By Huang Zhonghui & You Tao
"The most accurate model for vitamin D3 pharmacokinetics so far"
Reference
Huang & You. (2021) Personalise vitamin D3 using physiologically based pharmacokinetic modelling. CPT Pharmacometrics Syst Pharmacol. 10(7):723-734. doi: 10.1002/psp4.12640.
Fatigue, mood changes, insomnia, night sweats or pains in bone and joint? It might be due to vitamin D deficiency. As some of these symptoms are not unique and may be attributed to different factors, vitamin D deficiency can be misdiagnosed unless blood test is done.
If you live in the UK, either you are vitamin D deficient yourself or you know someone who is. Approximately 1 in 6 adults (aged 18-64) in the UK are severely deficient in Vitamin D (i.e. 25(OH)D < 25 nmol/L) (1). Vitamin D deficiency also affects about 1 billion people worldwide.
If you fit any of the following descriptions, you might be at risk of vitamin D deficiency:
Live in the UK
Do not eat any of these: oily fish, red meat, liver, egg yolks, fortified foods
Vegan or lactose-intolerant
Have less than 13 minutes under the sun between 11am-3pm every day
Dark skin (e.g., an African, African-Caribbean, or south Asian background)
If you suspect you are vitamin D deficient, you should take a blood test. This post helps you understand how much vitamin D you need every day and how long it takes for you to reach optimum. Here we discuss:
What is vitamin D important for?
How much vitamin D do I need daily?
Why do I need vitamin D supplementation?
What are the problems?
How much vitamin D do I need daily and how long does it take to reach optimum?
How should I use the app?
1. What is vitamin D important for?
Vitamin D helps absorb calcium and prevents rickets. Vitamin D deficiency is also statistically associated with the occurrence of the following:
Osteoporosis
Diabetes
Cancer
Immune system disorders,
Cardiovascular disease
COVID-19
Maintaining optimal vitamin levels is important for your wellbeing.
2. How much vitamin D do I need daily?
The US Food and Nutrition Board (FNB) classifies vitamin D levels into “deficiency”, “inadequacy”, “sufficiency”, “optimal level” and “adverse effect level” (Table 1).
Table 1. The Vitamin D status of different measurement values.
nmol/L* | ng/mL* | Vitamin D status |
<30 | <12 | Deficiency |
30 to 50 | 12 to 20 | Inadequacy |
50 to 75 | 20 to 30 | Sufficiency |
75 to 125 | 30 to 50 | Optimal level/Maximum effects |
>125 | >50 | Adverse effect level |
*The Food and Nutrition Board (FNB) at the National Academies of Sciences, Engineering, and Medicine (NASEM) (2). The optimal level is referred to the recommendation from previous studies (3,4).
However, the daily intake guidelines issued in different countries and regions are inconsistent and confusing (5):
l The UK Scientific Advisory Committee for Nutrition: 400 IU per day.
l European Food Safety Authority: 800 IU per day.
l The American Institute of Medicine: 800 IU per day.
(1 µg vitamin D = 40 IU)
In 2020, NICE at Public Health England revised the advice. Instead of taking 400 IU vitamin D daily during the winter months, all adults in the UK should take 400 IU vitamin D everyday all year round.
3. Why do I need vitamin D supplementation?
Vitamin D deficiency can be mainly attributed to the lack of skin synthesis and insufficient dietary intake.
Skin synthesis
Your skin synthesises vitamin D3 through exposure to sunlight, which is then metabolised in the liver into 25(OH)D3 and circulates in the body, before it becomes inactive in the kidneys in the form of 1,25(OH)2D3.
According to the NHS recommendations, from the end of March to the end of September, you need to expose to the sun between 11 am and 3 pm each day, meaning no covering of your forearms, hands, or lower legs (6). According to a simulation of residents in Greater Manchester, vitamin D status was sufficient (between 50 - 75nmol/L, see table 1) after a short period (13 minutes) of sunlight to 35% of the skin surface area in summer (7).
In winter (October to early March), the sun’s UVB radiation in the UK is not strong enough for your skin to produce enough vitamin D. Among the 45y UK adults, 25(OH)D averages pitiful 35 nmol/L in February, about half of what they are in September (8).
To make it worse, the COVID-19 pandemic has drastically reduced the amount of time people spend outdoors. It is not possible to obtain sufficient vitamin D via sunshine in the UK throughout the year.
Dietary intake
To meet the UK’s daily 400 IU vitamin D recommendation, we have calculated the vitamin D content of a portion of the foods rich in vitamin D (Table 2). Please note that for girls, women who are planning a pregnancy or may have a child one day, and pregnant and breastfeeding women, they are advised against having more than two portions of oily fish a week as the pollutants may accumulate in the body and affect foetal development.
If you do not eat any of these, it is difficult for you to obtain sufficient vitamin D from food alone.
Table 2. Estimated food intake to meet the daily vitamin need.
Description | Vitamin D per 100g (μg) | Portion size (g) | Vitamin D per portion (μg) |
Milk (evaporated, light; evaporated, whole; skimmed, dried, fortified) | 1.5-3.1 | 200 | 3.0-6.2 |
Breakfast cereal (malted flake, fortified; cornflakes, fortified) | 3.9-8.3 | 40 | 1.6-3.3 |
Oily fish (Bloater, herring, mackerel, flesh only, grilled)* | 8.5-25 | 140 | 12-35 |
Oily fish (Sardines, salmon, flesh only)* | 4-4.7 | 140 | 5.6-6.6 |
Chicken egg yolk (raw, boiled, dried) | 12.2-12.8 | 60 | 7.3-7.7 |
* Oily fish should be limited to 2 portions per week for the following people due to pollutant: girls, women who are planning a pregnancy or may have a child one day, and pregnant and breastfeeding women.
4. What are the problems?
Firstly, guidelines are inconsistent and confusing. Both the EU and the US recommend taking 800 IU vitamin D per day, while the UK recommends 400 IU per day. A paper questions whether the UK’s recommendation for vitamin D adequacy (25 nmol/L) is too low, and consequently whether the UK recommended dose (400 IU daily) is too low (5). That paper suggests that 800–1,000 IU (20–25µg) per day is needed for vitamin D sufficiency.
There is some consensus for the optimal vitamin D level. Some recent scientific publications recommend that adults should maintain a value of 75 nmol/L as the ideal level (3,4). An independent research suggests that vitamin D doses between 1800-4000 IU/d to achieve 75-110 nmol/L is associated with reduced rate of cardiovascular disease and colorectal cancer (9).
The bigger problem is everyone is different: people with different baseline levels of 25(OH)D respond to the same vitamin D dose differently. This begs the question how much vitamin D you need daily and how long it takes for you to reach optimum?
5. How much vitamin D do I need daily and how long does it take to reach optimum?
Between September 2018 and April 2021, we developed the most accurate model for vitamin D3 so far. It considers human physiology and is well trained and validated with high-quality clinical data from over 100 clinical trials, which capture a great variety of baseline vitamin D levels prior to dosing. Remarkably, this model is accurate for doses ranging from 400 IU to 2 million IU.
This question can be answered by using this mathematical model.
6. How should I use the app?
We have implemented an app using the model: https://beyond.shinyapps.io/vitamind3/
Figure 1. Initial user interface before simulation.
Figure 1 shows the user interface. A user needs to take a blood test and enter 25(OH)D baseline for simulation. The user also needs to select the start of treatment, a daily dose and the duration of daily dosing.
Figure 2. Simulated 25(OH)D level after 20µg per day for population with 10 nmol/L 25(OH)D baseline (left), with 50 nmol/L (right).
For example, we simulated the 25(OH)D plasma concentration profiles of two populations which is either severely deficient (10nmol/L) or sufficient (50nmol/L) (Figure 2). The treatment duration was set to half a year. The simulation start date was set to 2021/12/30. At 800 IU daily dose, optimum was reached by the person with 50 nmol/L baseline level after 5 months, but was not reached by the person with 10 nmol/L baseline.
To explore how 25(OH)D levels might reduce after the daily dosing stops, the user may select a simulation period that is longer than the dosing period.
Reference:
1. PHE (Public Health England). (2020) NDNS: results from years 9 to 11 (2016 to 2017 and 2018 to 2019). Available at: https://www.gov.uk/government/statistics/ndns-results-from-years-9-to-11-2016-to-2017-and-2018-to-2019.
2. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010.
3. MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2011;96:1911-30.
4. Rosen CJ, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, et al. IOM committee members respond to Endocrine Society vitamin D guidelines. J Clin Endocrinol Metab 2012;97:1146-52.
5. Griffin G, Hewison M, Hopkin J, Kenny RA, Quinton R, Rhodes J, Subramanian S, Thickett D. Preventing vitamin D deficiency during the COVID-19 pandemic: UK definitions of vitamin D sufficiency and recommended supplement dose are set too low. Clin Med (Lond). 2021 Jan;21(1):e48-e51. doi: 10.7861/clinmed.2020-0858.
6. NICE Guideline. Sunlight Exposure: Risks and Benefits. 2016. Available online: https://www.nice.org.uk/guidance/ng34/resources/sunlight-exposure-risks-and-benefits-1837392363205.
7. Rhodes LE, Webb AR, Fraser HI, Kift R, Durkin MT, Allan D, O'Brien SJ, Vail A, Berry JL. Recommended summer sunlight exposure levels can produce sufficient (> or =20 ng ml(-1)) but not the proposed optimal (> or =32 ng ml(-1)) 25(OH)D levels at UK latitudes. J Invest Dermatol. 2010 May;130(5):1411-8. doi: 10.1038/jid.2009.417.
8. Hyppönen E, Power C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr. 2007 Mar;85(3):860-8. doi: 10.1093/ajcn/85.3.860. PMID: 17344510.
9. Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E, Willett WC. Benefit-risk assessment of vitamin D supplementation. Osteoporos Int. 2010 Jul;21(7):1121-32. doi: 10.1007/s00198-009-1119-3.