Thursday, 23 April 2020

Covid-19, Vitamin D, and ethnicity - evidence


Covid-19, Vitamin D, and ethnicity

Sunset over the River Mekong, from Vientiane

The Covid-19 epidemic in the UK has highlighted the health disadvantage of those of black African and Asian ethnicity (BAME). For example, in respect of Covid-19, 72% of health and social care staff deaths, 35% of intensive care cases (13% of population), and in the USA 12% of deaths in California (6% of population).

This is usually assumed to be the result of socio-economic disadvantage, but it is now clear that this is not altogether true. The epidemic has seen a number of deaths of doctors in the UK, and the great majority of them have been of black African and Asian ethnicity. Doctors are neither socio-economically disadvantaged nor poor. They would not be living in overcrowded houses. 

All citizens of black African and Asian ethnicity have one thing in common: they have dark skins. Dark skin leads to deficiency of vitamin D. 

Melanin-pigmented skin is less efficient than white non-pigmented skin at synthesising vitamin D. Melanin can absorb or dissipate 99% of UV light  and therefore reduces its chemical effect on 7-DHC: there is less synthesis of vitamin D. 

Vitamin D is produced by the action of the sun on the skin, splitting the precursor molecule 7-dehydrocholesterol (7-DHC). Vitamin D enters a cascade process  that results in activation of genes concerned with the defensive immune process (Figure 1).

Figure 1. The activation of vitamin D and its effects


The other important factor is that people of black African and Asian ethnicity tend to have sun-avoiding behaviour, whereas white-skinned people in northern Europe have obvious active sun-seeking behaviour. They take their clothes off when the sun shines, they wear shorts and minimal tops, they go to the sea-side and lie on the beach in the sun, they go on holiday to sunny resorts. People of black African and Asian ethnicity tend not to behave in such ways.

Medoc peninsula, near to Bordeaux

Vitamin D measurements and units

Before looking at the results of studies, we might look at the measurement of the blood level of vitamin D, which is measured as cholecalciferol, 7-(OH)D. The “normal range “ of vitamin D is not an acceptable measure as it would be based on a range found within the population. It would include many who would be regarded as deficient, perhaps half the population. It is preferable to use the term “ideal range”, based on what experience tells us excludes those with disease states or risks that are associated with very low levels of vitamin D. This itself is controversial.

The most well-established disease state resulting from vitamin D deficiency is bone disease. It is due to the fact that ossification is impaired, that calcium cannot be incorporated into the basic fibrous structure of the bones, which is called matrix, a lattice-work of soft tissue. This bone disease is osteomalacia, softening of the bones. When it occurs in children, whose bones are still growing, it is called rickets. The bones bend as the toddler learns to walk. This is unlikely to occur if  the blood level of vitamin D is above 10ng/ml (25nmol/L). To achieve this a very low dose is necessary, perhaps 400units (10mcg) per day, as advised by the UK government through its Scientific Advisory Committee on Nutrition (SACN).

There is another factor. As I pointed out in a previous post, vitamin D when doubly activated to calcitriol in turn activates vitamin D receptors (VDR). VDR is inherited as part of our genome, but over millennia numerous mutations have occurred. When they become part of population genomics the mutations are called polymorphisms (“different shapes”). Some of these are not efficient and fail to activate adequately the intracellular vitamin D responsive elements (VDRE) so that the appropriate genes in the nucleus are not activated.  As a result of these polymorphisms the effects of vitamin D deficiency (such as osteomalacia) can occur even when the blood level of vitamin D is in the ideal range.

Many, if not all, of the researchers who are investigating the effects of vitamin D are of the opinion that the ideal blood level of vitamin D set at 20ng/ml (50nmol/L) is wrong. Long-term follow up of people according to blood level of vitamin D has shown that there advantages in having a level of 30ng/ml (75nmol/L) or even 40ng/ml (100nmol/L)

We see another problem in that there are two units of vitamin D in both blood levels and doses. There was a time when the only measure of vitamin D was to see how much of it would heal rickets in rats. This is the basis of the use of units, an international standard. In more recent years it has been possible to measure vitamin D chemically, hence shift to use microgrammes (mcg) rather than units. 

In many biochemical tests the use of mass measurement has changed to the use of SI units, the French Système International (d’unités). Most nations use this but some do not. For example the USA still uses mass units (milligrammes) for reporting blood levels of cholesterol whereas most the world uses millimoles (the amount rather than the weight of the substance). 

In respect of dose, 400units is equivalent to 10mcg (minimum dose), 2,000units is 50mcg (the daily one that I would recommend).

Sorry about the potential problems, and they can lead to errors.


Covid-19 in the Philippines

A study has just been undertaken in the Philippines by Dr. Mark Alippio, a clinical professor and medical radiation scientist in the College of Allied Health Sciences, Davao Doctors College. It is very recent and an observational study of 212 patients in three South-east Asian hospitals. The study looks at a possible association of vitamin D with Covid-19 clinical outcomes. He obtained information from the medical records of patients in the hospitals, where vitamin D testing was taking place during the Covid-19 epidemic.

We can see from the bar chart in Figure 2 the blood levels of vitamin D in the 212 patients studied. In 25.9% of the subjects  the level is greater than 30ng/ml, in 37.7% in the range 20 to 30ng/ml, and in 36.3% less than 20ng/ml.

Figure 2. Vitamin D status of 212 study subjects
30ng/ml = 75nmol/L,  20ng/ml = 50nmol/L

The study looks at the relationship between blood level of vitamin D and severity of the Covid-19 disease. All had positive tests for SARS-CoV-2 virus. The patients are divided into four groups for the purpose of analysis:

  • Mild disease, with normal chest X-ray.
  • Moderate disease, with evidence of pneumonia on the chest X-ray.
  • Severe disease, pneumonia with respiratory distress and abnormal blood gases (low oxygen +/- high carbon dioxide).
  • Critical, involving intensive care.
Patients who had died were not included in this study, which was a "snapshot" rather than a longitudinal study.

The associated blood levels of vitamin D with clinical status can be seen on the bar-chart on Figure 3.

Figure 3. Vitamin D in respect of severity of Covid-19

We see that a blood level of vitamin D greater 30ng/ml (75nmol/L) is found in 85% of those with mild disease.

A similar level of vitamin D is found in only 7.3% of those with moderate disease and in only 3.6% of those with severe or critical disease. It would be interesting to know if these patients had sub-optimal polymorphisms of VDR, but this is well beyond feasibility in this study.

Lower blood levels of vitamin D, less than 30ng/ml, are found in those with more severe and critical disease.

It is not entirely possible to avoid Covid-19 infection, but it is clear from this study that a high blood level of vitamin D is of enormous advantage in keeping the disease at a mild level. This is what we want to achieve.

This study could be repeated today in any UK NHS hospital, as I read is happening in Grenada, Spain. The only things to prevent it are inertia and ignorance. The result would be available within a few days.

In the meantime deaths continue, especially among those of black African and Asian ethnicity, including from the Philippines.

Vitamin D deficiency and Asian ethnicity

I would like to refer to a study that I undertook a number of years ago. It looked at the blood levels of vitamin D in 1574 people of Asian ethnicity and 818 white British. The averages are presented as the median, the middle of the range as will be seen on the bar charts.

First the results from the Asian ethnic group (Figure 4).

Figure 4. Distribution of blood levels of vitamin D with Asian ethnicity

In Figure 4 each vertical column (1574 of them) represents one individual, the height of the column is determined by the blood level of vitamin D in that individual. The orange arrow indicates the median, the middle of the range. 

We can see that the arrow crosses the distribution with the blood level of 9.8ng/ml (22nmol/L), indicated by the yellow line. This is very low and what is called “serious deficiency”. It indicates that more than half of the group are in a range were there is a risk of osteomalacia and seriously suboptimal immune defence mechanisms. It is the range in which Covid-19 might cause critical care need, or perhaps lead to death.

Only 119 out of the 1574 (7.6%) have blood levels above 30ng/ml (75nmol/L), a level indicted by the red line above which a Covid-19 sufferer might anticipate just mild disease. Many vitamin D investigators regard 40ng/ml (100nmol/L) as being the ideal level. Only 15 (1%) have a blood level greater than 40.

Greater than 80ng/ml (200nmol/L) is potentially harmful, but harm from vitamin D is very rare. It is not possible to have blood levels of vitamin D too high from sun exposure because circulation through the exposed skin de-activates surplus vitamin D.

Now we see the results of the subjects with white British ethnicity (Figure 5).

Figure 5. Distribution of blood levels of vitamin D in white British 

The middle of the range, the median, can be seen to cross the range on the yellow line indicating 17ng/ml (42nmol/L). This means that more than 50% of the subjects are deficient in vitamin D as judged by a cut-off level of 20ng/ml, and 150 (18%) are seriously deficient with blood levels below 10ng/ml.

Only 107 (13%) had a blood level above 30ng/ml and 47 (6.7%) above 40ng/ml (100nmol/L).

Implications

These results are alarming and show the extent of vitamin D deficiency in the UK, especially among ethnic Asian people but also among non-ethnic minority people.

Under normal circumstances there might be concern, but now  we are in a national crisis of a pandemic of Covid-19 with 17,333 deaths during the past six weeks. We know that those of black African and Asian ethnicity are over-represented in numbers of deaths and the need for intensive care support, but this information is given to us by the press and not by the government.

The study from the Philippines indicates that we need a blood level of 30ng/ml (75nmol/L) to be safe from serious disease. We can see that in my study of subjects in Blackburn, UK only 7.6% of the ethnic Asian group do the blood levels achieve this. 

We have seen the distribution of blood levels of vitamin D in the subjects of that study. We must remember that the Philippines lie only a short distance north the equator, Davao del Sur is at the southern tip of the Philippines and at only 6.8 degrees north. The British Isles lie between 50 and 60 degrees north, latitudes where the intensity of the sun and vitamin D synthesis are much less.

We can see from the Philippines study the practical demonstration of the danger of a low blood level of vitamin D in Covid-19 infection.


We can also see the proportion of people with black African and Asian ethnicity who are deficient in vitamin D. We know that vitamin D is necessary for our defence mechanisms to be boosted to maximum efficiency, and this is what we all need now.








Sunday, 19 April 2020

Covid-19 pandemic – more questions than answers




Covid-19 pandemic – more questions than answers

The Covid-19 pandemic has caused much consternation within the public and tremendous pressure on governments. However “lockdown” means that we do not really know what is happening outside our houses, apart from how we are informed by the media. Much of what happening is sensationalised. I personally am not aware of anyone who has become ill or died from Covid-19.

With lockdown I have a great deal of time on my hands. There are limits to the detail to which I tend my garden. Decorating has come to an end as I have run out of paint and delivery from internet purchase is slow. I have plenty of time to read and think.

The daily supply of international Covid-19 data from Worldometer gives a good opportunity for the adult game of “The Spreadsheet”. This game has been occupying some of my time each day and it led to some interesting questions. There is little access to any detail of the individuals who have died, but no doubt such details will emerge from individual countries in due course.

The main puzzle is the variation of case incidence and deaths in different countries, Such comparisons require data to be standardised for population size, and I have used cases and deaths per million population.

Cases.  The selection is mainly European nations or countries that interest me.



We do not hear about Luxembourg because the data that we are given by the government and media look at total deaths and Luxembourg is a small country with a population of less than one million. However Luxembourg has the highest number of cases per million, four times that of the Netherlands, Germany, Austria and the UK, all of which are very similar. Poland and Russia have very low numbers, similar to Malaysia. China has many fewer cases per million. 

Why is this, and what is “a case”? It should mean someone who is ill with respiratory symptoms and who tests positive for the Covid-19 antigen. The problem is that testing is itself not tested. The government advice is that testing will be a “game-changer” and that we must move as quickly as possible to 100,000 tests per day. The UK government has spent £3m on tests that “do not work” and have now been thrown away. Testing the tests takes a long time.

The main problem with the tests that have been available is that they give many “false positives”, they overestimate the number of “Covid-19 cases”. It appears that they detect the presence of several coronaviruses other than Covid-19. 

Despite lockdown, Switzerland and Belgium have overtaken Italy in the number of cases per million, with Ireland and France close behind.

A country might be searching for new cases by extensive testing, perhaps of people who are not sick. Assessment shows that between 50% and 80% of individuals who test positive are symptom-free. And we know that extensive testing will produce a lot of “false-positives”, that is people who test positive but do not have Covid-19.

Deaths per million is equally if not more interesting.



We hear little or nothing about Belgium in the UK media, other than its excellent national soccer team. But we have not heard that Belgium has the highest number of Covid-19 deaths per million population, now even higher than Italy and Spain. The UK and the Netherlands are similar to each other. Although Luxembourg has the highest case incidence, the number deaths is modest. Denmark, Germany, and Austria have low numbers of deaths. China and Russia have the lowest.

Within European countries there is a remarkable variation of deaths per million population, explanations of which are not clear.

We can look at a few north-west European countries that we might consider to be similar in terms of population structure, good government, affluence, and advanced medical provision. In this daily active graph I added Belgium only when I realised how serious a problem it seemed to have. The UK and Netherlands are again close together, with Switzerland and Luxembourg tending towards a peak. The end results of this graph of total numbers will be a steady-state plateau and there will be no dip (assuming no resurrection of the dead).



There is a striking difference between the highest number of deaths per million in Belgium and the lowest in Germany, adjacent affluent countries. The explanation of the ten-fold difference is not obvious. 

But is it true? Or is it apparent with greater similarity than meets the eye? Is it an issue of reporting? Is over-reporting or over-diagnosing more likely than under-reporting or under-diagnosing? This applies both to cases and deaths.

One thing is becoming clear from information about deaths from Covid-19. Death certification is far from clear: people can die with Covid-19 or of Covid-19. The two are very different but this will not be clear on a death certificate.

Underlying health conditions

Deaths from Covid-19 are very rare among the fit and healthy but are mainly among the frail, sick, and elderly. It is suggested that at the most 5% of deaths from Covid-19 are among the young fit and healthy. The bar chart show the dominance of underlying health conditions in “death from Covid-19”, and how variations between countries can be apparent rather than real. We might never know for certain.


When we see in the media the tragic news that a young person has died from Covid-19, the background appears later. For example, on the television I saw a photograph and description of a 21 year-old girl who had died, but it later emerged that she had advanced liver disease and was awaiting a transplant. What was really the cause of death? Fransisco Garcia was a 21 year-old Spanish youth team football coach. He developed Covid-19 pneumonia and went to hospital, where he died. It was found that he had undiagnosed leukaemia. 

However we are experiencing deaths in people of working age, and without obvious underlying conditions. They are nearly all of black African and Asian ethnicity. The reason for this has been been the subject of a previous post, and also an explanation of vitamin D and how deficiency of it results in reduced immunity.

The panic mode means that strange medical practices are taking place in care homes, and indeed in hospitals. A German palliative care physician states: “Very wrong priorities were set and all ethical principles were violated. There is a very one-sided orientation towards intensive care; the balance between benefit and harm is often not good. A new diagnosis of Covid19 would turn elderly patients, who in the past had mostly been treated palliatively, into intensive care patients and subjected to a painful but often hopeless treatment (ie ventilation). Covid19 is not always an intensive care disease as the severely affected people are typically people of old age who have multiple pre-existing conditions. When these people get pneumonia, they have always been given palliative care (ie peaceful death). With a Covid19 diagnosis, however, this would now become an intensive care case, but of course the patients still cannot be saved.” 

An elderly person in a nursing home might have existing illnesses such as diabetes, high blood pressure or, perhaps and, heart failure, all of which will be controlled. Subsequent death “with” Covid-19 will create a dilemma as to how to record the cause of death. Even without these underlying conditions, the inevitable rapid deterioration over a few days that will precede death from old age might now lead to Covid-19 testing. If positive, the test is likely to change the cause of death from “Old age” to “Covid-19”. This is when variation between nations might occur. Would “Old age” be more likely in Germany and “Covid-19” be more likely in Belgium? 

“Lock down”

The Covid-19 pandemic emerged in Wuhan in China. It spread rapidly and Wuhan was locked down and isolated from the rest of the world. But nevertheless it did spread throughout the world. The Chinese authorities acted very quickly and successfully as far as spread in China was concerned. However the epidemic escaped into the world at large. 

The world was informed that the virus had “jumped” from bats to humans in the Wuhan food market. But Covid-19 is a respiratory virus and eating a dead and presumably cooked bat would not be expected to cause pneumonia. It is suspected that the route of the virus from bat to human took place through for practice in the nearby Virology Institute in Wuhan, and emerged from the laboratory in its contaminated  new human host, by then containing millions of copies of the virus. Once again, we may never know for certain.

Wuhan Virology Institute
The apparent success of lockdown in Wuhan led to it being adopted in Europe, particularly in Italy which was the first European nation to experience a widespread epidemic. Italy was followed by Spain. Lockdown was rigidly enforced, but the epidemic progressed in both countries.

Other nations followed. In the UK the initial policy was to slow down the spread of the epidemic to avoid a sudden peak that would overwhelm hospital services, as had happened in Italy. The objective was to allow the development of herd immunity as this always brings an end to an epidemic.

Herd immunity is widespread immunity in a population. It comes about when a large proportion of the population develop immunity following a non-fatal and possibly symptom-free infection. The acquired immunity is locked into DNA and is thereby passed to offspring. This depends on young people acquiring an infection to which they are resistant but not initially immune.

As the epidemic developed in the UK, the popular feeling was that the approach of the governments’s medical advisor (Professor Chris Whitty) and scientific advisor (Sir Patrick Vallance) was not adequately active. This was fuelled by the mathematical modelling that the worst scenario forecast would be a possible  27 million cases in the UK with a need for 220,000 intensive care beds and 380,000 predicted deaths, assuming 1% morality rate. The government led by prime minister Boris Johnson had to change its approach and lockdown was introduced. 


Chris Whitty – Boris Johnson – Patrick Vallance

The need for lockdown has also been based on another mathematical model, this one called R0 (R nought) first used in epidemiology in 1952. This is a calculation of the infectivity of a micro-organism, the number of people that an individual can pass on the micro-organism. Once again it makes assumptions that might not be robust and which might change over a short period of time.

"All models are wrong, but some are useful”, attributed to the US statistician George Box in 1978. Models make assumptions and the weakness of the Covid-19 model is the assumption of a 1% mortality rate in those infected by Covid-19. This model might have amplified the mortality risk by a factor of ten, as it is now suggested that the overall mortality rate is closer to 0.1%. 

The problem is that we know neither the numerator nor the denominator. We do not know the overall infection rate (the denominator), only those who are also ill, that is the number of cases. We do not know the true death rate (the numerator). Is it closer to the German or the Belgian experience? Is the Covid-19 death of a 21 year-old who is fit and healthy equivalent to the Covid-19 death of a 21 year-old with either leukaemia or advanced liver disease, or the same as the Covid-19 death of a lady aged 108 in care home? Would my death from Civ-19 be equivalent to the death of one of my young grandchildren?

We simply cannot give the risk of death in the population as a whole, whether it be 1% or 0.1%. We can however give a realistic guidance to specific groups. The risk of death might be 0.1% in young healthy people. How many deaths would we anticipate in a school of 1,500 children? 1% would be 15 deaths, but I would regard this as very unlikely. 0.1% is 1 child, but it likely that no child would die without having a serious underlying illness.

Perhaps we might expect a mortality rate of 1% in those with black African and Asian ethnicity who are not taking a vitamin D supplement. The death rate might be close to 10% in the elderly (70 and above), and perhaps 25% in the very elderly nursing home residents.

It is necessary to protect those at greatest risk. We have effectively stopped cytotoxic chemotherapy, and also organ transplantation that requires immune suppression. We need to provide or recommend vitamin D supplement to those with a high probability of deficiency, those with black African and Asian ethnicity. The elderly need to keep within their homes and gardens.

But what of the great majority, those who are well and below the age of 70? Do they need to isolate in lockdown? Do all children need to kept off school? Keeping them away from at-risk grandparents would be sensible. Do universities need to close? Does the economy need to come to a halt?

Has lockdown been effective? The UK government insists that it has been, but it would not be in the traditional of a government to say, “Sorry we have got it wrong. Lockdown can end today”, after it has had such a devastating effect the national economy and the incomes of many individuals. Other governments are having second thoughts and are easing lockdown.

Lockdown cannot easily be evaluated but we have a control nation in Sweden. The Swedish government decided against lockdown. Schools and restaurants remain open, life goes on. Other nations watched anticipating that the epidemic in Sweden would be catastrophic, but not so. The experience of the epidemic in Sweden has shown very similar characteristics to that in the UK. In the UK the cumulative cases per million is 1610.3 and in Sweden 1308.5. 

In the UK deaths per million are almost twice those of Sweden. The graph show the cumulative deaths per million population in the two countries.


It is difficult to see how lockdown introduced in the UK on March  23rd (3-23) gave the citizens of the UK an advantage over the citizens of Sweden.

We now hear that many citizens of Sweden are starting to doubt the wisdom of their government (unusual in Sweden) because of the number of Covid-19 deaths in homes for the elderly. They make comparisons with their neighbours Denmark, Norway, and Finland, where Covid-19 deaths have been very low, similar to Germany. 




Compared to the UK, Sweden has modest numbers of deaths, but in all countries Covid-19 deaths are predominantly in the old and frail.  

Let us look at the number of cases in the UK. The graph shows a cumulative number and we are anticipating that it will flatten, showing no increase in number. We have not quite reached this point. We can see the situation when lockdown was introduced on March 23rd. By that day we had recorded 5,683 Covid-19 cases, now 108,692. There had been 281 deaths, now 14,576. I regret to say that I cannot see that lockdown has been of any benefit. 


I heard on the radio just as I was having lunch today (April 18th) a government minister telling the population that lockdown has been and still is of great importance, and that without it the epidemic would have been very much worse. This, I am afraid is a sterile argument. A friend of mine has been praying to God every day for deliverance from this pandemic, and she tells me that without her prayers it would have been very much worse.

Covid-19 seems to close to its peak in Europe. The value of antigen and antibody tests is uncertain. Active treatments are being put to clinical trial. Vaccines are being developed. 

People with black African and Asian ethnicity, mainly health workers, continue with a death rate that is much higher than the UK average. Vitamin D hardly gets a mention and it is not being distributed. The ignorance about ethnicity, immunity, and vitamin D is a disgrace, considering that so much is known. 

This is my main criticism of the handling of the Covid-19 epidemic and the government's responsibility to minimise deaths.







Tuesday, 14 April 2020

Vitamin D and Immunity – important against Covid-19

Vitamin D and Immunity – a brief introduction




Deaths from Covid-19 continue to increase worldwide. There is no immunisation; attempts at reducing numbers of cases and deaths by population isolation not seem to have a large effect in Europe.

The many trillions of virus copies cannot be destroyed. The way to protect the population from death is to maximise immunity and when necessary to provide intensive care life support.

I have drawn attention to three observations:
  • In the UK, six doctors, one nurse, and one health care assistant died from Covid-19. All were of black African or South Asian ethnicity. Shortly afterwards, on April 3rd 2020 a second nurse died, but she was white-skinned. However 8 out of 9 being of black African or South Asian ethnicity in the UK is more than a coincidence. 35% of those with Covid-19 requiring intensive care in the UK have black African or South Asian ethnicity. The USA has also experienced a proportionately higher risk of severe or fatal Covid-19 in BAME citizens. In Sweden it has been reported that 40% of Covid-19 deaths in Stockholm have been from the Somali community (<1% of the population). Skin pigmentation is obviously not itself the cause of the disease but it must be regarded as a very important susceptibility factor.
  • The greatest incidence of Corvid-19 cases and deaths in Europe has been in Northern Italy, which before the pandemic had the highest level of air pollution in Europe.
  • The pandemic of Covid-19 has occurred during the late winter in the northern hemisphere, and minor epidemics or clusters of viral "flu" always occurs at this time of the year (see EuroMomo)
All three are factors that are associated with low exposure to the sun and thus blood levels of  vitamin D: dark skin, air pollution, the winter.  Low blood levels of vitamin D will lead to poor defence against Covid-19. However it is reversible: if vitamin D deficiency is corrected in those at risk (which is effectively all of us in Europe, but especially those with dark skins) then there might be a reduction in the number of deaths.

It might be felt that this is supposition, but it has been established that vitamin D has an important role in immune defence mechanisms. It would be as well to look at this.

Vitamin D synthesis

Our skin, together with plankton living close to the surface of the oceans, are the most important sites of synthesis of the vitamin D that we need. Both produce initially the long-chain lipid squalene, also know as shark oil. The next stage is folding this molecule into the sterol 7-dehydrocholesterol (7-DHC). 

The critical part of the process, and a miracle accident of evolution, is that ultra-violet light of wavelength 270–300nm splits 7-DHC at a specific point, and as a result the molecule rotates and forms cholecalciferol, vitamin D. 






Three things can now happen. In humans the vitamin D (called cholecalciferol) which is synthesised in the skin enters the blood-stream. 

In furry animals the vitamin D is formed by UV light acting on the 7-dehydrocholesterol on the surface, in the oils that are secreted by the skin. Furry animals spend much time licking themselves and in this way they ingest the vitamin D, which is then absorbed from the intestine. 

The vitamin D in plankton enters the food chain via the plankton being eaten by small fish, and small fish being eaten by large fish, and large fish being eaten by humankind. The vitamin D is then absorbed by the intestine and it passes through the liver.

As the vitamin D passes through the liver it is activated by the addition of a hydroxyl (-OH) group to form calcidiol. Another hydroxyl group is added as the blood circulates though the kidneys to form the highly active hormone (chemical messenger) calcitriol.



Calitriol is a hormone that will activate vitamin D receptors (VDRs), protein enzymes found in cell walls. The calcitriol-VDR complex passes within the cytoplasm of the cell and reaches the cell nucleus. There it activates vitamin D responsive elements (VDRE) which can in turn activate a number of nuclear genes.




Response to infection

In response to infection, viral or bacterial, the body's defensive T-cells are activated as part of an enzyme cascade. This includes gene expression that stimulates further T-cell proliferation, and also increased synthesis of VDRs. As long as there is an adequate supply of vitamin D as calcitriol, there will be a feedback loop increasing the defensive immune response by a factor of up to 75.


The importance of vitamin D in defence against infection is clear, and it has been worked out in much greater cytogenetic detail than this brief sketch.

If you would like to see more detail, I would recommend:


Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)vitamin D: Genomic and non-genomic mechanisms
Haussler MR, Jurutka PW, Mizwicki,


https://www.ncbi.nlm.nih.gov/pubmed/21872797

(Not the easiest read.)

Another part of the pathway is that the defence cells macrophages ("big eaters") can themselves activate calcidiol to form calcitriol. This leads to the VDR-calcitriol complex enhancing gene expression via VDRE in the macrophage, and this further enhances immune defensive processes. Again, there must be a good supply of vitamin D to supply the substrate calcidiol.

Tuberculosis

The importance of vitamin D in defensive immunity was first recognised in observations of tuberculosis in the late 19th and early 20th centuries. 

The serious atmospheric pollution in the industrial cities of Europe led to the appearance of rickets, the childhood bone disease that is the direct result of vitamin D deficiency. This resulted from the failure of adequate penetration of sunlight through the polluted air to ground level. 

The movement of affected sick children to coastal fishing communities in Scotland and mountain-dwelling farming communities in Austria, and their consequent improvement,  led to the identification of vitamin D, which is obtained directly from the sun or indirectly from fish oil. However it was noted that rickets and tuberculosis frequently co-existed in families and communities, and that tuberculosis also improved on movement to an environment with clean air.

An interesting study undertaken in India and reported in 1922 demonstrated the close association between rickets and tuberculosis. However, unlike in Scotland, the families with these conditions were wealthy and it was the poor who were much more healthy. The poor spent all their time outside on the farms whereas the wealthy, and especially women and young children, were able to stay indoors and keep out of the sun.




Deaths from tuberculosis have declined dramatically but as we have seen in the late 20th century AIDS epidemic, tuberculosis becomes active when immunity is suppressed. Vitamin D deficiency is another form of acquired immuno-deficiency syndrome and is linked to activation of tuberculosis.. 

The reason for the decline in TB deaths is not clear, but it must have been due to an improvement in the resistance to the infection. This would be example of  "herd immunity", the spread of inherited immunity within the population. Additional factors would have been much-improved housing and nutrition towards the end of the 19th century. The provision of community parks and the opportunities for annual holidays to railway destinations would have helped improved sun exposure and vitamin D synthesis.