Greece - smoking and the sun (2)

At one time life was simple and we knew all the answers. The cause of disease (and everything else) was God, often acting in response to the sins of mankind. The public health officials of the time might have advised “less sin”, but either the population ignored the advice or the concept was flawed.

The most important discovery of the Age of Enlightenment was “ignorance”, the realisation that divine intervention was at the very best unreliable, and probably non-existent. We were therefore ignorant of the causes of disease.

Yuval Noah Harari, in his remarkable book “Sapiens - a brief history of humankind” proposes that the unique attribute of Homo sapiens, the present humankind, is our ability to create abstract ideas, to create fictions. Our many gods are clear examples of this. Fictions are our attempt to explain the world as we experience it. We use fictions to try to make sense of the diseases that afflict us. Often these indicate the blaming of the victims for the errors of their ways, eating the wrong foods, not taking sufficient exercise, or, the greatest sin of all, smoking.

In the absence of divine activity we must search for physical explanations for diseases. We can classify inherited disorders, which can be genetic (from the moment of conception) and congenital (abnormalities of our construction), and both of these in the past have been ascribed to divine retribution for the sins of the parents. Disease acquired after birth can be due to environmental factors, which can be physical (injury, heat, cold), chemical (poisons meaning too much, or deficiencies meaning too little), or biological (a wide variety of micro-organisms).

The elusive nature of “proof” is described and advanced by “Hill’s Criteria”, in an associated Post.

Science starts with observation. We look for clues to give us a way to construct a fiction of causation, called a theory or hypothesis, or a paradigm when it receives general acceptance. But fictions are not absolute truths and fictions change with increasing knowledge.

Causation is complex. For example we have seen that although we accept that cigarettesmoking is the major cause of lung cancer, the fact that only 10% of heavy smokers die from lung cancer indicates that other factors must be considered. These can be viewed as “susceptibility factors”, or perhaps “protective factors”. We can regard disease as the result of interaction between “the cause” together with susceptibility or protective factors, which might be genetic or environmental.

Clues to the identification of susceptibility and protective factors, and indirectly to causation, can be gained from comparing disease incidence in different populations, that is the geography of disease. This is an important dimension of epidemiology. An example is the “Greek paradox”.

I have been warned that data from Greece may not be entirely reliable as it is a country with an unusually well-developed culture of fiction. However WHO data that includes Greece is the best data that we have and we cannot ignore it.

Greece apparently has the highest prevalence of cigarette smoking in Western Europe, as we can see in Table 1. (cigarette smoking has a higher prevalence in the former Soviet countries in Eastern Europe)

Figure 1: percentage of adults who smoke

However Greece has within Europe the lowest age-standardised death rate from coronary heart disease (CHD). The paradox is that cigarette smoking is considered to be a major causative factor of CHD. Where there is a high prevalence of cigarette smoking we expect to find a high death rate from CHD, but not so in Greece. In Table 2 we see age adjusted death rates in men from myocardial infarction (data from WHO 1986).

Figure 2: age standardised death rates from myocardial infarction

Why is it that cigarette smoking in Greece does not cause the high incidence of premature death from CHD that it does in other countries?

“The Seven Countries Study” written Ancel Keys has been the subject of a previous Post. Although methodology was far from perfect and conclusions were not very objective, the study provides a great deal of data. It was very influential in its false conclusion that animal fats cause CHD, and this led to inappropriate diet manipulation over a period of 50 years, continuing to present time.

The study recorded CHD death rates in population samples in some countries within western and central Europe. From the data presented we are able to see that as expected the risk of a man dying from CHD increases with the number of cigarettes smoked. This is obvious if we look at countries in Northern Europe. 

Figure 3: CHD death rates and smoking - northern Europe

The slope of the graph-line rises steeply, indicating that as the number of cigarettes smoked increases, the CHD death rate increases substantially.

However the slope of the graph-line is different in what was then Yugoslavia, mainly Serbia (study population from Belgrade). In this more central country of Europe, the graph-line once again shows an increasing incidence of CHD death with an increasing number of cigarettes smoked, but the graph-line is not as steep.

Figure 4: CHD death rates - northern and central Europe

This indicates that the damaging effects of smoking in Serbia are not as great as in the northern countries.

If we now look at Greece and Italy, countries in the south of Europe we see a graph-line that is almost flat.

Figure 5: CHD death rates and smoking in Europe

This indicates that the risk of CHD death at the age in the study is very low in those who do not smoke, and this is what we expect. However the risk increases only marginally in those who smoke heavily.

What this means is that the risk of a heavy smoker dying from CHD increases dramatically as we move north through Europe. If we look at the low or no cigarette smoking rates in the three European regions we see little difference. If however we look at the heavy smoking group we see a major difference.

It appears to be fairly safe someone in Greece to smoke heavily but it is very dangerous for someone in the northern countries of Europe.

But this feature of Greece and Southern European countries is seen in more diseases than CHD. There is a similar observation of the incidence of breast cancer and colon cancer having a diminishing incidence in the south of Europe compared to the north.

Figure 6: cancer rates and latitude in Europe

The first observation of a latitude effect of cancer incidence was in North America.

Figure 7: Cancer and latitude in Americas

Death rates from cancer increase in the northern parts compared to the southern parts.

The obvious and most simple difference between places closer compared to more distant from the equator is the climate, and in particular the different intensity of the sun.

The observations of cancer death rates and the effect of cigarette smoking on CHD death supports the proposal that exposure to the sun (avoiding severe sunburn) is a great advantage to our health, and reduces the risk of damage from cigarettes.

There is evidence of a help from vitamin D and the sun in thosewho are diagnosed with lung cancer, in an associated Post.

If someone wishes to enjoy good health and a long life but nevertheless wishes to smoke, then it is advisable to live in Greece - see Post Sir Patrick Leigh Fermor (died aged 93).

Lung cancer and the benefit of the Sun (2)

We try to understand the world around us. This is the purpose of science, and the scientific process starts with simple and then carefully controlled observation. Experimentation is the final phase of the process, but this is not always possible due to a variety of constraints. We have looked at Hill’s criteria of proof, but observation is of great importance.

We all know as the result of careful observation that lung cancer isusually caused by cigarette smoking.  


People who smoke heavily have, after thirty years, a higher death rate from lung cancer than those who smoke few cigarettes or who do not smoke at all. About 10 % of heavy smokers will die from lung cancer, but it is exceptionally rare in non-smokers. There is an intermediate death rate in moderate smokers.

As only 10% of heavy smokers die from lung cancer, there must be co-factors. There must be one or more reasons why these 10% are subject to the bad luck of lung cancer whereas the majority of heavy smokers have managed to avoid this cause of death.

A reason why someone does not die from one disease is that he or she dies from something else earlier, perhaps warfare or childbirth. Although dying from something else might be a factor in protecting 90% of heavy smokers from dying from lung cancer, it is not just this. 

Coronary heart disease (CHD) is a major cause of death associated with cigarette smoking. We have also seen in a previous post that at the time of the study 20% of people died as a result of CHD, irrespective of whether they smoked or not. But cigarette smoking brings forward death from CHD by about 10 years. The death rate at the age of fifty years is twice as high in heavy smokers as in non-smokers, but cigarette smoking does not increase the lifetime CHD death risk.

Greece appears to be a location in which the population is somehow protected from the adverse effects of smoking. The gradient of increasing smoking related deaths as we move from southern Europe to northern Europe suggests that this might be an effect of the climate. The suspicion from this observation is that the sun might be protective, and there are many other examples of this.

Is there any other observation that the sun might be protective against lung cancer? The answer is "Yes". 

Dr AG Kargar of Basle recently reviewed 12 observational studies that have investigated people with lung cancer and compared them to controls without lung cancer. The objective was to review the relationship between lung cancer and vitamin D status, judged by either intake or blood levels. The higher the blood levels of vitamin D, the lower the risk of death from lung cancer (standardised for number of cigarettes smoked and duration of smoking).

Figure 1: Lung cancer risk and vitamin D status

The result was that the greater the vitamin D status, the less was the risk of lung cancer. We can see this in Figure 1. In column 2 the risk of lung cancer in people with the lowest blood level of vitamin D is standardised as 1. Those with the highest blood levels of vitamin D (column 1) have a lower relative risk of lung cancer at 0.84. We see then same when we look at the dietary intake of vitamin D. The risk of lung cancer is lower in those with high intake (column 3) compared to those with the lowest intake of vitamin D (column 4).

The author suggests that: “Further studies are needed to investigate the effect of vitamin D intake on lung cancer risk and to evaluate whether vitamin D supplementation can prevent lung cancer.” This is a standard way of ending the report of an observational study and it is of course self-evident. The scientific process is like a wheel that continually rotates to create an increasing understanding of the world about us.

However it must be remembered that there is more to the sun than vitamin D. Vitamin D is an index of sun exposure as well as being an active vitamin (pre-hormone). It is necessary to evaluate whether vitamin D supplement can “prevent” (that is, reduce the risk of) lung cancer, but also whether controlled sun exposure has a similar or even greater benefit.

This would lead us from observation to experimentation. It would require a prospective randomised controlled trial (RCT) of a volunteer group of people. It would take many years to reach a conclusion, perhaps 30 years. The organisational challenge would be immense and the cost very high. It is unlikely to take place because of these challenges and the lack of the financial rewards that are the hopes of pharmaceutical innovations.

There is another observation that suggests that the sun is of benefit in the outcome from lung cancer. If the diagnosis and treatment of lung cancer occurs in the summer as opposed to the winter, then the outcome is much better. It is difficult to think of an explanation other than that the sun gives a survival advantage. A further observation indicates an advantage in those taking vitamin D.

Figure 2: Survival from lung cancer and time of the year.

We can see in this Figure 2.  Survival from lung cancer is worse if diagnosis and treatment occur in the winter months (columns 1 and 5) compared tot he summer months (columns 2,3,4).

If we then add the effect of taking or not taking a vitamin D supplement we can see an additional important effect.

Figure 3: Outcome from lung cancer, season and vitamin D supplement.

In Figure 3 we see the season effect repeated, but now we can see the additional effects of taking (yellow column) or not taking (green columns). 

The best survival of 70% (yellow column) is in those who are diagnosed and treated in the summer and who are taking vitamin D supplements.

The worst survival (30%, green columns) is in those diagnosed and treated in the winter and not taking vitamin D supplement.

(Zhou W, Suk R, Liu G, et al. Vitamin D predicts overall survival in early stage non-small cell lung cancer patients. Am Assoc Cancer Res 2005; Abstract LB-231.)

If someone smokes of cigarettes, then it is advisable to stop. If not, it is advisable to improve vitamin D status by maximising sun exposure (but avoiding sunburn), or taking a vitamin D supplement by mouth, or both.


Perhaps the best plan is to live in Greece (see Post - Greece and also Post - Sir Patrick Leigh Fermor).


The important thing is that the way to reduce the risk of lung cancer is not to smoke. The purpose of this post is to draw attention to the importance of the sun on human health and its likely benefit in respect of cancer.

Sunset over the Mekong, from Ventienne - magic

The meaning of proof - Hill's criteria and Koch's postulates (2)

People tend to use the word “proof” without understanding what it means. When, in respect of a proposition, someone says: “There is no proof”, the response should be: “What do you mean by proof?”, a question that is usually met by a puzzled silence.

 

“Proof”, as originally defined in classical geometry, is the fulfillment of predefined criteria. Someone who asks for proof should be asked: “What are your predefined criteria of proof?”

This was understood by the great German pathologist Robert Koch. His challenge was to find the cause of tuberculosis, consumption or phthisis as it was known at the time in the latter half of the nineteenth century. At the time it was thought that tuberculosis was “constitutional” – it ran in families and, in the days before genetics, it was considered to be somehow inherited. Koch felt that the family clustering was the result of the transfer of a micro-organism.

Robert Koch 1943-1910

Much laboratory work led him to define what became known as the Koch Bacillus, what we now know as Mycobacterium tuberculosis. Although he felt that this was the likely cause and had to be certain. He needed proof that would be acceptable not only to himself but also to a scientific community that was clearly sceptical.




Understanding the concept of proof, Koch had to record his predefined criteria that, if fulfilled, would lead to the acceptance of the micro-organism being the cause of tuberculosis. His criteria were called “Koch’s Postulates”, and they are as follows:

1.  The specific organism should be shown to be present in all cases of animals suffering from a specific disease but should not be found in healthy animals.

2.  The specific micro-organism should be isolated from the diseased animal and grown in pure culture on artificial laboratory media.

3.  This freshly grown micro-organism, when inoculated into a healthy laboratory animal, should cause the same disease seen in the original animal.

4.  The micro-organism should be re-isolated in pure culture from the experimental infection.

Koch’s postulates were very demanding, and it can be seen that they required the following reach requirements:

•     the postulated cause must be a micro-organism;

•    the micro-organism must be isolated and grown in laboratory culture;

•    The micro-organism must be inoculated into a healthy animal and produce disease.

Not all micro-organisms can be isolated and grown, this applying to viruses and many recently-discovered bacteria. Not every micro-organism causing human disease will produce that disease in laboratory animals. Is inoculation into human, volunteers or in ignorance, acceptable? The answer to this is an emphatic “No!”

Koch’s Postulates have major limitations and in practice they are only of historic interest. They cannot be applied to non-biological likely causes of disease and a different approach became necessary.

Sir Austin Bradford Hill 1897-1991

The eminent British statistician Sir Austin Bradford Hill felt that proof of causation could be made using different criteria than Koch’s postulates, and he felt these to be necessary in the case of the inanimate causes of disease, for example cigarette smoking as the cause of carcinoma of the lung.  He identified the following criteria as being necessary for “proof” to be established:

1.  Strength of association

2.  Consistency of association

3.  Temporality

4.  Biological gradient

5.  Plausibility

6.  Coherence

7.  Experimentation

8.  Analogy

     

It is important to note that apart from Experimentation, all the criteria are part of the observational process of scientific investigation. The observations become increasingly controlled so as to avoid other factor. For example death rate must be standardised for age.

It is generally recognised that proof is pragmatic, the fulfillment of predetermined criteria. There is no absolute proof; we are looking for the best story that can be defined using existing knowledge. It might change with the passage of time as new knowledge becomes available.

Koch’s postulates identified absolutes; a bacterium did or did not grow. Hill’s criteria are not absolute and all criteria can be regarded as judgmental.

The strength of association is the association between the disease and the proposed cause. The strength is determined by statistical method.

Consistency is important, being the association being corroborated in several studies.

Temporality indicates that association at one point in time does not indicate cause-effect relationship, but we must look at the association over a time-line. The proposed cause must predate the disease.

The biological gradient indicates that in general the greater the exposure to the proposed cause, the great is the probability of disease (for example number of cigarettes smoked and the development of lung cancer).

All these add up to construct plausibility – does it make sense? Is there a coherent pattern – does it all hang together?

Experimentation is limited by ethical considerations. It might be possible to transmit the disease to others, if not to experimental animals then to other human beings. Such research is not tolerated today. However the effect of elimination of the proposed cause is ethical and highly informative.

Finally there is analogy. Does the proposed cause or something similar (biological or chemical) cause similar diseases?

Hill’s criteria of causation have been reviewed and refined by researchers at the US National Institute of Health (NIH) to look at the possibility of a microbe causing a disease, and in this particular case Crohn’s disease. The principles are equally applicable to the investigation of a possible microbial cause of coronary heart disease, for which there is no obvious cause at present (cholesterol and diet theories are not sustainable when the evidence is reviewed critically).

Hill’s Criteria are very valuable but little known. Most if not all doctors are aware of Koch’s Postulates, but Hill’s Criteria do not seem to be taught. We should all be more aware of them.