The vitamin D system forms a complex, adaptive control system. where concentrations of 25(OH)D3 are tightly regulated by the body in order to buffer against a highly variable input and thereby deliver a controlled supply for further processing.
The assumption that the system as a whole is controllable by oral supplementation is misguided in the extreme.
This page will look at the structure of vitamin D production and will look at the response of the body to seasonal variations in sunlight. From this perspective alone we can tell that levels of the hormone are a reflection of external input but not determined by it. There is no need to delve into molecular biology here, the subject is easily understood as a mechanism to transform an oscillating energy supply into a steady trickle of chemicals.
We will show that the following are evident from the data alone and that supporting evidence exists for the mechanisms involved:
- The observed rise and fall of measured levels is not a reflection of current sunlight levels but rather the accumulation of activity in recent months
- Production rates are regulated at by a negative feedback mechanism which maintains levels by actively inhibiting production almost all of the time
- The function of 25(OH)D3 within the system is that of a storage buffer, an accumulator
The diagram below, taken from a video by Ivor Cummins ‘D is for Debacle‘ shows the variant 25(OH)D3 at the heart of the vitamin D production system. It is produced in the liver from D3 which is, in turn, produced in the skin by the action of ultra-violet light acting on cholesterol. Concentrations of 25(OH)D3 are referred to as ‘vitamin D levels’.
It is this substance that is almost exclusively measured as an indication of overall status. Interventions, including supplementation, are attempts to manipulate this value and success is defined as the achievement of a stated target concentration.
Levels of the ‘active’ form of vitamin D, 1,25(OD)2D3 are said to remain very stable and are therefore almost never measured. Since the results are always the same they cannot give any information as to health status.
So ‘levels’ are not measures of the volume of D in the body but rather the concentration of the substance in the blood.
The chart below shows how the average concentrations of 25(OH)D3 vary according to the seasons.
At first sight, it might be thought that levels correlate with sunlight hours and indeed some influential health gurus have tried to argue precisely this. However, even a cursory examination shows that this is not the case and that the rise and fall of vitamin D levels lags behind the seasonal light variation by approximately 3 months or a quarter of a phase.
Seasonal variation in serum vitamin D concentrations (mean (95% confidence interval)) among 7,437 white British (1958 British birth cohort) at age 45. Dark red bar = male, red bar = female. – Royal College of Physicians [article]
This time lag is easily explained by viewing the system as a reservoir or buffer system. The input to the reservoir is a sinusoidal curve caused by the variation in D production as a result of the seasons, but the observed curve is a cumulative effect of 25(UH)D3 that has been stored up over the past few months.
In such a system we should expect that at maximum sunlight hours in mid-summer we do not see maximal levels but rather maximal production. This should show up on the chart as the levels rising at a maximum rate in summer i.e. a maximally rising slope on the graph in mid June. This is precisely what we see.
The slope on the chart peaks in September not because that is when UV levels are at their peak (they aren’t) but because this is when production of vitamin D is precisely balanced by depletion. Levels then fall as the rate of usage exceeds the rate of production and levels off again in spring when finally light levels rise and production again matches depletion.
Gender differences. The chart shows clear differences between men and women within the population that are small but significant. So are we really going to argue that men and women as a group are exposing themselves to sunlight in a consistently different way throughout the hemisphere or is the difference caused by physiological factors?
Rural workers in India who exposed their face, neck and torso for long hours each day were found to have lower vitamin D levels than Europeans but still remained healthy whilst dark skinned Inuit populations maintain healthy levels despite very little sunlight for half the year. So levels do not automatically depend upon hours of sunlight.
Africans living near the equator have levels so low as to be classed as ‘deficient’:
“The cut-offs for vitamin D deficiency have been debated for decades and the current cut off is derived from a Caucasian population. Studies done among black African adults in Africa are few with vitamin D deficiency ranging from 5 to 91%.”- Kagotho et al
25(OH)D3 is often referred to as ‘storage D’ and this does seem to reflect its function within the system as a whole. The body is subject to a highly fluctuating energy input in the form of sunlight but prefers a slow and steady supply of the hormone, so there must be some mechanism to effect this transposition and 25(OH)D appears to do the trick.
Look again at the chart above. The small black ‘T’ bars denote the variation of the population and show that 95% of the population have levels within these values. We all know people who shield from sunlight because of a skin condition and all know people who strip off every summer to maximise their exposure, sometimes even using tanning beds in winter. So even within a population we will have individuals with vastly differing inputs in the form of ultra-violet light, but vitamin D levels still remaining within quite a narrow band. Once again, measured 25(OH)D does not correlate with sunlight exposure in this respect.
Levels cannot rise indefinitely over the years and cannot drop indefinitely so they are regulated somehow in the long term.
Negative feedback. Levels do not appear to build up but are maintained somehow by the body as a somehow preferred seasonal pattern despite varying individual habits and possible variations in sunlight from year to year. A negative feedback loop is indicated; the system is somehow monitoring itself and restricting production according to some criteria.
It turns out that the skin itself forms a self-regulating system of production, producing less 25(OH)D the higher the existing levels:
“The increase in 25(OH)D level after UVB exposure was negatively correlated with baseline 25(OH)D level (P<0.001) and positively correlated with baseline total cholesterol level (P=0.005), but no significant correlations were found with constitutive or facultative skin pigmentation.” – Bogh et al
So long term stability is achieved by short term monitoring and by restriction of production. It is noted in several papers that:
- Vitamin D levels do not appear to correlate with latitude
- Stable levels vary between different skin types
- There is, however, no correlation with skin tone
- Migrant populations have no problem maintaining healthy levels
- It is as easy to live above the arctic circle as it is at the equator
These seemingly puzzling phenomena are now quite nicely explained. The feedback mechanism provides instant adaptation to almost any environment. The skin is so good at production and the body at storage that regulation is achieved largely by inhibition.
Summary so far
25(OH)D3 levels then are not a simple reflection of recent sunlight but instead form a sophisticated buffering system whose function is to mediate between the variability of sunlight and the requirements to produce constant levels of 1,25(OH)2D3 all year round. Annual levels are maintained within a safe zone by storage in the liver and fatty tissues and by actual suppression of production during the summer months.
Vitamin D as a Control System. Systems such as this are common in electrical engineering and are rather well studied. They can be represented in an abstracted form as a diagram (right) and there are many useful concepts and theorems that could prove useful in the field of bio-regulation.
Two key concepts are those of controllability and observability. A system is said to be ‘observable’ if its behaviour can be deduced from observation of a limited number of measurements and is said to be ‘controllable’ if the system can be controlled via a limited number of inputs.
The assumption that the vitamin D system as a whole is observable via 25(OH)D3 is clearly misguided as we are looking at a quantity which largely reflects variable external factors such as skin type and season.
Likewise, the idea that the system is controllable by raising levels of 25(OH)D3 is way off the mark as the system specifically operates so as to insulate the rest of of the network against changes in these levels.
Supplementation from this point of view is an attempt bypass the regulatory system of the skin, thereby forcing the levels out of their customary seasonal rhythm and safety zone. Now since the whole system seems designed to work in a particular way so as to actually prevent this happening, this is unlikely to have the desired effect.
The body is accustomed to receiving a continuous supply from the skin but popular health gurus are recommending large quantities of D3 to be input to the body in a single dose. Patients are reporting on social media that this is having negligible effect on their levels (not surprising since the system is specifically designed to buffer against this happening) and are then getting advised to raise the supplementation even further.
In a complex system such as this the rate of dosage, timing, route and are all likely to be salient factors in the response, as are skin type and the status of other vitamin and mineral levels. However, people are treating the body as if it were a car engine and D3 were simply ‘metabolic fuel’.
Low levels are the result of disease not the cause of it (Mangin et al) and long term pressure on the system cannot be beneficial long term.
How are levels calculated?
This is actually a highly non-trivial question as after concentrations are measured, a calculation is made in an attempt to correct for seasonal variations and some sort of estimate for an annual average is presented to the patient.
In the chart below from an Australian population, the diamonds represent individual’s hours of sunlight exposure, the solid black squares are the population average 25(OH)D3 levels and the continuous black line is an estimate for the population average. The T bars again are the 95% confidence intervals.
Relationship between mean daily solar exposure and serum 25(OH)D.
The estimate for the population average is a sine curve and individual measurements are assessed with respect to this reference.
One problem is that because of the modulation of the levels by the control system, the population average is not actually a sine curve. This is evident in June, above, where 95% of the population has measured levels of 25(OH)D3 that are above the estimated average!
So what does it mean to have low vitamin D?
Without further information we can’t say anything at all. There are too many causes and only one variable measured so we don’t know which of the causes it could be: seasonality, liver disorder, chemotherapy, skin type, cholesterol levels, many inflammatory disorders, or bad calculation of an average. In the case of the African population the problem is that a calculated norm from a largely white population in a seasonally varying environment has been transferred unmodified to a dark-skinned population within the tropics.
Inflammation and vitamin D: the infection connection – Meg Mangin, Rebecca Sinha, Kelly Fincher.
Vitamin D status in healthy black African adults at a tertiary hospital in Nairobi, Kenya: a cross sectional study – Kagotho, Omuse et al
Vitamin D production after UVB exposure depends on baseline vitamin D and total cholesterol but not on skin pigmentation – Bogh MK, Schmedes AV, Philipsen PA, Theiden E, Wulf HC.
Racial pigmentation and the cutaneous synthesis of vitamin D. – Matsuoka LY, Worstman J, Haddad JG, Kolm P, Hollis BW.
Vitamin D deficiency among northern Native Peoples: a real or apparent
problem? – Peter Frost
Renal potassium-wasting induced by vitamin D – Ferris, Levitin, Epstein
Measurement of Vitamin D for Epidemiologic and Clinical Research: Shining Light on a Complex Decision – Jukic, Hoofnagle, Lutsey
Make Vitamin D While the Sun Shines, Take Supplements When It Doesn′t: A Longitudinal, Observational Study of Older Adults in Tasmania, Australia