Posts Tagged ‘Gender’

Diverticular Disease and Nicotine Metabolism

Tuesday, June 13th, 2023

Colon diverticular disease (DD), previously a curiosity, increased in significance in Western countries in the 20th 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 20th 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 20th 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 20th 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.

% of CYP2A6*4 in ethnic group Ref (17) % with DD in right colon   Reference
JAPANESE   50.5 67 (18)
KOREAN     42.9 85.2 (19)
BLACKS      21.9 18.3 (20)
WHITES        9.1 2.7 (20)

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

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Diverticular Disease: Men and Women

Wednesday, February 9th, 2022

 

Diverticular disease (DD) is an acquired disease that was first demonstrated early in the 20th century. Its appearance and increasing importance occurred in cigarette-smoking western countries, particularly the USA and UK, where the habit and nicotine addiction was widespread in the population. These countries are the main source of reports and statistics. DD can no longer be considered the inevitable diet related disease of the elderly. DD can be a long term (26872402), progressive (13444546) and chronic disorder (22777341) as well as the acute infection of diverticulitis and its complications. Differences between males and females have always been apparent in hospital and mortality statistics where females predominate.

Diverticula – the small grape-like hernia – need to be seen on the colon before the disease can be diagnosed. Once they are present they are there for life. The data used to describe DD is in effect a measure of investigations, where and when they took place in the disease progression. For example, the same person could figure in post-mortem, mortality and hospital admission data but the diverticula could have been there for 40 -50 years. Similarly, ‘risk factors’ are for symptoms resulting in investigations revealing DD but are not the cause of DD. The current interpretation of data show DD in more men than women up to the age of 50 – 60 years, then proportions are reversed with more women in surveys measuring investigation of DD. No explanation has been offered for this effect (33727769) except hormone differences which of course cannot be disputed.

Eastwood (873339) considered factors which might influence a decision to investigate symptoms for a diagnosis of DD. Does a complicated selection process operate for a family doctor’s referral to a hospital consultant for an investigation? The presentation of symptoms or the seeking of medical advice, or social or geographical factors may affect data. Other influences mentioned in reports are costs and hospital capacity.

Because of low risk of colon cancer, internal examination, now usually by colonoscopy, are not considered necessary below the age of 50 years unless there are potentially dangerous symptoms. However, both diverticulosis, where diverticula are found without symptoms, and their infection ie diverticulitis, are found before the age of 50 years (15882243, 20604970). CT scanning for suspected appendicitis revealed 14% of the under 20 yrs. And 40% of those between 20 and 39 yrs. had evidence of diverticulosis. (33727769). Anybody with diverticulosis could get diverticulitis infection and nobody knows why. Symptoms of pain and dysfunction in males is more conspicuous than in females where it is part of their biology Males get investigation and diagnosis and earlier surgical treatment for DD than females (9860333).

Women with abdominal pain and bowel dysfunction are diagnosed quickly with Irritable Bowel Syndrome (IBS) (9262978). IBS is based on symptoms, but women have many symptoms peculiar to them that are not included in the research criteria for IBS (9096434). There are many potential causes of abdominal pain unique to females (31943595) that without relief can prompt repeated consultations more than males – a characteristic of IBS. Females can be told they have IBS as young adults, until after the menopause and even in old age. IBS will include people with diverticulosis and diverticulitis (19861955) but if found this does not change the diagnosis of IBS, some researchers think that only infected diverticula can cause pain (16678561). Data on the number of people with DD up to the age of 50 to 60 yrs. will show more males than females because more males are investigated and diagnosed.

Around the age of 50 yrs. screening for colon cancer by colonoscopy occurs. Finding diverticulosis is common and does not show different rates for males and females although females are slightly older. In older patient groups without significant symptoms, there is again no difference between the sexes (22573184). Symptoms such as constipation related to colon ageing at 60 to 70 yrs. old also appear to be the same. Differences between males and females appear if and when symptoms of DD become problematic and potentially serious. Females outnumber males when investigations are needed for episodes of diverticulitis or chronic complications of DD. This can be the first diagnosis of DD and younger age and female gender are independent risk factors (30647541). Frequently the female patients were found to have previously been diagnosed with IBS. Females and a preoperative diagnosis of IBS were also independent risk factors for persistent symptoms after sigmoidectomy (32077416).

For decades since the 1960s DD was considered a diet related disease of the elderly. Eating a low level of dietary fibre for at least 40 years produced diverticula. Adding wheat bran to meals was recommended to prevent the constipation then later any type of dietary fibre. This was supposed to prevent diverticula and diverticulitis development – now disproved. DD research concentrated in detail on diet and on hospital treatment for severe diverticulitis and life – threatening complications needing surgery. If and when dietary fibre was not helpful there were no other effective treatments for persistent, recurring or non-relenting, low grade inflammation symptoms that are now recognized (33727769, 22777341). Such symptoms have been described as ‘smoldering DD’ or ‘SUDD – symptomatic uncomplicated DD’ or the misnomer ‘post-diverticulitis IBS’ More females than males were diagnosed with SUDD in a survey (30023071) and this was a long-term condition (17431721). This is a painful part of some unfortunate patients’ experience of DD affecting quality of life and which does not reach the level of hospital treatment.

There is little information about DD in primary care (22572678). Extensive research at hospital level does not address the problems before patients see the specialists (17681003, 10601059). The number of diverticula can increase with age as can the extent if colon affected. There is no data on this aspect of DD to see if there is a difference between males and females. There are suggestions that more women than men are troubled by long term symptoms. In New Zealand NHS primary care, women had notably more antibiotics prescribed for them than men, particularly those under the age of 60 years, for 5 yrs. before they needed hospital attention for acute or non-acute problems. More antibiotic prescribing for women also continued for the next 5 yrs. of the survey (31314796). Chronic aspects of DD in women also appear in data from hospitals. Females were on average 5 years older than males when seen and had more chronic diverticulitis and strictures, but less bleeding than males (12907908).

This pattern continues in mortality studies. 300 unselected pathology colons found a higher incidence of DD in women and also the onset occurred at an earlier age. Before the age of 50, 21.7% of women and 4.2% of men had DD and diverticula were scattered along the colon in women (5679019). Men were more likely than women to have had surgery and have a surgical complication of diverticulitis as a secondary cause of death and are more likely to die in hospital. Women are more likely than men to die from chronic complications such as sepsis, obstruction or pelvic fistula and are more likely to die at home, in care or in a hospice (33216498, 33216487). Research is not providing reasons for these differences (30046356).

The situation with DD may be like emergency presentation at hospital for colon cancer (30734381). In 2 to 12 months before emergency, twice as many women than men had received a diagnosis of IBS or DD. This increased the risk for women aged 40 – 59 yrs. 20% of women had alarm symptoms before the emergency. These authors cite reports of longer diagnosis intervals, a higher risk of 3 or more consultations before specialist referral of women, different interpretation of symptoms in women compared with men and possible misattribution of symptoms in women to benign causes. New onset of ‘IBS’ in middle aged women was also of concern. Sex differences in health and medicine are increasingly recognized and women are disadvantaged (22699937). This includes DD were women appear to suffer a longer and chronic symptomatic disease which is less acknowledged or treated if and unless it becomes serious.

© Mary Griffiths 2022

REFERENCES

The numbers in the text are PMID references. PubMed is a free resource supporting search and retrieval of biomedical and life science literature with aim of improving health – both globally and personally. It is available at     https://www.pubmed.ncbi.nlm.nih.gov

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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.

(more…)

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