Het vitamine D deficiëntie syndroom Dr. Yvo Sijpkens, internist Haaglanden Medisch Centrum, Den Haag LAV Lezing Leiden, 10 april 2018

Vitamine versus hormoon Vitamine Een stof die het lichaam in kleine hoeveelheden nodig heeft, maar niet door het lichaam zelf aangemaakt kan worden en derhalve in voldoende mate via voedsel of als supplement ingenomen moet worden. Hormoon Stof die door een endocriene klier wordt aangemaakt, via het bloed wordt getransporteerd en elders in het lichaam van het organisme een effect uitoefent.

Vitamine D is een (pro)hormoon! Vitamine D deficiëntie is een syndroom!

Wereldkaart huidskleur Evolutionair voordeel lichtere huidskleur op hogere breedtegraad

Interpretatie 25(OH)D spiegel (nmol/l) > 200 (500) potentieel toxisch 75 - 200 optimaal 50 - 75 lichte deficiëntie 25 - 50 matige deficiëntie < 25 ernstige deficiëntie

Lifeguards: 25(OH)D ~ 200 nmol/l

25(OH)D spiegels in Den Haag bij diabetes ent nationwide survey in the United Kingdom showed that more than 50% of the adult population have insufficient levels of vitamin D and that 16% have severe deficiency during winter and spring.

Het vitamine D / zonlicht deficiënte syndroom Fysiologie vitamine D metabolisme Oorzaken vitamine D deficiëntie Gevolgen vitamine D deficiëntie Behandeling vitamine D deficiëntie Zonlicht deficiëntie syndroom

Vitamine D deficiëntie syndroom Fysiologie

D3 ≠ D2 ≠ 25(OH)D ≠ 1,25(OH)2D D3 wordt in oiv UVB in de huid gemaakt uit 7-dehydrocholesterol (of ingenomen als supplement) – NIET biologisch actief, opslag in vet en spieren Colecalciferol D2 is plantaardig (omgezet uit ergosterol), voeding Ergocalciferol 25-OH-D wordt in de lever gemaakt uit D2 en D3, circulerende vorm, NIET biologisch actief Calcidiol 1,25-(OH)2-D wordt gemaakt in de nieren, maar ook extrarenaal intracellulair – WEL biologisch actief Calcitriol

Vitamine D metabolisme 30 - 120 nmol/l T ½ 2-3 weken 40 - 140 pmol/l T ½ 4- 6 uur

Effecten actief vitamine D

Endocrine en autocriene effecten vitamine D

Vitamine D receptor abundant aanwezig! Vitamine D heeft invloed op ca 1000 genen (5% genoom)!

Pleiotrope effecten vitamine D Remming: Proliferatie Renine Auto-immuun reacties Stimulatie: Differentiatie Insuline Immuniteit (cathelicidine)

Vitamine D deficiëntie syndroom Oorzaken

Vitamine D deficiëntie - oorzaken

Oorzaken vitamine D deficiëntie patiënt Oudere leeftijd (70 jaar – 75% ) Bedekkende kleding Binnenleven, seizoen, latitude Nederland Zonnebrandecreme (factor 8 – 95%, factor 15 - 99% ) Onvoldoende vit. D inname met de voeding/multivitamine Adipositas (verdunning bij hoog vetpercentage) Nierinsufficientie (afname productie 1.25 (OH)2 ) Nefrotisch syndroom (verlies vit D bindend eiwit)

Onvoldoende zonlicht expositie

1,25(OH)2 deficiëntie bij nierinsufficiëntie Afname 1-hydroxylase activiteit Verminderde 1-hydroxylase productie Afgenomen niermassa Onvoldoende 25 (OH)D substraat 25(OH)D deficiëntie Remming 1-hydroxylase activiteit Hyerfosfatemie uremische toxines Acidose FGF-23 (fibroblast growth factor)

Vit D deficiëntie bij nierinsufficiëntie

Vitamine D deficiëntie syndroom Gevolgen

Vitamine D deficiëntie - gevolgen

Vitamine D suppletie en diabetes type 1 Babies who received vitamin D 2000 IU/d ended up by age 30 years, with only ONE FIFTH THE RISK OF TYPE 1 DIABETES Lancet. 2001 Nov 3;358(9292):1500-3. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Hyppönen E1, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Author information Abstract BACKGROUND:  Dietary vitamin D supplementation is associated with reduced risk of type 1 diabetes in animals. Our aim was to ascertain whether or not vitamin D supplementation or deficiency in infancy could affect development of type 1 diabetes. METHODS:  A birth-cohort study was done, in which all pregnant women (n=12055) in Oulu and Lapland, northern Finland, who were due to give birth in 1966 were enrolled. Data was collected in the first year of life about frequency and dose of vitamin D supplementation and presence of suspected rickets. Our primary outcome measure was diagnosis of type 1 diabetes by end of December, 1997. FINDINGS:  12058 of 12231 represented live births, and 10821 (91% of those alive) children were followed-up at age 1 year. Of the 10366 children included in analyses, 81 were diagnosed with diabetes during the study. Vitamin D supplementation was associated with a decreased frequency of type 1 diabetes when adjusted for neonatal, anthropometric, and social characteristics (rate ratio [RR] for regular vs no supplementation 0.12, 95% CI 0.03-0.51, and irregular vs no supplementation 0.16, 0.04-0.74. Children who regularly took the recommended dose of vitamin D (2000 IU daily) had a RR of 0.22 (0.05-0.89) compared with those who regularly received less than the recommended amount. Children suspected of having rickets during the first year of life had a RR of 3.0 (1.0-9.0) compared with those without such a suspicion. INTERPRETATION:  Dietary vitamin D supplementation is associated with reduced risk of type 1 diabetes. Ensuring adequate vitamin D supplementation for infants could help to reverse the increasing trend in the incidence of type 1 diabetes. Hyppönen et al 2001 Lancet 358: 1500–03

Vitamine D suppletie en diabetes type 1

Vitamine D suppletie en diabetes type 2 Combined daily intake of 1200 mg of calcium and 800 IU of vitamin D lowered the risk of type 2 diabetes by 33 % compared to daily intake of less than 600 mg calcium and less than 400 IU of vitamin D. (Pittas, Diabetes Care 2006) Proposed mechanism: The 1,25 OH vitamin D produced in the kidney enters the circulation and stimulates insulin secretion in the islet cells of the pancreas

Vitamine D deficiëntie en hypertensie Am J Hypertens. 2007 Jul;20(7):713-9. Links Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. Scragg R, Sowers M, Bell C. School of Population Health, University of Auckland, Auckland, New Zealand. r.scragg@auckland.ac.nz BACKGROUND: Populations with low vitamin D status, such as blacks living in the US or UK, have increased blood pressure (BP) compared with whites. We analyzed the association between serum 25-hydroxyvitamin D (25OHD) and BP to determine whether low 25OHD explains any of the increased BP in blacks. METHODS: The Third US National Health and Nutrition Examination Survey (NHANES III) is a cross-sectional survey representative of the US civilian population during 1988 to 1994. Analyses were restricted to 12,644 people aged > or =20 years with measurements of BP and 25OHD, after excluding those on hypertensive medication. RESULTS: Adjusted mean serum 25OHD was lowest in non-Hispanic blacks (49 nmol/L), intermediate in Mexican Americans (68 nmol/L), and highest in non-Hispanic whites (79 nmol/L). When participants were divided into 25OHD quintiles, mean (standard error) systolic BP was 3.0 (0.7) mm Hg lower (P = .0004) and diastolic BP was 1.6 (0.6) mm Hg lower (P = .011) for participants in the highest quintile (25OHD > or =85.7 nmol/L) compared with the lowest (25OHD < or =40.4 nmol/L), adjusting for age, sex, ethnicity, and physical activity. Further adjustment for body mass index (BMI) weakened the inverse association between 25OHD and BP, which remained significant for systolic BP (P < .05). The inverse association between 25OHD and systolic BP was stronger in participants aged > or =50 years than younger (P = .021). Ethnic differences in 25OHD explained about half of the increased hypertension prevalence in non-Hispanic blacks compared with whites. CONCLUSIONS: Vitamin D status, which is amenable to intervention by safely increasing sun exposure or vitamin D supplementation, was associated inversely with BP in a large sample representative of the US population.

Vitamine D deficiëntie en hypertensie Am J Hypertens. 2007 Jul;20(7):713-9. Links Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. Scragg R, Sowers M, Bell C. School of Population Health, University of Auckland, Auckland, New Zealand. r.scragg@auckland.ac.nz BACKGROUND: Populations with low vitamin D status, such as blacks living in the US or UK, have increased blood pressure (BP) compared with whites. We analyzed the association between serum 25-hydroxyvitamin D (25OHD) and BP to determine whether low 25OHD explains any of the increased BP in blacks. METHODS: The Third US National Health and Nutrition Examination Survey (NHANES III) is a cross-sectional survey representative of the US civilian population during 1988 to 1994. Analyses were restricted to 12,644 people aged > or =20 years with measurements of BP and 25OHD, after excluding those on hypertensive medication. RESULTS: Adjusted mean serum 25OHD was lowest in non-Hispanic blacks (49 nmol/L), intermediate in Mexican Americans (68 nmol/L), and highest in non-Hispanic whites (79 nmol/L). When participants were divided into 25OHD quintiles, mean (standard error) systolic BP was 3.0 (0.7) mm Hg lower (P = .0004) and diastolic BP was 1.6 (0.6) mm Hg lower (P = .011) for participants in the highest quintile (25OHD > or =85.7 nmol/L) compared with the lowest (25OHD < or =40.4 nmol/L), adjusting for age, sex, ethnicity, and physical activity. Further adjustment for body mass index (BMI) weakened the inverse association between 25OHD and BP, which remained significant for systolic BP (P < .05). The inverse association between 25OHD and systolic BP was stronger in participants aged > or =50 years than younger (P = .021). Ethnic differences in 25OHD explained about half of the increased hypertension prevalence in non-Hispanic blacks compared with whites. CONCLUSIONS: Vitamin D status, which is amenable to intervention by safely increasing sun exposure or vitamin D supplementation, was associated inversely with BP in a large sample representative of the US population.

Vitamine D deficiëntie en HVZ

Vitamine D deficiëntie en HVZ Framingham Offspring Study 1739 subjects (mean 59 yr, 55% F, all C) No prior CVD Mean 25-OH-D 19.7 ng/mL 28% with 25-OH-D <15 ng/mL 9% with 25-OH-D <10 ng/mL 5.4 yr follow-up 120 developed first CV event

Vitamine D suppletie en mortaliteit Arch Intern Med. 2007 Sep 10;167(16):1730-7. Links Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Autier P, Gandini S. International Agency for Research on Cancer, 150 cours Albert Thomas, F-69372 Lyon, France. autierp@iacr.fr BACKGROUND: Ecological and observational studies suggest that low vitamin D status could be associated with higher mortality from life-threatening conditions including cancer, cardiovascular disease, and diabetes mellitus that account for 60% to 70% of total mortality in high-income countries. We examined the risk of dying from any cause in subjects who participated in randomized trials testing the impact of vitamin D supplementation (ergocalciferol [vitamin D(2)] or cholecalciferol [vitamin D(3)]) on any health condition. METHODS: The literature up to November 2006 was searched without language restriction using the following databases: PubMed, ISI Web of Science (Science Citation Index Expanded), EMBASE, and the Cochrane Library. RESULTS: We identified 18 independent randomized controlled trials, including 57 311 participants. A total of 4777 deaths from any cause occurred during a trial size-adjusted mean of 5.7 years. Daily doses of vitamin D supplements varied from 300 to 2000 IU. The trial size-adjusted mean daily vitamin D dose was 528 IU. In 9 trials, there was a 1.4- to 5.2-fold difference in serum 25-hydroxyvitamin D between the intervention and control groups. The summary relative risk for mortality from any cause was 0.93 (95% confidence interval, 0.87-0.99). There was neither indication for heterogeneity nor indication for publication biases. The summary relative risk did not change according to the addition of calcium supplements in the intervention. CONCLUSIONS: Intake of ordinary doses of vitamin D supplements seems to be associated with decreases in total mortality rates. The relationship between baseline vitamin D status, dose of vitamin D supplements, and total mortality rates remains to be investigated. Population-based, placebo-controlled randomized trials with total mortality as the main end point should be organized for confirming these findings. Arch Intern Med 2007;167:1730–7

Vitamine D deficiëntie – associaties Bot/spier (vallen, fracturen, fibromyalgie) Maligniteiten (colon, mamma, prostaat, pancreas) Auto-immunziekten (MS) Huidziekten (eczeem, psoriasis) Longziekten (asthma, OSAS) Infecties (LWI, influenza, peridontitis, TBC) Neurologie (MS, Parkinson, CVA, Alzheimer) Gynaecologie (myoom, preecclampsie, PMS) Psychiatrie (autism, depressie, schizofrenie)

Vitamine D deficiëntie en sport Atleten vaak deficiënt Winter, hoge breedtegraad Binnensport Donkere huidskleur Zonblokkers Prestatievermindering Bot en spierpijn Blessures (stress#, rugpijn, overtraining) 25D spiegel > 125 nmol/l Behoefte aan 2000 IE/dag

Vitamine D deficiëntie syndroom Behandeling

Behandeling vitamine D deficiëntie Steefwaarde 25(OH)D: > 50 nmol/l voor ‘bone health’ 75 – 200 nmol/l voor pleiotrope effecten 1 g of D3 or D2 = 40 IE D10 = 10 g = 400 IE 50000 IE = 1250 g = 1,25 mg Voor elke 100 IU vitamin D3 ingenomen, stijgt de 25-OH-D spiegel met 2.5 nmol/l (1 ng/mL) 400 IE – 10; 800 – 20, 2000 – 50 nmol/l  Bij overgewicht 2-3 maal meer nodig om streefwaarde te bereiken

Advies gezondheidsraad - bevolking

Dosis cholecalciferol – effect relatie Behoefte ouderen: > 50 nmol/l: 1000 IE/dag > 80 nmol/l: 1600 IE/dag

Suppletie met cholecalciferol 50 nmol/l Streefwaarde: 25(OH)D 75 – 200 (optimaal 125-150) nmol/l

Behandeling met cholecalciferol Davitamon tab 100 IE 1 dd 8-10 Devaron/orthica/HEMA tab 400 IE 1 dd 2-4 Divisun 800 IE 1-2 dd 1-2 Calcichew/D3 500 of 1000 mg/800 IE 1 dd 1 CAD 1000mg/880 IE 1 dd 1 Vitamine D3 softgels 10000 IE 1 pwk (bol.com) Benferol softgels 25000 IE 1 pwk D-Cura ampullen 25000 IE 1 pwk Vitamine D3 drank FNA 50000 IE /ml 1-2 pmnd Zorg voor voldoende inname van magnesium, kalium en vitamine K2

Vitamine D intoxicatie is zeldzaam! Bij hypercalciemie denken aan sarcoidose, lymfoom en tbc Hypercalciemie pas bij dagelijkse D inname > 20k en 25D spiegel > 500 nmol/l

Vitamine D discussie Vitamine D tekort is geassocieerd met veel aandoeningen, maar RCTs met cholecalciferol laten een wisselend effect zien. Verklaringen hiervoor zijn een suboptimale studie opzet en de mogelijkheid van omgekeerde causaliteit Vitamine D tekort is een marker voor een tekort aan zonlicht. Zonlicht doet meer dan de productie van cholecalciferol. Een mooie vitamine D spiegel door genoeg zonlicht, goede voeding en een normaal gewicht is gezonder dan een spiegel door cholecalciferol suppletie alleen. Dagelijkse toediening van een of twee gecombineerde calciumcarbonaat/cholecalciferol tabletten met als streefwaarde een 25(OH)D-gehalte van meer dan 75 nmol/ kan een sterke stijging van het PTH met verhoogde botombouw voorkomen.Bij een tekort aan calcidiol, verlies van niermassa en hyperfosfatemie neemt in latere stadia van CNI de productie van calcitriol af. Behandeling met actief vitamine D, in de vorm van alfacalcidol is dan aangewezen om progressieve hyperparathyreoïdie te voorkomen.

Zonlicht deficiëntie syndroom

Zonlichtexpositie en bloeddruk Zonlicht maakt in de huid NO vrij!

Zonlicht expositie en mortaliteit The Winding Path Towards an Inverse Relationship Between Sun Exposure and All-cause Mortality. Lindqvist PG1. Author information Abstract For a long time, skin cancer has been known to be related to extensive UV exposure. New emerging data have, however, shown low UV exposure/low vitamin D levels to be related to increased mortality rate due to skin cancer. In addition, low sun exposure habits in regions of low solar intensity have been shown to be a major risk factor for all-cause mortality in the same range as that for smoking. This is mainly due to lower all-cause mortality due to cardiovascular disease (CVD) and non-CVD/non-cancer disease among women with active sun exposure. Women with active sun exposure habits were estimated to have a 1- to 2-year longer life-expectancy during the Melanoma in Southern Sweden study interval. These findings are in line with those to be expected from an evolutionary perspective and research findings, but in opposition to present guidelines and recommendations. Levensverwachting vrouwen met 1-2 jaar verlengd bij meer zonlichtexpositie

Behandeling zonlicht deficiëntie Zonlicht UVA (94-97%), UVB (2-5%) ontblote armen en benen tussen 10 uur ‘s ochtends en 15 uur ‘s middags gedurende 10-30 minuten levert snel tot 10000 IE cholecalciferol op, nooit teveel Zonnebank fluoriscerende lampen simuleren zonlicht (UVA+UVB) een a tweemaal per week 10-20 min genereert per keer 1000-10000 IE cholecalciferol

Verbranding voorkomen!

Zonnebank en huidkanker

Zonnebank, vitamine D en melanoom Anticancer Res. 2018;38(2):1187 Solarium Use and Risk for Malignant Melanoma:  Meta-analysis and Evidence-based Medicine Review. At present, there is no convincing evidence that moderate/responsible solarium use increases  melanoma risk. BACKGROUND:  There is an ongoing debate whether solarium use (indoor tanning/artificial UV) may increase the risk for primary cutaneous malignant melanoma. AIM:  A systematic literature search was conducted using MEDLINE and ISI Web of Science. Included studies were critically assessed regarding their risk of bias, and methodological shortcomings. Levels of evidence and grades of recommendation were determined according to guidelines of the Oxford Centre for Evidence-Based Medicine. Summary risk estimates and 95% confidence intervals for four different outcomes (ever exposure, exposure at younger age, high/low exposure vs. non-exposure) were derived from random-effects meta-analyses to account for possible heterogeneity across studies. RESULTS:  Two cohort and twenty-nine case-control studies were eligible. Overall, quality of included studies was poor as a result of severe limitations, including possible recall and selection bias, and due to lack of interventional trials. Summary risk estimates suggested a weak association (odds ratio (OR)=1.19, 95% confidence interval (CI)=1.04-1.35, p=0.009) for ever-exposure to UV radiation from a solarium with melanoma risk. However, sensitivity analyses did not show an association for studies from Europe (OR=1.10; 95%CI=0.95-1.27, p=0.218), studies with low risk of bias (OR=1.15; 95%CI=0.94-1.41, p=0.179), and studies conducted after 1990 (OR 1.09; 95%CI=0.93-1.29, p=0.295). Moreover, moderate associations were found for first exposure to UV radiation from a solarium at younger age (<25 years) and high exposure (>10 sessions in lifetime) with melanoma risk. However, for all outcomes analyzed, overall study quality and resulting levels of evidence (3a-) and grades of recommendation (D) were low due to lack of interventional studies and severe limitations including unobserved or unrecorded confounding. CONCLUSION:  Current scientific knowledge is mainly based on observational studies with poor quality data, which report associations but do not prove causality. At present, there is no convincing evidence that moderate/responsible solarium use increases melanoma risk Lagere 25D spiegels bij melanoom patiënten

Negatieve en positieve effecten zonlicht Bij verstandig gebruik zijn voor de meeste mensen de voordelen groter dan de nadelen!

Vitamine D / zonlicht deficiëntie syndroom Conclusies

Vitamine D / zonlicht deficiëntie syndroom Vitamine D is een prohormoon met endocriene en autocriene effecten met invloed op ca. 1000 genen (5% genoom). Vit. D deficiëntie komt veel voor, dat vooral wordt veroorzaakt door onvoldoende zonlichtexpositie, een gebrek aan vit. D in de voeding en adipositas. Vit. D deficiëntie is geassocieerd met veel aandoeningen over het hele spectrum van de geneeskunde. In afwachting van VITAL laat suppletie met cholecalciferol in (suboptimale) studies een wisselend effect zien. Adequate vitamine D spiegels (100-200 nmol/l) van conceptie tot overlijden door zonlichtexpositie, goede voeding en een normaal gewicht is de beste garantie voor een gezond leven.

Scoor zonlicht en zo nodig een supplement! Zonlicht maakt in de huid endorfines vrij