My Diverticulitis

Colon diverticular disease (DD), previously a curiosity, increased in significance in Western countries in the 20^th century. The earliest indications of colon abnormality were changes in the sigmoid colon which was shortened, thickened and corrugated. The longitudinal muscles appeared in a contracted  form like after defaecation, unable to relax.

Internal pressure increased, eventually producing blow-out hernia through hardened circular muscle giving grape-like appendages on the outside of the colon – the diverticula. At this stage a diagnosis of diverticulosis could be made when the diverticula were seen by scans, colonoscopy or during surgery. A clinical appraisal alone would not separate easily any symptoms from those of any other bowel disease. An attack of diverticulitis or severe pain however, often lead to diverticula recognition in the hospital setting and it is here where statistics on DD and its ramifications are generated, more often on elderly patients.

Early researchers recognized that the affected colon muscles responded differently to drugs such as acetylcholine, morphine, carbachol and neostigmine, also to physiological stimulation. Parks (1) considered a pharmacological stimulus that would cause such a change, would be uncommon in real life. The ‘nicotinic’ receptors in the autonomic nervous system were a missed clue. Birkitt (2) also recognized an environmental factor was responsible for the diseases in affluent countries compared with Africa. Unfortunately, he attributed non-infective disease of the bowel to diet. DD was supposedly caused by low levels of fibre. Also in the 1970s Painter (3) professed “The factors which cause this acquired disease (DD) are operating more and more effectively and that diverticulitis in young patients will become a greater problem in the future.” In 2023 this has happened (4,5). Hospital admissions continued to endemic proportions and diagnosis in younger people is rising. Diet has never explained the neuromuscular changes in the colon at the beginning of DD which has now been accepted (6,7).

Birkitt’s “geographic medicine” data was in fact the epidemiology in the 1970s which pointed to DD as one of the 20^th century ‘Western’ diseases, in time and place these correspond to the use of ‘Western’ cigarettes. Mortality statistics (8) show DD goes hand in hand through the 20^th century with lung and other cancers, cardiovascular disease and appendicitis for example. Does Crohn’s disease follow the same pattern? In cigarettes there are the carcinogens and nicotine. Nicotine is the pharmacological stimulus. Globally, DD appearance correlates with the marketing of ‘Western’ cigarettes from the beginning of the 20^th century. Firstly, in the USA, UK and Australia, in Europe after WW11 and in eastern countries after the US 1974 Trade Act with a rapid rise of DD in Japan. There is very little in African countries so far. The Japanese smokers merely changed their brands, not diet, as did Japanese immigrants in Hawaii. 

Nicotine is a drug and banned toxic pesticide. Addictive property means nicotine and active metabolites are in the body continuously, often for many years. Chronic effects are predictable. The action of nicotine on post-synaptic neurons is classic pharmacology. It stimulates then blocks normal acetylcholine transmission, leaving muscles contracted for longer. Its effects on the nitric oxide relaxation system may be complicated by nitrate levels in ‘Western’ cigarettes. Nicotine promotes fibrosis and changes to a firmer structure of collagen and elastin in the colon walls, like in the skin with smoker’s wrinkles and rigidity of walls in cardiovascular disease. In the colon walls, these are the neuromuscular precursors of diverticula and DD progression.

Nicotine is metabolized in the liver by enzyme CYP2A6 and its many variants which have ethnic differences in smoking diseases. Faster nicotine metabolism in females increases addiction and smoking habits and gender differences in smoking related diseases. Clinical results suggest that with DD, females have earlier and more extensive colon neuromuscular damage than males. Compared with males, females have more affected colon segments which increase with age (9). They are more at risk of persistent symptoms after sigmoidectomy (10) and diverticula are more scattered along the colon (11). More diverticula results in females having more episodes of diverticulitis and chronic complications and at a younger age (12). They had more chronic diverticulitis and strictures but less bleeding than men (13). Chronic complications such as sepsis, obstruction or pelvic fistula were more likely causes of death in women whose DD mortality rates have exceed men in the UK since WW11 (14,15). Gender differences must question the use and value of male only research cohorts. For example, male health professionals with only 10% smokers have been studied extensively since 1986 and resulted in a significant dietary treatment advice for all with DD irrespective of different disease progression and the basis of no gender differences in DD and diverticulosis rare before the age of 40 (16).

Research data from western countries shows DD usually in the sigmoid area of the colon. Muscles affected by nicotine in colon parts with mixing (ascending) or drying (transverse) movements would have different appearance and symptoms. Right sided disease is found in Eastern countries such as Japan. CYP2A6 polymorphism may be responsible for this difference. CYP2A6*4 variant produces different nicotine metabolic products, far less cotinine and less lung cancer. NakaJima (17) compared the frequency of CYP2A6*4 and other variants with reduced activity, with ethnicity. The table shows some possible association of CYP2A6*4 with the frequency of right-sided DD.

CYP2A6*4 and other liver enzymes have been demonstrated to affect the metabolism of nicotine with ethnic variations in smoking, also in drug and disease research. The long-term damage by nicotine in the autonomic nervous system has had less attention than cancer. How many smokers and non-smokers have DD depends on symptoms bad enough to be investigated. A familial pattern has been recognized which may be genetic or passive smoking. There are many unanswered questions. Nicotine as the cause of colon neuromuscular damage of DD is suggested by epidemiology, pharmacology and the link between genetics and environment. Many research reports show there is no doubt that smoking negatively affects all clinical aspects of DD.

The neuromuscular colon damage in DD is permanent. Lifestyle changes can alleviate some symptoms but there are no drug treatments except antibiotics and surgery. Anticholinergic side effects of drug treatments for other complaints might influence symptoms. Only prevention can make an impact on DD. The current situation with cheap, available, promoted nicotine products to reduce cigarette smoking seems to be producing a new generation of nicotine addicts without knowing long term effects. This is very reminiscent of 70 years ago with cigarettes and a frightening outlook for DD.

COMPARISON OF THE AMOUNT OF LIVER ENZYME CYP2A6*4 AND DIVERTICULAR DISEASE IN THE RIGHT COLON

© Mary Griffiths 2023

References

1. Parks T G. The pathogenesis of large bowel diverticula. Ulster Med J. 1971, 41, 45. PMID 5150065.
2. Birkitt D P. Epidemiology of large bowel diseases: the role of fibre. Proc. Nutr. Soc. 1973, 32, 145.  DOI:  10.1079/pns19730032
3. Painter N.S. Diverticular disease of the colon- a deficiency disease of Western civilisation. 1975. William Heinemann Medical Books Ltd. London. ISBN 0 433 24660x
4.  Fialo A. et al. Analysis of the epidemiological trends on inpatient diverticulosis admissions in the USA: a longitudinal analysis from 1997-2018. Cureus. 2023, 15, e34493. DOI:10.7759/cureus.34493
5. Broad J B. et al. Diverticular disease epidemiology: acute hospitalisations are growing fastest in young men.  Tech Coloproctol. 2019, 23, 713. DOI:10.1007/s10151-019-02040-8
6. Kupcinskas J. et al. Pathogenesis of diverticulosis and diverticular disease. J Gastrointestin Liver Dis. 2019, 28, suppl.4. DOI:10.15403/jgld-551
7. Schafmayer C. et al. Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms. Gut. 2019, 68 854. DOI:10.1136/gutjnl-2018-317619
8. National Statistics. Twentieth century mortality. 100 years of mortality data in England and Wales by age, sex, year and underlying cause. Crown Copyright 2003. CD ROM ISBN 0 11 621665 4.
9. Eide T J. et al. Diverticular disease of the large intestine in Northern Norway. Gut. 1979,20, 609. DOI:10.1136/gut.20.7.609
10. Choi K K. et al. After elective sigmoid colectomy for divertiulitis, does recurrence-free mean symptom-free? Am Surg. 2020, 86, 49. PMID 32077416
11. Parks T J. Post mortem studies on the colon with special reference to diverticular disease. Proc R Soc Med. 1968, 61, 932. PMID 5679019
12. Lightner A L. et al. Use of the Rochester epidemiology project for clinical research in colon and rectal surgery. Clin Colon Rectal Surg. 2019, 32, 8. DOI:1055/s-0038-1673349
13. McConell EJ et al. Population-based incidence of complicated diverticular disease of the sigmoid colon based on gender and age. Dis Colon Rectum. 2003, 46, 1110. DOI:10.1007/s10350-004-7288-4
14. Sell N M. et al. Are there variations in mortality from diverticular disease by sex. Dis Colon Rectum. 2020, 63, 1285. DOI:10.1097/DCR0000000000001711
15. Kang J Y. et al. Diverticular disease of the colon – on the rise: a study of hospital admissions in England between 1989/1990 and 1999/2000. Aliment Pharmacol Ther. 2003, 17, 1189. DOI:10.1046/j.1365-2036.2003.01551.x
16. Strate L L. et al. Nut, corn and popcorn consumption and the incidence of diverticular disease. JAMA 2008, 300, 907. DOI:10.1001/jama.300.8.907
17. Nakajima N. et al. Comprehensive evaluation of variability in nicotine metabolism and CYP2A6 polymorphic alleles in four ethnic populations. Clin Pharmacol Ther. 2006, 80, 282. DOI:10.1016/j.clpt.2006.05.012
18. Takano M. et al. An analysis of the development of colonic diverticulosis in the Japanese. Dis Colon Rectum. 2005, 48, 2111. DOI:10.1007/s10350-005-0111-z
19. Lee K M. et al. Clinical significance of colonic diverticulosis associated with bowel symptoms and colon polyps. J Korean Med Sci. 2010, 25,1323. DOI:10.3346/jkms.2010.25.9.1323
20. Golder M. et al. Demographic determinants of risk, colon distribution and density scores of diverticular disease. World J Gastroenterol. 2011, 17 1009. DOI:10.3748/wjg.v17.i8.1009