascorbate, calcium, and protein. Vitamin D may have seemed to offer a way out of this confusion because serum 25-hydroxyvitamin D [25-(OH)D] concentration is generally recognized as one of the best indices of status for any of a broad array of nutrients. Also, it is now readily measurable and widely utilized.

One of the reasons its promise has not been realized is that most studies of vitamin D efficacy have used a disease-avoidance model, which is the standard approach used by the Institute of Medicine (IOM) for most nutrients (2). Furthermore, disease prevention is the explicit focus of the USPSTF. Nevertheless, the IOM and USPSTF approaches effectively equate health with the absence of disease, an equivalence that nutritionists have long rejected. Instead, nutritionists focus on full nutrient repletion when possible. The inevitable gap between disease prevention and nutrient repletion is still largely unexplored territory. For many nutrients, it can be surprisingly wide, as suggested in this case by studies of the intake required to provide vitamin D in human breast milk in quantities sufficient to meet the needs of infants (3). The IOM’s adult requirement for vitamin D is 600 IU/d (4), which is judged to be sufficient to protect against osteoporotic fracture. In contrast, quantitative and empirical evidence indicates that vitamin D intake from breastfeeding needs to be approximately 6000 IU/d (3, 5). Although high compared with the adult recommendation, such an intake almost exactly reproduces the measured vitamin D status of contemporary Africans leading ancestral lifestyles (6). Such populations provide perhaps our best window on vitamin D levels prevailing during the millennia over which human physiology was adapted to its environment by natural selection.

Whatever the actual requirement or 25-(OH)D cutoff may be, there is another likely reason that the evidence is unclear. The USPSTF drew from systematic reviews and meta-analyses of studies of vitamin D effects, such as the one accompanying the current report (7). In general, the criteria for including studies in such reviews are methodological rather than biological. Of the 6 published biological criteria (8) for including published reports in meta-analyses, the review published in this issue met only 2 (comparable basal status and same chemical form), and several of its component studies met none. Including studies that could never have been informative in the first place (especially when they are large) inevitably biases any review toward the null.

What seems not to have been widely appreciated is that vitamin D exhibits flat response regions at both low and high values of vitamin D status, with a sharp rise in the approximate center of the physiologic range of 25-(OH)D values (8). Studies like the WHI (Women’s Health Initiative), which enrolled women with low vitamin D status values and used a vitamin D dose insufficient to move them into the response range, provide little useful information about vitamin D efficacy. Yet, precisely such studies were included in the review by LeBlanc and colleagues (7). This is not to criticize the WHI, which was designed more than 20 years ago (before vitamin D pharmacology was well-understood), but it is to criticize contemporary reviews and meta-analyses that fail to take advantage of newer information or to use critical biological criteria (8) for selection of studies for analysis of biological effects.

In addition, a disease-avoidance approach becomes problematic for micronutrients in general (and vitamin D in particular) when one understands that micronutrients do not actually cause any of the effects simplistically attributed to them. Although necessary for cell response, such micronutrients by themselves do not initiate or cause the response concerned. For example, vitamin D is a component of the biochemical apparatus that opens the genome to allow access to DNA information needed for a particular cell or tissue response. In terms of cell function, this dependence means that when supplies of the micronutrient are inadequate, cellular response is blunted. This is dysfunction, but not clinically manifest disease. Such dysfunction may indeed lead ultimately to various diseases, but disease prevention remains a dull tool for discerning the defect, and a disease-prevention approach clearly does not measure whether the organism has enough of the nutrient to enable appropriate physiologic responses, such as lactation.

Finally, and aside from the USPSTF’s findings, one must ask whether treating without first testing is sound practice. Certainly, it would be rational to do so if the condition being treated is prevalent and the treatment is safe and inexpensive. That is the case with another micronutrient, iodine, and the iodination of salt. However, the current situation is different because consuming sufficient iodine generally does not require conscious adherence to a particular regimen, whereas taking vitamin D does. Usually, testing improves patient adherence because it provides patient-specific, personally applicable information. General assurances that one probably needs extra vitamin D are not as compelling a motivator as knowing one’s number. Thus, whether the practitioner adheres to the widely divergent guidelines of the IOM (4), the Endocrine Society (9), or the American Geriatrics Society (10), measuring vitamin D status seems to be warranted, not so much to diagnose deficiency but to determine patient status relative to the selected guideline.

update  20 Jan 2015 a new USA study Ng et al. Vitamin D status and survival of metastatic colorectal cancer patients  at the 2015 Gastrointestinal Cancers Symposium found that patients with metastatic colorectal cancer with higher vitamin D levels survived a third longer than those with lower levels – 32.6 months compared to 24.5.

update 12 Jan 2015        As the poet Juvenal (died 130AD) wrote: Mens sana in sano corporis– a healthy mind in a healthy body. Its great how the prime  antistress homeostatic hormones- a pinch of natural  melatonin at night, with ENOUGH  daytime  anabolic soltriol calciferol vitamin D3, restores good sleep, orchestrate homeostasis of all other hormones especially of  the crucial adrenals and gonadals and thus thyroid hormones. ..

Sleep. 2015 Jan 12. Massa ea, Harvard.  Low Vitamin D and Poor Sleep in Older Community – Dwelling Men   :  vitamin D3 is important for sleep duration and quality. 16% of this study population had very low levels of vitamin D (< 20ng/mL 25(OH)D). Lower serum vitamin D levels linked with short (< 5 h) sleep duration,doubled the odds ratio [OR] 2.15 for the highest (≥ 40ng/mL) versus lowest (< 20 ng/mL) quartile of 25(OH)D,; Ptrend = 0.004) and lowering  sleep efficiency. And low vitamin D is a major associate of  major depressionJózefowicz ea Univ Lodz, Poland 2014..

Thanks to global human (mostly male)  greed enslaving the masses the past 7 millennia ie since at least Sumerian times, we have moved rapidly in our lifetime post WW2  from  global homeostatic (food, commodities) plenty to a world of dyshomeostasis- cacostasis stress chaos – in most countries  from Afghanistan to Zimbabwe. Just a few years ago South Africa led Africa in productivity and skills, and still has the biggest reserves of riches- minerals-  in the world; with boundless natural power (sun, sea) and manpower to drive industry and food production. But in  20 years post apartheid, the ruling ANC under Mbeki and the Zumas  has with  selfserving treasonous greed  brought South Africa to its knees with cacostasis, destruction of continuous water, electricity ; school education,  organized and quality  food provision ie agriculture, social security, the post office, the national airline, health services, Home Affairs and pensions). Now there are  rapidly increasing functionally illiterate or  old  16 million on state grants supported by the 6 million capable of meaningfully working and paying taxes if they dont emigrate. And state grants have now been extended to age 23yrs because state school leavers are practically unskilled for  anything but being labourers. .

The national powergrid and oil reserves have been degraded so that total indefinite blackouts are now imminent, never mind weekly “outages” crippling work-  the economy – and destroying appliances. Never mind increasingly pandemic influenza and HIV, antibiotic resistance puts us in the post-antibiotic era in this age of deadly resistant TB and STDs, with  reckless immoral  leaders  like Zuma and Vavi leading the mob in extramarital sex and provoked violence. .

So as never before, everyone from conception to grave needs realistic regular vitamin D3 supplement at about R3 a month to bolster mental and physical health of children, mothers and the working , never mind the ailing aging, to reduce illhealth costs. . Stress- through raised thyroid, sympathetic and cortisol levels and depressed gastrointestinal, cardiovascular, musculoskeletal and immune control, grossly disrupts homeostasis and shifts victims into catabolic estrogen-dominance , insulin resistance mode- which only the hormone supplements  D3 and melatonin, and the essential vitamins and minerals  if not  risk-laden androgenics can try to balance,

George Chrousos ea.  University Athens, Greece since Nat Rev Endocrinol. 2009 and now   Neuroimmunomodulation. 2015 write: Stress – glucocorticoids – and disorders of the stress system- cacostasis vs homeostasis.      All organisms must maintain complex dynamic equilibrium-  homeostasis- which is constantly challenged by internal or external adverse forces – stressors. Stress occurs when homeostasis is threatened or perceived; homeostasis is re-established by various physiological and behavioral adaptive responses. Neuroendocrine hormones have major roles in the regulation of both basal homeostasis and responses to threats, and are involved in the pathogenesis of diseases characterized by cacostasis – dyshomeostasis. The stress response is mediated by the stress system, partly located in the central nervous system and partly in peripheral organs. The central, greatly interconnected effectors of this system include the hypothalamic -pituitary-adrenal (HPA) axis and hormones arginine vasopressin, corticotropin-releasing hormone  and autonomic norepinephrine centers in the brainstem.  Optimal basal activity and responsiveness of the stress system is essential for a sense of well-being, successful performance of tasks, and appropriate social interactions. By contrast, excessive or inadequate basal activity and responsiveness of this system might impair development, growth and body composition, and lead to a host of behavioral and somatic pathological conditions.. Glucocorticoids, the end-products of the HPA axis, play a fundamental role in the maintenance of both resting and stress-related homeostasis and, undoubtedly, influence the physiologic adaptive reaction of the organism against stressors. If the stress response is dysregulated in terms of magnitude and/or duration, homeostasis is turned into cacostasis with adverse effects on many vital physiologic functions, such as growth, development, metabolism, circulation, reproduction, immune response, cognition and behavior. A strong and/or long-lasting stressor may precipitate and/or cause many acute and chronic diseases. Moreover, stressors during pre-natal, post-natal or pubertal life may have a critical impact on our expressed genome.

VITAMIN D ECONOMY & GOAL OF SCREENING: Heaney and Armas, Creighton University  QUANTIFYING THE VITAMIN D ECONOMY: Nutrition Reviews  Dec 2014; and Screening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion? Ann Intern Med. Nov 2014   write:  sunlight and food  contribute only modestly  to the relevant optimal total serum vit D and 25OHvit D levels: unsupplemented individuals who average blood 25OHvit D of 20 ng/mL are receiving about 2,000 IU/day from nonsupplement sources (i.e food and sun) – whites double the amount  compared to dark blacks  from skin. . It has been established for 30 years that in fair-skinned individuals, a single exposure to UV-B at one whole-body minimum erythema dose can produce a rise in serum 25D that is equivalent to an oral dose of D3 in the range of 10,000 to 25,000 IU, ie by as little as 10–15 min of whole-body exposure at mid-day in mid-summer in a pale-skinned individual. Pale-skinned northern Europeans show a rise in serum 25D of 9 ng/mL (23 nmol/L) at the end of 4 weeks of exposure. By contrast, in dark-skinned individuals, the rise was  half  ie 4.5 ng/mL . Meat  eaters exhibit higher human 25D status . Input gaps left after estimating solar inputs (on the order of 1,300–1,600 IU/day, as noted above) could well be filled by hitherto unrecognized food sources. For example, Taylor et al.21 report a combined (D3 plus 25D) content of 112 IU vitamin D equivalents for 200 g of beef tenderloin or  an egg, associated with 2 ng/mL greater level of serum 25D.      The Grassroots Health project collects data on supplement type and has found no difference in the 25D concentration achieved with either 5,000 or 10,000 IU daily doses, irrespective of whether the D3 was delivered via a gel cap in oil or as dry powder in a tablet (unpublished data; S. McDonnell, personal communication). vitamin D could be absorbed from orange juice. On the other hand, fat malabsorption syndromes are known to lead to vitamin D deficiency, and the mechanism is generally considered to be a specific impairment in the absorption of fat-soluble vitamin D. However, poor absorption may reflect not so much mucosal dysfunction, as simple sweeping of any fat-soluble compound out of the gut, dissolved in the unabsorbed fat. Dawson-Hughes et al.,35 using pharmacokinetic methods in individuals with normal absorptive function, reported equal absorbability for D3 under fasting and high-fat meal conditions, with slightly better absorption from a low-fat meal. Mulligan and Licata,36 in an observational study of 17 poor responders to oral D preparations, reported greater absorption from a large meal containing fat than from intake on an empty stomach. However, the limited data, taken as a whole, suggest that the effects of dosage form or vehicle are probably small.

Finally, the issue of D2 versus D3 needs brief mention. Formerly considered controversial, there now seems to be a growing consensus37 that, for equimolar quantities, orally administered D3 raises serum 25D by about twice as much as D2.38–42 This has been shown for bolus doses, short-term continuous administration (12 weeks), and long-term continuous administration (12 months).

Intestinal absorption of D3 is mainly from the jejunum and ileum. Absorbed vitamin D can be found in both the portal venous blood and the lymph that drains the small intestine.  The lymphatic pathway may have particular physiological significance for orally acquired vitamin D, since it avoids a first pass of the absorbed vitamin D through the liver. This suggests that the quantitative relationship between vitamin D and 25D will be the same regardless of whether vitamin D enters from the skin or the gut.

Diffusion from the skin into the blood is slow, with a half-time of about 3 days.7 This half-time means that when regular sun exposure is the principal source of D3, serum D3 concentration will be essentially constant.

it is reasonably certain  that the concentration of vitamin D in fat tissue is substantially higher than the concentration in serum. – a given volume of fat tissue contains approximately 12 times as much vitamin D as the same volume of serum. However, a several-fold gradient is not surprising as D3 solubility in fat is effectively limitless, while DBP capacity, which is large, is finite.

Assuming a diffusional mechanism and a total body fat mass of 35% of body weight,  total body stores in an individual weighing 70 kg would range from 900 to 2,800 µg (37,000 to 113,700 IU). Using the calculations set forth in the prior section and applying them to an individual with a serum 25D level of 20 ng/mL, whose metabolic consumption would be ∼2,000 IU vitamin D/day, the total amount in the reservoir would provide enough of a reserve for 18–57 days at that same rate of utilization. At a serum 25D level of 40 ng/mL, that same reserve would support consumption for only 9–28 days. Neither estimate comes close to compensating for the “vitamin D winter” of most temperate latitudes. The smallness of this reserve explains why even outdoor summer workers who had high daytime skin exposure experienced reductions in 25D averaging approximately 20 ng/mL (50 nmol/L) by late winter. Of note, their 25D values had reached >50 ng/mL (125 nmol/L) by late summer, which is roughly the same as that reported for East Africans living ancestral lifestyles.48 This study indicates both that existing stores at the end of summer were not adequate to maintain the achieved summer level and that the late winter level (∼30 ng/mL) represented a utilization of approximately 3,000 IU/day.

Chemical partition
Extracellular 25(OH)D  The first step in the chemical conversion of D3 is 25-hydroxylation.Bikle et al.51 showed that skin cells contain all the requisite enzymatic apparatus to produce both 25D and 1,25D. However, it is doubtful that under ordinary circumstances, skin is a major source of the extracellular 25D measured in serum (D. Bikle, personal communication). Other sources remain to be identified.

The efficiency with which D3 is converted to 25D varies widely from individual to individual.  Various reasons can be put forth for these inter-individual differences that, though studied in somewhat less detail, have been reported by many investigators. One example is the variable methylation of the CYP2R1 gene and, hence, variable expression of the hepatic 25-hydroxylase.53 While there is currently no final answer, it is clear that differences in intestinal absorption of D3 could not explain the slow rise in participant B, relative to participant A. Moreover, the internal consistency in the shape of the respective curves virtually excludes methodological variability as a cause of the difference.

Extracellular 1,25(OH)2D  The second hydroxylation, which produces extracellular 1,25D, occurs predominantly in the proximal convoluted tubular cells of the kidney. While 25-hydroxylation is not highly regulated, the opposite is true for 1,25D, the synthesis of which is upregulated by parathyroid hormone and low serum inorganic phosphorus concentration and downregulated by fibroblast growth factor-23. Note that 1,25D is a principal regulator of intestinal absorption of calcium; during this process, it acts by upregulating expression of the calcium transport apparatus of the enterocyte. This is an endocrine effect as it is mediated through serum endocrine-like activity and exhibits a typical negative feedback control loop. Under usual conditions, 1,25D is necessary for regulation of calcium absorption. However, it is not the only factor involved in this process. It should also be noted that in the absence of other vitamin D metabolites, 1,25D by itself has been reported not to be sufficient to elevate intestinal calcium absorption.55,56

As would be expected for regulator molecules, the serum half-time of 1,25D is short (hours). Its concentration in serum is a reflection mainly of relative calcium need—being high in individuals on low-calcium diets or in those with calcium malabsorption and low in individuals with high calcium intakes. Also, 1,25D has long been recognized to be calcemic when used therapeutically. The mechanism is generally attributed to intestinal calcium absorption, but this cannot be a satisfactory explanation, as increased metabolic input alone (i.e., without considering output) is rarely sufficient to elevate the serum concentration of any metabolite. Moreover, 1,25D and its analogs do not elevate calcium absorption in patients with end-stage renal disease,57 a condition in which the calcemic effect of 1,25D is often readily apparent. While not adequately explored, there remains another possibility, i.e., an effect of 1,25D on bone-lining cells, where a fall in bone fluid pH to just below 7.0 is enough to solubilize bone mineral sufficiently to elevate serum calcium.58
Physical partition

The distinction between the endocrine and the autocrine pathways is one aspect of the physical partition between extracellular and intracellular processing of the vitamin. The prevailing assumption seems to be that most or all of the D3 entering the body is 25-hydroxylated and that the resulting 25D circulates in the blood, where it serves as the substrate for both renal and extrarenal 1 -α-hydroxylation, with the renal 1,25D product circulating in the blood like 25D and with the extrarenal 1,25D never being expressed in the only accessible body compartment, i.e., the blood.

As Hollis and Wagner59 have pointed out, D3 enters cells more readily than does 25D and, as noted above, there are several enzymes other than the hepatic CYP2R1 that are capable of 25-hydroxylation of D3.49,50 Hence, a physical partition of the vitamin D pathways prior to the 25-hydroxylation step has to be given serious consideration. That this is more than just a theoretical possibility is suggested by the fact, noted earlier, that oral 25D elevates serum 25D to a substantially greater extent than does oral D3.28–30 This was shown first by Barger-Lux et al.28 in a 10-week dosing study involving the two molecules. Figure 9 plots the 25D response to the two agents observed in a group of 54 healthy adults and shows a clear divergence of the dose response curves, with a greater than seven-fold difference in slopes. Cashman et al.,30 using a different design, found an approximate five-fold difference in response after 10 weeks of dosing, and Bischoff-Ferrari et al.,29 an approximate four-fold difference after 17 weeks of dosing.

Figure 9
Change in serum 25D plotted as a function of intake for varying oral doses of 25D and D3. Data from Barger-Lux et al.28
That there should be a greater rise in 25D when oral 25D is the source is, in a sense, trivial, as oral 25D is immediately reflected in the serum, while oral vitamin D must first be 25-hydroxylated, a process that, as described above, is necessarily slower, sometimes substantially so. Only a proper pharmacokinetic study that compares area-under-the-curve values for the two agents can fully quantify this difference. Such a study must either be long enough to allow the 25D plateau to be reached while on continuous dosing of D343 or, if using a bolus dose design, must follow the time course for the two agents for probably 4 months so as to allow full 25-hydroxylation of the administered D3 and full consumption of the administered 25D. No such data are currently available, and this aspect of the physical partition must remain speculative. Nevertheless, the issue is an important one, not just for the therapeutics of 25D but also for a full understanding of the vitamin D economy (see below).

The 25D half-time (as measured by Clements et al.60–62 using tracer-labeled 25D) presents certain puzzling features in its own right. A half-time of, say, 20 days (toward the lower end of the range found by Clements et al.) translates to a daily turnover of about 3.47% of the total mass of extracellular 25D. If the size of daily utilization is known, it is possible to calculate the size of the 25D mass from that fractional utilization rate. If all of the vitamin D input to the body is converted to extracellular 25D, then at a serum 25D concentration of 20 ng/mL (requiring, as shown above, a daily input of ∼50 µg), that 50-µg input is numerically equal to the daily turnover. So, total 25D mass would be 50/0.0347, or close to 1,500 µg. This figure is larger by an order of magnitude than that of the measurable total serum content of 25D, and the discrepancy becomes even larger at higher serum 25D concentrations or longer half-times. This seeming discrepancy has not been noted previously, with one potential reason being the computational difficulty of harmonizing biological units (IU), first with mass concentrations (µg/mL), then with SI units (nmol). However, if a substantial fraction of daily input of D3 is 25-hydroxylated intracellularly, after which it is immediately activated to 1,25D, then only the 25D in the extracellular compartment would be labeled by a tracer-based approach to kinetic analysis, and the calculated daily utilization of the circulating 25D would be lower and the corresponding 25D mass estimate would be closer to what is known from blood and soft tissue content. These calculations provide support for the suggestion of Hollis and Wagner59 that “parent compound D” has more functional significance than has usually been thought.

There is one quantitative aspect of the physical partition, whether occurring prior to or after the 25-hydroxylation step, which seems inescapable. Whether one takes as optimal a serum 25D concentration of 20 ng/mL or 40 ng/mL, the molar equivalent D3 inputs required to sustain either level are far higher than the moles of 1,25D required to support the calcium economy. As noted above, a serum 25D of 40 ng/mL requires approximately 4,000 IU/day, or 100 µg/day, and a serum 25D of 20 ng/mL requires approximately 2,000 IU/day, or 50 µg/day. By contrast, the calcium economy requires between 0.5 µg and 2.0 µg of 1,25D/day. (Higher doses, as noted above, produce hypercalcemia.) It follows that >90% of D3 utilization is occurring along the intracellular/autocrine pathway. If that is not the case, then most of the D3 input to the body is degraded metabolically and not used at all. The latter possibility seems quite improbable, particularly in view of the marginal or subadequate vitamin D status that seems nearly universal. Answering this question of the relative potency of oral D3 and 25D will illuminate the partition of D3 between the extracellular and intracellular pathways and will be an important step in unraveling the puzzle of the physical partition.

One instance in which the pre-25D intracellular pathway is operative is the transfer of vitamin D activity into human breast milk.59,63 25D does not transfer across the secretory mucosa of the mammary gland with sufficient efficiency to produce enough vitamin D activity in milk to nourish the infant, while D3 does. However, for this to occur, D3 must be present in the blood that bathes the mammary secretory apparatus. In earlier work, Hollis et al.63 showed that the concentration of vitamin D in human milk was about 28% of the concentration of D3 in maternal blood. In subsequent work (B. Hollis, personal communication), that figure was shown to be closer to 32%, and a recent study by Oberhelman et al.64 showed a transfer fraction that can be calculated to be about 44%. Based on recommendations of both the American Academy of Pediatrics and the Institute of Medicine for infant intake (400 IU vitamin D/day, which requires a milk concentration of about 520 IU/L, i.e., ∼34 nmol/L), these transfer fractions would require a maternal serum vitamin D concentration of about 30–40 ng/mL (78–120 nmol/L). (The corresponding 25D concentration would be >50 ng/mL [125 nmol/L]; see Figure 8.) Hollis and Wagner59 estimate that the total input of D3 needed to maintain a milk concentration sufficient to meet the infant’s needs for vitamin D was approximately 6,000 IU/day. The equivalence value derived above produces a needed input of approximately 6,000 IU/day, which is essentially identical to the empirical estimate of Hollis and Wagner.
Dosing schedules and serum D3 concentrations

Dosing frequency for oral vitamin D supplementation regimens will affect serum concentration of D3 in predictable and often very striking ways. This fact has been largely overlooked to date, as the serum concentration of D3 has been generally considered to be of no particular interest in its own right. The rationale for infrequent (or bolus) dosing is that it leads to better adherence and that an excess amount ingested today will be stored in fat for use tomorrow. However, this assumption overlooks the effect of infrequent dosing regimens on D3 blood concentrations.

Serum D3 has a half-time variously estimated to be in the range of 0.5–3.5 days, with most investigators favoring a value of about 1.0 days. In contrast, D3 produced in skin moves into the blood with a half-time of about 3 days. This means that when skin synthesis is the principal source of D3, serum D3 concentration will be essentially constant around the clock, as D3 input to the blood from the skin (though produced mainly at mid-day) is effectively constant. With oral ingestion, intestinal absorptive input of D3 occurs mainly during a 4-h period following ingestion. (In one study, a TMAX of as much as 12 h was reported.65 As this is well beyond the usual mouth-to-cecum transit time, the 12-h figure, if confirmed, would suggest appreciable colonic absorption, or small bowel mucosal retention, or a delay pool in the intestinal lymphatics.) In any case, assuming a 1.0-day half-time, serum D3 concentration will inevitably follow a sawtooth pattern, particularly if oral ingestion is the principal input. Figure 10 displays the patterns for purely cutaneous input and for daily, weekly, and biweekly oral administration. With a once-a-week schedule, as is evident from Figure 10, serum D3 concentrations are close to zero for several days each week and below the reference level for most of the interdose interval. Thus, in the practical order, a nursing woman who takes her total weekly dose of vitamin D once each week would produce milk with little or no D content for roughly 4 of the 7 days in each week. This irregular delivery will be even more pronounced with biweekly or less frequent dosing schedules.

Figure 10
Calculated time courses for serum D3 concentration for varying oral dosing intervals. The reference level is the serum concentration for continuous (as contrasted with intermittent) dosing. Each dosing scheme provides the same cumulative intake, according to one of the following regimens: once daily, or 7 times the daily intake once weekly, or 14 times the daily intake once every 2 weeks.
It should be stressed that Figure 10 illustrates the concept and is not a depiction of actually measured serum concentrations of D3. Under input conditions in excess of daily use, unused D3 will accumulate in fat, and its concentration there would be predicted to damp the oscillations of D3 concentration in serum to some extent.

An additional feature of interval dosing is the high D3 concentration peaks achieved in the days following each dose. The impact of such high D3 levels is unclear, although Vieth66 has pointed to the induction of the 24-hydroxylation pathway as a likely consequence, with a corresponding reduction in effective vitamin D activity. Further, as the binding capacity of DBP is approximately 4.7 µmol67 (or ∼78,000 IU/L), with true Stosstherapie, as in several recent studies,68,69 the DBP will be fully saturated by the ingested D3, resulting in displacement of both 1,25D and 25D off DBP and into circulation as free or unbound moieties for several days after dosing (i.e., until fat uptake lowers serum D3 sufficiently). This effect amounts to a transient vitamin D intoxication of uncertain physiological import. Unfortunately, there is essentially no published information about vitamin D concentrations in the immediate post-dosing period following large bolus doses. Whatever else may be said of Stosstherapie, it certainly is not physiological.
Factors influencing serum 25D concentration

Aside from the possible importance of D3 concentration as the substrate for autocrine activity of vitamin D, there is general agreement that serum 25D concentration is currently the principal indicator of vitamin D status.70 This is because extrarenal conversion of 25D to 1,25D operates at concentrations below the kM for the tissue 1 -α-hydroxylases; hence, serum 25D concentration limits the amount of 1,25D a tissue can synthesize when its cells are stimulated to produce a vitamin D-dependent response. While there is no consensus as to the optimal serum 25D concentration, there is also no disagreement about the importance of the substrate, regardless of which concentration may be deemed optimal.

Input of D3, a factor that manifestly affects 25D concentration, has been the subject of much of the previous discussion. Attention is now focused on the effect on serum concentration of 25D produced by variations in body size and in D3 output, i.e., utilization and/or degradation of the 25D in serum.
Obesity

One widely recognized influence on 25D concentration is obesity, with serum 25D being lower in obese individuals. This was originally attributed to a phenomenon termed “sequestration” (implying trapping of vitamin D in adipose tissue of obese individuals).71 However, Drincic et al.72 have shown that simple volumetric dilution is both a more logical explanation and one that fully explains the weight-based difference. Curiously, body mass index works in various regression models almost as well as body weight (and somewhat better in some datasets). This is surprising as body mass index is not a measure of mass but of fatness. The reason is presently unclear, and this observation suggests the possible existence of further mechanisms operating in obese individuals.
Parathyroid hormone-1,25D axis  Clements et al.60–62 showed that 25D half-time in serum ranged from 15 to >35 days, with 25D half-time being inversely related to parathyroid hormone concentration. The parathyroid hormone effect, noted both in patients with hyperparathyroidism and in animals subjected to calcium deprivation, was, in turn, mediated by serum 1,25D concentration. Why 25D utilization (or degradation) should rise in the face of calcium need is physiologically unclear, particularly as renal 1,25D synthesis is not as dependent on 25D concentration as the autocrine functions of vitamin D.

Inflammation.  The other major influence on serum 25D concentration is inflammation. It has been reported that vitamin D status is reduced in the face of systemic inflammatory processes.73–78 For example, Duncan et al.75 reported an inverse correlation of 25D with serum C-reactive protein, with 25D being 40% lower as serum C-reactive protein rose from <5 mg/L to >80 mg/L. Autier et al.,79 in a metaanalysis of the several reports on this relationship, confirmed the existence of the association but attributed the reduced vitamin D status to underlying illness rather than to the inflammation itself. That conclusion may be partly correct, at least for some chronic illnesses, but it cannot apply to the many documented cases in which vitamin D status drops acutely across an inflammatory episode, as with total knee arthroplasty.73,77 In one case study, Henriksen et al.73 reported a 12% drop in 25D by day 2 after total knee arthroplasty and a nearly 80% drop by post-surgery week 8. Reid et al.77 evaluated a series of 33 patients who underwent total knee arthroplasty and reported an approximate 40% drop in total 25D and a 33% drop in calculated free 25D by day 2 after surgery, which was associated with large increases in C-reactive protein.

Decreases in 25D of this magnitude and rapidity cannot be explained by decreased synthesis and must, therefore, reflect increased utilization, degradation, or loss. Depending on which values may be estimated for the total 25D mass (see above), reductions in 25D concentration of the size reported by Reid et al. translate to a loss of several hundred micrograms from the body, which is substantially greater than ordinary daily utilization of vitamin D. While increased utilization cannot be ruled out, it seems unlikely to be the sole explanation. Another possibility, which was suggested by Waldron et al.,76 is the loss of DBP (with its bound ligand) in the urine. In 30 patients undergoing elective orthopedic surgery, the ratio of DBP to creatinine in urine rose 2.5× by the second day post-surgery; this was associated with a >20-fold increase in C-reactive protein. Renal loss could certainly explain much or all of the change in 25D observed in these studies and could be the result of interference with the kidney’s megalin–cubilin system, possibly produced by the anesthesia or inflammatory cytokines associated with the surgery.

Although not directly related to the major focus of this review, the conclusion reached by several of the authors of the studies just reviewed, i.e., that, while inflammation clearly reduced D status, this reduction was without nutritional significance, is in no way supported by data in any of the papers concerned, nor is it consistent with the importance of serum 25D concentration as the principal limiting factor in the autocrine pathway.

METABOLISM AND UTILIZATION   the data assembled here make clear that, even with today’s widespread vitamin D inadequacy, total vitamin D inputs are far higher than previously thought, food sources are greater than previously recognized, and solar input, though theoretically capable of fully meeting any plausible vitamin D requirement, is actually only a minor present-day contributor to total vitamin D input at the population level. That does not mean that the human requirement is more easily met. Rather, it indicates that the requirement is higher than previously recognized, with populations still short of meeting that requirement by the amount needed to move prevailing serum 25D concentrations from current values to putatively healthier levels.

These analyses also make clear that at prevailing inputs (i.e., <4,000 IU/day), D3 is rapidly 25-hydroxylated and little D3 circulates in the blood or is shunted into adipose tissue for storage. Additionally, the recent recognition that oral 25D may raise serum 25D to a significantly greater extent than does oral vitamin D suggests the possibility of a hitherto little recognized or explored intracellular pathway in which the entire metabolic sequence is handled within certain target tissues and is not reflected in blood. A related finding in this respect is the importance of a maternal serum D3 concentration sufficient to support production of human milk capable of meeting infant needs for vitamin D.

Several of these insights have implications for the human requirement. For example, the vitamin D input needed to support an adequate amount of vitamin D in human milk has implications not just for lactation but also for human success as a species under presupplementation conditions. Inadequate vitamin D input in newborns would be expected to lead to skeletal abnormalities (for which the paleo-fossil record provides no evidence), in addition to possible consequences for immune system development.89 A total input of approximately 6,000 IU in modern humans equips them to feed their infants with a nearly full range of the nutrients needed for healthy growth.

CONCLUSION    Precise quantification of vitamin D inputs, transfers, conversions, and compartment sizes are essential for a full understanding of how the human body utilizes this essential micronutrient, why it is important, and what the consequences are of an inadequate vitamin D input.

Since its founding, the U.S. Preventive Services Task Force (USPSTF) has  provided  firm evidential base for early detection strategies, evaluating such screening methods as mammography and prostate-specific antigen testing. Although it has also evaluated a few interventions, its predominant focus has been testing for markers that identify persons at risk who are likely to benefit from preventive action. Only recently has  USPSTF entered  the (mine)field of nutrition, a territory distant from screening tests and risk assessment, with different and unfamiliar landmarks.

The USPSTF now reports it is unable to find evidence for or against vitamin D deficiency testing  (1),  the likely reasons being the absence of a scientific consensus on both the level of vitamin D status that should be judged “deficient” and what the measurable manifestations of deficiency might be. These are also issues for many other nutrients, such as folate, ascorbate, calcium, and protein. Vitamin D may have seemed to offer a way out of this confusion because serum 25-hydroxyvitamin D [25-(OH)D] concentration is generally recognized as one of the best indices of status for any of a broad array of nutrients. Also, it is now readily measurable and widely utilized.                 

One of the reasons its promise has not been realized is that most studies of vitamin D efficacy have used a disease-avoidance model, which is the standard approach used by the Institute of Medicine (IOM) for most nutrients (2). Furthermore, disease prevention is the explicit focus of the USPSTF. Nevertheless, the IOM and USPSTF approaches effectively equate health with the absence of disease, an equivalence that nutritionists have long rejected. Instead, nutritionists focus on full nutrient repletion when possible. The inevitable gap between disease prevention and nutrient repletion is still largely unexplored territory. For many nutrients, it can be surprisingly wide, as suggested in this case by studies of the intake required to provide vitamin D in human breast milk in quantities sufficient to meet the needs of infants (3). The IOM’s adult requirement for vitamin D is 600 IU/d (4), which is judged to be sufficient to protect against osteoporotic fracture. In contrast, quantitative and empirical evidence indicates that vitamin D intake from breastfeeding needs to be approximately 6000 IU/d (3, 5). Although high compared with the adult recommendation, such an intake almost exactly reproduces the measured vitamin D status of contemporary Africans leading ancestral lifestyles (6). Such populations provide perhaps our best window on vitamin D levels prevailing during the millennia over which human physiology was adapted to its environment by natural selection.

Whatever the actual requirement or 25-(OH)D cutoff may be, there is another likely reason that the evidence is unclear. The USPSTF drew from systematic reviews and meta-analyses of studies of vitamin D effects, such as the one accompanying the current report (7). In general, the criteria for including studies in such reviews are methodological rather than biological. Of the 6 published biological criteria (8) for including published reports in meta-analyses, the review published in this issue met only 2 (comparable basal status and same chemical form), and several of its component studies met none. Including studies that could never have been informative in the first place (especially when they are large) inevitably biases any review toward the null.

What seems not to have been widely appreciated is that vitamin D exhibits flat response regions at both low and high values of vitamin D status, with a sharp rise in the approximate center of the physiologic range of 25-(OH)D values (8). Studies like the WHI (Women’s Health Initiative), which enrolled women with low vitamin D status values and used a vitamin D dose insufficient to move them into the response range, provide little useful information about vitamin D efficacy. Yet, precisely such studies were included in the review by LeBlanc and colleagues (7). This is not to criticize the WHI, which was designed more than 20 years ago (before vitamin D pharmacology was well-understood), but it is to criticize contemporary reviews and meta-analyses that fail to take advantage of newer information or to use critical biological criteria (8) for selection of studies for analysis of biological effects.

In addition, a disease-avoidance approach becomes problematic for micronutrients in general (and vitamin D in particular) when one understands that micronutrients do not actually cause any of the effects simplistically attributed to them. Although necessary for cell response, such micronutrients by themselves do not initiate or cause the response concerned. For example, vitamin D is a component of the biochemical apparatus that opens the genome to allow access to DNA information needed for a particular cell or tissue response. In terms of cell function, this dependence means that when supplies of the micronutrient are inadequate, cellular response is blunted. This is dysfunction, but not clinically manifest disease. Such dysfunction may indeed lead ultimately to various diseases, but disease prevention remains a dull tool for discerning the defect, and a disease-prevention approach clearly does not measure whether the organism has enough of the nutrient to enable appropriate physiologic responses, such as lactation.

Finally, and aside from the USPSTF’s findings, one must ask whether treating without first testing is sound practice. Certainly, it would be rational to do so if the condition being treated is prevalent and the treatment is safe and inexpensive. That is the case with another micronutrient, iodine, and the iodination of salt. However, the current situation is different because getting sufficient iodine generally does not require conscious adherence to a particular regimen, whereas taking vitamin D does. Usually, testing improves patient adherence because it provides patient-specific, personally applicable information. General assurances that one probably needs extra vitamin D are not as compelling a motivator as knowing one’s number. Thus, whether the practitioner adheres to the widely divergent guidelines of the IOM (4), the Endocrine Society (9), or the American Geriatrics Society (10), measuring vitamin D status seems to be warranted, not so much to diagnose deficiency but to determine patient status relative to the selected guideline.

THE NEAR-IMPOSSIBILITY  OF OVERDOSING WITH VITAMIN D3 – except  by persistent repeated  injection  A Report  in Feb 2014 from Bansai & Arora ea New Delhi show how  extreme the overdose of vitamin D3 must be to cause hypercalcemic toxicity: an Asian  woman given 6million iu  imi over 10 days  after knee surgery presented 2 months later with 6 wks of persistent vomiting, fatigue, with moderate hypercalcemic renal failure  and 25OHvit D level of 150ng/ml; that normalized in 2 weeks.. So her peak level after the initial 2 weeks on an average ~50 000iu/day may have been around 500-600ng/ml..  Bansai and Arora quote two series from  endemically vit D deficient Kashmir (Pandita ea 2012 in Jammu and 2011  Koul ea Srinagar)   of a total 25 elderly  given chronic overdoses  D3 600 000iu monthly , who were found to have similar moderate hypercalcemia and renal failure with peak 25OHvit D of 100 – 300ng/ml: a mean vit D3 dose of between 20 000iu and >1million iu/day?, mean s. creat 2.5; mean 25OHvitD of 100 – 200ng/ml; mean calcium 13.1mg/dl. 20 000iu a day indefinitely in these frail small elderly averages at least 400iu/kg/day, at least 5 times the chronic recommended dose in the literature the past decades- and to boot, routinely given them with a highdose calcium supplement- when it is rather magnesium that should if any be boosted. .  Koul ea do note that about 100 000iu vit D a day ongoing  is required to cause hypercalcemia, the mean lethal dose being about 8million iu.

By contrast, previous reports below- eg from the Netherlands report of 2million iu single  overdose  in  90 year olds; and planned 600 000iu orally monthly dose in Pakistani men  wasted with TB (Salhuddin ea below)   showed no overdose signs.  So a single loading dose of 1 to 2  million units is unlikely to give overload. By these  precedents (eg 600 000iu p.o monthly- apparently official policy of the Pakistani Endocrine Society) one may  in acute infections  give up to 600 000iu as a loading dose (a million in an obese ill patient) in acute infection situations, then 50 000- 80 000iu weekly depending on weight, to maintain level around 90ng/ml.

Am J Clin Nutr March 2008  Pharmacokinetics of a single, large dose of cholecalciferol 100 000iu  IlahiArmas, and  Heaney   Creighton University Medical Center, Omaha,  Design: followed for 4 mo, 30 subjects were  supplemented with a single oral dose of 100 000 IU cholecalciferol. 10 subjects served as a control group to assess seasonal change of calcidiol.   The subjects were healthy with limited sun exposure (<10 h/wk) and milk consumption (<0.47 L daily);  excluded granulomatous conditions, liver disease, kidney disease, or diabetes or  taking anticonvulsants, barbiturates, or steroids.  Results: Serum calcidiol rose promptly after cholecalciferol dosing from a mean (±SD) baseline of 27.1 ± 7.7 ng/mL to a concentration maximum of 42.0 ± 9.1 ng/mL. Seven percent of the supplemented cohort failed to achieve 32.1 ng/mL at any time point. The highest achieved concentration in any subject was 64.2 ng/mL. The control group had a nonsignificant change from baseline of −0.72 ± 0.80 ng/mL during 4 mo.   Conclusions: Cholecalciferol (100 000 IU) is a safe, effective, and simple way to increase calcidiol concentrations. The dosing interval should be ≤2 mo to ensure continuous serum calcidiol concentrations above baseline.

THE IMPORTANCE OF IMMUNOSYNERGY BETWEEN ADEQUATE ANABOLIC HORMONES- VIT D3, MELATONIN (Berman 1926, Carrillo-Vico 2013), AND PROGESTERONE   in planned and current pregnancy, and aging?  Thangamani, Kim ea Purdue & Indiana Universities in   J Immunol. 2014 Dec 29:  Cutting Edge: Progesterone Directly Upregulates Vitamin D Receptor Gene Expression for Efficient Regulation of T Cells by CalcitriolThe two nuclear hormone receptor ligands progesterone and vit.D play important roles in regulating T cells.., we report that progesterone is a novel inducer of vit.D receptor (VDR) in T cells and makes T cells highly sensitive to calcitriol even when vit. D levels are suboptimal. This novel regulatory pathway allows enhanced induction of regulatory T cells but suppression of Th1 and Th17 cells by the two nuclear hormones. The results have significant ramifications in effective regulation of T cells to prevent adverse immune responses during pregnancy.

A recent review of vitamin D from Mike Holick (Boston Mass.) and a German team  again reminds us of two opposing forces limiting natural sunshine vitamin D supply: on the one hand the skin shuts down active vit D production if the sunlight burns, while on the other, there is simply not enough sunlight  beyond  35degrees latitude from the equator. Thus Germany and Canada-northern USA for example, at >45degrees north,  get far too little sunlight for vit D needs ; eg London is at 51degrees north; Cape Town-Florida-San Diego, Sydney-Buenos Aires, Hawai  and the Med. countries are at the 35degree south latitude. Even this close to the equator, many overdress- especially more observant religious  women-  and thus minimize  benefit from summer sunshine.

J Assist Reprod Genet. 2014 Dec 30.Vitamin D and assisted reproductionvitamin D should be routinely screened and repleted prior to ART? Pacis , Segars ea Dartmouth-Hitchcock Medical CenterLebanon NH  systematic review.  review  current literature regarding the role of vitamin D status & repletion  in pregnancy outcomes in women undergoing assisted reproductive technology (ART).  Thirty-four articles were retrieved, of which eight met inclusion criteria. One study demonstrated a negative relationship between vitamin D status and ART outcomes,  two studies showed no association. The remaining five studies concluded that ART outcomes improved after vitamin D repletion.The majority of reviewed studies reported a decrement in ART outcomes in patients with vitamin D deficiency. Cost-benefit analyses suggested that screening and supplementing vitamin D prior to ART might be cost effective.

25 Dec 2014 ANOTHER AVOIDABLE TRAGIC  TB DEATH:   Dr Nerissa Pather and countless other infectious disease sufferers – health workers and their patients :

 Sunshine Cures:  why did TB  sanatoria work (before there were  antibiotics)? was it indeed the boost of copious sunshine secosteroid antimicrobial soltriol in the skin destroying the M TB porphyrins? or was it belief, then-cleaner  air, high altitude,    rest, care and better nutrition?

Not for nothing was  skin ie CTB  Lupus Vulgaris a relentless scourge  in the clothed  in darker climes and times, except perhaps in ancient sunny Pharanoic medicine, until the Danish Faroe Islander   physician Niels  Finsen-  trying to treat his own Niemann–Pick disease–  used his  invention phototherapy generator on his patients  and found that it magically rolled back skin TB (for which in  1903 he  got the only Nobel prize  apparently ever awarded for dermatology!). This light therapy antimicrobial effect has recently 2005 been attributed by Danish researchers    Møller,  Wulf ea  to the lethal effect of light oxidation on Mycobact  TB porphyrins.    However, this Danish study abstract ignores the antimicrobial benefit of cholecaliferol activated by light on the skin from  the Karolinska Inst in Sweden. A Georgetown Univ paper 2005 details the complexities of   Sunlight, Vitamin D, and the Innate Immune Defenses of the Human Skin , further set out in Optimal Skin Protection with  Vitamin D.    Unfortunately the circle is not yet squared off, there is still no study showing that vitamin D (like bcarotene and likely  melatonin) improves the disease porphyria?

A recent 2009 Mt Sinai NY report of a case of CTB cutaneous TB stresses how rare this skin complication is despite the increasing spread of TB with AIDS- perhaps partly because of the higher prevalence of HIV in poorer peoples in sunnier warmer ie relatively better sunshine-cholecalciferol-endowed climates.

We easily make our optimal vit D3 ~100iu/ kg per day living playing and working outdoors in warm lands. But since we dress more in cooler climates, with aging and dress-conservative cover-up tribal eg Arabic and Hasidic and Mormon customs; and avoid sunburn, and from early middle age lose 3/4 of our skin vitamin D production by 70years, we  aging thus need the bulk of our vit D requirements as supplements ie ~7000iu/day or 50 000iu/week.

A century ago, TB, polio, measles, scarlatina, and syphilis were rampant, and infections rather than wars killed most – ending in the 1919 flu holocaust that devastated the family of Dr Sir  Arthur Conan Doyle (whereas the Flu pandemic took just  one of my   parents’ score of siblings- and polio just left my Mom with a limp..)..

2014  is the centenary  of  recent  recognition of the  cod liver oil  antirickets steroid factor – calciferol/soltriol -briefly misnamed “vitamin”  D – by McCollum, Davis (USA 1913)  and Mellanby(UK); so that in 30 years  by 1945, rickets had been all but abolished in USA. But the recognition of the antirachitic factor was facilitated by discovery in the preceding decade of vitamins A, B and C. The antiscurvy benefit of fresh uncooked coloured crops (and thus their juice)  had indeed been recognized for millennia – eg the Royal  Navy limejuice- , but a specific micronutrient vitamin deficiency  was first only recognized in 1907. Vitamin C ascorbic acid  identification also took another 25years . For 90 years, it has been recognized that a  lightly cooked exclusively fatty meat diet can provide enough vitamin C (let alone all micronutrients)  for  health in eg  atheroma- and scurvy-free Eskimos and anyone who cares to eat thus (Stefansson ) .

Sadly, the lifegiving vitamins have  been diluted,  all but eliminated from retail bottled codliver oil, a ml  of which now generally supplies perhaps only 125iu vit D, and vitamin A 1000iu … So even a tablespoon supplies only about 1200iu vit D.. The Weston Price Foundation discusses  why modern commercial codliver oil is good with its balance of vits A and D– but the vitamin D level is  still  far too low for cooler darker countries.  However we recommend, (apart from far cheaper vit D3 powder 50 000iu/1ml scoop) – a tsp cod liver oil at least 3 times a week because it is the cheapest natural- and with Scandinavian manufacturing controls, safe-  source of vital  EPA+DHA available as well as some vitamins A and E.

As real summer begins here between the southern oceans,  cold winter in the northern hemisphere, we must constantly remind that vitamin D3 cholecalciferol  is NOT an  exogenous vitamin ie a biological  nutrient essential (Funk’s ‘vitamine’, shortened by Jack Drummond  because they are not amines to the more appropriate ‘vitamin’) in the human diet ( like vits A, B, C, E & K) because humans cannot make them. . But since we make  vit D  with light exposure of our skin, since most humans dont get enough sunlight on our skin,  it is certainly  a conditioned essential anabolic steroid, which like other anabolic steroids (the balance especially of androgens) is vital at optimal blood levels through life for optimal health,  healthspan.

Unlike the real vitamins and essential minerals,  Calciferol is (like eg  CoQ10,  alphalipoic acid, nitric oxide, EPA and DHA)   made in limited quantities in humans with adequate organ function and sunshine; but none of them generally in anywhere near optimal quantities for healthspan against all diseases. So given humans’ capacity to live well to a century, we need such supplements from youth to ensure chronic health so as to die of old age in good health. .

How does this relate to the death this month of Dr Nerissa Pather? Multiresistant TB contracted on duty 12 years ago  eventually killed her,    whether or not such  high-risk people are  ever advised to take the best prevention- zinc, selenium, multivites but especially highdose vit C and D3.

D3  bio-insufficiency fragility and  dysimmunity  is further complicated  since to  correct  it requires both plenty of skin sunshine exposure, eaten vitamin C and it’s daughter cholesterol,   and optimal kidney and liver  function. Even then optimal vitamin D3 bloodlevel and effect may be blocked by foolhardy cholesterol blockade eg statins, and  by excess intake and thus bloodlevel of vitamin D2 ergocalciferol – which   authorities eg in South Africa and USA  still negligently promote/ dispense as the dangerously misnamed “strong calciferol”. It is indeed D3 cholecalciferol, not D2   that is the miracle sunshine strong calciferol steroid;  egocalciferol dominance, like insulin and estrogen  dominance,  is  harmful, and can and must  be avoided. .

So it is increasingly apparent that, just as intake/manufacture of  vitamin C the true sunshine vitamin (those colourful veg/ fruit orchards etc) , and  thence cholesterol, should each be at least a few gms a day, the human  (clothed indoor-dwelling) adult synthesis +  intake  of sunshine hormone  vitamin D3 soltriol  should be nearer to 10 000iu ie 250mg/day, or more practically 50 000iu  vit D3 a week  (at a trivial supplement  cost of eg R6/month or $5 a year) for a bigger adult- especially in longer darker winter (starting with perhaps  about 25000iu every fortnight  for babies) .. of course balanced  in most societies with the other supplements especially water, vitamin K2, zinc, selenium iodine  and magnesium (and iron for children and reproductive mothers) .

So, how many more millions must suffer and die from lack of the cheapest, best, safest conditioned essential antimicrobial antioxidant anabolic nutrients available?

An undated (post 2003) Pharmacology Bulletin from Canterbury NZ at least gives conservative  realistic vit D3 advice: a loading dose of D3  500 000iu , then 50 000iu/month. This compares with our routine loading dose of about 200 000 to 400 000iu to start, then 50 000iu every week or two (proportionate to body mass and illness). But Lennons here negligently still continues to  advertise their Strong Calciferol datasheet (updated 2004) as calciferol- last year they in fact confirmed it is D2 ergocalciferol, not cholecalciferol. Only their website http://www.ndrugs.com/?s=lennon-strong%20calciferol confirms that their strong Calciferol is D2;  whereas they also make low strength D3 tabs.

From today’s press “The South African Medical Association (SAMA) extends heartfelt condolences on  the passing of 38yr old Dr Nerissa Pather on  18th December 2014 . Whilst on community service at a  Kwazulu Natal clinic, Dr Pather contracted well-publicised multi-drug resistant spinal TB in 2002 , that rendered her paralyzed and in constant pain. The loss  to a communicable disease acquired in the course of duty is an incalculable tragedy. SAMA reiterates its call to all health departments and facilities to ensure that  basic TB prevention methods are available to all healthcare workers in our facilities. Sadly, this is not the case in many of our hospitals and clinics and continues to place health professionals at enormous risk. The potential consequences of infection and even acquiring drug resistant TB are tragically evident in the death of Dr Pather.  SAMA bows its head to a colleague who has paid the ultimate price in caring for her fellow human beings.”

A current report from Tehran  Calcium and vitamin D plasma concentration and nutritional intake status in patients with chronic spinal cord injury: stresses the  obvious, the  terribly low intake and levels of vitamin D in spinal cord injury patients. Why are we inflicting this further deprivation on the most vulnerable patients?

The tragedy is that with general authoritarian nihilism about universal vitamin supplements- some calling their promotion  quackery- unrecognized  deficiency eg  vit D3, rickets,  and vit C scurvy  are on the increase even in the more affluent eg USA and in sunnier climates- especially with increasing geriatrics and the frail surviving with eg HIV, TB, cancer, chronic bowel disease,   gross overuse of warfarin (vit K deficiency) and  statin (CoQ10 deficiency) etc. .

Vitamin D Deficiency in Critically Ill Patients  is rarely considered or treated .. N Engl J Med 2009 Lee, Eisman & Center   studied vitamin D status in ICU patients  referred to   St. Vincent’s Hospital, Sydney in  2007. Among approximately 1100 ICU patients per year, the mean  25-hydroxyvitamin D in 42 referred patients was ~17ng per milliliter, with a high prevalence of hypovitaminosis D . Moreover, three patients died (from metastatic thymic carcinoma, glioma, and lymphoma), and  had undetectable levels of 25-hydroxyvitamin D.   The current study of  ICU patients reveals high prevalence of hypovitaminosis D that was associated with adverse outcomes, independently of hypocalcemia and hypoalbuminemia. Supplementation with  vitamin D (at a mean dose of 820 IU per day) before admission was not protective.   Vitamin D deficiency is associated with increased mortality.However, vitamin D has pleiotropic effects in immunity, endothelial and mucosal functions, and glucose and calcium metabolism. The association between hypovitaminosis D and common conditions (e.g., the systemic inflammatory response syndrome, septicemia, and cardiac and metabolic dysfunctions) in critically ill patients may be important. Vitamin D–deficient and vitamin D–insufficient states may worsen existing immune and metabolic dysfunctions in critically ill patients, leading to worse outcomes.  A total of 17% of  ICU patients in our study had undetectable levels of vitamin D. hypocalcemia was identified as a reason for referral in only 5% of the patients. These findings highlight the need for consideration of vitamin D status and supplementation in patients in the ICU.

Arch Intern Med. 2008;168:1629-37 25-hydroxyvitamin D levels and risk of mortality in the general population.   Melamed , Astor ea. Albert Einstein College of Medicine, NY tested the association of low 25(OH)D levels with all-cause, cancer, and cardiovascular disease (CVD) mortality in 13 331 nationally representative adults 20 years or older from the NHANES III linked mortality files.  In patients on  dialysis, therapy with  vitamin D agents is associated with reduced mortality. Observational data suggests that low  (25[OH]D) are associated with diabetes mellitus, hypertension, and cancers. However, whether low serum 25(OH)D levels are associated with mortality in the general population is unknown.   Participant vitamin D levels were collected from 1988 through 1994, and individuals were passively followed for mortality through 2000.    RESULTS:  In cross-sectional multivariate analyses, increasing age, female sex, nonwhite race/ethnicity, diabetes, current smoking, and higher body mass index were all independently associated with higher odds of 25(OH)D deficiency (lowest quartile of 25(OH)D level, <17.8 ng/mL , while greater physical activity, vitamin D supplementation, and nonwinter season were inversely associated. During a median 8.7 years of follow-up, there were 1806 deaths, including 777 from CVD. In multivariate models , compared with the highest quartile, being in the lowest quartile (25[OH]D levels <17.8 ng/mL) was associated with a 26% increased rate of all-cause mortality (mortality rate ratio, 1.26; 95% CI, 1.08-1.46) and a population attributable risk of 3.1%.    The lowest quartile of 25(OH)D level (<17.8 ng/mL) is independently associated with all-cause mortality in the general population.

ANABOLIC STEROID SYNERGY?: the steroids cholecalciferol and androgen are both immune and anabolic -switch  protein/muscle/bone promoters, without apparent mutual antagonism or suppression; calciferol also lowers SHBG levels, freeing up more active unbound testosterone ie reducing estrogen dominance.

 Subst Abuse Rehabil. 2014 Dec 10;5:121-7. Effects of different doses of testosterone on gonadotropins, 25-hydroxyvitamin D3, and blood lipids in healthy men. Gårevik, Ekström ea. At the Karolinska Inst Sweden,   Twenty-five healthy male volunteers aged 27-43 years were given 500 mg, 250 mg, and 125 mg of testosterone enanthate as single intramuscular dosesAll doses investigated suppressed the LH and FSH concentrations in serum. LH remained suppressed 6 weeks after the 500 mg dose. These results indicate that testosterone has a more profound endocrine effect on the hypothalamic-pituitary-gonadal axis than was previously thought. There was no alteration in 25-hydroxyvitamin D3 levels after testosterone administration compared to baseline levels. The 250 and 500 mg doses induced decreased concentrations of ApoA1 and HDL, whereas the lowest dose (125 mg) did not have any effect on the lipid profile.

Pediatrics. 2014 Dec . Rapid Normalization of Vitamin D Levels: A Meta-Analysis.  McNally. Menon ea @Univs Ottowa, Thailand & Ireland  systematically reviewed pediatric clinical trials administering high-dose vitamin D to evaluate  (25[OH]D) response and characteristics of  final 25(OH)D levels . Uncontrolled and controlled trials reporting 25(OH)D levels after high-dose (≥1000 IU) ergocalciferol or cholecalciferol were selected. Two of 6 studies that administered daily doses approximating the Institute of Medicine’s Tolerable Upper Intake Level (1000-4000 IU) to vitamin D-deficient populations achieved group 25(OH)D levels >75 nmol/L within 1 month. Nine of 10 studies evaluating loading therapy (>50 000 IU) achieved group 25(OH)D levels >75 nmol/L. In meta-regression, baseline 25(OH)D, regimen type, dose, age, and time factors were associated with final 25(OH)D levels. Adverse event analysis identified increased hypercalcemia risk with doses >400 000 IU, but no increased hypercalcemia or hypercalciuria with loading doses <400 000 IU (or 10 000 IU/kg). Few studies in adolescents evaluated loading dose regimens >300 000 IU.
CONCLUSIONS:   Rapid normalization of vitamin D levels is best achieved by using loading therapy that considers disease status, baseline 25(OH)D, and age (or weight).

Diabetes Res Clin Pract. 2014 Dec A randomised controlled trial of ‘high” dose vitamin D in recent-onset type 2 diabetes .Elkassaby,  Fourlanos ea, Melbourne Australia.  Vitamin D insufficiency is associated with impaired pancreatic beta-cell function. Fifty adults with type 2 diabetes diagnosed less than 12 months, with normal baseline serum 25-OH D (25D), were randomised to 6000IU D (n=26) or placebo (n=24) daily for 6 months. In the D group, median serum 25D (ng/ml) increased from 24 to 60 (3 months). change in FPG (mmol/l) was significantly lower in D (-0.40) compared to placebo (+0.1) (P=0.007), as was the change in PPG in D (-0.30) compared to placebo (+0.8) (P=0.005). Change in HbA1c (%) between D (-0.20) and placebo (-0.10) was not different (P=0.459). At 6 months, changes from baseline in DCP, FPG, PPG and HbA1c were not different between groups.    ie modest Oral D3 supplementation   in type 2 diabetes was associated with transient improvement in glycaemia, but without a measurable change in beta-cell function.  this effect is unlikely to be biologically significant. This modest   dose D3  ie 42000iu/ week to eventual bloodlevel of only 50ng/ml therefore appears to offer little or no therapeutic benefit in type 2 diabetes.   THE DOSE THEY USED IN FACT PRODUCED STEADYSTATE VIT D3 LEVEL HALF THE POSTULATED TARGET LEVEL OF 90-100 ng/ml FOR SERIOUS ILLNESS.

J Asthma. 2014 Nov  Efficacy of high-dose vitamin D in pediatric asthma: a systematic review and meta-analysis.
Pojsupap , McNally ea Univ Ottowa :   studies  suggest a relationship between vitamin D status and asthma-related respiratory outcomes.  benefit of vitamin D supplementation for pulmonary function, symptoms and exacerbations is not well established.   Clinical trials reporting asthma-related respiratory outcomes following vitamin D administration at a dose equal or greater than 500 IU per day were included. Results:  five studies  met study eligibility and assessed final data synthesis. The median trial size was 48 participants (range 17-430) and the average daily dose of cholecalciferol ranged from 500 to 2000 IU/day. Meta-analysis suggested a statistically significant reduction (RR 0.41, CI 0.27-0.63) in asthma exacerbation with vitamin D therapy.

   J Infect Dis. 2013 Feb .  Vitamin D status and incidence of pulmonary tuberculosis, opportunistic infections, and wasting among HIVinfected Tanzanian adults initiating antiretroviral therapySudfeld,  Fawzi ea . Maintaining vitamin D sufficiency may decrease the incidence of pulmonary tuberculosis and other infectious diseases. We present the first prospective study of vitamin D among human immunodeficiency virus (HIV)-infected adults receiving antiretrovirals in sub-Saharan Africa.   Serum 25(OH)level was assessed at antiretroviral therapy (ART) initiation for 1103 HIVinfected adults enrolled in a trial of multivitamins (not including vitamin D) in Tanzania.After multivariate adjustment, vitamin D deficiency (defined as a concentration of <20 ng/mL) had a 3 fold significantly greater association with incident pulmonary tuberculosis, compared with vitamin D sufficiency (HR, 2.89;  [CI], 1.31-7.41; P = .027), but no association was found for vitamin D insufficiency (defined as a concentration of 20-30 ng/mL; P = .687). Deficiency was also significantly associated with incident oral thrush (HR, 1.96; 95% CI, 1.01-3.81; P = .046), wasting (HR, 3.10; 95% CI, 1.33-7.24; P = .009), and >10% weight loss (HR, 2.10; 95% CI, 1.13-3.91; P = .019). Wasting results were robust to exclusion of individuals experiencing pulmonary tuberculosis. Vitamin D status was not associated with incident malaria, pneumonia, or anemia.

update 22 Dec 2014:  as the solstice rolls by,  infections especially viral  flourish north and south,  from flu to gastro , HIV to ebola; HPV  to HZV to childhood exanthems;

so more reason to aim for optimal growth, mental and physical health with the peak anabolic antidepressant energizing anticancer antiinfective steroid –  cholecalciferol D3 – intake and levels.   About 65 000iu a week (with my multivit-multimineral combo)  puts my measured trough 25OHvit D  bloodlevel at 92ng/ml with normal blood calcium. Women can live long  without much androgen apart from frail bones, but not well without vigorous cholecalciferol D3 intake. Humans who live mostly bare  mostly outdoors- us  naked apes-  most of the year closer to the equator  make plenty of D3 from sunshine; but the darker our skins, the sooner vit D production shuts down; so  most of us need vigorous D3 supplement costing perhaps US$6 a year retail. .

update 19 Nov 2014  when this column on vit D started 5 years ago, there were 46000 vit D entries on Pubmed- this has mushroomed 40% to 61000 (compared now to 46000 on vit A; to 53000 on vitamin C; 37000 on vitamin E; 17000 on vit K; and 133000 on all  the 8 B vitamins ); whereas in 2009 there were 272500 entries on all vitamins– now up only 22% to 335 000. ie the papers on the secosteroid  vitamin D have risen at double the rate of the  vitamins.. (D3  C27H44O and D2 C28H44O, vs testosterone C19H28O2).

As the end-of-year solstice approaches, its time to review the crucial role of giving vigorous doses of vitamin D3, whether via   non-burn sunshine, or via the correct lowpressure tanning bed, or directly as vitamin D3  (not vit D2) supplement as appropriate TOGETHER WITH A MULTINUTRIENT PLUS EXTRA MAGNESIUM AND VIT K2. . Ironically, dermatologists would recommend vit D supplement not suntan for what many  consider the wrong reason- that suntanning does more harm than good, which it doesnt. :

at least THIRTEEN   VIT D  studies the past 16 years  SINCE 1998, from ~8 nations-  USA, Canada, Belgium, Spain , Germany, Denmark, UK  &  New Zealand,   – show  POORER   RESULTS  FROM TAKING TOO LITTLE VIT D; OR FROM USING VITAMIN D2 not D3, apparently by suppressing the crucial vit D3 level, and because vit D2 is metabolized faster. :

a new OBSERVATIONAL study in Am J Clin Nutr. Nov 2014  from the Cambridge EPIC-NORFOLK  group by  Kay-Tee Khaw,  Nicholas Wareham ea   Serum 25-hydroxyvitamin D, mortality, and incident cardiovascular disease, respiratory disease, cancers, and fractures: a 13-y prospective population study    examined prospective relation between serum  [25(OH)D] concentrations [which comprised 25(OH)D3 and 25(OH)D2] and subsequent mortality  in 14,641 men and women aged 42–82 y in 1997–2000  in Norfolk, UK followed up to 2012; categorized into 5 groups according to baseline serum concentrations of total vit D from below 30nmol/L to above 90nmol/L..  mean serum total 25(OH)D was 56.6 nmol/L 22ng/ml, which consisted predominantly of 25(OH)D3 (mean: 56.2 nmol/L; 99% of total). The age-, sex-, and month-adjusted HRs  for all-cause mortality (2776 deaths) for men and women by increasing vitamin D category were 1, 0.84 (0.74, 0.94), 0.72 (0.63, 0.81), 0.71 (0.62, 0.82), and 0.66 (0.55, 0.79) (P-trend < 0.0001). When analyzed as a continuous variable and with additional adjustment for body mass index, smoking, social class, education, physical activity, alcohol intake, plasma vitamin C, history of cardiovascular disease, diabetes, or cancer, HRs for a 20-nmol/L increase in 25(OH)D were 0.92 (0.88, 0.96) (P < 0.001) for total mortality, 0.96 (0.93, 0.99) (P = 0.014) (4469 events) for cardiovascular disease, 0.89 (0.85, 0.93) (P < 0.0001) (2132 events) for respiratory disease, 0.89 (0.81, 0.98) (P = 0.012) (563 events) for fractures, and 1.02 (0.99, 1.06) (P = 0.21) (3121 events) for incident total cancers.    Conclusions: Plasma 25(OH)D concentrations predict subsequent lower 13-y total mortality and incident cardiovascular disease, respiratory disease, and fractures but not total incident cancers. For mortality, lowest risks were in subjects with concentrations >90 nmol/L ie 36ng/ml, and there was no evidence of increased mortality at high concentrations, suggesting that a moderate increase in population mean concentrations may have potential health benefit, but <1% of the Norfolk population had concentrations >120 nmol/L 48ng/ml.

Chowdhury , Franco  ea  also University of Cambridge,  UK. BMJ. 2014 Apr .   Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies.    Study specific relative risks from 73 cohort studies (849,412 participants) and 22 randomised controlled trials (vitamin D given alone versus placebo or no treatment; 30,716 participants). In the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements. In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D3 supplementation and 1.04 (0.97 to 1.11) for vitamin D2 supplementation. The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods.

in a systematic review and meta-analysisTripkovic ,, Lanham-New  ea . Univ Surrey  Am J Clin Nutr. 2012Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: In the collective 10 studies, 1016 participants aged 18–97 yrs, men to women  ∼1:3;  vitamin D3 had a significant and positive effect in the raising of serum 25(OH)D concentrations compared with  vitamin D2 (P = 0.001). When the frequency of dosage administration was compared, there was a significant response for vitamin D3 when given as a  BOLUS dose (P = 0.0002) compared with administration of vitamin D2, but the effect was lost with daily supplementation.. The studies were  in the United States, Canada, United Kingdom, Australia, Denmark, and Italy; all studies were single-center studies. Seven studies were conducted in healthy, free-living participants (4, 6, 7, 12, 13, 15, 17);

WE so far FIND AT LEAST 12 RELEVANT COMPARATIVE VIT D3/D2  TRIALS in humans and one in cows:

1.  Karen Hansen ea at Univ Wisconsin 2014  An evaluation of high-dose vitamin D for rheumatoid arthritis   show  that  giving vitamin D2  (not D3)  50 000iu fortnightly for a year is actually adverseIT DEPRESSES – perhaps halves – THE BIOLOGICALLY ACTIVE blood 25OHVIT D3 while boosting perhaps 5 fold the far less active blood 25OHvit D2 levels , and actually worsens  rheumatoid arthritis clinically and serologically .

     2. Vitamin D2 supplementation amplifies eccentric exercise-induced muscle damage in  athletes. Nutrients.  Nieman , Luo  EA. A, North Carolina  2013:6:63-75. Six weeks vit D2 (3800 IU/day) increased serum 25(OH)D2 fourfold  and decreased 25(OH)D3   by a fifth  versus placebo (p<0.001, p=0.036, respectively), with no influence on muscle function test scores, AND worsened  muscle damage .

    3. Swanson, Barrett-Connor, ea USA & Belgium May 2014 : In a cohort of older men,   Higher 25(OH)D2 is associated with lower 25(OH)D3 and 1,25(OH)2D3  , suggesting that vitamin D2 may decrease the availability of D3 and may not increase calcitriol.

4.Lehmann,  Dierkes ea  Germany 2013    in the same leading scientific journal  Bioavailability of vitamin D(2) and D(3) in healthy volunteers, a randomized placebo-controlled trial-  giving vit D2 2000iu/day for 8 wks in healthy volunteers actually halves the crucial 25hydroxy vit D3 level;  whereas giving vit D3 2000iu/d  doubles the vit D3 level. Earlier studies have suggested that vitamin D2 is less biologically active  than vit D3.

5. Biancuzzo, Holick ea Boston Mass. 2013 Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation  in healthy adults 18 to 79 years consuming 1000 IU vitamin D2 or vitamin D3 per day for 11 weeks at end of winter was analyzed.  Of the adults, 82% were vitamin D insufficient (serum 25-hydroxyvitamin D [25(OH)D <30 ng/mL]) at the start of the study. Administration of vitamin D2 and vitamin D3 induced similar increases (from baseline ~20ng/ml 25OH vit D)  in total 25(OH)D as well as in 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, respectively. Compared with placebo and adjusting for baseline levels, 1000 IU daily of vitamin D2 was associated with a mean increase of 7.4 pg/mL (95% confidence interval, 4.4-10.3) in 1,25(OH)2D2, and  decrease of 9.9 pg/mL (-15.8 to -4.0) in 1,25(OH)2D3. No such differences accompanied administration of 1000 IU daily of vitamin D3.

    6. Leventis P1, Kiely PD. London 2009 in  Scand J Rheumatol. Good Tolerability and biochemical effects of high-dose bolus vitamin D2 and D3 supplementation in patients with vitamin D insufficiency in 69 RHEUMATOLOGY patients with vitamin D insufficiency [25-hydroxyvitamin D (25(OH)D) <40 nmol/L]  50 patients study 1 received 300 000 IU i.m. vitamin D2 (ergocalciferol), 19 patients  in study 2 received 300 000 IU oral vitamin D3 (cholecalciferol) . Bolus i.m. vitamin D2 or oral vitamin D3 was well tolerated.  change from baseline in serum 25(OH)D was significantly greater at 6 and 12 weeks in study 2 (p<0.0001 ). In study 1, a modest increase in mean serum 25(OH)D at 6, 12, and 24 weeks was observed but no patients achieved a serum 25(OH)D concentration > or = 50 nmol/L. PTH remained elevated in 42% of patients with secondary hyperparathyroidism at 12 weeks. In study 2, 100% and 89% of patients had serum 25(OH)D>50 nmol/L at 6 and 12 weeks, respectively. All patients with elevated baseline PTH were fully suppressed at 12 weeks. No hypercalcaemia was observed in either group. The 300 000-IU bolus of vitamin D2 or D3 was practical, well tolerated, and safe. Vitamin D3 had greater potency than equimolar vitamin D2, with a higher, sustained serum 25(OH)D response and efficacious PTH suppression.


    7.  Sempos CT1, Picciano MF ea . USA  J Clin Endocrinol Metab. 2013 Jul;98(7):3001-9..  Is there a reverse J-shaped association between 25-hydroxyvitamin D and all-cause mortality? Results from the U.S. nationally representative NHANES.       A reverse J-shaped association between serum 25-hydroxyvitamin D (25[OH]D) concentration and all-cause mortality was suggested in a 9-year follow-up (1991-2000) analysis of the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). We repeated  the analyses with 6 years additional follow-up  in 15 099 participants aged ≥ 20 years with 3784 deaths, to evaluate whether the association persists through 15 years of follow-up. The reverse J-shaped association became stronger with longer follow-up and was not affected by excluding deaths within the first 3 years of follow-up. Similar results were found from both statistical approaches for levels <20 through 119 nmol/L. Adjusted RR (95% confidence interval [CI]) estimates for all levels <60 nmol/L were significantly >1 compared with the reference group. The nadir of risk was 81 nmol/L 32pg/mL (95% CI, 73-90 nmol/L 29-36pg/ml). The association appeared in men, women, adults ages 20 to 64 years, and non-Hispanic whites but was weaker in older adults.  A reverse J-shaped association between serum 25(OH)D and all-cause mortality appears to be real. It is uncertain whether the association is causal.

    8.  Logan  Houghton ea   Br J Nutr. New Zealand 2013;109:1082-8.   Long-term vitamin D3 supplementation is more effective than vitamin D2 in maintaining serum 25-hydroxyvitamin D status over the winter months.  Public health recommendations dont distinguish between vitamin D2 and vitamin D3, yet disagreement exists on whether these two forms should be considered equivalent.  over the winter in healthy adults living in Dunedin, New Zealand (latitude 46°S), Participants aged 18-50 years were randomized   to 1000 IU vitamin D3 (n 32), 1000 IUvitamin D2 (n 31) or placebo (n 32) daily for 25 weeks beginning at the end of summer. After 25 weeks, participants randomised to D2 and placebo had a significant reduction in serum 25(OH)D3 concentrations over the winter months compared with vitamin D3-supplemented participants (both P< 0.001). Supplementation with vitamin D2 increased serum 25(OH)D2 but produced a 9 (95 % CI 1, 17) nmol/l greater decline in the 25(OH)D3 metabolite compared with placebo (P< 0.036). Overall, total serum 25(OH)D concentrations were 21 (95 % CI 14, 30) nmol/l lower in participants receiving vitamin D2 compared with those receiving D3 (P< 0.001), among whom total serum 25(OH)D concentrations remained unchanged. No intervention-related changes in PTH were observed. Daily supplementation of vitamin D3 was more effective than D2;

    9  Seijo M1Oliveri B. ea  Spain  Medicina (B Aires). 2012;72:195-200.  [Is daily supplementation with vitamin D2 equivalent to daily supplementation with vitamin D3 in the elderly?].    equivalence of cholecalciferol (D3) and ergocalciferol (D2) as well as their corresponding doses and administration route remain controversial to date. Twenty-one ambulatory postmenopausal women from Buenos Aires with a mean  age of 77 ± 6.8 years  were randomly assigned to one of the following groups: GD2 (n = 13): 800 IU (drops) and GD3 (n = 8): 800 IU (pills).  Nineteen out of twenty one women showed deficient levels of 25OHD at baseline (< 20 ng/ml): GD2: 14.0 ± 4.8 ng/ml and GD3: 13.2 ± 4.9 ng/ml (NS). Whereas only GD3 exhibited an increase (≈ 25%) at 7 days, both groups showed a significant increase at the end of the study. However, neither attained adequate 25OHD levels (GD2: 17.4 ± 5.5 vs. GD3:22.9 ± 4.6 ng/ml; p < 0.001). Administration of 800 IU of vitamin D3 during 45 days was more effective than D2 in increasing 25OHD, but both failed to achieve adequate levels of 25OHD (= 30 ng/ml). but neither succeeded in achieving adequate levels of 25OHD (= 30 ng/ml).

    10 Holick  Tannenbaum ea usa   J Clin Endocrinol Metab. 2008;93:677-81. Epub 2007 Dec 18.IN LOW DOSE eg 1000iu/d,   Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin A 1000 IU dose of vitamin D2 daily was as effective as 1000 IU vitamin D3 in maintaining serum 25-hydroxyvitamin D levels and did not negatively influence serum 25-hydroxyvitamin D3 levels. Therefore, vitamin D2 is equally as effective as vitamin D3 in maintaining 25-hydroxyvitamin D status.
     11 Armas ,  Heaney ea.Creighton Univ Nebraska.  J Clin Endocrinol Metab. 2004 ;89:5387-91. Vitamin D2 is much less effective than vitamin D3 in humans.Vitamins D(2) and D(3) are generally considered equivalent in humans. Nevertheless, physicians commonly report equivocal responses to seemingly large doses of the only high-dose calciferol (vitamin D(2)) available in the U.S. market. Relative potencies of vitamins D(2) and D(3) were evaluated by administering single doses of 50,000 IU of the respective calciferols to 20 healthy male volunteers, following the  serum vitamin D over 28 d.. The two calciferols produced similar rises in serum concentration, indicating equivalent absorption. Both produced similar initial rises in serum 25OHD over the first 3 d, but 25OHD continued to rise in the D(3)-treated subjects, peaking at 14 d, whereas serum 25OHD fell rapidly in the D(2)-treated subjects and was not different from baseline at 14 d. Area under the curve (AUC) to d 28 was 60 ng.d/ml for vitamin D(2) and 204 for vitamin D(3) (P < 0.002). Calculated AUC(infinity) indicated an even greater differential, with the relative potencies for D(3):D(2) being 9.5:1. Vitamin D(2) potency is less than one third that of vitamin D(3). Physicians resorting to use of vitamin D(2) should beware of its markedly lower potency and shorter duration of action relative to vitamin D(3)

    12 Trang,  Vieth ea  University of Toronto, Am J Clin Nutr. 1998Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. In all species tested, except humans, biological differences between vitamins D2 and D3 are accepted as fact.  Subjects took 260 nmol (approximately 4000 IU) vitamin D2 (n=17) or vitamin D3 (n=55) daily for 14 d.  With vitamin D3, mean (+/-SD) serum 25(OH)D increased from 41+/-18 nmol/L before to 65+/-17 nmol/L after treatment. With vitamin D2, the 25(OH)D concentration went from 434+/-18 nmol/L before to 57+/-13 nmol/L after. The increase in 25(OH)D with vitamin D3 was 23+/-16 nmol/L, or 1.7 times the increase obtained with vitamin D2 (14+/-11 nmol/L; P=0.03). There was an inverse relation between the increase in 25(OH)D and the initial 25(OH)D concentration.  In the highest tertile [25(OH)D >49 nmol/L] the mean increase in 25(OH)D was 13.3 nmol/L (P < 0.03 for comparison with each lower tertile). Although the 1.7-times greater efficacy for vitamin D3 shown here may seem small, it is more than what others have shown for 25(OH)D increases when comparing 2-fold differences in vitamin D3 dose. The assumption that vitamins D2 and D3 have equal nutritional value is probably wrong and should be reconsidered.

13.  Hymøller L1, Jensen SK.Denmark   J Dairy Sci. 2011;94:3462-6.  Vitamin D₂ impairs utilization of vitamin D₃ in high-yielding dairy cows in a cross-over supplementation regimen.   D(3) given after D(2) is less efficient at increasing the plasma status of 25(OH)D(3) than D(3) given without previous D(2) administration.

A Vitamin D Expert’s Take on the Latest Warning to Stay Out of the Sun to Avoid Skin Cancer

By Dr. Mercola  16/11/2014  The US Surgeon General recently came out with a warning on skin cancer,1 claiming that the sun is dangerous and that you need to stay away out of it.

pioneer Dr. John Cannell, founder of the Vitamin D Council, has dedicated a large part of his professional career to the study of vitamin D and its health benefits, and he has a warning of his own to those who take this narrow-minded advice to heart.

It’s worth noting that the acting Surgeon General, Boris Lushniak, is a dermatologist. And of all the medical specialties out there, dermatologists are clearly the most biased against sun exposure, & as a result, against vitamin D.

This isn’t surprising, since they primarily see the ill effects of sun overexposure. But in taking an overly narrow view, the advice to avoid sun exposure as much as possible can have equally if not greater adverse health effects.                      The Connection Between Sun Exposure and Skin Cancer Unquestionably, UV   radiation can be dangerous; it can increase your risk for certain skin cancers such as squamous cell, basal cell, and melanoma. But there are significant differences even between these cancers, and appropriate sun exposure may actually be more beneficial than detrimental in some cases. Dr. Cannell explains:

“Squamous cell carcinoma is clearly associated with chronic sun exposure. It is more common on the face, the hands, and the scalp.

It is related to radiation burden over your lifetime, and together with basal cell carcinoma, which is sort of intermediate, it accounts for approximately 1,500 deaths a year in the United States…

Basal cell is sort of intermediate. There are studies showing that it is associated with chronic sun exposure, and there are studies showing that it’s not associated with chronic sun exposure.

And then there’s melanoma, which is responsible for almost 9,000 deaths a year and is the deadly skin cancer that is feared. The relationship that melanoma has with the sun is quite complicated.

It is clearly associated with sunburn, especially sunburns when you’re young (that’s incontrovertible) or sunburns in a sun tanning bed.”

However, there are at least two studies showing that melanoma is more common in indoor workers than outdoor workers. And the most likely places for melanoma to appear are actually NOT the face and the hands like squamous cell carcinoma, but rather the lower back and the upper leg—areas that are usually not chronically sun-exposed.

According to Dr. Cannell, there’s a vocal minority in the dermatological community that thinks the emphasis dermatologists have on avoiding sun exposure is wrong, because while sunburn is a risk factor, chronic sun exposure is not.

“A number of studies show that chronic sun exposure is related to melanoma, but they don’t separate out the sunburns, which is very hard to do because you have to do that by memory,” Dr. Cannell says.   Two Decades-Long Study Finds Sun Avoidance Doubles Risk of Death  Dr. Cannell notes a recent study2 done in Sweden, which followed nearly 30,000 middle-aged to older women for up to 20 years. The average follow-up was 15 years.

At the outset, they asked a number of questions about sun exposure, such as: Do you sunbathe? Do you take vacations in sunny areas in the winter? Do you garden with short sleeves and shorts? And, do you use sunbeds?

What they found, and this appears to be the only study of this kind, is that the women who avoided the sun were twice as likely to die over the course of the study. The researchers attributed this finding to a vitamin D mechanism.

What this study actually shows is that chronic sun exposure appears to be associated with less mortality. It’s also the first study to show that women who use tanning beds live longer than those who don’t.

This is in direct conflict to what almost every dermatologist will say, including the Surgeon General. It’s unfortunate, but the danger of almost any specialist is that they don’t take the broader perspective.

What the Surgeon General and almost every other dermatologist fail to take into account is the overall mortality, which is referenced in this recent study.  Risk-Benefit Analysis In addition to this study, dozens of others document the benefits of appropriate sun exposure. This includes a reduced risk of about 16 different cancers of Dr. Garland’s studies suggest this reduction is close to 50 percent.

So many hundreds of thousands of people are put at risk from other cancers as opposed to 10,000 people who are dying from skin cancer caused by sunburn. It’s really a matter of making an educated risk-benefit analysis.

“When you do a risk-benefit analysis and you look at all the data we have, the risk in my opinion appears to be in those who avoid the sun,” Dr. Cannell says.

“Now, if you avoid the sun, your risk for non-melanoma skin cancer goes down. That’s clear. But if you look at studies of either latitude or of 25-hydroxyvitamin D levels in relation to cancer, you find this inverse relationship: the higher the vitamin D level, the lower the internal cancer rate.”

Dr. William Grant of Sunlight, Nutrition, and Health Research Center (SUNARC) estimates that if everyone in the United States had a vitamin D level of 40 nanograms per milliliter (ng/ml), it would save approximately 150,000 lives a year.3

That’s 100 times the rate of squamous cell cancers, which are the only ones that are definitively linked to UV exposure. In Canada alone, it is estimated that 37,000 lives a year are lost due to vitamin D deficiency.4 Also, use of sunscreen has risen in the last 30 years, so if dermatologists were correct, there should be a decrease in stage 1 melanoma. But there’s not. As sunscreen use increased, stage 1 melanoma diagnosis increased…

“It’s thought that by blocking out UVB, patients are able to stay out in the sun longer than they would have otherwise and expose themselves to the more dangerous, or at least potentially dangerous, UVA radiation that’s in the sunshine,” Dr. Cannell says. “What we recommend is what’s called safe, sensible sun exposures. The Australian Cancer Council now recommends the same thing. I think in England there’s now a change in their recommendation from strict sun avoidance to some safe, sensible sun exposure. There are some movements in large organizations to realize that safe, sensible sun exposure is a healthy thing.”            

How Much Sun Exposure Is Sensible?    On its website, Cancer Research UK reports that “by enjoying the sun safely and avoiding sunburn, people can reduce their risk of skin cancer and enjoy the beneficial effects of the sun.” Cancer Research UK’s sun advice is endorsed by the British Association of Dermatologists, Cancer Research UK, Diabetes UK, the Multiple Sclerosis Society, the National Heart Forum, the National Osteoporosis Society, and the Primary Care Dermatology Society. The UK National Health Service5 also recommends sensible, individualized sun exposure to help optimize vitamin D.

It’s important to recognize is how quickly sunlight can make vitamin D in the skin. You don’t need to be outside for hours on end. But you do need more than just a few minutes of sun on your face and arms. According to Dr. Cannell, sunbathing at solar noon in the summer, at most latitudes in the United States you will make between 5,000-10,000 international units (IUs) of vitamin D within 30 minutes.

“You can ask yourself why nature would evolve a mechanism that made so much vitamin D so quickly,” Dr. Cannell says. “When I thought about that question, the only answer I could come up with is nature did it for a good reason. The organism needs vitamin D, so the system in the skin evolved to make it very quickly upon exposure to sunlight.

We recommend full-body sun exposure for up to anywhere from a few minutes to 30 minutes every day. On those days when you cannot get a full-body sun exposure, we recommend a vitamin D supplement or sensible exposure in a low-pressure UVB bed.”

If you’re getting regular sun exposure, I think the need for an oral supplement is really minimal to non-existent. When you swallow a pill, there’s no self-regulating ability. Your body doesn’t have an ability to selectively limit its absorption. But your skin has the ability to control how much vitamin D is being produced based on how much is in your blood.

I personally have not taken oral vitamin D for five years and my level runs from 50-70 g/ml. Lifeguards, roofers, and gardeners who work with their shirt off, all tend to have levels between 40 and 80 ng/ml in the summer. This also brings up an interesting question about the difference between normal and natural. Normal vitamin D levels are an average of what indoor workers have in both winter and summer. Natural are levels of a population with widespread sun exposure. The latter is going to be closer to ideal, or optimal.

vitamin d levels
References for establishment of optimal levelsThere are also other reasons to strive for sun exposure rather than swallowing a pill. As noted by Dr. Cannell, aside from producing vitamin D, sunlight also affects nitric acid levels and endorphins in the skin. Researchers at the University of Wisconsin recently discovered that there may be a system at 311 nanometers that is separate from the vitamin D system (which is at 298 nanometers), and that there may be an entirely new undiscovered biochemical system in the skin that makes yet another substance, besides vitamin D. Time will tell what comes out of that research, but there are indications that sunlight may be responsible for other biological processes that are unrelated to vitamin D production.

Dr. Cannell’s Recommendation on Tanning Beds There are basically two
types of tanning beds:

  1. 1. High-pressure UVA beds. They tan you the quickest because it’s UVA that tans the skin. They contain only a limited UVB spectrum, and will therefore give you color but not much vitamin D
  2. Low-pressure beds, which contain less UVB than sunlight at most latitudes, but still contain a significant amount of UVB. These are the beds Dr. Cannell recommends, provided you’re using a sensible approach that avoids sunburns. It’s important to realize that you can easily get burned after only a couple or a few minutes when using a tanning bed

Another important factor when selecting a tanning bed is the type of ballast it employs, to avoid excessive electromagnetic field (EMF) exposure. Most tanning units use magnetic ballasts to generate light. These magnetic ballasts are well known sources of EMF fields that can contribute to cancer. If you hear a loud buzzing noise while in a tanning bed, it has a magnetic ballast system. I strongly recommend you avoid magnetic ballast beds, and restrict your use of tanning beds to those that use electronic ballasts.

On days you cannot get either regular sun exposure or use of a tanning bed, Dr. Cannell suggests taking 5,000 IUs of vitamin D3. Other vitamin D experts recommend similar amounts. It’s worth noting that, according to the federal government’s Food and Nutrition Board (FNB), the no observed adverse effects level (NOAEL) of vitamin D is 10,000 IUs a day. This means there has never been a replicated reliable study showing that 10,000 units a day is in any way detrimental.

Many individuals who have reported side effects from taking high doses of oral vitamin D have noticed that when they supplemented with magnesium, they were able to tolerate the high oral doses of vitamin D. Dr. Carolyn Dean has written in her book, The Magnesium Miracle, that she has seen this so many times that she doesn’t advise taking more than 2,000 units of vitamin D without magnesium supplementation. Be sure to also have an adequate amount of vitamin K2 along with D to slow the progression of arterial calcification. Remember though that the best form of vitamin D is the one your body produces when it is exposed to sunlight that has sufficient amounts of UVB.

Five Tips to Get an Appropriate, Sensible Amount of Sun  Again, sunshine offers substantial health benefits, including vitamin D production, but you do need to exercise a few simple precautions to protect yourself from overexposure. Virtually all of the harm from sun exposure is related to sunburn. Here are my top five tanning tips:   *  Expose large amounts of your skin (at least 40 percent of your body) to sunlight for short periods daily. Optimizing your vitamin D levels may reduce your risk of as many as 16 different types of cancer, including pancreatic, lung, ovarian, breast, prostate, and skin cancers. If using a sunscreen, give your body a chance to produce vitamin D before you apply it. *When you’ll be in the sun for longer periods, cover up with clothing, a hat, or shade (either natural or shade you create using an umbrella).  *Consider the use of an “internal sunscreen” like astaxanthin to gain additional sun protection. Astaxanthin is a potent antioxidant (and pigment) produced by marine algae in response to their exposure to UV light. Typically, it takes several weeks of daily supplementation to saturate your body’s tissues enough to provide protection. *Consuming a healthy diet full of natural antioxidants is another useful strategy to help avoid sun damage. Fresh, raw, unprocessed vegetables and fruits deliver the nutrients that your body needs to maintain a healthy balance of omega-6 and omega-3 oils in your skin, which is your first line of defense against sunburn. Vegetables also provide your body with an abundance of powerful antioxidants that will help you fight the free radicals caused by sun damage that can lead to burns and cancer.

How Vitamin D Performance Testing Can Help Optimize Your Health  A robust and growing body of research clearly shows that vitamin D is absolutely critical for good health and disease prevention. Vitamin D affects your DNA through vitamin D receptors (VDRs), which bind to specific locations of the human genome. Scientists have identified nearly 3,000 genes that are influenced by vitamin D levels, and vitamin D receptors have been found throughout the human body.

  14  Oct 2014 update:  MORE ON OPTIMAL VITAMIN D3  DOSE, AND THE DIFFICULTY OF ACHIEVING CLINICAL  OVERDOSE:      Four  new reports highlight  how  difficult, and important  it is to achieve adequate optimal bloodlevels of vitamin D with vigorous vitamin D3 supplements, let alone overdose with any significant adversity: note three   used the  recommended vitamin D3,   not the long-condemned mislabeled Lennons/Aspen vitamin D2 (which is misleadingly labelled  “caciferol” without disclosing that it is D2 not D3). Even a single  2 million iu overdose of vit D3 in nonagenarians had no adverse effect-since the bloodlevel was back to zero by 3 weeks, thats above 100 000iu/day on average….

 with serum 25-hydroxy vitamin D (25(OH)D) < 30 ng/mL  on  placebo or vitD3 (n = 35)   60,000 units/week for 6 weeks.   mean baseline level of 25(OH)D was 9.6+-9.6 ng/mL, and after 6 weeks doubled to 19.5 ± 4.3 ng/mL,  (P < 0.0001). After discontinuing supplement at 6 weeks, serum 25(OH)D level dropped moderately  by  12 weeks (16.1 ± 8.3 ng/mL) as compared with the baseline.  The change in serum 25(OH)D level from baseline to 6 weeks in the intervention group was inversely related to baseline 25(OH)D levels and patient’s weight. In the control group, change in 25(OH)D was not significant.  Thus  vit D3 about
10 0000iu/day in these small and often malnourished people raises bloodlevel by only about 10ng/mL.
        Kearns ,Tangpricha ea, Emory University Georgia USA   in Eur J Clin Nutr. 2014 Oct 1 describe    The effect of  single  250 000iu bolus of vitamin D3  in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial.   At baseline, young healthy participants had a mean plasma 25(OH)D concentration of 17.5±6.1 ng/ml. Only two subjects exhibited plasma 25(OH)D concentrations >30 ng/ml. At 5 days, subjects on  vitamin D3 had  only doubled mean plasma 25(OH)D (39 vs 19 ng/ml, P<0.001). Plasma 25(OH)D concentrations returned to baseline by  90 and 365 days in the vitamin D3 group,  remained unchanged in the placebo group. PTH and calcium concentrations were unrelated to changes in 25(OH)D levels and similar between groups over time.

   van den Ouweland ,  Vollaard ea  Nijmegen, The Netherlands in    BMC Pharmacol Toxicol. 2014 Sep 30   describe  Pharmacokinetics and safety issues of an accidental oral overdose of 2,000,000 IU of vitamin D3 in two nonagenarian nursing home patients: a case report.    Oral overdose of 2,000,000 IU of vitamin D3 in two nonnagenarian  nursing home patients was monitored from 1 hr up to 3 months . Peak blood 25(OH)D3 concentrations were observed 8 days after intake (210  and 162ng/mL, respectively (ref: 20-80 ng/mL),   followed by a rapid decrease to undetectable levels after day 14.  Remarkably, plasma calcium levels increased only slightly up to 2.68 and 2.73 mmol/L, respectively (ref: 2.20-2.65 mmol/L) between 1 and 14 days after intake,; phosphate and creatinine levels remained within reference range. No adverse clinical symptoms were noted.   CONCLUSION:A single massive oral dose of 2,000,000 IU of vitamin D3 does not cause clinical toxicity requiring hospitalization. Toxicity in the long term cannot be excluded as annual doses of 500,000 IU of vitamin D3 for several years have shown an increase in the risk of fractures. This means that plasma calcium levels may not be a sensitive measure of vitamin D toxicity in the long term in the case of a single high overdose. 

            As previously reported, to avoid dehydration stones and vascular calcification – especially in hot dry climates – , the precautions with vigorous vit D3   are to add some vit K2 and magnesium to the supplement, and maintain good water intake .
           The fourth current paper, from Morocco, reports inexplicable use of dangerous massive dose of vit D2 in neonates- amounting to about 120 000iu/kg ie about 12 times the maximum adult dose reported :   Hmami , Bouharrou  ea Morocco University,  Arch Pediatr. 2014 Oct;21:1115-9.        [Overdose or hypersensitivity to vitamin D   Vitamin D intoxication with severe hypercalcemia is rare in the neonatal and infancy period. 9 babies between ages of 25 and 105 days were admitted  for treatment of severe dehydration  8 to 15% with  hypercalcemia, with preserved diuresis and loss weight between 100 and 1100 gm secondary to taking 600,000 units of vitamin D (Sterogyl(®). The pregnancies & deliveries  were normal. Clinical signs were dominated by weight loss, vomiting, and fever. The vitamin D values in nine patients were toxic (mean 220: 139 – 300 ng/mL, ; normal >20ng/mL; toxicity if >100ng/mL). Nephrocalcinosis was shown  in seven patients. DNA study  in eight patients, did not reveal a mutation of the vitamin D 24-hydroxylase gene (CYP24A1). Treatment consisted of intravenous rehydration with diuretics and corticosteroids. Serum calcium returned to  normal range within 4-50 days, with weight gain progressively over the following weeks. The follow-up (2 years for the oldest case) showed persistence of nephrocalcinosis. Genetic susceptibility and metabolic differences appear to modulate the threshold of vitamin D toxicity. However, respect for recommended doses, recognized as safe in a large study population, reduces the risk of toxicity.
and as in adults,    Yao ,  Huang  ea  Prediction of Allergies in Taiwanese Children (PATCH) Study Group in  J Pediatr. 2014 Oct 1 demonstrate a significant relationship between insufficient serum vitamin D levels and worse lung function in children in the community with a suggested dose-response effect.

VITAMIN D3 DOSE: We get excellent results in outpatient adults with loading oral dose of  vit D3 of about 200 000 to 400 000iu depending on illness severity and body mass; then pro rata about 50 000iu  per week till better, tapering to fortnightly when well; pro rata in kids. We monitor calcium and 25OH vitamin D3 levels occasionally  if affordable – but with the tapering regime, and published data, do not see or expect hypercalcemic problems from a mean conservative weekly maintenance dose of about 3500iu/d longterm, with predicted bloodlevel of 25OHvitD of about 35-40ng/ml.  As a senior with average chronic dis-ease load, I take ~63 000iu vit D3 weekly, but double it occasionally if I do get a bad cold; so I never miss a day’s work;   recent stress-related shingles (2nd attack in 30 years)  was just a nuisance, settled in 3 weeks with this regime plus multigrams of buffered vit C a day; oral lysine and alphalipoic acid each about 1/2 gm/day; and for a few days some weak steroid and humic acid cream topically for the neuritis and blistering, which has already healed to almost invisible.  This week at a family practice clinic I saw two successive women with shingles – now a frequent occurrence, even  without HIV…

Khan in Toronto in OHDM  this September  describes a ~60yr old man with tongue cancer who was treated inter alia with Vit D3 10 000iu a day; after a year his 25oH vitD level was ~106ng/ml,  when his dose was halved; his dose response  bore out the general experience that at average adult mass, vit D level rises by about 10ng/ml for every 1000iu vit D3 per day or pro rata dose weekly etc  eg 50 000iu/wk or 100 000iu fortnightly may give average vit D level of ~70ng/ml.  .

Singh & Bonham 2014 at Kansas University describe  A Predictive Equation to Guide Vitamin D Replacement Dose in Patients. The recommended daily allowance for vitamin D is grossly inadequate for correcting low serum concentrations of 25-hydroxyvitamin D in many adult patients.  In their population (average BMI 31.5) ,about 5000 IU vitamin D3/day is usually needed to correct deficiency, and the maintenance dose should be ≥2000 IU/day. The required dose may be calculated from the predictive equations specific for ambulatory and nursing home patients”   A BMI of 31.5kg at a mean height of about 1.7m gives a mean weight of 91kg, which at the consensus daily  vit D3 dose of 80iu/kg/d totals ~7100iu/d or 50 000iu/wk- perhaps a reasonable maintenance dose for winter, half  that in summer if reasonable weekly sun exposure. .

29 Sept 2014:       As detailed elsewhere in this column, there is at least 70 years of strong experience worldwide that  all microorganism infections are greatly diminished by natural  prevention (not synthetic vaccines loaded with toxic heavy metals and allergenics eg egg) , and  easily treated ie  thrown off, with vigorous immune-boosting supplements:  (mega)grams a day of vitamin C or as kgs/day of fresh produce;        vitamin D3 80+ iu/kg/d to  >10 000iu/d ie 300 000  to 600 000iu loading dose; then    +-50 000iu/wk,  plus  plenty of skin exposure to sunshine; iodine; zinc; selenium; silver; the other vitamins; Ecchinacea etc.  This applies both to acute and chronic infections and degenerative conditions.

To be used in highrisk cases eg MERS, AIDS, ebola etc: The  landmark trial  Effect of High-Dose Vitamin D3 on Hospital Length of Stay in Critically Ill Patients With Vitamin D Deficiency– The VITdAL-ICU Randomized Clinical Trial  by Amrein, Dobnig ea ,   published   today in JAMA  from Austrian hospitals  is most encouraging about the immense value of vigorous dose and bloodlevels of vitamin D3 against all types of severe disease.  The dose used in this trial (loading dose 540 000iu  =~18000iu/d 1st month, but averaging only ~8000iu/d in the first 3mo) did not achieve vigorous vit D bloodlevel, presumably because the loading dose of vit D3 in oil (540 000iu) was given by tube into the stomachs of critically ill patients; it would have better been given by transdermal injection, or else a much higher loading gastric dose given so as to speedily achieve a bloodlevel of around 70 (60 to 80) instead of half of this that was achieved in the crucial first few weeks .                                      from May 2010 through September 2012 at 5 ICUs the trial recruited  492 medical (60%) and surgical (40%)  critically ill adult white patients , 35% women, BMI mean 27, mean age  64.6 years (SD, 14.7) with vitamin D deficiency (≤20 ng/mL) assigned to receive either vitamin D3 540 000 IU, or  placebo    given orally or via nasogastric tube; ;  followed by monthly maintenance doses of 90 000 IU for 5 months- ie= about 18000iu/day for the first mo, then 90 000iu   mthly ie only 3000iu/d.           .     RESULT: on placebo the 25hydroxyvit D3 level doubled  from 13 at baseline to 17 at a month to 26ng/ml at 6mo.. By contrast, on vit D3 supplement it doubled to 34 at days 3 and 7 and day 28, but up to 46 at 6 months ie only 80% higher than the control group – thus 1/3 to 1/2 of the optimal target; with this, where 100% of patients were below 25OHvitD at baseline ie on admission to ICU, by 7 days, 87% were still in this bracket and none above 60ng/ml on placebo vs 25%  below 20  and 13% above 60 on vit D3; and by 6mo 35% were still that low on placebo, vs 5%  at that low, but 22% above 60 on vit D3. So it is not surprising that Median hospital stay 20 days was not significantly different between groups  Hospital mortality and 6-month mortality were also not significantly different (hospital mortality: 28% for vitamin D3 vs 35% for placebo; hazard ratio [HR], 0.81  P = .18; 6-month mortality: 35.0%  for vitamin D3 vs 42.9%  for placebo; HR 0.78  P  = .09). For the severe vitamin D deficiency subgroup analysis (n = 200), length of hospital stay was not significantly different between the 2 study groups: 19.5 days. Hospital mortality was significantly 40% lower with 28 deaths among 98 patients (28.6% ) for vitamin D3 compared with 47 deaths among 102 patients (46.1% ) for placebo (HR, 0.56 P for interaction = .04), but not 6-month mortality (34.7%] for vitamin D3 vs 50.0%  for placebo- ie 31% lower; HR, 0.60, P for interaction = .12). No serious adverse events were observed. The highest 25-hydroxyvitamin D levels measured were 107 ng/mL on day 7 and 106 ng/mL at month 6- well below the theoretical minimum toxic threshold of 150 or 250ng/ml..”

BUT  compared to the Austrian trial in overweight 27+kg BMI elderly whites given 540 000iu to start  by tube,              in   Salahudfin ea’s  randomized controlled trial in young emaciated   Pakistani men BMI 17.2kg, Vitamin D3 600 000iu  injection (which achieved twice the blood 25OH vit D3 level of the Austrian patients), had  accelerated clinical recovery from tuberculosis with  “impressive clinical (weight gain, chest xray and sputum clearing)  improvement  over 3 months on outpatient TB therapy (Directly Observed Therapy (DOTS) with 2 months of  4 antituberculous drugs followed by 6 months Isoniazid and Ethambutol)  with two doses 600 000iu vit D3 imi (vs placebo inj)  a month apart-  ie = ~20 000iu/d for the first 2 months, but equivalent to about 7 000iu/day over the 3 months treatment period . This dose  of vitamin D is as recommended for vitamin D supplement by the Pakistan Endocrine Society.  Trough  25OH vit D levels increased from about 20 to 90ng/ml.    After 12 weeks, the vitamin D supplemented pts (mean 28 yrs, BMI 17.2kg, 85% moderate to far advanced lung disease)  had  significantly greater mean weight gain (kg) + 3.75,  versus + 2.61, p 0.009; lesser residual disease by chest xray-  30% fewer zones involved 1.35 v/s 1.82 p 0.004,   and 50% or greater reduction in cavity size 106 (89.8%) v/s 111 (94.8%), p 0.035. Vitamin D supplementation led to significant increase in MTBs-induced IFN-g secretion in patients with baseline ‘Deficient’ vitamin D serum levels (p 0.021). Patients in the vitamin D arm and serum < 30 ng/mL (‘Insufficient’ and ‘Deficient’ groups) at enrollment had significantly greater improvements in TB severity scores compared to patients with normal baseline vitamin D levels; p 0.014.”

         “This corresponds with the earliest reports of the benefits of vitamin D in TB patients published in 1848 [21] that describes disease arrest, weight gain and reduction in mortality in patients with TB treated with cod liver oil compared to standard therapy alone. More recently, Martineau et al  [7]  demonstrated that a single oral dose of 2.5 mg (100,000 IU) of vit D2 significantly reduced growth of mycobacteria . A randomized, placebo controlled study on 67 Indonesian patients, by Nursyam et al , Jakarta  [22] reported that pulmonary TB patients given 420,000 IU of vitamin D over 6 weeks  ie 10 000iu/day had significantly higher sputum conversion rates as compared to placebo (p 0.002). Martineau et al. [8] showed that 100,000 IUs of 25-hydroxyvitamin D3 supplementation significantly improved sputum conversion rates in patients with the Taq1 25-hydroxyvitamin D receptor polymorphism of the tt genotype. ”                                                                    .

As Salahuddin ea note, the good results in Pakistan in only 3 months with vigorous  INITIAL dose vit D3  contrasts with Two recently published large randomised, controlled trials of conservative vitamin D3 over months  that achieved far lower blood vitamin D levels found no difference in clinical outcomes or mortality after 400,000 IU of 25-hydroxyvitamin D3 or placebo were given by   Martineau ea  in London, UK to 146 pulmonary TB patients – where mean (trough  or midpoint)  vit D level  (after 100 000iu vitamin D(3) or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment) – was surprisingly only  40ng/ml at 56days – ie after a mean of 7000iu/d by  56 days,  vs 10ng/ml  on placebo)- less than half of the bloodlevel  achieved on vit D3  in the Pakistan trial.

So the Austrian ICU patients would undoubtedly have done much better if given more effective  (ie in critically ill pts intramuscularly imi or subcutaneously) loading dose like the Salhuddin trial did.

 TIME   To SWOP FROM MISNAMED  “STRONG CALCIFEROL” VIT D2 TO THE REAL VIT  D3:     as the winter solstice approaches here, with fierce weather linking to  the expected influenza-like outbreak (while the MERS-CoV outbreak abates with summer in the severely vitamin D deficient Saudi Arabians), a new major study shows the supremacy of vitamin D3 for supplementation, and confirms that vitamin D2 benefit if any  is so mediocre as to be unethical..

Its sad that despite the strong evidence against using vitamin D2 supplement discussed last year,  it seems no one acted on  it despite the confirmatory paper from Bergen of last September.

Thus vit D3 is again confirmed as four times as potent as D2. But crucially, that giving vit D2 may actually SUPPRESS the optimal  serum vit D3  level.

We health professionals with our highly vulnerable populations in South Africa and worldwide   (epidemic/endemic  HIV, TB, cancer, drug addiction, MERS-CoV, asthma, diabetes, cardiovascular,  malnutrition, alcoholism and violence) therefore surely have no choice but to swop promptly from prescribing vit D2 “Strong Calciferol” (a dangerous misnomer) to prescribing vitamin D3 at vigorous dose (with if possible occasional blood level check of 25OHvit D3)- at a trivial imported and distributed cost (100cws)  to South African state clinics  of perhaps<1/4 of the cost of D2 eg  R1 per patient per month for a conservative 100 000iu monthly  (ie  after an appropriate germicidal  loading dose of eg 3000 iu/kg) if not the more realistic dose double that- still at only eg US$0.2 a month.

Health Authorities everywhere have an obligation to enforce the use of vitamin D3 and not vitamin  D2 globally ..

update 3 Sept 2014:  while the MERS outbreak in Arabia may at last be dying down, real highly infections plagues eg ebola malaria cholera typhoid, MRSA,  TB and HIV etc continue rampant, maiming and killing even more than the manmade wars raging on some continents. .

So it is ironic – or typical of the couldnt-care-less greedy politicians and potentates who run the world- that the medical authorities they employ  worldwide apparently continue to ignore the dramatic benefits of at least safe antimicrobial supplements like multivite, zinc, iodine, selenium,   and especially vigorous dose vitamin D3 at negligible cost, and highdose buffered vitamin C to tolerance, and colloidal silver.

Already 35 years ago Italian researchers published on Pubmed that vitamin D3 should be used orally  rather than injected D or as  oral vitamin D2:                   [Behavior of serum vit D in  humans after administration of vitamin D.   Boll Soc Ital Biol Sper. 1979   Coen G, Casciani CU ea.     “evaluated  Serum levels of 25 hydroxy-vit D  following injected and oral vit. D2 and D3 . While no rise in 25OHD3 serum levels was  observed after i. m. administration , a marked rise  was found following the oral administration. However the peak values were largely impredictable.”

We quote above  trials and evidence  that oral vit D2 may be actually harmful, that it is vit D3 in vigorous dose that is needed to at least treble if not quadruple the blood vit D level from the usual deficient levels we find, to between 60 and 100ng/ml during illness.  Unfortunately locally this is not only not grasped, but also the vit D assay kit  being used by  private laboratories measures only total 25OHvit D level, not the needed active 25OH vit D3 level  plus the potentially harmful (vitD receptor-blocking ) 25OHvit D2. This is a crucial omission which has been corrected by eg the Mayo Clini Lab, which routinely reports both D3 and D2 levels.

In the person not on vit D supplements, the mediocre ie insufficient total vit D level may mask that the crucial vit D3 level is actually seriously low- deficient.  In the person on vigorous vit D2 supplement (the spuriously named “strong calciferol” 50 000iu tab no longer prescribed in USA  but commonly in RSA,  that neglects to state it is D2 not D3), the total 25OH vit D assay will be even more misleading if the level  is well up, without the unwary being informed that it is harmful D2 that is elevated, and blocking the needed vit D3 level that the D2 is suppressing.

        15 June  2014 CRUCIAL EFFECTIVE VITAMIN D3 DOSING: A major new  metaanalysis of the benefit of Vitamin D3 and Respiratory Tract Infections RTI in PLOS 2013   at  Sweden’s Karolinska  Institute Bergman ea  showed that in the 11 relevant trials (published between 2007 and 2012 ie done through the first decade of this century) using vit D3,Overall, vitamin D showed a protective effect against RTI (OR, 0.64; 95% CI, 0.49 to 0.84). And the average vit D level at baseline was only 24ng/ml, but with the mediocre  vit D3 doses used then  of average 2000iu/d (300 – 4000iu/day) given for between 7wks and 3 yrs, the average bloodlevel achieved on replacement was only 50% higher at 36ng/ml”.

     This confirms more direct experience  with higher doses that blood level increment, and benefit,  is proportionate to vit D3 dose, at least up to the proven speculative  safe upper dose of at least 10 000iu/day (whereas the proven safe longterm daily dose is up to 50 000iu/day). “More important, the protective effect was larger in studies using once-daily dosing compared to eg monthly  bolus doses (OR = 0.51 vs OR = 0.86, p = 0.01)”. This concurs with our experience of major benefit  against respiratory infection that is  based on published studies giving a loading month’s dose of about 80-100 iu/kg/day  ie ~3000iu/kg; then that monthly dose split conservatively eg 50 000iu every week or two depending on mass, and severity of ill-health; to a more successful blood-level of 60 to 100ng/ml.

Similarly, the  2014 VIDA trial   across USA-    Effect of Vitamin D3 on Asthma Treatment Failures in Adults With Symptomatic Asthma and Lower Vitamin D Level, Castro ea,  showed “Vitamin D3 for 28 weeks did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma”But this trial had the same severe limitation as the Swedish metanalysis of vit D3 benefit- it also used only 4000iu/d. “While all were vitamin D insufficient ie below 30 ng/ ml  before the trial and half were deficient with levels below 20 ng/mL, supplementation brought levels above the 30 ng/mL threshold for 82% in that group – mean levels were 41.8 ng/mL at week 28 in the supplement group, while the mean stayed in the deficient range for those who got placebo. ”  So 4000iu/day merely doubled the bloodlevel to only about 40ng/ml – only about half of the putative optimal dose. 

These recent studies force us to conclude that bad weather, and  bad prevalent respiratory viruses,  and especially with major acute, or chronic illness as in those with or at risk of serious infections eg major trauma or sepsis,   MERS-CoV, Ebola, malaria, cholera, cancer, diabetics, smokers, asthmatics, bronchitics,   AIDS-TB., pneumonia and old age  sufferers, and especially hospital, laboratory  and clinic- health workers-  we should  give a loading dose of about 4000iu/kg, then 10 000 iu/d for an average 70kg adult,  or 50 000iu every 5 days, or more simply 75000iu (about 1.5ml of 100cws vit D3 powder) weekly; or at a stretch, 300000 if not 400 000iu monthly. . As  the common  imported powder concentrate  is 100 000 iu / Gm ie per 2 ml, it is simple to take the slightly sweetish powder up to  2 or more 4 ml teaspoons ie 200 000  -400  000 iu on the tongue.   

The majority of residents of developed countries now live urbanised with mechanized transport, do not live and work / walk  all day stripped in the sun. The poor malnourished  peasants  live crowded in ghettoes , and  the poorest are generally the darkest skinned and therefore make the least vitamin D3. So with rare exceptions, everyone needs the vigorous vitamin D 3 doses discussed above.

But at the prevalent bulk vit D3  powder price of  at most about  $0,o2 per 100 ooo iu, at a mean population age of around 20 to 25 yrs -outside  Europe- it would cost a country of eg 50 million people perhaps $o.5 per head per  year ie conservatively $25 million a year to prevent > 90% of common illnesses including drugging and violence consequences.  Of course no government can tolerate  such massive loss of jobs and taxes  in a decimated disease industry that turns over $ trillions annually – up to 18 % of national budgets.     So it’s up to individual adults, especially householders, educators and employees ,  to see that the cheapest cure- all  after clean water – vitamin D3 – is recommended and freely available.

We health professionals with our highly vulnerable populations in South Africa and worldwide   (epidemic/endemic  HIV, TB, cancer, drug addiction, MERS-CoV, asthma, diabetes, cardiovascular,  malnutrition, alcoholism and violence) therefore surely have no choice but to swop promptly from prescribing vit D2 “Strong Calciferol” (a dangerous misnomer) to prescribing vitamin D3 at vigorous dose (with if possible occasional blood level check of 25OHvit D3)- at a trivial imported and distributed cost (100cws)  to South African state clinics  of perhaps<1/4 of the cost of D2 eg  R1 per patient per month for a conservative 100 000iu monthly  (ie  after an appropriate germicidal  loading dose of eg 3000 iu/kg) if not the more realistic dose double that- still at only eg US$0.2 a month.
Health Authorities everywhere have an obligation to enforce the use of vitamin D3 and not vitamin  D2 globally ..

2 February 2014 VITAMIN D 3 DENIALISM:                                                       Dr John Cannell psychiatrist and nutritionalist  of the Vitamin D Council has posted a comprehensive rebuttal of the Autier review’s damnation of vitamin D at http://www.vitamindcouncil.org/blog/a-look-at-the-recent-lancet-review-study/.

Queries  and rebuttals    all over the world are questioning the negative French  (Autier ea)   Vitamin D status and ill health: a systematic review   published last month by the UK Lancet            Low serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been associated with many non-skeletal disorders. However, whether low 25(OH)D is the cause or result of ill health is not known. We did a systematic search of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes in individuals aged 18 years or older. We identified 290 prospective cohort studies (279 on disease occurrence or mortality, and 11 on cancer characteristics or survival), and 172 randomised trials of major health outcomes and of physiological parameters related to disease risk or inflammatory status. Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality. High 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer. Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 μg per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 μg vitamin D per day seemed to slightly reduce all-cause mortality. The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin D status is reported in a wide range of disorders. In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.

and the accompanying anonymous Lancet editorialchasing a myth?

Ongoing randomised clinical trials assessing the ability of vitamin D supplementation to reduce the risk of several non-skeletal disorders involve a population larger than that of Cambridge, UK, and will cost millions  of research dollars. VITAL, for example, will enroll 20 000 participants and has US$22 million in funding.  This vast investment of effort by patients, researchers,  and funders is laudable, as it is almost certain that it will be sufficient to answer a question that has long kept the medical community in the dark.
                 Vitamin D first became a medical success story when its importance in bone health and calcium homoeostasis was proven decades ago. Since then, epidemiological  evidence has been accumulating to support a role for vitamin D in the protection of individuals from various   non-skeletal disorders including cancer, cardiovascular diseases, autoimmune and inflammatory diseases, dementia, and diabetes; it might also reduce all- cause mortality. Many of these studies show a strong association between low vitamin D concentrations anddisease. However, the results of myriad recent small randomised controlled trials are almost unanimous in  concluding that vitamin D supplementation provides  protection from few, if any, of these outcomes.
      Vitamin D is a steroid hormone with pleiotropic and tissue-specific effects owing to the wide expression of  the nuclear vitamin D receptor in many different tissues,and the many genes that are targeted by its actions.  In the skeletal system, vitamin D promotes healthy development and remodelling of bone. In other tissues,   vitamin D is postulated to mediate potentially beneficial  effects via a wide variety of mechanisms: some evidence  suggests that it exerts anticancer activity by limiting hyperproliferation of certain cell types, that it promotes metabolic health by regulating lipid metabolism in adipocytes, and that it limits autoimmunity by  suppressing inappropriate immune responses.  In a systematic review in   The  Lancet Diabetes &  Endocrinology editorial , Philippe Autier and colleagues discuss a large number of observational studies suggesting  That high serum concentrations of vitamin D   might be protective.
      For example, those with high vitamin D had decreased risk of cardiovascular events      by up to 58%), diabetes (by up to 38%), colorectal  cancer (by up to 33%), and all-cause mortality (by  up to 29%). However, they also compare these findings with the results of randomised clinical  trials, which reveal a very different picture: no reduction in risk was found, even in trials involving adequate supplementation of participants with lowvitamin D levels at baseline (less than 50 nmol/L). Autier and colleagues also did a new meta-analysis  of 16 trials that assessed the effects of vitamin D supplementation on blood HbA1c, a biomarker mainly   used for monitoring disorders of glucose metabolism.
Although type 2 diabetes is associated with  low vitamin D, the results show that vitamin D supplementation does not reduce HbA1c
. Thus, it looks increasingly likely that low vitamin D is not a cause but  a consequence of ill health.
Despite the growing body of evidence indicating  that vitamin D is unlikely to prevent non-skeletal   disorders, there is strong support for its use from  many prominent members of the research community,  which is fuelled by the relatively low toxicity of vitamin D, the glimmer of positivity from some trials,and the large body of evidence from prospective  observational studies. For those who ‘believe’, the  lack of benefi t found in most trials completed thus  far can be attributed to issues including inadequate  supplementation, testing of a population not  sufficiently vitamin D deficient at baseline, incorrect
formulation, underpowering, or insufficient follow-up.  Vitamin D might not be safe in all settings, however.
Supplementing at high doses could cause harm in  people with already high concentrations of serum  vitamin D, particularly in those with liver, kidney, or  vascular problems. This is a concern, given the large  number of people taking vitamin D supplements (up  to 50% of adults in the USA).
Large clinical trials to assess the effects of vitamin D on non-skeletal health outcomes are  therefore justified. It would be a real boon to patients if the results are positive, but unless effect sizes for clinically important outcomes are large, the results will only confirm the neutral effect reported by most clinical trials thus far. Although this investment might  therefore have little effect on current guidelines, the results will at least allow the research community to  move on.
This French  review of Vitamin D is the sort of tactic regularly concocted by Big Pharma and the Disease Industry for the media,  to discourage patients and doctors  from taking/prescribing  effective doses of supplements (beyond a lowdose  multivite a day), instead force them to take Big Pharma poisons- synthetic new risky designer drugs- like antibiotics, antipain,  anticancer, anticholesterol, antiosteoporosis, antiplatelet,antihypertensive, vaccines, antiflu,  –    to make massive profits for the Disease Industry,  but not address or cure the deficiency causes of disease.     At the behest of Big Pharma like Roche, their lobbyists the FDA, the  European Medicines Authority and the UK NHS are  trying to push through legislation that will make anything but lowdose multisupplements available to the public solely on doctors’ prescription.
Meanwhile, Big Pharma companies are paying fines of over $10 billion  a year for promoting their snakeoil  prescription designer drugs by fraud, when these drugs are allowed to be registered for chronic use after small trials of only 6 to 12 weeks, and the researchers who  publish the trials for megadollar fees are regularly caught out, fired but rarely  jailed.                                                                            ……         The Big Pharma guys simply bill the cost of the fines into their marketing expenses- their bosses, and the politicians they buy off,  are too big to jail… Regulators then allow the drugs to be prescribed for years  until enough patients sicken and die for there to be an uproar and cancellation- as  happened recently with Prot(e)os the synthetic ranelate ‘osteoporosis’  snakeoil;.      Now a top Dutch researcher has been fired for falsifying trials to promote betablockers for hypertension – when these have been discredited as routine therapy  for this purpose  for over a decade.
yet the Regulators led by the FDA – which is massively funded solely  by Big Pharma as their ally- insists that vitamins, minerals and other long-proven natural supplement therapeutics, prime human hormones  like melatonin and physiological human sexhormone creams , have to undergo $multimillion trials before they can be marketed as already  long-evident safe effective therapies.

none of the vit D   trials used the dose of vit D3 now recommended on solid evidence  that we should all take   – 80 (to 100)iu/kg/day or 2400-3000iu/kg/month of vitamin D3- ie about 150 000 – 200 000 iu to start and then per month for average adults –  to maintain healthy 25OH vit D levels around 60-100ng/m (here our bloodlevels are usually between 10 and 20 !  because we take little dairy products, nuts and sunshine- we cover up and live indoors.)  .

Most  of the reported trials used only about 5% of the recommended  vit D  dose ie ~200 to 400iu/day ie 6 iu/kg/day!  this dose does nothing except partly prevent rickets-  in infants!  Pregnant women are still routinely given such weak near-nonsensical doses of vit D.

and as Cannell’s review of the Autier analysis  points out, the vitamin D  trials trials under way – * in USA-Boston VITAL study 20 000pts)   ,           Finland (FIND 18000 pts    and     UK(VIDAL 1600pts ) ,  in some 40 000 subjects, due for publication only  between 2017-2020-  are using only 1600 to  3200iu vit D a day or about 48  000 to 96000iu/month ie perhaps 32iu (25 to 40) /kg/day. So  they are testing still modest doses and blood level targets. .

Read about the fraud of the Disease Industry at https://healthspanlife.wordpress.com/2014/01/20/vitamins-c-d3-avoiding-vitamin-denialism/ – especially about the dodgy ” Strong Calciferol’ tabs (Lennons)- which are not what you expect (vit D3) but vit D2 (the label, and package insert, dont tell you this) . vit  D3 powder is half the price but apparently 4 times as strong as D2.

ideally you should check your 25OH vit D and calcium levels to make sure you are on the right dose- but always taking some magnesia supplement, and at least 2 liter of water/ sodawater/clear fluid a day to avoid dehydration, kidney stones and vascular disease (which  highdose calcium supplement eg 1000mg  & vit D3   400iu/day cause).

8 April 2013  UPDATE: VITAMIN D3 THE AMAZING SUPPLEMENT

It is sad to record that Dr Walter Stumpf died suddenly a few months ago during ongoing correspondence. The world  has lost a teacher  of the century in both biological sciences and the humanities, metaphysics and philosophy,..

This week – as flu mushrooms  in the southern hemisphere autumn- the Canadian Medical Association Journal  April 3-8 features  early-release articles on concerns about the Asian flu viruses and especially the SARS-nCorVirus. Is mass vaccination the answer?  or did this in fact worsen mortality in previous North American  epidemics of eg H1N1?  which brings us back to global protection against infections and all major diseases with lowcost safe VitaminD3 at say 50 000iu(~700iu/kg)/week plus the other all-system protective  supplements – eg multivitamins (especially vit C and K) and minerals especially  magnesium, zinc, idine  and selenium; and during epidemic times, major daily boost in vits D3 and C.

In December 2012 the University of San Diego published a useful researched update on vitamin D3 and breast cancer; pointing out again that while the increase in benefit obviously drops off with increasing dose, safe dose is up to at least 10 000iu a day or 70 000iu a week, to a bloodlevel around 100ng/ml; and toxic dose requires at least 40 000 iu a day chronically (if not 600 000iu/d as other evidence suggests). The projections for breast cancer reduction fit with the same team’s predictions in 2007.

So apart from maintaining good water intake, and avoiding taking ill-advised unbalanced solo calcium supplement, for optimal dosing   in those with cancer or any other high risk, blood levels of both 25hydroxy vit D3,   1,25 calciferol, calcium, phosphate  and creatinine, should be monitored occasionally, to avoid the rare risk of kidney stones and arterial/breast calcinosis.

Remember that magnesia, phosphate and vitamin C  and K2 supplements are amongst the most important of at least 40  to accompany vitamin D3.

Last month three new studies affirmed the importance of vigorous vitamin D3 levels for genetic, heart and all health.

Holick’s group at Boston University   show the profound .Influence of vitamin d status and vitamin d3 supplementation on genome wide expression of white blood cells. No studies have reported on how vitamin D status and vitamin D3 supplementation affects broad gene expression in humans. A randomized, double-blind, single center pilot trial was conducted for comparing vitamin D supplementation with either 400 IUs (n = 3) or 2000 IUs (n = 5) vitamin D3 daily for 2 months on broad gene expression in the white blood cells collected from 8 healthy adults.   in the winter.   CONCLUSION SIGNIFICANCE: Our data suggest that any improvement in vitamin D status will significantly affect expression of genes that have a wide variety of biologic functions of more than 160 pathways linked to cancer, autoimmune disorders and cardiovascular disease with have been associated with vitamin D deficiency. This study reveals for the first time molecular finger prints that help explain the nonskeletal health benefits of vitamin D

Tehran University  http://www.ncbi.nlm.nih.gov/pubmed/23517460  showed clearly that    Vitamin D Supplementation Improve the Severity of Congestive Heart Failure. In  100  heart failure patients with (NYHA) class I ,   Only 6% of the participants had a sufficient serum concentration of 25(OH) D >30 nmol/L. Patients with insufficient or deficient serum levels of 25(OH) D (<30 ng/mL and <20 ng/mL, respectively) received oral vitamin D3 for 4 months. Vitamin D supplement increased mean serum 25(OH) D from 12.6 nmol/L to 54 nmol/L (P<.001). After vitamin D supplement, the serum level of pro-brain natriuretic peptide markedly decreased (P<.001). Cholecalciferol significantly decreased high-sensitivity C-reactive protein level (P<.001). Restoration of serum 25(OH) D level was also associated with substantial improvement in hear tfailure (P<.001) and 6-minute walk distance (P<.001).

 and Robert Heaney’s group at Creighton University   http://www.ncbi.nlm.nih.gov/pubmed/23514768  that .  All-Source Basal Vitamin D Inputs Are Greater Than Previously Thought and Cutaneous Inputs Are Smaller.    

The magnitude of vitamin D inputs in individuals not taking supplements is unknown.. they reanalyzed 3000 subjects’  individual 25(OH)D concentration data from 8 studies involving vitD3  supplement.  The total basal input (food plus solar) was calculated to range from a low of 778 iu/d in patients with end-stage renal disease to a high of 2667 iu/d in healthy Caucasian adults. Consistent with expectations, obese individuals had lower baseline, unsupplemented 25(OH)D concentrations and a smaller response to supplements. Similarly, African Americans had both lower baseline concentrations and lower calculated basal, all-source inputs. Seasonal oscillation in 4 studies ranged from 5.20 to 11.4 nmol/L, reflecting a mean cutaneous synthesis of cholecalciferol ranging from 209 to 651 iu/d at the summer peak. We conclude that: 1) all-source, basal vitamin D inputs are approximately an order of magnitude higher than can be explained by traditional food sources; 2) cutaneous, solar input in these cohorts accounts for only 10-25% of unsupplemented input at the summer peak; and 3) the remainder must come from undocumented food sources, possibly in part as preformed 25(OH).

Update March 2010

August 2009  SUMMARY: Evidence is overwhelming  that the prime sun-induced steroid hormone Vitamin D3 cholecalciferol – soltriol- is  invaluable in  20fold   higher  dose ie   perhaps  5000 to 10 000iu/day rather  than has been preached to date (200- 400iu/d), as part of lifelong  hormone replacement  HRT to prevent all major chronic degenerative diseases in all humans living and working indoors.  Effective dose of vitamin D3 supplement can reduce deathrate and disease by an astonishing 20%- that is indeed a panacea almost as good as other natural micronutrient supplements eg  fish oil, metformin, and appropriate sex hormone replacement SHRT.   It is becoming clear that with rare exceptions everyone- especially those  with serious disease eg cancer, heart, lung, brain, nerve/muscle/bone/joint  or inflammatory bowel diseases or  chronic infections like TB  HIV  influenza  or human papilloma virus –   should take a daily supplement of about 10 000iu (1/4 mg)  vitamin D for as little as ~ R10 US$1  a month ; ideally  under supervision of some  health professional.  All that is required is occasional check of blood chemistry, and good diet and  fluid intake.

And obviously because of vitamin D3’s  benefits in lowering all diseases, when using vigorous dose vitamin D, one must  expect to need to lower  prescription drug treatments for diabetes, hypertension, depression, heart disease, lung disease, arthritis, infections  etc  as these ailments  improve from the vitamin D  replacement over months.

INTRODUCTION:  Battling to help some desperate patients this week – mostly women-  with cancer, vascular, rheumatoid, lupus, diabetic, depressive, osteoporotic  and infective disease- especially now the quadruple perils of infections  influenza; human papilloma virus; AIDS and tuberculosis – let alone nuisances like shingles  candida or  herpes –  prompts a thorough review of the polyfunctional vitamin of this decade- vitamin D3, cholecalciferol, soltriol (Stumpf WE).

This  review is especially appropriate on our Womens’ Day 9 August 2009 for a natural product so important for the health of women , that commemorates the year  1956 when 20 000 women marched in defiance of  male despots’  fascist apartheid pass laws. The ages-old discrimination against women is epitomized by the pragmatic liberal economist Professor Ken Galbraith’s lecture to the Royal Society of Medicine in 1973 on the problem of unequal development and centralization of power in male technostructure – profit maximization.

No-where in business is this better shown than in Big Business creating demand  by saturation marketing,  including the medicalization of health.  This  involves  disease-mongering through creating unnecessary  concerns so as to expand markets among the well  for  patents eg  blanket cholesterol or mammography or colonoscopy  screening,  or remedies   for eg female arousal disorder, anxiety, reactive depression, mild-to-moderate hypercholesterolemia – when very few have been proven to  need or benefit from such labels, procedures and drugs.

VITAMIN D3  SOLTRIOL : INFORMATION EXPLOSION:

The first  of 46200 entries on Medline  on vitamin D is  from Oxford by Heaton 1922 . There are 272 500 entries on vitamins since 1918,  the first specific one by Jack Drummond in 192o, but of course vitamin D was first identified by Mellanby 1919, preceded by vits A, B1 and C between 1909 and 1912. From a recent historical review (table 1) of hormones, vitamin D3  was  perhaps the 7th hormone recognized  after testosterone and  estrogen (China 2600 years ago) ,  thyroid (1891)  epinephrine secretin parathyroid and antidiuretic hormone.

Soltriol is an  exquisite description  for a sun-activated steroid, the  cardinal prohormone vitamin D3  made  from cholesterol via sunlight exposure. Soltriol is not in a 1964 Oxford Dictionary, nor is it’s etymology detectable on Google search; it was indeed invented by  the pioneer polymath neurologist Dr  Walter Stumpf . On Medline search for soltriol, the first result is  Corradino 1973…

It is intriguing to read that Dr Stumpf  graduated in medicine in 1952- and 50 years later  in 2005 he wrote on his website: “From the microautoradiographic target recognition and related actions it follows that vitamin D has healing potential for prevention and treatment of various deficiencies and ailments, including old age: a PANACEA? If there is any compound that deserves being designated a panacea, the multifunctional heliogenic vitamin D appears a suitable candidate.   Philosophical consideration: “Vitamin D”, the term does not reflect its significance. I have used instead SOLTRIOL in several publications as a more appropriate designation. – Is there not a link to Heraclitus emanation of “ ever-living fire ”? The cosmic solar fire (Soltriol) as the sustaining life force, providing wave length energies for Temperature, Visible Light , and Ultraviolet B “. ”  The Main Biological Role of Vitamin D is Seasonal Adjustment of Vital Functions: These include regulation of growth, reproduction, survival stress response; endocrine and exocrine secretion, cell proliferation, cognition and mood; neuro-motor, neuro-endocrine, and neuro-sensory functions, immune response, cardio-vascular and gastro-intestinal functions, regulation of calcium and other mineral levels, cell proliferation and protein synthesis-differentiation.

Considering the decades of vitamin D use for its other benefits, it is ironic that a 1999 University California website on The History of Vitamin D has never been updated to cover more than the anti-rickets protection from vitamin D. But as Prof Stumpf writes to  me today, ultimately it is the sun that is the panacea, transmitting it’s healing powers via the skin-activated messenger hormone vitamin D.

 

It is now almost  a year since this column last reviewed vitamin D3’s benefits against all major diseases   (see table) – during which year  scores of new randomized controlled trials RCTs of vitamin D have appeared- there are now some 1680 RCTs on it since  1965.  Carpenter 1999 reviews Forgotten Mysteries in the History of Vitamin D.

Women have a raw deal:  due to their prime role and innate sense for survival of the species, for nuturing and caring, they live  about 10% longer than their mates, but as a result endure far more illness, as well as assault, disability and murder (mostly  inflicted by the careless male).

PROTEAN STEROIDS, PROTEAN FUNCTIONS: Calcitriol is one of many human steroids that include the sex hormones, aldosterne and digoxin; as well as  nonhuman steroids which also have important medicinal use- like phytosteroids, equine steroids like the equilins eg premarin, and the important ecdysteroids in insects and some plants.   Stumpf has again stressed the wide distribution in humans  of vitamin D receptors VDRs, indicating their importance in protean human functions far beyond calcium regulation.

VITAMIN D AND ALL-CAUSE MORTALITY: it is just a year since Melamed ea from USA showed that  having low vitamin D (as opposed to high level)  increases all-cause mortality by 26%- thus taking submaximum safe dose of vitamin D  can improve chance of survival by about 20%.  This for as little as R10/month – $1-  in South Africa.

In 2000,  the Seven Country Study Group showed that  ” saturated fat,vitamin C and smoking are the major determinants of all-causemortality at the population level” ie the higher the fat and smoking intake and the lower the vitamin C, the higher the deathrate. We now know better-  serious vitamin D deficiency joins the list, which of course includes alcoholism. .

VITAMIN D AND CARDIOVASCULAR DISEASE CVD

Pizzorno 2009 reviews the strong evidence of the importance of balanced vitamins A D and K supplements in reversing the epidemics of both CVD and osteoporosis.

VITAMIN D AND DEPRESSIVE/NEURODEGENERATIVE DISEASE

over 20 articles already this year attest to the importance of vigorous vitamin D levels in reducing these diseases.

VITAMIN D AND AUTOIMMUNE / INFLAMMATORY BOWEL DISEASE AND MUSKULOSKELETAL DISEASE:

The much higher incidence of autoimmune diseases in women – especially SLE systemic lupus erythematosis and RA rheumatoid arthritis-    let alone far higher younger  female  risk for fractures- must have  been obvious for millennia.  So obviously genetic female factors play a major role in these diseases – now surely attributable   largely to  the reproductively necessary absence of the Y chromosome, and thus the 100fold lower testosterone: estradiol T:E2 ratio in women (perhaps 2:1) than in men (in youth, >200:1).. It is common cause that estrogen is immunostimulant whereas testosterone  and progesterone (like vitamin D) are immunomodulating. Hence testosterone and progesterone levels soar during pregnancy to prevent the mother rejecting her foetus. This partly also explains why vigorous vitamin D supplement also greatly improves fertility and pregnancy outcome.

VITAMIN D AND RHEUMATOID ARTHRITIS: many studies  show  the benefits of the prime anabolic steroids- vitamin D and androgen (Devis 1950)  supplements-  in treatment of all inflammatory disease, especially when inflammation itself weakens bone and all other tissues. The latest – last month (Chabchoub 2009)- shows “a possible role for XCI mosaicism in the pathogenesis of RA and thyroid disease  and may in part explain the female preponderance of these diseases”. But the first and only randomized controlled trial of the effect of vitamin D on modifying  RA  appears in  1973 (Brohult)  and the only open  trial (Andjelkovic  1999) in RA  showed that            “alphacalcidiol is a powerful immunomodulatory agent with fairly low hypercalcemic activity”.

VITAMIN D INTOXICATION:  The low toxicity of vitamin D3  is fortunate because while it is ideal to monitor vitamin D levels on effective replacement, the blood test costs about R660- $80- locally;  hence all one needs to do is exclude kidney problems (which may need even higher dose of vitamin D3), and risk of kidney stones- but perhaps checking blood calcium and creatinine  at baseline and occasionally, and ensuring balanced supplement of calcium-magnesium – boron-zinc-manganese-(iron if deficient)  and vitamins B, C, D and K.   Since vitamin D intoxication (toxic rise in blood calcium- hypercalcemia) in some opinions  requires ~>600 000iu/day for months, ths is inconceivable unless one were to swallow say twelve  50 000iu vitamin D every day for months.   So the only recognized form of vitamin D intoxication could be an industrial accident involving mistaken use of vitamin D concentrate in medicine.

HYPERCALCEMIA HIGH BLOOD CALCIUM: medical causes  are rare without gross calcium overdose (milk alkali syndrome) or other specific symptomatic diseases – eg primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma.And fortunately most patients with these diseases and hypercalcemia are far more likely to benefit from therapeutic treatment with vitamin D than worsen on it.

OVERDOSE:      HYPERVITAMINOSIS D: WIKI says   “Vitamin D stored in the human body as calcidiol (25-hydroxy-vitamin D) has a half-life of about 20 to 29 days.[17] Ordinarily, the synthesis of bioactive vitamin D hormone is tightly regulated, and prevalent thinking is that vitamin D toxicity usually occurs only if excessive doses (prescription forms or rodenticide[38] .   Serum levels of calcidiol (25-hydroxy-vitamin D) are typically used to diagnose vitamin D overdose. In healthy individuals, calcidiol levels are normally between 32 to 70 ng/mL (80 to 175 nmol/L), but these levels may be as much as 15-fold greater in cases of vitamin D toxicity. Serum levels of bioactive vitamin D hormone (1,25(OH2)D) are usually normal in cases of vitamin D overdose. Symptoms include Dehydration Vomiting Decreased appetite (anorexia) Irritability Constipation Fatigue.

Overdose of vit D3 has been observed at 1925 µg/d (77,000 IU per day). Acute overdose requires between 600,000 and 1,680,000 IU per day over a period of several days to months, with a safe intake level being 10,000 IU per day.

A 2007 risk assessment suggested that 250 micrograms/day (10,000 IU) in healthy adults should be adopted as the tolerable upper limit.[39] In adults, sustained intake of 100,000 IU can produce toxicity within a few months.[2] For infants (birth to 12 months) the tolerable UL is set at 1000 IU, and 40,000 IU has been shown to produce toxicity within 1 to 4 months.  All known cases of vitamin D toxicity with hypercalcemia have involved intake of or over 40,000 IU)[42].

Although normal food and pill vitamin D concentration levels are far too low to be toxic in adults, people taking multiples of the normal dose of codliver oil may reach toxic levels of vitamin A, not vitamin D, [43] if taken in an attempt to increase the levels of vitamin D. Most officially-recorded historical cases of vitamin D overdose have occurred due to manufacturing and industrial accidents.[42]

Some symptoms of vitamin D toxicity are a result of hypercalcemia caused by increased intestinal calcium absorption. Vitamin D toxicity is known to be a cause of high blood pressure.[45] Gastrointestinal symptoms of vitamin D toxicity can include anorexia, nausea, and vomiting. These symptoms are often followed by polyuria (excessive production of urine), polydipsia (increased thirst), weakness, nervousness, pruritus (itch), and eventually renal failure. Other signals of kidney disease including elevated protein levels in the urine, urinary casts, and a build up of wastes in the blood stream can also develop.[2] In one study, hypercalciuria and bone loss occurred in four patients with documented vitamin D toxicity.[46] Another study showed elevated risk of ischaemic heart disease when 25D was above 89 ng/mL.[47] Vitamin D toxicity is treated by discontinuing vitamin D supplementation, and restricting calcium intake. If the toxicity is severe blood calcium levels can be further reduced with corticosteroids or bisphosphonates. In some cases kidney damage may be irreversible.[2]

Exposure to sunlight for extended periods of time does not normally cause vitamin D toxicity.[42] This is because within about 20 minutes of ultraviolet exposure in light skinned individuals (3–6 times longer for pigmented skin) the concentration of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D that is produced is degraded.[48] Maximum endogenous production with full body exposure to sunlight is 250 µg (10,000 IU) per day.[42]”

VITAMIN D AND SEX:

Biologically, the most imperative function for species survival is sex- reproduction.   Vitamin D is clearly a potent  anabolic reproductive steroid like testosterone:   The first paper on this association on Pubmed appears in 1963 from Russia (Gokinaeva).

Stumpf 1989 at Univ N Carolina reported that “vitamin D (soltriol)  regulates and modulates reproductive processes in the female and male, controlling  reproductive processes from onset of puberty to  fertility, pregnancy, lactation, and probably sexual behavior.”

Mirzahossein in 1996 showed that,” given in the critical period of foetal imprinting, vitamin D  may  influence steroid hormone-receptor commanded events for life in a way similar to synthetic steroid hormone analogues”. So as with marine omega3., it is crucial that future parents take enough vitamin D.

Friedrich 2002 showed that  even prostate, colon and   normal cervical tissue and cervical cancer cells have VDRs – vit D receptors- and may be new targets for cancer prevention or cancer treatment.

Kalueff 2005 showed that it influences even neurological receptors eg grooming behaviour in mammals.

And now Blauer 2009 shows that it reduces growth by up to 60% in human uterus muscle and fibroids- leiomyomas.

VITAMIN D AND PAIN: this week Khan ea from Kansas University describe Effect of vitamin D supplement  on  joint pain and fatigue in women starting adjuvant letrozole treatment for breast cancer. But the first Pubmed reference on vitamin D and pain is from von Wendt 1951.  Gerwin 2005 recognized vitamin D deficiency as a cause of fibromyalgia- chronic fatigue syndrome.

and Glueck ea from Cincinnati show that vitamin D supplement for low vitamin D abolishes statin – induced  myalgia.

VITAMIN D AND SLE- SYSTEMIC LUPUS ERYTHEMATOSIS: on medline the first reference to immunosuppression with vitamin D was  by Bourdial  1963 on nasal allergy, and the first  for vitamin D and immunomodulation is by Nagler & Pollack 1986.:

However, the first paper  on the importance of Vitamin D3 deficiency   in  SLE appeared in Germany  1963, but the first paper in English and from an English country  only in 1979 (O’Regan).

The focus throughout has been on the benefit of vitamin D in reversing the hyperimmunity  of SLE, but of course vitamin D is equally important in preventing both the osteoporosis of inflammation, the fracture and wasting risks  of cortisone treatment, and the vascular disease associated with SLE.  In the last year alone there have been 10 such SLE – vitamin D major studies – 7 from the Americas and 3 from Europe.

SLE as well as plain lupus of the skin are  generally regarded as disease that requires protection from the sun.

Now this week Wright 2009 shows that in children,  SLE is  associated with vitamin D deficiency, particularly among those subjects with SLE who are overweight.

VITAMIN D, SUNLIGHT,  SLE AND CANCER:

The first case of SLE associated with cancer ( meningioma and cervix)-  is reported by Williams  1956. The latest – last month- highlights increased risk of  lymphoma, cervix and bronchus cancers.

Search for malignant melanoma MM and SLE finds the first reference in 1963. yet most of the papers are about reactions to interferon therapy, or immune markers- there is one solitary case report (1991 Sulkes, Israel) of a patient with indolent SLE who after 15 years developed and died of rapidly spread of MM. These authors comment on the infrequent association of SLE & solid cancers, the commonest  being uterus and bladder.

So it is exciting that while more sun exposure causes skin cancer and especially cutaneous melanoma  CMM, (Tuohimaa  2007),  sun exposure also improves survival from CMM-  and from a wide range of internal cancers – (especially stomach, colorectal, liver and gallbladder, pancreas, lung, female breast, prostate, bladder and kidney cancers). This favourable effect of more sunshine is obvious when comparing the lower cancer and heart disease deathrates in sunnier southern versus the darker northern countries. Only rare skin diseases eg porphyria cutanea tarda are contraindications to sun exposure of the skin. But at least one study Holme 2008 shows vitamin D deficiency in erythropoetic porphyria.

Professor Halstead 2008 (and many others)  conclude  that the high fructose corn syrup routinely used in fast foods and cooldrinks in first-world manufacturing is rapidly increasing obesity, lipidemia (and metabolic syndrome and cancer);  while folic acid  food fortification is causing low  B12 levels and thus possibly increasing dementia, vascular disease and advanced precancerous colorectal adenomas and breast cancer.   This trend is aggravated by at least  three scientifically unvalidated  obsessions of Regulators and the Medical hierarchy:

1.   low diet cholesterol in those with mild to moderate cholesterolemia;

ii.  low vitamin D –  low intake dairy products and less  sunlight exposure for fear of skin cancer; and

iii. warfarin (which blocks essential vitamin K) to reduce thromboses- whereas it worsens  both fracture risk  and vitamin D and K deficiency, and thus  arterial calcification, cancer and fractures;   all of which are reversed by vigorous vitamin B3-6-9-12 , C, D  & K supplementation.

Protection from both cancers and SLE is probably  associated with higher vitamin D level above ~100nmol/L.  Both lupus and cancers are due to altered immunity.  But SLE is due to increased autoimmunity- hence cancers   are infrequent during active SLE;  whereas cancers are due to reduced immunity – hence are associated with immune suppression, whether by cortisone (including stress) / chemotherapy, or deficiency of vitamin D – dietary and lack of sunshine..

It is now common cause that more  cancers occur with suppressed  blood  cholesterol – whether  the low cholesterol is cause d by or due to the cancer remains to be clarified; and at least one of the major statin cholesterol-lowering trials showed increase in breast cancer cases.

While there is no clear overall  relationship of statins to osteoporosis or cancer,  Kunitomo   1989showed that cholesterol reduces and corticosteroids enhance the toxicity of vitamin D in rats.  Montagnani 1994 showed that pravastain does not  interfere with the circulating levels of the main vitamin D metabolites.

VITAMIN D AND INFECTION:

For an acute infection, Cannell and Hollis 2008    suggest  vitamin D in an antimicrobial  dose of 2000iu/kg eg 120 000 iu a day for 3  days- to produce enough of the naturally occuring antibiotic cathilicidin.  Ginde 2009 show that those with high vitamin D levels have less respiratory infections. This column has previously reviewed the dramatic benefits of vitamin D on infection mortality in AIDs- TB patients.   Obviously one is going to be cautious pushing vitamin D  in a patient with known kidney stones, or hypercalcemia.

VITAMIN D : WHY THE INCREASING DEFICIENCY, NEED FOR SUPPLEMENT ?

Never mind the poor and chronically ill, the aging especially need much more vitamin D, and benefit the most. Even in a sunny fishing nation like Spain, elderly women do not get enough vitamin D from fish or other foods, and most have suboptimal blood levels of it.

Apart from  dietary intolerance and obsession reducing intake of cholesterol and dairy products, the vitamins and minerals in particular have been greatly depleted and imbalanced in commercially produced- and especially genetically-modified  food.   And while increasing longevity,  food scarcity -poverty and   mushrooming prices (cartel pricefixing that is ignored by well-paid politicians and regulators) – are prime causes,  Politicians and Regulators have worsened this by falling decades behind in ignoring the leading 20th pioneer nutritionist/ economists  like the USA’s Professors Linus Pauling the unique double Nobel prizewinner prophet of vitamin C and peace; Ken Galbraith; and  the UK’s  Sir Jack Drummond. The latter two respectively brought the Allies (under FD Rooseveld and WS Churchill)  through  WW2 by putting farming- healthy food production and pricing- as the painfully obvious priority- which selfserving  gluttonous politicians  like Nixon, Bush,  Kissinger, Mugabe and Mbeki, and most others leaders (who support, not just tolerate such despots)  simply ignore since they detest “surplus people”- the honest  poor;  if not also  hardworking farmers.

It is no coincidence that Pauling and Galbraith both graduated from agricultural colleges.  And no coincidence that all three nutritionists were the targets of  politician-business moguls because of the obstacles they posed to the profiteering national economic sabotage that is the lifeblood of ruthless businessmen-capitalists from before Nixon- Connolly- Reagan- Kissinger  and Thatcher, through to the Bushes and Blair and Montsano-GD Searle, Mbeki and Zuma,  and the arms, oil, banking, mining, media,  food, sex, tobacco-alcohol and medical-big pharma industry mafiosi cartel  who make or break  presidents and  governments.

James Ferguson makes a strong case for The Vitamin Murders, that Drummond (and his family) were butchered in  a Vitamin Industry contract  in France as a lesson to do-gooders because his advocacy of the primary role of good natural  nutrition and vitamins  was such an obstacle  to the fast food and synthetic drug industry.    Conspiracy theorists could argue that, like Pauling’s vitamin C, the Drug Industry have through the FDA managed to ensure that only this year is the FDA grudgingly moving to raise the Recommended daily Allowances of vitamin D (and C)  even fractionally above the present rickets- (and scurvy) preventing doses, as opposed  to their   modest 25 to 50fold  fold   higher intakes that have been known already for decades to be both safe and major benefit against all diseases.

John Le Carre’s The Constant Gardner echoes that ongoing conspiracy scenario, the battle between Big Pharma with it’s drug lobbyists (including the USA FDA and the European Union’s European Medicine’s Authority, and leading politicians) to promote their lucrative modern synthetic chronic  drugs (none of which have been shown to reduce all-cause disease and mortality as do natural supplements), versus nutritionists and informed consumers who know that broad natural supplements (vigorous vitamins, minerals and biologicals)  to bolster the failing adulterated food chain are more important and effective  than any patented designer drugs in combating all disease. Unfortunately the necessary advocacy for natural supplements has been muddied by fraudsters  like the Big Pharma- FDA- academia  cartel (who swamp the medical literature with trial and review papers favouring their snake oils), the Rath Foundation, and our local dissidents against reason  like  Mbeki, and Drs Manto Tshabalala-Msimang, Nkosasama Zuma and Olive Shishana.

CONCLUSION: In 2006 Dr Walter Stumpf in THE DOSE MAKES THE MEDICINE wrote:  “in recent years, discussion raged  about the negative effects of   estrogen-replacement therapy and its relationship to cancer.  In numerous articles, the side-effects of estrogen treatment were highlighted in a generalized fashion and, although consideration was given to the duration of treatment, the relationships to dose (let alone type and route of estrogen) were frequently left out. And yet, considerations of dose and time in pharmacology and toxicology are paramount.
Similarly, a
wareness of proper dosage is crucial to the development of future vitamin D therapies. Physiologic dosing of vitamin D does not cause hypercalcemia – hypercalcemia is related  to overdosing ie closer to 100 000iu/day. Considering the many target tissues that are unrelated to systemic calcium regulation, most therapeutic effects of vitamin D occur independently of the high-dose systemic calcium effects. Because of the biased focus on calcium, the many other effects tend to remain unnoticed and hidden.  Future research needs to give more consideration to dose-effect relationships by monitoring target functions independently of systemic calcium regulation.
New therapeutic applications of vitamin D can be established for cardiovascular, neurological, endocrine, immune, gastrointestinal, reproductive and other diseases, including posttraumatic and gerontological deficiencies, in which the polyfunctional effects of  the hormone not only come to bear, but can also be controlled and maximized for optimal health.”

Since the global population shift from rural to   city life and work the past century ie in our lifetispan,  humans have largely gone from being healthy longlived outdoor food-producing  workers living on their own fresh produce including organically grown unadulterated fresh  food and dairy products – or fish- (rich in micronutrients),   to working mostly indoors and consuming largely  micronutrient-depleted  food  as well as multiple noxious deliberate industrial pollutants- from sugar and alcohol  to estrogenics, pesticides, heavy metals, cornsyrup and aspartamate.

Like fish oil is the most important food extract we have (and businessmen are ruthlessly harvesting to extinction), vitamin D3  has become the anti-disease vitamin  of the past decade,  joining vitamins C & B as the  panacea vitamins that can and should be supplemented in far higher dose than anti-vitamin  “Regulators” and professional researchers and associations (with vested interests in protecting  their funder- Big Pharma) approve.

But as the more affluent age and increase in numbers,  the micronutrients that deplete (with longevity, the deteriorating food chain, and unnecessary drugs),- especially  vitamins  K, chondroglucosamine, N-acetyl cysteine, alphalipoic acid, Co-Q10, arginine, carnitine, carnosine,  riboseand the marine  EPA and DHA-   are  fast becoming the “vitamins”  of the next decade.

Tragically, edible marine products especially marine omega3 EPA+DHA are rapidly becoming so scarce that the vast majority of people  can  neither  source nor afford the minimum optimal gram a day, until science breaks through  to synthesize these uniquely beneficial free fatty acids. But at least the supply of minerals, and vitamins including D3, is inexhaustible and therefore freely available at reasonable cost.

ndb

dedicated to Dr Walter Stumpf, whose  >300 papers (~24% on vitamin D) on Medline apparently  span 1963 to 2008- on vitamin D the first  in 1979, the last  30years later appropriately on Vitamin D and the digestive system.  By comparison,  Pubmed lists only 3 papers by Albright,   in 1938-9.

SPECIALIST NATURAL MEDICINE CLINIC 2015

SPECIALIST NON-XRAY PAIN, BONE, BREAST, BRAIN,  HEART, CHEST, GENITOURINARY, HORMONE RISK SCREENING  @ NATURAL MEDICINE CLINIC

for appointments for consultations,   or non-xray procedures by registered practitioners :  Sure Touch breast prescreening on  Saturday mornings next on  7 February 2015  by Sister Zeneath Ismail – cash R650 (then R450 if followup scan desired within 3 months);   -QUS  ultrasound quantitative bone density  cash R450 -tariff item 3612-  anytime;  Unlike radiologists’  and thermography reports (which describe only  the imaging finding), the rates quoted include relevant breast or bone consultation and management planning  by specialist nurse & physician.

IF BOOKED TOGETHER, (not necessarily the same morning) then combined breast and bone screening is R1000.

OTHER SERIOUS health problems ARE DEALT WITH BY CONSULTATION DURING THE WEEK (OR ON A DIFFERENT SATURDAY MORN) : heart- ECG,  fatigue, HRT, sexual health, hypertension, depression, memory/dementia, lung & lungfunction, anaemia-haematology; kidney/bladder/pelvic, hormone-endocrine, depression, osteoporosis, sleep, diabetes, thyroid, adrenal; cramp; skin,  infection including STDs & HIV/AIDs, stroke, epilepsy-neurology, dizziness, heartburn/digestive/liver,  neuropathy,  sexual health, menopause, HRT, genitourinary; immune problems, or arthritis relief;

Thermography no-touch infrared screening  for suspicious  cancer /inflammatory  changes:  by Radiographer Melinda-next 23 March 2015.   R900 breasts; R1100  head and  upper;  or lower body & pelvis;  R1300 whole body.

Bookings/queries contact Evelyn/ Reyhana / Val at  the Natural Medicine Clinic, 1st Floor no 15, Grove Medical Bldg, opp ABSA (parking ABSA Parkade )  near Warwick/Cavendish  Square Claremont Cape Town RSA, ph +27216831465 or a/h +2783 4385248 or reyhanadaya@yahoo.com  .

For the disabled – by arrangement  drive  up the ramp  to the Clinic door on the Grove Bldg 1st floor  parking deck.

Under CMS Council for Med Schemes Reg 10(6), open Medical schemes eg hospital plans  have to pay from their own funds (not members’ savings) for appropriate outpatient consultation (tariff item 0191) for  PMBs ie major conditions eg  cancer,   depression, neck/spinal problems, serious heart, lung, other disease., etc. Breast and osteoporosis concerns are generally part of menopause consultations N95.9   (if not already eg breast cancer code C50) and thus are often billable  med scheme benefits. The menopause billable item only applies if you are 45yrs upwards, unless you have had total hysterectomy.

On patients’ requests, appropriate invoice can be prepared and submitted to your scheme for refund of your due benefits. Some schemes eg hospital plans  falsely deny due benefits until reported to their regulator  CMS. For medical plans where the billable tariff benefit rate is higher than the breast screening fee paid, the med plan rate 0191  will be charged eg R790 by the contracted  specialist,  and refundable by Discovery to the member. some basic schemes eg Keycare, Bonitas require preauthorization, or referral by their contracted GP  .

29 SEPT 2014 OVARIAN CANCER UPDATE: PROGESTERONE REPLACEMENT IS IDEAL; WHY USE ORAL HT? WHEN ESPECIALLY LONG TERM PROGESTINS GREATLY INCREASE RISK OF OVARIAN AS WELL AS BREAST CANCER.

: ABSTRACT:  since last review in  this column 5 years ago, what progress has there been with ovarian cancer OvCa? On Pubmed there are 81000 references,  45500 reviews on OvCa

5 Oct 2014:  Ovarian Cancer Often Arises from Precursor Endometriosis    Frontline Medical News, 2014 Sep 29, B Jancin

   29 Sept 2014  The good news is that if ovariectomy is not done at hysterectomy, then at least salpingectomy should be done- it does not cause earlier menopause.  And the modern fashion for progesterone cream as baseline hormone balancing in this age of estrogen dominance, the feminization of nature,  also adds major protection for heart, bone, memory, mood,  and against cancer, without the risks of estrogen.

Before this month’s update,  the latest, an Australian cancer review  Mette ea 2013, shows that cigarette smoking increases the risk of OvCa by 30% to 60%.

The latest   review 2013 Modugno ea at Univ Pittsburgh/Mayo Clinic  Hormone response in ovarian cancer: time to reconsider as a clinical target?   said “Ovarian cancer is the sixth most common cancer worldwide among women in developed countries and the most lethal of all gynecologic malignancies. There is a critical need for the introduction of targeted therapies to improve outcome. Epidemiological evidence suggests a critical role for steroid hormones in ovarian tumorigenesis. There is also increasing evidence from in vitro studies that estrogen, progestin, and androgen regulate proliferation and invasion of epithelial ovarian cancer cells. Limited clinical trials have shown modest response rates; however, they have consistently identified a small subset of patients that respond very well to endocrine therapy with few side effects. We propose that it is timely to perform additional well-designed trials that should include biomarkers of response.The most consistently reported reproductive and hormonally related factors found to protect against EOC are use of oral contraceptives (OCs), increasing parity, and having a tubal ligation. In contrast, increasing age and nulliparity have been consistently shown to increase EOC risk. 

    Recent studies, including the prospective Women’s Health Initiative (WHI) (Anderson et al. 2003) and the Million Women Study (Beral et al. 2007), report an increase in risk for both estrogen-only (ET) and estrogen–progestin (EPT) formulations, although the risk associated with EPT was lower than that of ET. A recent meta-analysis of 14 published studies found risk increases 22% per 5 years of ET use compared with only 10% per 5 years of EPT use, suggesting that risk differs by regimen (Pearce et al. 2009).               Exogenous androgens may be associated with EOC. One case–control study found that use of Danazol, a synthetic androgen commonly used in the treatment of endometriosis, significantly increased EOC risk (Cottreau et al. 2003), although this finding has not been replicated (Olsen et al. 2008). Ever use of testosterone (tablets, patches, troches, or cream) has been associated with a threefold increase in EOC (Olsen et al. 2008).             

     Reproductive disorders and other reproductive factors :  Factors affecting childbearing have also been shown to be associated with EOC. In most studies, infertility has been associated with an increased risk, which may be greatest among women who fail to conceive (Vlahos et al. 2010). In general, infertility treatment does not appear to increase EOC risk, although the subset of treated women who remain nulliparous may be at an increased risk (Vlahos et al. 2010).

         Endometriosis, defined as the presence and growth of endometrial tissue outside the uterine cavity, has also been associated with EOC. A recent pooled analysis of 13 case–control studies showed a threefold increase in the incidence of clear cell EOC and a twofold increase in endometrioid EOC among women with a self-reported history of endometriosis (Pearce et al. 2012).

    An increased risk of EOC was reported by one case–control study (Schildkraut et al. 1996) among women with polycystic ovary syndrome (PCOS), a condition associated with menstrual dysfunction, infertility, obesity, the metabolic syndrome, hyperandrogenism, and insulin resistance. However, the finding was based on a small number of cases (n=7) and the association was limited to nonusers of OCs and thin women. Further case–control and prospective studies have failed to confirm this relationship (Pierpoint et al. 1998, Olsen et al. 2008, Brinton et al. 2010).

   Tubal ligation has been consistently shown to be associated with reduction in EOC risk (Cibula et al. 2011). This protection appears similar in magnitude to OC use and child bearing (about 30%) and is protective in high-risk women (i.e. BRCA1/2 carriers) as well. Hysterectomy has also been shown to reduce EOC risk, although the magnitude of the association is not as great nor as consistent as that reported for tubal ligation (Riman et al. 2004). Finally, reproductive factors associated with other hormonally linked cancers, such as age at first menarche, age at menopause, and length of reproductive years, have not been consistently associated with EOC (Riman et al. 2004).

    Estrogens and androgens –  The evidence linking these  to EOC are mixed. The majority of women who develop ovarian cancer are postmenopausal at the time of diagnosis. In postmenopausal women, the major source of circulating estrogen is from the peripheral conversion (in skin and adipose tissue) of androstenedione by the enzyme aromatase.

    Progesterone and progestins- Epidemiological data suggest that progestins and progesterone may have a protective role against EOC. Importantly, there is some evidence that progesterone might synergize with chemotherapeutic drugs to induce apoptosis.

Now this month  comes exciting news about  a  Paradigm Shift: Prophylactic Salpingectomy for Ovarian Cancer Risk Reduction   Frontline Medical News, 2014 Sep 24, B Jancin     :   Removing the fallopian tubes at the time of pelvic surgeries as a potential means of reducing ovarian cancer risk appears to be a movement that’s picking up steam in clinical practice.
       A recent survey of 234 U.S. gynecologists showed prophylactic bilateral salpingectomy is catching on when performed in conjunction with hysterectomy, but far less so for tubal sterilization, Dr. Austin Findley observed at the annual Minimally Invasive Surgery Week.                                                                       A total of 54% of respondents indicated they routinely perform salpingectomy at the time of hysterectomy in an effort to reduce the risk of ovarian cancer as well as to avoid the need for reoperations. However, only 7% of the gynecologic surgeons said they perform salpingectomy for tubal sterilization, even though 58% of respondents stated they believe the procedure is the most effective form of tubal sterilization (J. Minim. Invasive Gynecol. 2013;20:517-21).
  “In my experience at various hospitals, I think these numbers are a pretty accurate reflection of what folks are doing,” commented Dr. Findley of Wright State University in Dayton, Ohio.
     The prophylactic salpingectomy movement is an outgrowth of the tubal hypothesis of ovarian cancer.
    “There is now increasing and dramatic evidence to suggest that most ovarian cancers actually originate in the distal fallopian tubes. I think this is a concept most people are unaware of or are just becoming accustomed to. The tubal hypothesis represents a major paradigm shift in the way we think about ovarian cancers. The previous belief that excessive ovulation is a cause of ovarian cancer is no longer regarded as accurate,” he explained at the meeting presented by the Society of Laparoscopic Surgeons and affiliated societies.
      Ovarian cancer is the No. 1 cause of mortality from gynecologic malignancy, accounting for more than 14,000 deaths per year, according to National Cancer Institute data. The lifetime risk of the malignancy is 1.3%, with the average age at diagnosis being 63 years.
       Only 10%-15% of ovarian cancers occur in women at high risk for the malignancy because they carry a BRCA mutation or other predisposing gene. The vast majority of ovarian cancer deaths are caused by high-grade serous tumors that have been shown to be strongly associated with precursor lesions in the distal fallopian tubes of women at low risk for the malignancy.
            There is no proven-effective screening program or risk-reduction method for these low-risk women. However, with 600,000 hysterectomies and 700,000 tubal sterilizations being performed annually in the United States, prophylactic salpingectomy has been advocated as an attractive opportunity to potentially reduce ovarian cancer risk. Other common pelvic surgeries in which it might be used for this purpose include excision of endometriosis and laparoscopy for pelvic pain. It also has recently been shown to be feasible and safe post partum at cesarean or vaginal delivery (Obstet. Gynecol. 2014 [doi: 10.1097/01.AOG.0000447427.80479.ae]).
   But the key word here is “potentially.” It must be emphasized that at present the ovarian cancer prevention benefit of prophylactic salpingectomy remains hypothetical; in theory, the procedure should reduce ovarian cancer risk, but there is not yet persuasive evidence that it actually does, Dr. Findley emphasized at the meeting, presented by the Society of Laparoendoscopic Surgeons and affiliated societies.
            In contrast, one well-established ancillary benefit of prophylactic salpingectomy is that it eliminates the need for future reoperation for salpingectomy. This was demonstrated in a large Danish cohort study including close to 10,000 women undergoing hysterectomy and a similar number undergoing sterilization procedures. Among the nearly two-thirds of hysterectomy patients who had both fallopian tubes retained, there was a 2.13-fold increased likelihood of subsequent salpingectomy, compared with nonhysterectomized women.
        Similarly, Danish women who underwent a sterilization procedure with retention of the fallopian tubes – typically tubal ligation with clips – were 2.42 times more likely to undergo subsequent salpingectomy, most often because of the development of hydrosalpinx, infection, ectopic pregnancy, or other complications (BMJ Open 2013;3 [doi:10.1136/bmjopen-2013-002845]).
     The most commonly cited potential risk of prophylactic salpingectomy – decreased ovarian function – now appears to be a nonissue. This was demonstrated in a recent retrospective Italian study (Gynecol. Oncol. 2013;129:448-51) as well as in a pilot randomized controlled trial conducted by Dr. Findley and his coworkers (Fertil. Steril. 2013;100:1704-8), which appears to have answered many skeptics’ concerns. Indeed, Dr. Findley’s coinvestigator Dr. Matthew Siedhoff said he has recently been approached by researchers interested in collaborating in a larger confirmatory randomized trial, but all parties eventually agreed it was a no-go.
    “It’s a little hard to demonstrate equipoise for a larger randomized controlled trial. We’re beyond that now, given that prophylactic salpingectomy really doesn’t seem to make a difference as far as ovarian function,” according to Dr. Siedhoff, director of the division of advanced laparoscopy and pelvic pain at the University of North Carolina, Chapel Hill.
         Another oft-expressed reservation about salpingectomy as a means of reducing ovarian cancer risk in women seeking sterilization is that salpingectomy’s irreversibility may lead to “tubal regret” on the part of patients who later change their mind about further pregnancies. However, Dr. Findley cited a recent editorial whose authors criticized colleagues who made that claim. The editorialists argued that the tubal regret concern indicates surgeons weren’t really listening to their patients’ true desires during the informed consent conversation.
     “We should not have started thinking about salpingectomy for female sterilization only once a decrease in ovarian cancer risk became part of the equation,” they declared (Obstet. Gynecol. 2014;124:596-9).
           Dr. Findley noted that Canadian gynecologists are leading the way forward regarding prophylactic salpingectomy as a potential method of ovarian cancer prevention. The Society of Gynecologic Oncology of Canada in a 2011 policy statement recommended patient/physician discussion of the risks and benefits of bilateral salpingectomy for patients undergoing hysterectomy or requesting permanent sterilization. The Society of Gynecologic Oncology followed suit with a similar clinical practice statement in late 2013.
        Additionally, the Canadian group declared that a national ovarian cancer prevention study focused on fallopian tube removal should be a top priority.
    Gynecologic oncologists in British Columbia recently reported the eye-catching results of a province-wide educational initiative targeting gynecologists and their patients. In 2010, all British Columbia gynecologists had to attend a course on the role of the fallopian tubes in the development of ovarian cancer, during which they were advised to consider performing bilateral salpingectomy for ovarian cancer risk reduction.
              Surgical practice changed dramatically in British Columbia in response. In 2009 – the year prior to the physician education initiative – salpingectomy was utilized in just 0.3% of permanent sterilization procedures. In 2010, it was 11.4%. By 2011, it was 33.3%.
           Similarly, only 7% of hysterectomies performed in British Columbia in 2009 were accompanied by bilateral salpingectomy. This figure climbed to 23% in 2010 and jumped further to 35% in 2011. Meanwhile the rate of hysterectomy with bilateral salpingo-oophorectomy remained steady over time at 44% (Am. J. Obstet. Gynecol. 2014;210:471.e1-11).
     This project was conducted in collaboration with the B.C. Cancer Agency, which maintains comprehensive province-wide registries. Over time, it will be possible to demonstrate whether prophylactic salpingectomy is indeed associated with a reduction in the incidence of ovarian cancer. “I think this study demonstrated that there’s a lack of awareness on this issue, but also [that there’s] potential effectiveness of introducing an educational initiative like this in changing our practice patterns. As we start talking more about this issue amongst our colleagues and our patients, we’re more likely to see a practice pattern shift in the United States as well,” Dr. Findley commented.

17 July 2009     A new cancer study of  over 7 million women years is another major coffin for unopposed estrogen ET, for progestin Pg, and for oral  sex hormone therapy SHT.

Danish  Universities prospectively document  the incidence of ovarian cancer OvCa in a million postmenopausal women PMW  from 1995 through 2005.  Compared to non-users, use of HT increased OvCa (mean age 62yrs) by about 40%   for up to 2 years after stopping Ht, ie increased the absolute incidence  of clinically diagnosed OvCa from ~ 0.04 to ~0.052% ie per 100 patient yrs.

Transdermal TD ET alone  increased risk by 13%; vaginal ET by 23%;                                            Oral ET alone increased  risk by  34%; oral E+ progestin Pg by  48%;          TDE+Pg by 67%.

Thus the relative incidence of OvCa rose about 33% by 7 years on HT, to 48% if HT continued beyond 7years.

In 2004 Glud ea reported an increase risk of 31% for OvCa in Danish women on OHT use – total ET dose of ~5gm ie for about  for 15yrs – at a time when the standard premarin  dose was 0.625mg/d (equivalent to l mg E2)  if not double that .

For perspective,  the relative incidence of cancers in similar mostly 1st world European women from the  the USA SEER data for 2006 age over 50  years  are: BrCa 0.33%,  uterus 0.07%, ovary o.03%(ie very similar to the baseline Danish figure of 0.04% above), colon 0.15%,and cervix 0.01%. The new (Norwegian)  analysis in the latest BMJ suggests that screening mammography may result in overdiagnosis of BrCa by up to 50% (the other 50% may arguably never have been clinically significant-diagnosed- during life) , so the provocative could argue that the relative incidence of clinically significant BrCa to OvCa is more like eg BrCa 0.2 to ovary 0.03 ie just below 10:1. But OvCa is notoriously about 70% fatal within a few years, so  the absolute  mortality rate – at age 60-64yrs-  from  the same SEER  source and period are as relevant: BrCa 0.063%, uterus 0.011%, ovary 0.033%, colon 0.03% & cervix 0.005%. ie new OvCa may be only 1/10th as common as newBrCa, but BrCa  kills only twice  as many PMW as OvCa.

And finally the 2007  survey by  Rossing ea of  Menopausal Hormone Therapy and Risk of Epithelial Ovarian Cancer in women in Washington State 2002-2005 showed that  ET -mostly premarin (but not ET + progestin- MPA medroxyprogesterone provera) – especially in  low-parity  younger slim women increased OvCa compared to non-users, and that this risk  was highest- up to 90%-  in  users of OET  for more than 6 years.

By comparison – BREAST CANCER BrCa and HT: Hoover ea  1976  are the first on Pubmed to report doubling in  risk of breast cancer  BrCA after 15yrs on premarin in USA ie at least 5gm cumulative dose.

In Denmark by 1994 Ravn ea reported that if there was a risk of BrCa from OHT, it was small, and only after prolonged use of estrogen (15-20 years).  But by 2004 -2005 Tjønneland ea , Stahlberg ea  and Ewertz ea  found increased risk for BrCa  of 61 to 112%  associated with current use of HT.  Stahlberg ea already in 2003 concluded from recent studies from both the USA and Europe that the combined treatment regimens with estrogen and progestin increase the risk of BrCa  beyond the risk of unopposed estrogen.

In Norway, a recent Tromso study suggested that the dominant HT therapy used in Norway was oral estradiol E2 plus the progestin norethisterone acetate. . An earlier Tromso study in only 35000 PMW was too small- it showed that use of such OHT for >5yrs trebled the incidence of breast cancer BRCa, but did not influence that of OvCa.

Apart from smokers’ lung cancer, the commonest cancer in older women- BrCa- clinically affects perhaps 5% of PMW  lifelong – but  with prompt therapy after clinical presentation kills as few as 5% of sufferers- and with appropriate OHT (premarin +- provera)  for up to 8years in the Women’s Health Initiative both the incidence of and mortality from BrCa, and all-cause mortality,  were reduced by about one-third. Hence appropriate HT saves many from both BrCa and from premature death and disability from the commonest degenerative diseases- vascular, dementing and fracturing. 75% of women who develop BrCa  die with it –  not from it but from far more prevalent degenerative diseases after an  otherwise normal lifespan. But the Danish evidence is that combined OHT will increase OvCa by >50%.

Ovarian Ca kills 70% of victims, and is it so rare compared to BrCa? .

Hence with the perhaps 2/3  lower incidence of OvCa, it is a relatively trivial problem for women overall- except for the 4  in  10 000 women  who develop it, who have <50% 5year survival, ie 3 out of 4  of whom it will kill within a few years- compared to <25% of breast cancer victims who will be killed by the BrCa.

However, it becomes clear that these hormone-dependent cancers are both  duration-  and total-dose HT related; but even more important, that unopposed OET is a risk if persisted more than about 12 yrs; and even if used in far lower dose parenterally, the risk of OvCa is far higher if combined with the European fashion of androgenic synthetic progestins Pg – even parenterally; whereas the American MPA for up to 8years at least apparently if anything mitigates the OvCa risk of ET..

By contrast this column has repeatedly reviewed evidence that balancing physiological ERT with physiological testosterone replacement TRT eliminates the risk  for BRCA and endometrial cancer of unopposed ERT +- PRT in PMW.  Intuitively this should also apply to ovarian cancer.

Hence the message strengthens that PMW should not be exposed for  any length of time at any stage to the much higher oro-hepatic HT doses (needed for symptom control) or OET+- Pg; but as in all other endocrine replacement for permanent  multisystem prevention – let alone sexual function-  patients with gonadal deficiency should have physiological sexhormone balance restored  ie with balanced parenteral  human androgen, estrogen and progesterone replacement.

It is common cause that (reproductive cycles and pregnancy aside) all the physiological  prime sex hormones-DHEAdehydroepiandrosterone, P4, T, E2, E3 – are as important as all other human hormones, essential life long  for optimal health; and that estrogen dominance (due to inadequate  androgen and progesterone levels) is deleterious. Hence most PMW require both physiological progesterone and androgen replacement- sometimes to balance excessively high endogenous estrogens, usually to accompany necessary ERT for full balance.

ndb

UPDATE: LEGISLATING REDUCED ADVERSE FOOD ADDITIVES, MANDATING ADDED MICRONUTRIENTS

  The  Mail and Guardian Health supplement (11 April 2013)  featured the dynamic South African Health Minister   Dr Aron Matsoaledi legislating lower salt -sodium chloride-  in staple processed foods  eg in cereals, butter, potato crisps,     by about half  over the next 6 years.
         This is long overdue since salt-related hypertension and often associated.  obesity are  historically  major killers not just in Afro-Americans  but in any longer-living people and especially stressed poverty-stricken  peoples as in Africa.

The linked bad nutritional -and lifestyle – choices – Salt-Stroke  – smoking- – hypertension- obesity – diabetes – heart – kidney disease – are  quoted by S.A. Stats  2010 from death certifications as rising  to 24%  of deaths after age 50 years, leading even infections at  20%  as the commonest causes  of  seniors’ death in South Africa. Nonnatural causes ie violence account for only 5%, and cancers only about 4%.

           This in a population that ( both by self- choice and by State- and supply-chain corporates)   heavily self-poisons with industry-promoted salt,  concentrated   fructose-   sucrose, ethanol , unsafe sex, and smoking –  the deadly self-abuse quintet  causing the great majority of premature deaths and  disability – diabesity- brain-heart-vascular-renal-cancer -arthritis, infections, Alzheimers(type 3 diabetes) and violence. – ie the team of  high-profit horsemen (alcohol, smoking, sugar, fructose, salt and other addictive drugs; television, sex, guns, knives, fast motoring, and ruthless medical practices)  of the global marketting corporates .
          But not a word was  said in those two salty  pages  about simultaneously legislating for  processed consumables  the other greatly needed adjustments:
REMOVING from the environment, from  consumables (water and processed food , toothpaste, sweetened  drinks and sweeteners, baby milk formulae, hygiene products, vaccines, etc,)  or at least steadily reducing, other notorious and unnecessary  toxic  marketed hazards- aluminium, aspartame + sucralose, mercury, fluoride, bromine, refined sugars, cooked fats, and pesticides, hormones, antibiotics, and estrogenics eg soya ( unless fermented) used in food, medicine,  and vaccines ; and REPLACING in processed foods commonly and increasingly deficient  micronutrients in the regional diet especially for the poor masses and children – eg minerals (magnesium, calmag phosphate, zinc, iodine, lithium,  selenium,  sulphur, boron); vitamins (especially A, B, C, D3, K2, coQ10; and other crucial  essential  antiinflammatory  antioxidant  anti-obesity insulin sensitizers eg virgin coldpressed  coconut oil and uncooked marine omega3.
      From scientific studies there is little doubt that hypertension is proportionate to sodium chloride overload, as it  is especially to deficiency of magnesium, potassium, iodine, water, and vits  B, C, D3 and K2.  But scientific evidence is still unclear as to whether it is just the excess  essential halogen mineral CHLORINE.  in NaCl that  is the dietary cause of  hypertension,  not SODIUM in NaCl- but not in other essential forms eg with carbonate.
HALOGENS  in nature are the four major  elements – fluorine, chlorine, bromine and iodine from the lightest, ie lowest atomic number,  upwards.  Fluorine as  the lightest  is one of the most reactive ie corrosive of all materials. Halogens with metals eg sodium form sea- salts. As their weight/atomic number rises, they become less reactive,   Apart from  bromine they are disinfectants.
 IODINE is certainly  the heaviest and thus least reactive halogen iodine is the  essential  mineral that in adequate intake is  major anti infection- (among the strongest antimicrobials we have)-  anticancer, healer, thyroid metabolism and thus heart regulator, and major chelator – detoxifier- against the lighter  halogens – the toxic bromine and fluorine, and excess chlorine.
 The food and drug industry needs cudgeling to stop polluting water, medicines and food with unhealthy fluorine, chlorine and bromine.
FLUORINE is still misguidedly used , promoted in drinking water , toothpaste and antibiotics ; while  for obscure reasons BROMINE.  has replaced iodine in eg bread. FLUOROSIS and BROMaiSM  are notorious poisonings – and unlike iodine and chlorine,  the fluorine and bromine have no human essential  biological benefit as even trace elements. Fluorine – like aluminium, bromine, cadmium, mercury, iron, – may be invaluable in industry, but Fluorine is not essential for mammals or humans. Its use in dentistry has with mercury amalgams long been scientifically debunked as harmful and unnecessary, and is being phased out by preventative dentists everywhere. .
         Tricyclics and other pre-1980s antidepressants had several side effects due to their nonselective interference with neurotransmitters other than the serotonin target; the fluorinated fluoxetine was selective and one of the first avoiding this problem. but the serotonin deficiency hypothesis has never been proven to be a major factor in depression.  Many current antidepressants receive this same treatment, including the selective serotonin reuptake inhibitors citalopram But antidepressants have major adverse effects, are rarely as good as talk therapy, and often do  worse than natural mood-improving nutrients eg vitamins and fish oil.
Quinolones are artificial antibiotics often fluorinated to enhance their effects,eg ciprofloxacin. But these antibiotics are notorious for terrible advese effects including crippling weakening  – rupture of tendons, and are never essential. 
 BROMINE. Africa.   is still listed as a food supplier to the baking industry in South Africa!    But Wiki writes: bromine has no proven essential function or need in humans. an unwanted side effect is ozone depletion. As a result, many organobromide compounds that were formerly in common use—such as the pesticide, methyl bromide—have been abandoned. It reacts vigorously with metals, especially in the presence of water, to give bromide salts. It bonds easily with many elements and has a strong bleaching action. Like chlorine, bromine was used as a wartime poison gas, and disinfectant / pesticide- ie a poison! so bromines were removed from medical/vet use in the 1970s. Long-term use of potassium bromide (or any bromide salt) can lead to bromism. Yet it is used in: production of brominated vegetable oil, which is used as an emulsifier in many citrus-flavored soft drinks (for example, Mountain Dew). After the introduction in the 1940s the compound was extensively used until the UK and the US limited its use in the mid 1970s and alternative emulsifiers were developed. But .Soft drinks containing brominated vegetable oil are still sold in the US (2013).  Bromine, like chlorine, is used in maintenance of swimming pools, Water purification compounds, disinfectantsinsecticides, and photographic processes. .
        Dr Joe Mercola wrote in the Huffington Post 2010: “Bromines are common endocrine disruptors. What makes it so dangerous is that it competes for the same receptors that are used to capture iodine. If you are exposed to a lot of bromine, your body will not hold on to the iodine that it needs. And iodine affects every tissue in your body — not just your thyroid.  You are already exposed to far too much chlorine and bromine. Bromine can be found in a number of places in your everyday world, including: plastics, Bakery goods and some flours often contain a “dough conditioner” called potassium bromate; •Soft drinks (including Mountain Dew, Gatorade, Sun Drop, Squirt, Fresca and other citrus-flavored sodas), in the form of brominated vegetable oils (BVOs); Medications such as Atrovent Inhaler, Atrovent Nasal Spray, Pro-Banthine (for ulcers), and anesthesia agents; Fire retardants (common one is polybromo diphenyl ethers or PBDEs) used in fabrics, carpets, upholstery, and mattresses       According to van Leeuwen, who has extensively studied the effects of sodium bromide on thyroid function:   “Although the bromide ion is widely distributed in nature, the main route of exposure in humans stems from bromide residues in food commodities as a result of the abundant use of bromide-containing pesticides, like methylbromide and ethylene dibromide, for soil fumigation in intensive horticulture and for postharvest treatment.”      One clinical consequence of overexposure to bromine is suppression of your thyroid, leading to hypothyroidism, .
         
   Another is bromide toxicity: .Bromine — The Bully of the Halide Group:  When you ingest or absorb bromine, it displaces iodine, and this iodine deficiency leads to an increased risk for cancer of the breast, thyroid gland, ovary and prostate — cancers that we see at alarmingly high rates today. This phenomenon is significant enough to have been given its own name — the Bromide Dominance Theory.   Aside from its effects on your endocrine glands, bromine is toxic in and of itself. Bromide builds up in your central nervous system and results in many problems. It is a central nervous system depressant and can trigger a number of psychological symptoms such as acute paranoia and other psychotic symptoms.  In fact, in an audio interview, physician Jorge Flechas reported that, between 1920 and 1960, at least 20 percent of all hospital admissions for “acute paranoid schizophrenia” were a result of ingesting bromine-containing products. In addition to psychiatric problems, bromine toxicity  eg from the old BromoSelzer can manifest as the following: Skin rashes and severe acne; Loss of appetite and abdominal pain; Fatigue; Metallic taste; Cardiac arrhythmias. . These effervescent granules, developed by the Emerson Drug Company of Baltimore, were used to treat heartburn, upset stomach, indigestion, headaches and hangovers. Bromides were withdrawn from the American market in 1975 due to their toxicity.  Bromo-Selzer still  on the market  no longer contains bromide.                                                                                                                   
       
          Bromines in Your Bread Box: Potassium Bromate:  The ban on bromines have not prevented them from sneaking into your foods and personal care products.  You probably are not aware of this, but nearly every time you eat bread in a restaurant or consume a hamburger or hotdog bun you are consuming bromide, as it is commonly used in flours.  The use of potassium bromate as an additive to commercial breads and baked goods has been a huge contributor to bromide overload in Western cultures.  Bromated flour is “enriched” with potassium bromate. Commercial baking companies claim it makes the dough more elastic and better able to stand up to bread hooks. However , successful companies manage to use only unbromated flour without any of these so-called “structural problems.”  Potassium bromate is also found in some toothpastes and mouthwashes, where it’s added as an antiseptic and astringent. It has been found to cause bleeding and inflammation of gums in people using these products. Mountain Dew, one of the worst beverages you can drink, uses brominated vegetable oil as an emulsifier. Not only that, it contains high fructose corn syrup, sodium benzoate, more than 55 mg of caffeine per 12 ounce can, and Yellow Dye #5 (tartrazine, which has been banned in Norway, Austria and Germany.)  A weapon of mass destruction — in a can.   .Even drinking water can be a source of bromide. When drinking water containing bromide is exposed to ozone, bromate ions are formed, which are powerful oxidans.
   Sodium bromate can also be found in personal care products such as permanent waves, hair dyes, and textile dyes. Benzalkonium is used as a preservative in some cosmetics.    Finally, bromine and chlorine were the most common toxic elements reportedly found in automobiles, according to  David Brownstein, MD (March 2007). They showed up in the seats, armrests, door trim, shift knobs and other areas of the car.  The United States is quite behind in putting an end to the egregious practice of allowing bromine chemicals in your foods. In 1990, the United Kingdom banned bromate in bread. In 1994, Canada did the same. Brazil recently outlawed bromide in flour products.    Iodine Levels and Cancer Risk:  Iodine levels have significantly dropped due to bromine exposure; declining consumption of iodized salt, eggs, fish, and sea vegetables; and soil depletion. In the U.S. population, there was a 50 percent reduction in urinary iodine excretion between 1970 and 1990. What’s this doing to our country’s health?   The Japanese consume 89 times more iodine than Americans due to their daily consumption of sea vegetables, and they have reduced rates of many chronic diseases, including the lowest rates of cancer in the world.
            The RDA for iodine in the U.S. is a meager  0.15 mg/day, which pales in comparison with the average daily intake of 13.8 mg/day for the Japanese.  There is a large body of evidence suggesting that low cancer rates in Japan are a result of their substantially higher iodine levels. Iodine has documented antioxidant and anti-proliferative properties.   A strong case can be made that your iodine RDA should be closer to what the Japanese consume daily, if breast cancer rates are any indication. Low iodine can lead to fibrocystic breast disease in women (density, lumps and bumps), hyperplasia, and atypical mammary tissue. Such fibrocystic changes in breast tissue have been shown to reverse in the presence of iodine supplementation after 3-4 months.   If youwant to be tested  for iodine deficiency, the urine iodine challenge test is the best way to assess your iodine level.
              Bromine and Your Thyroid   Adding to the negative health effects of bromine, the damage to your thyroid health deserves special mention. bromine exposure depletes your body’s iodine by competing with iodine receptors. Iodine is crucial for thyroid function. Without iodine, your thyroid gland would be completely unable to produce thyroid hormone. Even the names of the different forms of thyroid hormone reflect the number of iodine molecules attached — T4 has four attached iodine molecules, and T3 (the most biologically active form of the hormone) has three–showing what an important part iodine plays in thyroid biochemistry.   Hypothyroidism is far more prevalent than once thought in the U.S. The latest estimates are that 13 million Americans have hypothyroidism, but the actual numbers are probably higher. Some experts claim that 10 to 40 %  of Americans have suboptimal thyroid function.   Many of these folks may actually have nothing wrong with their thyroid gland at all — they may just be suffering from iodine deficiency.
        Seven Tips for Avoiding Bromine and Optimizing Iodine   Trying to avoid bromine is like trying to avoid air pollution — all you can do is minimize your exposure. That said, here are a few things you can do to minimize your risk:
       1. Eat organic as often as possible. Wash all produce thoroughly. This will minimize your pesticide exposure. 2. Avoid eating or drinking from (or storing food and water in) plastic containers. Use glass and safe ceramic vessels.
        3. Look for organic whole-grain breads and flour. Grind you own grain, if possible. Look for the “no bromine” or “bromine-free” label on commercial baked goods. 4. Avoid sodas. Drink natural, filtered water instead.          .
         5. If you own a hot tub, look into an ozone purification system. Such systems make it possible to keep the water clean with minimal chemical treatments. 6. Look for personal care products that are as chemical-free as possible. Remember — anything going on you, goes in you,                                                                                          
        . 7. When in a car or a building, open windows as often as possible, preferably on opposing sides of the space for cross ventilation. Utilize fans to circulate the air. Chemical pollutants are much higher inside buildings (and cars) than outside.
           Avoid Unfermented Soy Another major contributor to thyroid dysfunction that I did not discuss above is unfermented soy. Soy isoflavones – estrogenics- can wreak havoc on your thyroid. Kaayla Daniel’s groundbreaking book, The Whole Soy Story: The Dark Side of America’s Favorite Health Food is a powerful exposé that reveals the truth about the soy myths that have infiltrated our culture. So if you want to keep your thyroid healthy, you’ll definitely want to avoid bromines, and unfermented soy products of all kinds, including soy milk.”
               These changes  – removing fluoride, bromine, aluminum, mercury, lead, unfermented soy-  from consumables, and cutting added iron and chlorine – may possibly add fractional cost to production?  but will hugely improve educability and health, productivity and employability, and reduce premature disability and death  far more than just  hypertension- vascular risks;  and greatly reduce acute and chronic illness and infections, hospitalization and need for risky modern  chronic prescription medication..  And since iodine deficiency is widely endemic ,  increasing population iodine intake up to 12mg a day  like Japanese get,  – not 0.15 mg/ d – will  hugely reduce premature aging,  common goiter and hypothyroidism, infections, vascular disease  and cancer
But of course Corporates, Governments and the Disease , Drug and Hospital Industries  dont want disease ,  jobs and profits to be decimated by natural supplements avoiding most common diseases- the Fraud of Modern Medicine since Only Disease Pays.

update: THE END OF PROT(E)OS: TAKE NATURAL STRONTIUM SALTS [not the synthetic RANELATE-PROT(E)OS]- AGAINST OSTEOPOROSIS, CARIES, ARTHRITIS..

UPDATE 10 January 2014:  PROTOS SUSPENDED -another snakeoil bites the dust- strontium ranelate. It has apparently never been registered in USA anyway.

EU Panel Recommends Suspension of Prot(el)os/Osseor

Miriam E. Tucker  January 10, 2014

This does not affect the physiological use of natural strontium salts as one of a score of natural bone anabolic elements along with the other essential minerals, vitamins proteins and hormones  in our Milieu intérieur  .

neil.burman@gmail.com

update 11 Dec 2010

once again, a relevant comment from a reader (qv Doris Bevans below) prompts an update- and a title revision. The risk  is not strontium, but the patent designer drug Protos/Proteos /Protelos – strontium ranelate- ie as this column has stressed from the start, it appears to be the synthetic anion ranelate that is the problem, not the metal cation  strontium. This is similar to the sodium situation, where it is the anion chloride in table salt that is mostly the hypertension- fluid retention problem, not sodium.

These strontium comments by users  mostly generalize- as this review has- about  strontium . But of course as a useful comments website  shows, there are many natural salts of strontium in use.

The focus of this strontium review column the past three years has naturally been on the potentially hazardous designer patent drug Proteos, Protos, Protelos  strontium ranelate StRan – for which there is absolutely no need considering the numerous perfectly safe and multisystemically  far better alternatives.

Perusal of Google makes it obvious that  StRan is not a natural salt- in fact there is no mention of ranelic acid or strontium ranelate  (Sr2SN2O8) until some 20 years ago when someone first created it-  to enable patenting of a strontium salt for osteoporosis. Imagine how long industrial chemists must have schemed to find a new molecule to carry the useful strontium cation? But the story has apparently yet to be revealed on the internet. One can only speculate why the story of it’s invention has not been put on the internet.

But the common earth metal  strontium was already ‘discovered’ over 200 years ago  – in Scotland-   and has numerous industrial uses  as diverse natural salts. Ward Dean MD points out that strontium salts have been used medicinally for well over a century-  against osteoporosis but especially painful cancer in bone, against dental caries and arthritis; with the optimal dose apparently around 600mg strontium a day.  Usefully, this is about the same optimal dose as calcium, since  as Dean says   “a  comprehensive regimen of synergistic bone-enhancing substances should provide the optimum regimen for preventing and treating osteoporosis. We know that obviously the optimal regime includes  appropriate sex hormones.

So far there  are at least twelve agreed biologically valuable  metal(oid)s  ie cations for humans:  sodium, potassium, calcium, magnesium,  iron, zinc, copper,  boron, manganese, chromium, molybdenum, chromium, vanadium, cobalt; and arguably lithium, gold, silver, silica and nickel.

However, no-one has yet   shown that strontium  is an essential (trace) element like the recognized lighter metals.. .

But just as lithium salts were recognized to have major multiple medicinal benefits within 50 years of discovery ( by the mid 19th century),  natural strontium salts have been recognized and promoted as useful for osteoporosis prevention and management since at least Shorr and Carter 1950 .

And of course the designer StRan  has still not been registered for use in the USA. The detailed data sheet for strontium ranelate warns chillingly of its deadly risks of venous thromboembolism and dermatitis; that it contains phenylalanine;  and that it confounds calcium level measurement.

So the glowing testimonials by consumers to the benefits of strontium salts in USA can only be from the use of natural strontium salts there, unless Protos/Proteos was brought into that country by patients.

And indeed, there do not appear to be any adverse effects to natural strontium salts used in sensible dose the past century.

Rousselet ea showd already in 1975  tight feedback regulation between calcium, strontium and vitamin D:  “Oral administration of strontium to calcium wellfed rats blocks intestinal absorption of calcium. When high doses of vitamin D are given over long period, the inhibition of calcium intestinal absorption disappears. Under these conditions the absorption of strontium is increased. It is suggested that there is only one absorption mechanism for these two cations. An overdose of vitamin D increases the renal elimination of strontium but under these conditions the plasma concentration of the strontium is unchanged. Vitamin D brings about the same action on  bone fixation of the strontium as it does on  bone fixation of calcium. Bone fixation is increased with low dosages,  decreased with high dosages.”

So like lithium and silica, there is no apparent reason not to use moderate  doses of  natural strontium  salts orally in supplements.

Phosphates are indeed , like zinc and  copper , calcium and magnesium, biologically essential in the right balance. It looks like strontium may be the same. .  But that doesnt make the synthetics bisphosphonates or strontium ranelate safe- indeed they may cause deadly complications. So why risk them when the only winner is the manufacturer?

And this time the FDA has been wise to deny registration of StRan. As a designer drug it is not in the category of lithium and metformin, enormously beneficial drugs in recommended doses which the FDA denied  without reason to Americans for at least 20years, (except could it have been to protect their own drug company profits?) costing vast numbers of lifeyears and lives.

Hence in future correspondents praising strontium  need to state what form of strontium they are taking.

update 14 November 2010

Crystal comments today: “My mother has taken strontium Sr for the past 2 years and her bone density from her last bone scan has improved greatly.  I am a believer!

Dear Crystal,

Assuming you are talking about the topic of this column- strontium ranelate-  is that  great? I am also a believer in faith and prayer; but  faith doesnt prove anything  objectively, in fact it still leaves  billions starving and in abject poverty, and  all of us in major jeopardy from mankind’s madness, greed and  ruthlessness .

If doctors  rely on faith,  prayer and Big Pharma, regulators- not  critical evidence, common sense  and experience  – heaven help Mom, all patients.

Improvement in bone density doesnt translate into longterm benefit, healthy  longevity.  What real benefit is strontium  ranelate having for Mom, on fracture rate, muscle ie strength, and all other aging systems?

The biggest risk for osteoporotic fracture is not low  DXA bone density (a very profitable designer hi-tech technology that irradiates patients totally unnecessarily)  but failing muscle, co-ordination, balance- for which strontium apparently does nothing.  Overall, the top disablers and killers  of old age are  not fractures but vascular disease, cancer, dementia, strokes.  At no age do fractures appear in the top 10 causes of death in the USA.
And there is still no evidence of StRan’s longterm SAFETY- in fact the potential risk of the DRESS syndrome makes strontium ranelate contraindicated when the proven safe more-than-twenty  natural proven  bone multinutrients that greatly improve all systems are so effective and available.

Why take a snakeoil designer drug like Proteos when natural works both better and safer?
Look at how bisphosphonates improve bone density- but at terrible multihazard risk of  later disaster –  teeth and jaw loss, fractures from harder but more brittle bones, skin & gullet complications.

Why risk  strontium ranelate’s “memory loss and diarrhoea during longer-term treatment” (Deeks ea 2010), or venous thromboembolism (Osborne 2010) .    And in a massive study, Guerra-Garcia ea 2010 have just shown that over the 5 years 2004-2008 in 12 000 patients, the prescription of  StRan  has risen 10fold and bisphosphonates 50%- but without reduction in the incidence of hip fracture.

Yet the current Wiiki entry on strontuim ranelate still omits the horrendous risk of the DRESS syndrome; and still tells the lie that the drug reduces hip fractures by a third. Presumably  the StRan  manufacturer Servier uses Wiki as its carefully sanitized advertorial.

Focusing just on medium-term fracture benefit (up to 5-10years) and ignoring all-system benefits and risks,  is absurd negligence- the criminal deception practiced by Big Pharma and blissfully ignored by the FDA and the leading journals and “expert reviewers” who depend on big pharma’s  handouts .

Appropriate natural supplements reduce  premature ALL-CAUSE disease and deaths by almost half.

If you are taking StRan, you and your doctor have conned yourselves, as intended by  Big Pharma, ( the Disease Industry and the Governments- politicians- who  are well paid to  support  their Disaster Capitalism ) . Only Disease Pays. And worst of all, they have conned you  into taking potentially lethal costly poison that does  overall no good. Has anyone checked her height, her spinal xray, her memory, bloodpressure, carotid calcification, kidney function  to show that these markers  havent deteriorated  despite StRan?

Drug companies NEVER allow the true adverse effects to be published in their fabricated trial result reports – thats why the big mafia companies  – Pfizer, Bayer, GSK- are fined $billions every year. They could care when a raincheck con like Proteos, a statin, a Vioxx  or a fosamax can bring them a few-score $billion in profits in the years before it is canned due to increasing patient disasters. They simply budget into the price patients pay for  the fines and litigation, and the few million in compensation they pay out for the disasters since American law deliberately PROTECTS them, as it did in the biggest medical scam ever,  the Swine Flu swindle  of 2009. And in 2010 the even bigger  Professor Scott Reuben scandal -over which Pfizer and Bayer get off scot free.. .
No new trials have been published the past few years to justify the use of StRan as being superior to other snakeoil designer drugs designed for osteoporosis, let alone against multipurpose natural preventatives.
This confirms the destitution of Big Pharma.
 No chronic synthetic drug of the past 40 years has been shown to reduce  premature ALL-CAUSE major common disease and deaths as the basket of natural supplements does.    I will be delighted when another such  drug is discovered- as the 90year old natural plant extract metformin is, and fish oil  is, and appropriate HRT hormone replacement is. .

update: 22 Dec 2009:  on this radiant southern summer solstice day, there is no good news  on strontium ranelate because no new trials have been published in the past 19 months.

In their Cochrane Review of 2006, Reginster ea could find just 4 trials of strontium ranelate for  3 to 4 years ; these showed 37% fewer spinal fractures but only 14% fewer non-spinal fractures -results no-where near as good as with safe lowcost multisystem protection with appropriate non-oral human estrogen and testosterone, and vigorous dose of a blend of  calmag boron zinc manganese, proline,  the vitamins B6-9-12, C, D and K .

And as with SERMS eg tamoxifen, and bisphosphonates, why use StRan for osteoporosis  when there is better safer natural multisystem prevention and  treatment?  Severe complications may be rare (<1 in 10,000 cases) but as reported by Reginster ea,  except for the profit of manufacturers, why risk life-threatening reactions? – Stevens Johnson syndrome (SJS) and TEN toxic epidermal necrolysis with bisphosphonate,  but with StRan  TEN syndrome,   and DRESS – angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), let alone renal failure and alopecia..

Again, Prescrire sums it up:  “Strontium: confusion and hallucinations. Do not use strontium”. We now acknowledge this should read strontium ranelate.

Only the crazy or the malicious  would recommend aspirin or designer anti-inflammatory drugs  (with their  major risks)  for mild to moderate pain  when paracetamol or, better, a simple safe mix of natural anti-inflammatory-analgesics would suffice eg MSM-curcumin-pantothenate-catsclaw-bromelain-boswelia.

Osteoporosis occurs mostly in the elderly ie those at far higher risks- osteoporosis is a late sign of multisystem deficiency risks, with patients far more likely to die from the concomitant other degenerative diseases – frailty, vascular, malignant, dementing- than from fractures .  So it is criminal to delay effective prevention till osteoporosis is present, then prescribe risky drugs like SERMS, bisphosphonates or StRan when far more multisystem effective and safe therapy has long been available and proven.

22 May 2008

The promotion of essential micronutrients like sex hormones, vitamins and minerals for multisystem health including bones is vital.

But what evidence for longterm cost:benefit is there for strontium ranelate StRan  for anything let alone bones?

A warning was published in 2005 (Prescrire Int. ) Strontium: new drug. Postmenopausal osteoporosis: too many unknowns. [No authors listed]). . No new trials have appeared since. .

There is in fact only one solitary major trial published of sodium ranelate  SrR in osteoporosis, the SOTI-TROPOS trial by Reginster,  Meneur ea for the strontium ranelate  SrR manufacturers (Servier) at 72 centers in 11 European countries and Australia, in some 5000 postmenopausal women recruited from 1996 through 1998 ie till about 2003, with either previous postmenopausal fracture or frank osteoporosis: All on 1 to 1.5gm calcium and vitamin D 400-800iu/day, they were randomized to placebo or StRan 2gm/day. After a mean of 3 years, compared to placebo, vertebral fractures in 1442 women at a mean of 69yrs were reduced by 49% from baseline , but in the entire cohort nonvertebral fractures were reduced by only 16% from baseline at mean age of 77yrs.. All fractures were reduced from 12.9% to 11.2% ie 4.3%pa to 3.7%pa; hip fractures from 3.4% to 2.9%, vertebral fractures from 14% to 7.7%.

Are these differences significant for patient care, when the longterm effects of StRan therapy are unknown, and the longterm adverse effects of biphosphonates are becoming horrifically clear?

But these trials of StRan used only weak baseline prevention of lowdose calcium and vitamin D . Numerous other preventative bone-and muscle-strengthening supplements were apparently specifically excluded or omitted – magnesium, estrogen. vigorous-dose vitamin D eg 2000iu/d, vitamin K, androgen, boron, zinc.
And like the concurrent Womens’ Health Initiative, the SOTI-TROPOS trial was stopped woefully too soon instead of letting it run for at least 10 years to see the longterm benefit (if any). Worst of all, it did not test whether StRan adds any benefit on a sensible baseline of all the proven supplements that we have used for decades.

As Winzenberg ea ask in a recent 2007 Australian review, Strontium ranelate Does it affect the management of postmenopausal osteoporosis? Strontium ranelate did not cause gastritis, back pain or death, but more or less doubled numerous adverse effects :
*50% more (ie six out of 100 women taking strontium ranelate) experienced diarrhoea compared to four out of 100 taking placebo,
• The risk of vascular system disorders including venous thromboembolism (two trials, n=6669, 2.2 vs. 1.5%, OR: 1.5, 95% CI: 1.1–2.1) , pulmonary embolism (two trials, n=6669, 0.8 vs. 0.4%, OR: 1.7, 95% CI: 1.0–3.1) * as well as nervous system disorders such
as headache (3.9 vs. 2.9%), seizures (0.3 vs. 0.1%), memory loss (2.4 vs. 1.9%) and disturbance in consciousness (2.5 vs. 2.0%) is
slightly increased with taking 2 g of SrR daily over 3–4 years
• There were no RCTs identified which compared StRan to other treatments of postmenopausal osteoporosis.”

It is common cause that the chief risk factor for fracture is not bone density but frailty, falls; and that the only microsupplements that strengthen muscle are apparently androgen, zinc, calcium and magnesium and the vitamins D3 and B6, 9 and 12. There is no absolute contraindication to appropriate long term human androgen plus estrogen replacement .

Now Fuchs ea show that “Strontium ranelate does not stimulate bone formation in ovariectomized rats” – sex hormones are necessary for strontium to benefit bones.

With the oldfashioned calmag, zinc, boron, fluoride ,vitamins A-E, and parenteral androgen plus estrogen, we have seen bone density rise by 1%pa and hip density by 1/2% pa over 15years from age 52 in a frail woman with severe rheumatoid arthritis, despite management with corticosteroid and other remittive drugs, and repeated surgeries to replace destroyed joints. She has never sustained an osteoporotic fracture.

So what is the indication to add the costly long-term (ie >10year) unproven strontium to proven effective supplements?

Strontium ranelate may work in the medium term (3 to 5 years) but there is still apparently no more justification for using strontium ranelate  routinely for preventing/ treating ageing osteoporosis than there is for biphosphonates or calcitonin.

UPDATE 2014 ON LACK OF LIVER DAMAGE FROM HERBALIFE, BLACK COHOSH and KAVA

neil.burman@gmail.com

1/1/2014  again, its comforting that no new evidence of hepatotoxicity of genuine black ohosh; or kava; or (USA-grade) Herbalife  products have been reported  the  past two years.

Teschke ea from Germany make the important point that herbaltoxicity is  likely due to the “kava paradox”,  that no toxicity is reported  with  ancient time-tested herbal remedies used appropriately by tradition in their fresh natural state and their countries of origin eg Pacifi islands; ,

but that adverse events occur with commerial eg alcohol-extracted and often preserved and old  preparations, and in untested combinations with other substances especially statins,  ethanol, and unknown viruses. .

The Herbalife company has just had to publish again  an update rebuttal of bad papers wrongly implicating and accusing Herbalife.  Their summary says:

World J Hepatol. 2013 Oct 27;5(10):601-2..              A correction of misinformation regarding Herbalife. Appelhans K, Najeeullah R, Frankos V. Herbalife International of America Inc, Torrance, CA     The authors of the subject article by Senadhi et al from Indiana State University  have misrepresented the safety and regulatory status of Herbalife‘s products. While we are very concerned with the unwarranted and unfavorable publicity that the inaccuracies listed could generate for Herbalife, we would welcome any inquiries that these authors may have to better clarify our commitment to the safety and quality of our products as has been demonstrated in part by our ability to establish positive relationships with regulatory authorities worldwide through continued cooperation and compliance. This letter clarifies the misinformation presented about Herbalife in the subject article

16 March 2012   it is comforting to note that there have been no new reports the past year of toxicity from these products.

In fact  some lab work seems to favour black cohosh for cancer prevention;

Anticancer Res. 2012 Jan;32(1):21-30.   Chemopreventive potential of black cohosh on breast cancer in Sprague-Dawley rats. Einbond LS, Soffritti M, Degli Esposti D, Tibaldi E, Lauriola M, Bua L, He K, Genovese G, Su T, Huggins L, Wang X, Roller M, Wu HA.  Columbia University, HHSC-1518, 701 W. 168th Street, New York, NY 10032, USA. lseinbond@gmail.com     This study examines the chemopreventive potential and action of the herb black cohosh on Sprague-Dawley rats. CONCLUSION:Our results suggest that black cohosh may have chemopreventive potential for mammary cancer.
while Herbalife has published objective rebuttals of toxicity from Herbalife other than in isolated countries where irregular ingredients were used in local manufacture:
World J Hepatol. 2011 Oct 27;3(10):275-7. Revisiting acute liver injury associated with herbalife products.  Appelhans K, Smith C, Bejar E, Henig YS  Herbalife International of America Inc., Torrance, CA 90502, United States.   In the November 27, 2010 issue of the World Journal of Hepatology (WJH), three case reports were published which involved patients who had consumed various dietary supplements and conventional foods generally marketed as weight loss products. The reference to Herbalife products as contaminated and generally comparable to all dietary supplements or weight loss products is not scientifically supported. The authors provided an insufficient amount of information regarding patient histories, concomitant medications and other compounds, dechallenge results, and product specifications and usage. This information is necessary to fully assess the association of Herbalife products in the WJH case reports. Therefore, the article does not objectively support a causal relationship between the reported cases of liver injury and Herbalife products or ingredients.
Pharmacoepidemiol Drug Saf. 2012 Mar;21(3):333-4. doi: 10.1002/pds.3203. Misconceptions regarding the association between Herbalife products and liver-related case reports in Spain.
Appelhans K, Frankos V, Shao A.  Source  Product Compliance and Safety, Herbalife International of America, Inc, Torrance, CA, USA.

2 Feb 2011

Since June 2010 there have been no new cases of toxicity from Black Cohosh, herbalife or kava reported on Pubmed.

BLACK COHOSH: BEGGING THE QUESTION OF INDICATION- NEED.

The new literature analysis Suspected black cohosh hepatotoxicity: no evidence by meta-analysis of randomized controlled clinical trials for isopropanolic black cohosh extract  by Naser et al from Yale , and Germany(the main producer of black cohosh BC products)- begs the question.

As this colunm has previously reviewd about BC,  women have died from or needed liver transplants after taking it.. Hence most Authorities have Black Box warning requirements Recurrences of liver reaction have been reported on rechallenge. These scattered cases can be argued away on metanalysis, but they cannot be ignored. One death or acute liver failure is unacceptable when BC is never an essential drug without other safe options.

Another study also published now (Wang ea from the FDA Centre for Drug Evaluation ) http://www.ncbi.nlm.nih.gov/pubmed/20920542 contradicts the German metanalysis with more basic toxicological data: “Computational analysis of positively predicted constituents showed … specifically, protocatechuic acid from black cohosh… predicted positive for liver toxicity endpoints also confirmed with literature findings”

Black cohosh is not physiological hormone replacement, BC is recommended by its proponents solely for menopause symptoms (it has no other benefits) for up to 6 months.

So why risk, use black cohosh at all?

Appropriate balanced hormone replacement – preferably human hormones, not xenohormones ie hormones not found in the healthy women, and not by swallowing it- is indicated permanently in all women .

As previouslly pointed out in this column, the International Menopause Society has summed it up in putting approriate HRT as the main agent(s) for menopause symptoms as well as  for its permanent multisuystem benefits;  and the human hormone gamma-aminobutyric acid GABA as the only alternative that is both safe and cleearly proven better than placebo for improving both hot flashes and sleep, anxiety. Used appropriately and with sensible monitoring and dose titration, all such hormone balance has no longterm risks.

MDICOLEGAL LIABILITY: under the new Conumae Protection Act CPA in South Africa, the pendulum has gone ridiculously too far. irrespective of the onus on manufacturers and promoters of any product, the onus is on the end-prescriber, end-dispenser to warn consumers of potential risks,  and any consumer claim for consequent damages is legally against only the final and retail supplier.

So no supplier of black cohosh is protected against consequent liability unless he gets a signed waiver from the purchaser after the recorded warning about its potential toxicity.

16 June 2010

there are no new adverse toxicity reports on Hebalife, black cohosh or kava  so far in 2010 .

Both Herbalife,  and black cohosh products, remain marketed and in demand  in South SAfrica.

There are  no new serious adverse reports or concerns published  on Pubmed or Google about Herbalife products in 2009.

On Pubmed there were 2 new cases of liver and coagulation problems associated with black cohosh in mid2009, from a Germanic and an Italian institute; and 14 hepatitis cases associated with kava ingestion confirmed  from around the world .

4 Jan 2009

This review  is not about benefit of black cohosh (independent trials show none for menopause symptoms) or Herbalife (trials support that Herbalife is indeed a weight loss aid), or kava (it is a confirmed anxiolytic analgesic euphoriant); but about toxicity potential however rare – considering that none of these  products can make any claim to being a necessity.

Contamination aside, there are no new  relevant reports  on Herbalife the past two months on Pubmed,

but indeed  4 new reports on black cohosh; and one on kava.

Lessons for black cohosh and Herbalife may be learnt from kava. Kava-kava was hastily banned  eg  in Europe and South Africa early this decade owing to reputed association with hepatotoxic deaths. But on careful study these toxicity claims appear to be uncertain.

The claimed benefits of kava are analgesic, euphoriant and relaxant, without addiction potential. The four trials of Kava (between 1991 and 2003, in Italy and Germany) confirmed that kava has anxiolytic benefits in the menopause syndrome.) . The hepatotoxicity (not reported from the source – Polynesia – unless taken by alcoholics) was reported largely from western countries, where commercially sold  kava extract was apparently differently extracted, and from the aerial leftovers of the kava; whereas in Polynesia it is extracted only from the root. A recent website from the NIH shows it is not banned there, but expresses much caution.

A careful analysis of kava hepatotoxicity by Teschke ea in Germany last month again finds little evidence of toxicity if kava is taken from a reputable manufacturer  at prescribed dose and for short duration  – as applies equally to alcohol, and most drugs.

Herbalife

An objective  NICUS  Nutritional Institute of University of Stellenbosch Report critical of  Herbalife is quoted verbatim in the Summer 2008  Newsletter of the Association of Dieticians of SA. NICUS- a world authority in Nutrition – confirms it stands by this report. It could thus be taken as a directive (to condemn Herbalife)- to dieticians for whose professional advice some patients wrongly substitute diet supplements;  where these modalities- careful  professional diet advice and counselling, and supplements-  are actually complementary..

But there does not appear to be any  more  evidence to condemn Herbalife than there was a year ago. As far as Pubmed and Google reveals,  the reports  [to date end of 2008 on Pubmed) of adverse effects  were from 4 discrete European regions [ Iceland; Switzerland; Spain & Israel) , apparently wth locally formulated Herbalife, not the USA main factory product, leading to assumption of a local production fault. There appear to have been 2 cases of liver failure in some 33 affected patients, in one of whom liver transplant became necessary but the patient died.. .

One cannot condemn all  babyfood because some is deliberately adulterated with melamine by ruthless Chinese sham factories. Commercial babyfood is arguably a necessity for many.

We await an updated rebuttal from Herbalife in the new year- but there does not seem to be anything for them to add to their rebuttal of last year..There has been no published evidence to justify update on Herbalife during 2008.

The accusation (by one patient, and a  convicted fraudster, Minkow) of a claimed lead-contaminated  Herbalife batch  in California   has, strangely, generated no updates for months now- but on the wiki herbalife update , it says “In August 2008, Minkow retracted all accusations against Herbalife and removed any mention of the company from his Web site.[30]” – there is no report of whether Herbalife bought his silence or not , which is a pity- see also. ;   but see also heavy flak against Minkow , suggesting that his whole campaign was a successful bear scam  to profit from Herbalife shares.

The  current  Wiki Herbalife  review also quotes a new trial validating benefit for weightloss. Caveat Emptor.

It may be asked why a Nutritional authority like NICUS:  warns  against Herbalife but not against the potentially fatal black cohosh. New independent analyses are both for and against them:

ie

Black Cohosh:

Analyses of case reports from Univ Florida (Palacio 2009) and Italy (Borrelli 2008)  recommend caution about black cohosh for humans in view of adverse case reports; while a German analysis (Teschke 2008) exonerates black cohosh in every single case till then.

A trial from USA (Davis 2008) found that “black cohosh significantly increased the incidence of lung metastases in tumor-bearing mice compared with mice fed the isoflavone-free control diet”.

Clearly the valid divergence of opinion comes down to complex statistics of probability.

Black cohosh has been associated with severe liver failure and  transplantation in a number of women on a number of continents, for which reason the local Health Products Association, like all responsible authorities , finally agreed and issued recommendations that Black Cohosh label must be black-boxed- there is no justification for it’s sale as a useful product, unlike the role than can be argued for food substitute powders.

So why should anyone use black cohosh for menopause symptoms (when it’s benefit seems to be largely placebo, with grave doubt about safety) , when there are proven safe symptom relievers eg GABA (no adverse reports); or lowdose balanced appropriate parenteral human sex hormones (no adverse reports, and have numerous longterm multisystem benefits- which neither black cohosh nor GABA can claim..).

This review  is not about benefit, but safety. Regulators remain silent about drastically curtailing sale of the most lethal substances in widespread unregulated (and unnecessary)  use- paracetamol, other nonsteroidal anti-inflammatories, statins for uncomplicated  mild-to-moderate lipidemia, alcohol, tobacco and sugar, and pollution of everything by industrial adulteration with synthetic (often estrogenic) endocrine disruptors and virtually all fast foods with cornstarch and/or sugar.

The hysterical approval of diethylstilbestrol  DES by the FDA by 1950, and for a massive  1950 maternity trial  against all evidence (even though it’s toxicity was recognized by 1953,  it’s sale anywhaere was finally banned only 20 years later) continues to torment the original myriads of  guineapig women, their children and now grandchildren. These scandals are dictated by individual opportunist, corporate and governmental greed, and indifference to medical evidence and prevention.

The analogy for black cohosh, kava  and Herbalife  is perhaps:

#the ~20year delays before the FDA would licence the lifesaving lithium salt, and metformin, in USA;

#the ~5year hysteria over HRT after the Women’s Health Initiative – when the over-estimated risks of inapproriate use of  OHT in elderly women were stupidly and harmfully (for thousands of women) extrapolated to young women and other  HRT preparations;

and

#the melamine- baby milk formula catastrophe – the problem for the latter was exclusively some contaminated  babyfood batches made in China especially for the lucrative export market. .

The jury can thus be considered as still out on both black cohosh, kava  and Herbalife,  until manufacturers of commercial  products (not traditional preparations of  eg kava and black cohosh taken by residents who grow these)  can produce evidence, confirm  that the risk was limited  to specific batches of the commercial product  and adherence to accepted recommendations, and not due to other possible risk factors.

LIVER DAMAGE IN EUROPE ASSOCIATED WITH HERBALIFE USE:

4 Sept 2007 Review
The following reports below of HerbaLife-associated liver failure appear on Medline – from Spain, then Israel and Switzerland.
:The July 2007 reports of the two dozen Herbalife-associated hepatitis cases from Israel & Switzerland reveal that liver problems occurred after about 5 months on the products; and that relapse occurred in about 20% on rechallenge with Herbalife ie in this percentage the association is proven.

Herbalife results for weight control have been reported as good. The only problem is historical according to the current Wikipedia entry: “Some of the original Herbalife weight loss products contained the active ingredient Ma Huang or Sida cordifolia, two herbs containing ephedrine alkaloids.

Adverse reactions involving the company’s Thermojetics original green tablets were recorded by the U.S. Food and Drug Administration and Herbalife subsequently stopped using ephedrine in its products in the face of rising insurance premiums.[3][4] The U.S. FDA banned supplements containing ephedra in 2004.[5]“

It is possible that the case reports below are unrelated to Herbalife itself , or that in those countries ephedra-containing Herbalife was still in use at the time, or that potentially hazardous herbs etc were added locally.

From Yahoo.com, there is an authoritative rebuttal from Iceland dated February 2007.

A score of drugs and herbs can cause liver damage, topical ones – albeit rarely- include mushrooms; black cohosh and kava – see a recent list.

Drugs like ticrynafen, methyldopa and cerivastatin were discarded among other reasons because of liver problems, which are among many reasons why necessary sex hormone contraception and replacement should rather not use designer patent ie synthetic drugs, and especially not by mouth (hepatic first pass effect).

So it is always difficult to blame a single product, as the ongoing debate about black cohosh shows – which many “first world” regulators have “black boxed” ie added a compulsory warning to black cohosh warnings.

As with black cohosh, with a rare adverse event report, users of such products must weigh up for themselves.

As they say, since Herbalife tends to be custom-made in each country, with numerous ingredients (some undisclosed), it is so far impossible to incriminate whether the cause was local product corruption, or some appreoved component, of which the known possible culprits are ephedra and camelia.

Other known hepatotoxic herbs like black cohosh, kava and mushrooms were not mentioned. A few of the patients had viral hepatitis. Only 7 cases had also taken other known potential liver sensitizers – some synthetic sex hormones (4), aspirin (3), statin (1) and hydrochlorothiazide(1), of which 2 cases had positive recurrence of hepatitis on rechallenge with Herbalife.

UCT Medicines Information Centre is unaware of any such problems locally, and can recollect only perhaps 2 queries about Herbalife in some 23 years. Clarification is awaited from Herbalife headquarters.

From Swiss data the estimated incidence was below 2 cases per million Herbalife users, but both studies were based only on hospital records.

Considering the severe global problem of hepatitis from other causes (due to alcohol; obesity/diabetes (steatohepatitis, sulphonylureas, glitazones); numerous infections; carbon tetrachloride; synthetic sex hormones (oral contraception and postmenopausal hormone therapy) , mushrooms, antibiotics and antivirals, , autoimmune disease, antiepileptics, nifedipine, amitryptiline, allopurinol, nonsteroidal anti-inflammatories including aspirin and paracetamol , black cohosh, kava, antifungals and paracetamol), and that the rare adverse association of herbalife with liver damage may well have been limited only to Herbalife products made in those three “European” countries at that time, there is clearly no cause for alarm about Herbalife – just awareness.

The urgent problem of endemic liver disease is rather the avoidance of infections and potentially hazardous antimicrobials; mushrooms; carbon tetrachloride, alcohol excess; sale pf paracetamol without inclusion of protective vitamins and N-acetyl cysteine; and avoidance of potential hepatotoxins which are rarely if ever justified considering their risks, and safe effective alternatives available for eg statins, sulphonylureeas, glitazones, black cohosh, kava, non-steroidal anti-inflammatories; oral sex hormones; and sulphonylureas.

The centuries-proven plant galega officinalis (extract) metformin after 85years of modern use remains the only drug proven in longterm use to both reduce liver damage, lipidemia, thrombosis, adiposity and insulin resistance, and thus almost halve the incidence of new diabetes, hypertension/vascular disease, cancer and thus all-cause premature medical mortality.

Thus appropriate general use of metformin with long-proven vitamins, minerals, biologicals, safe herbs, fish oil and systemic human sex hormones – combined with prudent lifestyle and largely natural fresh foodstuffs- – does away with most of the well-known potential hepatitis drug risks listed above.

In defence of free market enterprise and choices, those who choose convenience safe proven food substitutes or other complementary products as part of an acceptable balanced regime advocated by suppliers like Herbalife do well, they should just be sure of the ingredients and supplier; and they should report and discuss what they use with some knowledgable up-to-date healthcare provider.

Response from Herbalife

04.09.07
Herbalife’s South Africa CEO responds reassuringly:

Good day,
Herewith a statement from Herbalife in response to the issues raised by yourself earlier in the week:

While we are aware of reports of abnormal liver function blood tests such as those reported by Dr. Oneta, our extensive consultation with internationally recognised liver experts has led repeatedly to the conclusion that these associations in time cannot be linked to any Herbalife product.

These small numbers of reports are anecdotal and millions of satisfied customers all over the world have been using our products for more than 27 years. All Herbalife products are formulated and manufactured in accordance with strict standards overseen by the Herbalife Scientific Advisory Board, which is chaired by David Heber, M.D., Ph.D., F.A.C.P., F.A.C.N. Quality control is overseen by our Scientific Affairs Group, chaired by Y. Steve Henig PhD and made up of an international panel of experts in nutrition and botanical dietary supplements.

Herbalife products, which are now sold in 65 countries, are formulated, registered and labelled in accordance with the regulatory requirements in every market where sold. All Herbalife products are safe to consume as directed.

Many consumers who choose to use Herbalife weight-management products for weight loss are overweight, some significantly so. Pre-existing medical conditions such as obesity and diabetes can be associated with non-alcoholic fatty liver disease, a disorder that may return certain types of abnormal blood test results. These test results, therefore, may have nothing to do with any herbal supplement, but rather are the result of a pre-existing medical condition. In addition, it is possible for an individual to have an allergic reaction to our products, the same way one might to any food product; for example, strawberries or shellfish. Herbalife supports the recommendation that consumers visiting their doctors for medical treatment inform them of any supplements they may be taking.

As a socially responsible company, we operate an adverse event reporting procedure that deals with the small number of queries we have from doctors and consumers and we operate an open dialogue policy with the medical community. All adverse event reports are investigated thoroughly in consultation with the consumer and the physician (if they are available) to fully understand the facts. None have resulted in the compulsory withdrawal of any product, ever. In the United States, Herbalife actively lobbied Congress to pass legislation mandating the submission of all dietary supplement and over-the-counter drug serious adverse events to the Food & Drug Administration. That new law takes effect December 22, 2007.”

REFS:

J Hepatol. 2007 Oct;47(4):521-526. Herbal does not mean innocuous: Ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife((R)) products. Schoepfer AM, ea.University Hospital Bern, Switzerland.
METHODS: To determine the prevalence and outcome of hepatotoxicity due to Herbalife((R)) products. A questionnaire was sent to all public Swiss hospitals. Reported cases were subjected to causality assessment using the CIOMS criteria. RESULTS: Twelve cases of toxic hepatitis implicating Herbalife((R)) preparations (1998-2004) were retrieved, 10 sufficiently documented to permit causality analysis. Median age of patients was 51 years (range 30-69) and latency to onset was 5 months (0.5-144). Liver biopsy (7/10) showed hepatic necrosis, marked lymphocytic/eosinophilic infiltration and cholestasis in five patients. One patient with fulminant liver failure was successfully transplanted; the explant showed giant cell hepatitis.     Causality assessment of adverse drug reaction was classified as certain in two, probable in seven and possible in one case(s), respectively. CONCLUSIONS: We present a case series of toxic hepatitis implicating Herbalife((R)) products. Liver toxicity may be severe. A more detailed declaration of components and pro-active role of regulatory agencies would be desirable.

J Hepatol. 2007 Oct;47(4):514-520. Association between consumption of Herbalife((R)) nutritional supplements and acute hepatotoxicity. Elinav E, ea -Hebrew University Medical Center, Israel.
: In 2004, identification of four index cases of acute hepatitis associated with Herbalife((R)) intake led to a ministry of health investigation in all Israeli hospitals. Twelve patients with acute idiopathic liver injury in association with consumption of Herbalife((R)) products were investigated.
RESULTS: Eleven of the patients were females, aged 49.5+/-13.4 y. One patient had stage I primary biliary cirrhosis and another had hepatitis B. Acute liver injury was diagnosed after 11.9+/-11.1 months of initiation of Herbalife((R)) consumption. Liver biopsies demonstrated active hepatitis, portal inflammation rich with eosinophils, ductular reaction and parenchymal inflammation with peri-central accentuation.
. CONCLUSIONS: An association between intake of Herbalife((R)) products and acute hepatitis was identified in Israel. We call for prospective evaluation of Herbalife((R)) products for possible hepatotoxicity.

Med Clin (Barc). 2007 Feb 17;128(6):238-9.
[Hepatotoxicity associated with the consumption of herbal slimming products] Duque JM,ea. [Article in Spanish] Letter