Two previous articles relate to this theory of the cause of diverticular disease (DD). “Colon wall muscles in diverticular disease” and “Diverticular disease: updated epidemiology” can be found on this website. Because of the length of this article, many details with supporting references have not been included and a summary is provided.
SUMMARY
The worldwide epidemiology of diverticular disease (DD) is the same as that of the smoking epidemic used by many organisations and charities to show the relationship between smoking and lung cancer and many Western diseases. The grouping of countries by the timing and extent of DD correspond historically with the introduction of “Western” cigarettes. The types of tobacco and additives in the Western products and their promotion are related to the pattern of disease and they are designed to deliver the maximum amount of nicotine into the body. The changes in the colon wall with DD reflect the pharmacological action of nicotine in the chronic dosing produced by cigarette smoking. Ethnic differences in the metabolism of nicotine and different sensitivity in longitudinal and circular colon wall muscles could explain differences in the sites of disease particularly between Eastern and Western countries. Changes in the colon wall structure with DD are similar to those found in blood vessels caused by smoking. Such changes are found in the lungs of children subjected to passive smoking. Could DD also start this early in life?
THE CAUSE OF DIVERTICULAR DISEASE
There is a plethora of reports of research and opinions on what might be the cause of diverticular disease (DD). Research is often carried out in the hospital situation where the diagnosis of diverticulosis, diverticulitis or the treatment of complications takes place. Patients can then be surveyed to find out why they came to be in that situation. This tends to result in the cause of symptoms being blamed for the disease which is not the same as why or when the disease started in the first place. The formation of diverticula, the basis of diagnosis, is a later stage in its progression.
‘Symptoms’ such as excessive flatus (1), straining on defaecation (2) or constipation (3) have been suggested as the cause of DD. Statistical analyses point to ‘risk factors’ such as red meat or alcohol consumption, low physical activity or ageing. ‘Associations’ are found with obesity, hypothyroidism, industrialisation and Western diseases. ‘Predispositions’ are found with certain genetic diseases and familial environment. Recent research on twins with DD estimated that 40% of the chance of DD was inheritable with the environmental effects at 60% (4). Another study estimated that 53% of susceptibility to DD resulted from genetic factors (5).
Research has produced some facts about DD which cannot be disputed –
- The muscles in parts of the colon are in an apparent contracted state which is not reversible
- Collagen and elastin components of the colon wall have changed to a more rigid form
- Nerves and cells controlling the muscles have changed
- Electrical activity and colon movements are disordered
- There is increased sensitivity to acetylcholine – the normal neurotransmitter in colon function – due to increased numbers of receptors
- There is damage to nitergenic neurones which affect relaxation of colon wall muscles
- Pressure inside the colon can be increased during normal function or by drugs, resulting in the blow-out of diverticula
Opinions have varied on the order in which these changes occurred. Pressure and the formation of diverticula came before the other effect (6) or the muscle and nerve changes are a result of inflammation (7). Deterioration in the vagus nerve with age has been hypothesized (8). The greatest influence on opinion has been the dietary fibre theory of the early 1970s (9). Low levels of dietary fibre have been promoted as the cause of all the colon changes. The theory still persists in some research (10), while other reports consider human and animal experiments on diets to be unreliable (11) and that fibre can be detrimental to DD (12).
The idea, that the changes in the colon precede and predispose to the formation of diverticula, rather than as a consequence of the disease, has recently been published (13). Research on the cause of DD needs a rethink without a preconceived or traditional basis. Information available publically can be used to give a plausible explanation of what might cause DD and some of its characteristics.
References
1 Wynne-Jones G. Lancet 1975, Aug 2, 211.
2 Sikirov BA. Med Hypotheses 1988 26, 17.
3 Jones DJ. BMJ 1992, 304, 1435.
4 Granlund J et al. Aliment Pharmacol Ther 2012, Mar 20. Epub ahead of print.
5 Strate LL et al. Gastroenterology 2013, 144, 736.
6 Floch MH et al. World J Gastroenterol 2006, 12, 3225.
7 Spiller R. J Clin Gastroenterol 2006, 40(3 suppl), S117.
8 Yun AJ et al. Med Hypotheses 2005, 64, 252.
9 Painter NS et al. BMJ 1971, 2, 450.
10 Floch MH. J Clin Gastroenterol 2006, 40(3 suppl), S121.
11 Commane DM et al. World J Gastroenterol 2009, 15, 2479.
12 Peery AF et al. Gastroenterol 2012, 142, 266.
13 Mattii L et al. PLoS One 2013, 8, e57023.
© M Griffiths 2013
EPIDEMIOLOGY
A previous article (Diverticular disease: updated epidemiology) on this website used data from barium enema and colonoscopy examinations to update the worldwide pattern of occurrence of DD and illustrated this in graphical form. Countries with insufficient data were not included. The results showed four groups of countries distinguished by the date of appearance of DD and subsequent changes in its levels.
Group 1. Australia, England, USA, Sweden. DD appeared before the 1930s, peaked at about 60% between 1970-1980 then fell slowly.
Group 2. European countries. DD appeared about 1960 and reached 50% around 1980
Group 3. Asian countries and Brazil. DD has been rising since its appearance about 1970.
Group 4. African and Middle East countries, Peru, China. DD first appeared about 1970 but levels have remained low.
People in Group 1 countries have been smoking ‘Western’ cigarettes since the beginning if the 20th century when they were invented. Group 2 reflects the import and flooding of ‘Western’ cigarettes into Europe and the take over of national cigarette companies after WW11. Group 3 is the effect of aggressive trading in the Far East by ‘Western’ tobacco companies around 1970. Group 4 countries have largely resisted the impact of ‘Western’ cigarettes due to trade restrictions, poverty or preference for their own forms of nicotine administration. These groups of countries are in keeping with the model of the cigarette epidemic described by Lopez et al in 1994 (1) which has been cited and used by researchers, charities and organisations since.
The appearance of DD corresponds to the consumption of ‘Western’ cigarettes or those manufactured from ‘Western’ tobaccos and not from previous local or national products. This explains some of the anomalies which have been highlighted. The Japanese were heavy smokers without much DD around 1970 but émigrés to Hawaii had developed DD within a generation. This has been attributed to diet change but the brands of cigarettes available to them certainly changed. In Japan after 1970, cigarette consumption reduced with the ‘Western’ type cigarettes but the levels of DD began to increase. Another paradox is China – the world’s heaviest smoking population. China has resisted international tobacco companies and has low levels of DD. ‘Western’ cigarettes are smoked by ethnic Chinese in Hong Kong or Singapore with significant DD levels. Birkitt (2) noted patches of low DD prevalence in the West, Mormons and Adventists are averse to cigarette smoking and only 10% to 15% of vegetarians smoke (3). The differences in DD levels between Uganda and Britain around 1970, the relationship to urban and industrial societies, wealth and Western diseases, have been used to support the dietary fibre theory but they are all related to smoking of ‘Western’ cigarettes. Most of the old research on colon function with DD ignored the smoking habits of patients, concentrating only on diet.
Some countries were opened up to transnational tobacco companies around 1990 e.g. Taiwan and DD was diagnosed there in 2.5% of ultrasound examinations in 2001 (4). The collapse of the Soviet Union produced newly independent countries. These have been targeted by international tobacco companies with imported cigarettes and privatisation of local tobacco farms and manufacturing. A report in 2011 showed that 16.2% of colonoscopy patients in a Moscow survey had diverticulosis (5). Will there be a Group 5 of countries where the DD epidemic starts around the new millennium? By the 1950s 80% of adults smoked in Britain and even more were subjected to passive smoking. With changing attitudes to smoking, the prevalence of DD may never again be as high as in Group 1 countries, particularly when that generation has passed.
References
1 Lopez AD et al. Tob Control 1994, 3, 242.
2 Birkitt DP British Medical Bulletin 1984, 40, 387.
3 Crowe FL et al. BMJ 2011, 343, d4131.
4 Chou YH et al. Am J Surg 2001, 181, 122.
5 Prilepskaia SI et al. Eksp Klin Gastroenterol 2011, 2, 22.
© M Griffiths 2013
HOW ARE WESTERN CIGARETTES DIFFERENT?
Western cigarettes have different characteristics compared with locally produced products in emerging countries or other forms of sustaining nicotine addiction using tobacco. Flue-dried, ‘blonde’ tobacco varieties are blended to give a less irritant smoke of lower pH. This makes deep inhalation easier. The addition of menthol in some products and flavourings enhances the sensory and addictive potential (1)
Tests for nicotine and tar levels using standard mechanical ‘puffs’ related to older, cruder types rather than the cigarettes largely redesigned in the 1950s. Filter tips, types of paper and the blending of tobacco enabled reduction in nicotine and tar levels to legal conformity in countries. However, smokers compensated by more and deeper puffs to achieve their nicotine fix (2). The USA had no product standards for cigarettes or other tobacco products until June 2009 so that industry could have made any changes for marketing advantage (3).
Winder (4) describes how the reduction in delivery of nicotine and tar from cigarettes after the 1950s paralleled an increase in nitrate content from 0.5% to 1.5%. This enhanced combustion and increased yields of nitrogen oxides and N-nitrosamines in the smoke. The nitric oxide from the smoke opened up airways then deeper inhalation increased nicotine and tar uptake and promoted cancer at sites deeper in the lungs. Vleeming et al (5) concluded that nitric oxide contributed to nicotine addiction. Wu et al (6) compared levels of tobacco specific nitrosamines (TSNAs) from a global brand of cigarettes with TSNAs from local brands. In 10 out of 14 countries the global brand produced higher levels of TSNAs. An exception was Brazil where local cigarettes were higher. (Brazil was also an oddity in Group 3 countries of the epidemiology results).
The international tobacco companies aim to control their products from start to finish – from the genetic selection of tobacco plants, their growth conditions, use of pesticides, harvesting, drying, blending, additives, cigarette design, production and marketing. There are no lists of ingredients as on food and drugs. Genetically modified tobacco plants have been allowed in Europe since 1994. Companies were also interested in nicotine analogues – biologically active compounds which would not affect nicotine levels in statutory tests (7).
Farm workers harvesting tobacco leaves are susceptible to nicotine exposure producing symptoms of ‘Green Tobacco Sickness’ (8) which requires treatment by anticholinergic drugs. In one study a mutagenic change was found more often when farmers were applying pesticides to the crops. One particular liver metabolic enzyme variant was associated with DNA damage induced by pesticides (9). Pesticides are used to protect the tobacco crop from insect damage. If the insecticides used were of the type that interferes with the enzyme (acetylcholinesterase) which breaks down acetylcholine in the gut nervous system, then there may be another detrimental effect of cigarettes on the human colon which has not so far received much attention. Neonicotinoid insecticides, if used, have activity similar to nicotine and might enhance its effects.
References
1 Yerger VB. Tob Control 2011, 20, ii29.
2 Hoffmann D et al. J Toxicol Environ Health 1997, 50, 307.
3 Tynan M et al. Morbidity & Mortality Weekly Report 2010, 59, 487 (CDC)
4 Wynder EL et al. Environ Health Perspect 1995, 103 Suppl 8, 143.
5 Vleeming W et al. Nicotine Tob Res 2002, 4, 341.
6 Wu W et al. Nicotine Tob Res 2005, 7, 443.
7 Vagg R et al. Addiction 2005, 100, 701.
8 Satora L et al. Pol Arch Med Wewn 2009, 119, 184.
9 Da Silva FR et al. Environ Mol Mutagen 2012, 53, 525.
© M Griffiths 2013
THE ACTION OF NICOTINE ON THE COLON
Messages are transmitted between one nerve ending and the next nerve cell by the chemical acetylcholine. This also bridges the gap between the second nerve fibre and the muscle to relay the message to contract. An enzyme, acetylcholinesterase, is secreted by nerves to inactivate acetylcholine and limit the time and intensity of the contraction. Stimulation of the second (postsynaptic) nerve cell also elevates the production of nitric oxide (NO) which is the neurotransmitter for the relaxation of the colon muscles (1). This all takes place in the networks of nerves in the colon known as the gut brain. The cyclic contraction and relaxation of the longitudinal and circular muscles is the basis of all types of coordinated movements in different parts of the colon.
Nicotine fits and blocks the receptors on the second nerve cell and sends its own signal to produce acetylcholine at the colon muscle. A feedback controlling mechanism may also be affected (2). Nicotine is not inactivated by acetylcholinesterase and continues its activity until the transmission system is blocked. Also blocked is the production of NO to relax the colon muscles. These effects are also the basis of the insecticidal properties of nicotine. Reduced levels of NO would normally increase propulsive activity of the colon (3) but not when the stimulation system is also blocked. The net effect is the locking of muscles in the ‘on’ position and with uncoordinated movements. An increase in the numbers of receptors for acetylcholine is a response to the chronic effects of nicotine, this also alters the response to neurotransmitters and drugs (4).
The effect of nicotine on smooth muscle (the type of muscle fibre) in the colon has had little attention compared with that in the walls of blood vessels. The chronic effects of nicotine from cigarette smoke produce narrowed, stiffened and less responsive artery walls (5). There are the same changes in collagen structure in arteries as there are in colon walls where it is considered a major factor in the onset of structural changes in diverticular disease (6). Changes in muscle elastin content are the same in diverticular disease as in the pulmonary artery (7). Arteries to the colon would also be affected. Are the weak places in the colon where diverticula form, a result of movement between rigid arteries and rigid colon wall?
References
1 Kodama Y et al. J Smooth Muscle Res 2010, 46, 185.
2 Mandl P et al. Brain Res Bull 2007, 72, 194.
3 Dinning PG et al. Neurogastroenterol Motil 2006, 18, 37.
4 Ke L et al. J Pharmacol Exp Ther 1998, 286,825.
5 Enevoldsen MS et al. J Biomech 2011, 44, 1209.
6 Bode MK et al. Scand J Gastroenterol 2000, 35, 747.
7 Ludeman L et al. Best Practice & Research clinical Gastroenterology 2002, 16, 543.
© M Griffiths 2013
NICOTINE METABOLISM
Nicotine is broken down in the liver by an enzyme known as CYP2A6. The main chemical formed is cotinine which is excreted from the body in urine. This provides a convenient marker for smoking and the rate of inactivation of nicotine. Cotinine and other chemicals produced are also known to have activity in the body but have not had much attention (1). Most of the research relates to activity in the brain where variations in CYP2A6 are a genetic contribution to addiction (2).
The enzyme CYP2A6 is not a single entity, some 40 variants have been found which produce differences in the rates and pathways by which nicotine is broken down and other chemicals produced. This has a great effect on smoking behaviour and disease. People who metabolise nicotine rapidly smoke more to sustain the body level of nicotine and at the same time increase the intake of carcinogens (3). There are reports that females process nicotine faster that males and are more likely to become addicted. Current smokers also have increased metabolism (4).
Liver enzymes such as CYP2D6, CYP2C19 or CYP2A6*18 have been shown to vary with ethnicity (5) (6). However a variant of CYP2A6 known as CYP2A6*4 is perhaps the most significant in producing ethnic differences in the effects of cigarette smoking. CYP2A6*4 is not active in the metabolism of nicotine. People with this variant enzyme produce different metabolic chemicals, have far less cotinine excreted in urine and have significantly reduced rates of lung cancer. Nakajina (7) compared the frequency of CYP2A6*4 and other reduced activity variants present in ethnic groups. The results were, Whites 9.1%, Blacks 21.9%, Korean 42.9% and Japanese 50.5%. There are differences between individuals in the ethnic groups but the different metabolic pathway for nicotine in Eastern populations, particularly Japanese, is well documented.
References
1 Schroff KC et al. Toxicology 2000, 144, 99.
2 Tutka P et al. Pharmacological Reports 2005, 57, 143.
3 Derby KS et al. Cancer Epidemiol Biomarkers Prev 2008, 17, 3526.
4 Bloom J et al. Pharmacogenet Genomics 2011, 21, 403.
5 Benowitz NL et al. J Natl Cancer Inst 2002, 94, 108.
6 Vasconcelos GM et al. Pharmacogenomics J 2005, 5, 42.
7 Nakajima M et al. Clin Pharmacol Ther 2006, 80, 282.
© M Griffiths 2013
POSITION OF DIVERTICULA IN THE COLON
The longitudinal and circular muscles in the colon wall contract and relax rhythmically to move along the residues of digestion. Different movements are found in different parts of the colon to enable mixing, drying and evacuating functions. To achieve this, the longitudinal and circular muscles differ in their response to neurotransmitters. Sensitivity can also vary along the colon length. There are examples of different responses to drugs and neurotransmitters including those related to the acetylcholine and NO systems affected by nicotine. The chemicals produced by the metabolism of nicotine differ in Western and Eastern ethnic populations, cotinine is an example. A greater effect on longitudinal muscle, used for example, in mass peristalsis and evacuation of faeces, would give the typical Western pattern of colon changes in the descending and sigmoid colon on the left side of the body. The level of the enzyme CYP2A6*4 in ethnic groups appears to relate to the position of diverticula in the colon.
COMPARISON OF THE AMOUNT OF LIVER ENZYME CYP2A6*4 AND DIVERTICULAR DISEASE ONLY IN THE LEFT COLON
| % of CYP2A6*4 in ethnic group
Ref (1) |
% with DD only
in left colon |
Reference |
| JAPANESE 50.5 | 13.3 | (2) |
| KOREAN 42.9 | 15.5 | (3) |
| BLACKS 21.9 | 41.7 | (4) |
| WHITES 9.1 | 80.0 | (5) |
References
1 Nakajima M et al Clin Pharmacol Ther 2006, 80, 282.
2 Takano M et al. Dis Colon Rectum 2005, 48, 2111.
3 Lee KM et al. J Korean Med Sci 2010, 25, 1323.
4 Golder M et al. World J Gastroenterol 2011, 17, 1009.
5 Painter NS et al. BMJ 1972, 2, 137.
© M Griffiths 2013
DIVERTICULAR DISEASE AND AGE
Diverticular disease is diagnosed when diverticula are found in examinations because of symptoms or screening for bowel cancer mainly in the over 50s. It was considered an inevitable consequence of old age, but this has changed. The mean age of people admitted for hospital treatment has dropped, more are under the age of 50 and need emergency surgery (1). The lowest age is often in the 20s when surveys report the age range of people with DD. A study in California found hospital admissions increased most rapidly in patients 20 to 34 years old (2). The relatively recent DD epidemic in Japan resulted in 2.2% of patients below the age of 29 and only 14.3% over 70 years old (3). This suggests that people get DD before they grow old. Diverticulitis in teenagers has been reported without reference to the hereditary diseases which affect collagen and predispose to diverticula formation. It is accepted that passive smoking increases the risk of cardiovascular disease and lung cancer. Passive smoking by children causes changes in elasticity and collagen and gives structure and function disorder in the lungs (4). Such changes are found in the colon before the formation of diverticula, could DD start in children subjected to passive smoking?
References
1 Jeyarajah S et al. Int J Colorectal Dis 2008, 23, 619.
2 Etzioni DA et al. Am Surg 2009, 75, 981.
3 Kubo A et al. Jpn J Med 1983, 22,185.
4 Bosdure E et al. Rev Mal Respir 2006, 23, 694.
© M Griffiths 2013
DIVERTICULAR DISEASE AND GENDER
The ratio of males to females in surveys of DD varies according to countries. There are ethnic, social and cultural reasons why women may not smoke and this reduces the incidence of DD and the pattern can be retained after immigration. Women, especially the elderly, are reported to have different responses to the drug carbachol (acts like acetylcholine and nicotine) and to NO release (1) which are relevant to the effects of smoking. Passage through the colon was slower in females than males (2) and smoking slows colon transit time in males. There is evidence that females have different activity of liver enzymes including CYP2A6 which metabolises nicotine (3). This explains why females have a greater addiction to nicotine, greater difficulty in giving up smoking and are a target of tobacco companies. Are females more susceptible to DD if they smoke?
References
1 Maselli MA et al. Dig Dis Sci 2011, 56,352.
2 Sadik R et al. Scand J Gastroenterol 2003, 38, 36.
3 Anderson GD Int Rev Neurobiol 2008, 83, 1.
© M Griffiths 2013
DISCUSSION
In the past there have been pointers to a relationship between cigarette smoking and DD. It has been estimated that over 90% of lung cancer was caused by cigarette smoking. During the 20th century there was significant correlation between deaths from DD and deaths from lung cancer for both men ( r =0.68 ) and women ( r =0.92 ). Women’s deaths from DD rose steeply with their cigarette consumption ( r =0.87 ). This relationship for men was distorted by the supply of cigarettes to the armed forces during the two world wars and the death toll in the conflicts resulting in two waves of low male population through the rest of the century. In the approach to the 21st century, increasing smuggling and counterfeiting of cigarettes made such studies irrelevant.
Nicotine from cigarettes has considerable effects on colon function of otherwise healthy people but most research on DD ignored the smoking habits of patients. Parameters such as transit time are not only affected by the level of fibre in the diet. Diet has never explained different levels of DD in males and females, or the differences in DD characteristics in different countries. Cigarette smoking, nicotine and its metabolism does offer an explanation. Comparisons between countries should take into consideration changes in the ethnic composition of its residents.
Effects on neurotransmitters and hormones other than acetylcholine have been produced by smoking and changes in these in people with DD are unfolding. Nitric oxide has been implicated as a key molecule in the control of colon movement and pain perception. More research is needed on the effect of nitric oxide supplied externally from smoke on that produced by the body to effect normal colon function.
The epidemiology of DD is dynamic, as is the smoking epidemic and probably the contents of cigarettes. Information is now available on the physiological effects of smoking, neurotransmission and nicotine metabolism which was not available to pioneers of research into DD and other diseases have had much more attention. There are many unanswered questions but this jigsaw of evidence suggests a picture of the cause of DD which merits consideration.
Some researchers did not find that smoking cigarettes had a significant effect on DD but trial design could affect conclusions. Recent research has shown that cigarette smoking increases the risk of complications in patients with DD (1), and Turunen et al. (2) found that the development of complicated disease proceeded more rapidly in smokers. Usai et al. concluded that smoking was a predictive factor for diverticulitis (3). Women who smoked had increased risk of symptoms and perforation/abscess complications than non-smokers (4). Crowe et al (5) found greater risk of admission to hospital or death with heavy smokers compared with light smokers. Cigarette smoking is implicated in many ‘Western’ and ‘affluence’ diseases. There is now evidence that DD should be added to that list
References
1 Papagrigoriadis S et al. Br J Surg 1999, 86, 923.
2 Turunen P et al. Scandinavian Journal of Surgery 2010, 99, 14.
3 Usai P et al. Dig Liver Dis 2011,43, 98.
4 Hjern F et al Br J Surg 2011, 98, 997.
5 Crowe FL et al. BMJ 2011, 343, d4131.
© Mary Griffiths 2013
Tags: ageing, Cause, Cigarettes, Complications, epidemiology, Gender, Metabolism, Nicotine, Smoking