Posts Tagged ‘Cigarettes’

Diverticular Disease: Progression, Smoking and Nicotine

Sunday, April 14th, 2019

 

Diverticular disease (DD) can progress from changes in the gut nerves and muscles to formation of diverticula (diverticulosis), to symptoms of colon dysfunction, to infections and inflammation (diverticulitis), to chronic symptoms, and to serious abdominal complications. The number of sufferers along this pathway diminishes greatly at every stage, only a minority ever need surgical treatment. On the other hand, progression and ageing go hand in hand.

The causes and risk factors of progression after diverticulosis are as varied as the people with DD.  Nobody knows what brings on diverticulitis which can be a gateway to problems. Historically, a diet low in fibre was thought to be responsible for all of the disease spectrum and could be easily remedied. This is no longer accepted. In the second half of the 20th century nobody considered an effect of smoking on the gut. Most Western adults smoked despite the risks of lung cancer and heart disease. Cigarettes had calmed the soldiers of the war, they were glamorous and macho, and nicotine was strongly addictive.

Cigarette use was aligned much closer to the appearance of DD in the world than diets which were variable and often assumed. Articles on this website in 2012 and 2013 have details of this epidemiology and also explain the pharmacology of nicotine where chronic use can cause the damage to the colon characteristic of DD.

Diverticula on the colon have to be identified before a diagnosis of the disease can be made. This happens in a hospital setting when symptoms or severe illness leads to investigative scans, x-rays or colonoscopies. Diverticula have already been formed then. The development of diverticula was described by interested pathologists early in the 20th century. Recent genetic and epidemiology research confirms that nerve and collagen changes are involved (1,2). These are the chronic effects of nicotine.

Hospital researchers have used diagnosed patients and their memories to produce “risk factors” and “associations” for DD based mainly on diets. Now, screening for colon cancer by colonoscopy around 50 years of age uncovers symptom-free diverticula. Participants can provide data on their lifestyles. Including smoking is a new opportunity to see if this was relevant to the presence or absence of diverticula. Also, increasing numbers of surveys are providing clinical evidence that cigarette smoking has a major effect on DD and its potential progression.

DIVERTICULA FORMATION

Data about smoking in 18-20 year old military conscripts in 1969-1970 was compared with Swedish national registers in 2009. Smoking increased the diagnosis of DD (3). The use of tobacco was greater in the 41.7% of colonoscopy outpatients found to have diverticula. The traditional risk factors for the presence of diverticula (low dietary fibre, constipation, red meat intake, low physical activity) were not confirmed (4).These authors thought that diverticula were most certainly present for many years before they were observed. Other American researchers (5) also considered that diverticulosis was longstanding before it was revealed. Two Japanese studies (6,7) related smoking to finding diverticula in outpatients. A history of smoking was revealed in Ulcerative Colitis patients who had diverticulosis (8). Recently in China (9) smoking was associated with diverticula in men (odds ratio = 2.14) and even more so in women (odds ratio = 10.2). Pooling together the data from several surveys (meta-analysis)  increases the validity of results. Two such studies (10,11) implicated smoking with diverticulosis and also increased risk of complications of the disease.

SYMPTOMS

Past and current smokers had increased risk of symptomatic disease in Swedish women (12). In Swedish men, heavy smokers had increased risk of developing symptoms and there was some evidence of a dose/response relationship compared with non-smokers (13). The risk of changing from diverticulosis to diverticulitis was significantly higher in cigarette smokers in a report from Italy (14). Red meat was associated with increased risk of diverticulitis (15) but red meat eaters smoked more, used NSAID drugs and paracetamol, and had less vigorous exercise.

HOSPITAL ADMISSION

Present and previous smoking increased the risk for women of hospital admission for acute diverticulitis (16) and recurrent episodes (17). Compared with patients with no or minor symptoms, smoking was associated with hospital admissions because of complicated diverticulitis and severe infections (18,19).  Health conscious participants were used in a study by Crowe et al (20) to compare hospital and death records of DD between vegetarians and non-vegetarians. Smoking levels were only between 10% and 15%. Vegetarians and high dietary fibre intake gave a lower risk of hospital admission than meat eaters, but the vegetarians were younger. Compared with non-smokers, the increased risks for former smokers, light and heavy smokers were 31%, 34% and 86% respectively.

SURGERY

A Canadian survey of patients who underwent a partial colectomy found that current and former smokers had increased risk of surgery compared with non-smokers (21). Smoking was a risk factor for leakage of the join in the colon after part of it had been removed (22).

Removal of the sigmoid colon affected by DD was needed at a younger age in smokers compared with non-smokers, and the complications had developed more rapidly in smokers (23).

STUDIES SHOWING NO EFFECTS OF SMOKING

Some studies have not found any link between smoking and DD (24,25,26,27). These can be difficult to assess with gaps in details such as patient selection and their particulars, and ages. End points can be right sided disease or bleeding. Bleeding has so far not been related to smoking, but age, condition of blood vessels and drug side effects are relevant (28). The most quoted study is that of Aldoori et al (29) and their analysis of US male health professionals followed since 1986. In the 4 years between 1988 and 1992 there were 500 new cases of DD, 382 with symptoms and 118 without. Smoking was positively associated with the risk of symptoms, increasing with the number of cigarettes smoked per day and decreasing with the time since stopping smoking. These results were attenuated when dietary data was included in the analysis. The authors concluded that smoking was not associated with any substantial increased risk of symptomatic DD.  Another recent statistical assessment of the same group of health professionals found that smoking was independently associated with increased risk of diverticulitis (30).

DISCUSSION

This collection of reports is not exhaustive and more studies are likely. Some reviewers do not include data but an author’s opinion is cited. A mixture of positive and negative results is also found for other risk factors for DD. Bohm (31) emphasises the importance of differentiating risk factors between those for diverticulosis and for the other effects of the disease. This separation has been attempted here. The end point of a study is also relevant. For example, eating nuts, grains, corn and popcorn had no effect on hospital admissions for complications. Dietary avoidance of these foods was dismissed as irrelevant (32), but the long-standing avoidance of these foods for DD was based on pain. Many patients suffer from chronic and severe pain outside the hospital setting which is rarely researched. In fact, information about less serious symptoms and their treatment dealt with at primary care level is largely absent (33).

Age, sex and genetics are risk factors which cannot be changed, but many lifestyle choices, co-existing diseases and drug treatments also affect DD. Increasing opinion is that diverticula take years to form and are evident through symptoms a long time, even decades, after their cause by smoking. The cause of DD is distinct from many other factors which cause symptoms and complications. However, smoking is detrimental to all aspects of the disease and this should be reflected strongly in patient information.

Computer statistical assessments are used to uncover factors relevant to diseases, symptoms and progression, but the data used is subject to human choices and interpretation of results. The effect of smoking on DD was only included as a confounding factoring in studies relatively recently. Are older dietary studies still relevant if this was not included? The article by Labos (34) and its on-line comments are recommended reading on the subject. He considers a result found in several patient populations carries weight when the trials cannot be accurately replicated. In the case of smoking and DD, there is world-wide epidemiology, the pharmacology of chronic nicotine use and now, increasing clinical evidence of its profound effects.

The effect of smoking on DD and other diseases will be more difficult to asses in the future when people replace tobacco cigarettes (smoking) with e-cigarettes (vaping) for their nicotine fix. Many countries have banned e-cigarettes but some official organisations and powerful charities seem to be advising their use. Avoiding the carcinogenic chemicals from tobacco smoke is welcomed to reduce the risks of cancer, but people are then classed as ‘non smokers’ in surveys. The number of smokers will reduce, but the effects of continued use of nicotine should not be dismissed lightly. E-cigarettes are not regulated and long-term effects have still to be revealed. E-cigarettes are not medical devices, they will not overcome addiction to nicotine without commitment, determination and any help available. Retail outlets are increasing to make vaping commonplace and accessible. Its use by under 18s is increasing. Tobacco companies view e-cigarettes as their next generation products and aim to increase promotion and sales, just like they did in the mid 20th century for cigarette smoking.

Déjà vu.

© Mary Griffiths 2019

REFERENCES

1.      Schafmayer C. et al. Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms. Gut, 2019, Jan, 19th Epub.

2.      Broad JB et al. Diverticulosis and nine connective tissue disorders: epidemiological support for an association. Connect Tissue Res. 2019, Feb 5th. Epub.

3.      Jarbrink-Sehgal ME et al. Lifestyle factors in late adolescence associated with later development of diverticular disease requiring hospitalization. Clin Gastroenterol Hepatol. 2018, 16, 1474.

4.      Peery AF. et al. A high-fiber diet does not protect against asymptomatic diverticulosis. Gastroenterology, 2012, 142, 266.

5.      Strate LL. Diverticulosis and dietary fiber: rethinking the relationship. Gastroenterology, 2012, 142,205.

6.      Tarao K. et al. Recent trends in colonic diverticulosis in Yokohama City: a possibility of changing to a more western profile. Intern med, 2015, 54, 2545.

7.      Nagata N. et al. Alcohol and smoking affect risk of uncomplicated colonic diverticulosis in Japan. PloS One, 2013, 8, e81137.

8.      Kinnucan J. et al. U.S. patients with ulcerative colitis do not have a decreased risk of diverticulosis. Inflamm Bowel Dis. 2015, 21, 2154.

9.      Yang F. et al. Sex differences in risk factors of uncomplicated colonic diverticulosis in a metropolitan area from Northern China. Sci Rep. 2018, 8, 138.

10.  Wijarnpreecha K. et al. Smoking and risk of colonic diverticulosis: a meta-analysis. J Postgrad Med. 2018, 64, 35.

11.  Aune D. et al. Tobacco smoking and the risk of diverticular disease – a systematic review and meta-analysis of prospective studies. Colorectal Dis. 2017, 19, 621.

12.  Hjern F. et al. Smoking and the risk of diverticular disease in women. Br J Surg. 2011, 98, 997.

13.  Humes DJ. et al. PTU-230 Smoking and the risk of symptomatic diverticular disease: a Swedish population based cohort study. Dis Colon Rectum. 2016, 59, 110.

14.  Usai P. et al. cigarette smoking and appendectomy: effect on clinical course of diverticulosis. Dig Liver Dis. 2011, 43, 98.

15.  Cao Y. et al. Meat intake and risk of diverticulitis among men. Gut, 2018, 67, 466.

16.  Jamal Talabani A. et al. Risk factors of admission for acute colonic diverticulitis in a population-based cohort study: The North Trondelag Health Study, Norway. World J Gastroenterol. 2016, 22, 10663.

17.  El-Sayed C. et al. Risk of recurrent disease and surgery following an admission for acute diverticulitis. Dis Colon Rectum. 2018, 61, 382.

18.  Papagrigoriadis S. et al. Smoking may be associated with complications in diverticular disease, Br J Surg. 1999, 86, 923.

19.  McGarr S. et al. Cigarette smoking increases the risk of infectious complications associated with diverticular disease of the colon. Am J Gastroenterol, 2000, 95, 2543.

20.  Crowe FL. et al. Diet and risk of diverticular disease in Oxford cohort of European prospective investigation into cancer and nutrition (EPIC): prospective study of British vegetarians and non-vegetarians. BMJ, 2011, 343, d4131.

21.  Diamant MJ. et al. Smoking is associated with an increased risk for surgery in diverticulitis: a case control study. PLoSOne 2016, 11, e0153871.

22.  Baucom RB. et al. Smoking as dominant risk factor for anastomotic leak after left colon resection. Am J Surg. 2015, 210, 1.

23.  Turunen P. et al. Smoking increases the incidence of complicated diverticular disease of the sigmoid colon. Scandinavian Journal of Surgery. 2010, 99, 14.

24.  Storz C. et al. Characteristics and associated risk factors of diverticular disease assessed by magnetic resonance imaging in subjects from a Western general population. Eur Radiol. 2018, 29, 1094.

25.  Adamova Z. et al. Recurrent diverticulitis – risk factors. Rozhi Chir, 2013, 92, 563.

26.  Jamieson CG. et al. An investigation into the relationship between cigarette smoking and diverticular disease of the colon.  Can J Gastroenterol. 1990, 4, 193.

27.  Lin OS. et al. Dietary habits and right sided colonic diverticulosis. Dis colon Rectum. 2000, 43, 1412.

28.  Jansen A. et al. Risk factors for colonic diverticular bleeding: a Westernised community based hospital study. World J Gastroenterol. 2009, 15, 457.

29.  Aldoori WH. et al. A prospective study of alcohol, smoking, caffeine, and the risk of symptomatic diverticular disease in men. Ann Epidemiol 1995, 5, 221.

30.  Liu PH. et al. Adherence to a healthy lifestyle is associated with a lower risk of diverticulitis among men. Am J Gastroenterol. 2017, 112, 1868.

31.  Bohm SK. Risk factors for diverticulosis, diverticulitis, diverticular perforation and bleeding: a plea for more subtle history taking. Viszeralmedizin, 2015, 31, 84.

32.  Strate LL. et al. Nut, corn and popcorn consumption and the incidence of diverticular disease. JAMA , 2008, 300, 907.

33.  Humes DJ. Changing epidemiology: does it increase our understanding? Dig Dis. 2012, 30, 6.

34.  Labos C. Epidemiology: separating the wheat from the chaff. Aug 14th 2018. https://www.medscape.com/viewarticle/900381

IBS, Smoking, E-cigarettes and Nicotine

Thursday, November 13th, 2014

IBS and other diseases of the digestive system, including diverticular disease, are affected by cigarette smoking. Tobacco smoking is rapidly being replaced by the use of e-cigarettes known as ‘vaping’. This system is clamed to be safer than tobacco cigarettes, giving the pleasurable effects of nicotine with only trivial side effects. However, the pharmacological effects of nicotine are still relevant to all nicotine delivery systems.

This article appeared in Gut Reaction, the magazine of the IBS Network, Issue 93, Oct 2014


IBS sufferers are well aware that diet and the passage of food residues through the gut can influence their problems. Similarly, worry and stress affect the digestive system through nerve connections between the head brain and gut brain. Less attention is paid to substances which reach the bowel through it’s blood supply to modify nerve and muscle behaviour. Drugs and their side-effects are an example.

Cigarette smoking delivers many chemicals into the blood stream (more…)

Diverticular Disease And Colon Cancer

Thursday, April 3rd, 2014

Does having diverticular disease (DD) increase the risk of colon cancer (CC)?  One expert would say “yes” and another would answer “no”. Much depends on the design of studies, choice of patients, what data is fed into the computer for statistical analysis, interpretation of the results and what opinions and conclusions are made.

Research can be based on the occurrence of the two separate diseases, how many people with DD have CC and how many people with CC have DD (1). Comparison can be made with the levels of CC and DD which would be expected in the general population. Information can be expanded by including different types of cancerous lesions and their position in the colon. The diagnosis of DD is not so stable. Diverticulitis but not diverticulosis was indicated to be in a long-term causal relationship with increased risk of left-sided CC (2). However, these conditions at diagnosis can change. Diverticulitis can revert to diverticulosis with few further problems, or, diverticulosis can later progress to diverticulitis or even further to serious complications. This is a basic problem in DD research. (more…)

Cigarette Smoking: The Cause Of Diverticular Disease?

Wednesday, June 19th, 2013

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