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Pathophysiology of diverticular disease
Best Practice & Research Clinical Gastroenterology Vol. 16, No. 4, pp. 563±576, 2002
doi:10.1053/bega.2002.0298, available online at http://www.idealibrary.com on
3 Pathophysiology of diverticular disease Toshiki Mimura
MD
Consultant Surgeon Department of Gastrointestinal Surgery, University of Tokyo, 7±3±1 Hongo, Bunkyo-ku, Tokyo, 113±8655 Japan
Anton Emanuel
MD, MRCP
Senior Lecturer, Consultant Gastroenterologist
Michael A. Kamm
MD, FRCP, FRACP
Professor of Gastroenterology St Mark's Hospital, London, UK
There is substantial evidence that colonic diverticulosis is related to civilization, industrialization and a `Western' lifestyle and diet, being described as `a disease of Western civilization'. Its increased incidence during the 20th century and the morbidity and mortality associated with complications, demand that this condition should receive greater attention in terms of aetiology, prevention and management. It is generally believed that low dietary ®bre and ageing are the two main pathogenic factors involved in this disease. Physiological studies have also demonstrated that there is a higher intraluminal pressure in the large bowel with diverticula. This chapter provides the evidence currently available for the pathophysiology of colonic diverticulosis and discusses its aetiological factors, including low dietary ®bre, ageing and intraluminal pressure as well as extracelluar matrix such as collagen and elastin. The dierence between the left-sided diverticulosis commonly seen in Caucasians and the right-sided predominantly observed in Asians is also presented. Key words: colonic diverticulosis; civilization; dietary ®bre; ageing; intraluminal pressure; collagen; elastin.
COLONIC DIVERTICULOSIS: A 20TH CENTURY AND A CENTURYOLD PROBLEM Colonic diverticulosis is, in general, most commonly an acquired disease, developing as mucosal and submucosal herniations through the circular muscle layer at vulnerable All correspondence to: Dr Toshiki Mimura. Tel: 81 (0)3 3815 5411 ext 35144; Fax: 81 (0)3 5800 9734; E-mail: [email protected] c 2002 Published by Elsevier Science Ltd. 1521±6918/02/$ - see front matter *
564 T. Mimura et al
points where it is penetrated by blood vessels (false- or pseudo-diverticulosis).1 Whilst there are a small number of apparently congenital cases, in which the diverticulum is covered with the muscle layer (true diverticulum), this chapter will concentrate on the pathophysiology of the pseudo-colonic diverticulosis that is most commonly encountered in our clinical practice. In 1975, Painter & Burkitt2 described diverticular disease as `a 20th century problem'. In 1999, the American Society of Colon and Rectal Surgeons celebrated its 100th anniversary. Schoetz3 reviewed this disease in one of the society's `Centennial articles' entitled `Diverticular disease of the colon. A century-old problem', published in Diseases of the Colon and Rectum. Since we have just welcomed the 21st century it might be prudent to recognize that we still have an incomplete understanding of the aetiology and pathophysiology of this common and clinically important condition.
EPIDEMIOLOGY: A DISEASE OF WESTERN CIVILIZATION Although the epidemiology of colonic diverticulosis has been reviewed in detail in Chapter 1 of this volume, some of the historical and geographical aspects of its epidemiology will also be addressed in this chapter, because the clinical evidence for the role of low dietary ®bre as its pathogenesis is largely derived from them. Historical review As is shown in Table 1, this condition was ®rst described as `saccular outpouchings of the colon' by Littre in 1700 (cited in Finney)4, and the risk of infective sequelae of this disease was subsequently appreciated by Cruveilhier in 1849 (see p 593).5 In 1899, 50 years later, Graser6 introduced the term `peridiverticulitis' and suggested that mucosal herniation through areas of penetration of the vasa recta was the probable pathogenesis of this disease (Figure 1). In 1904, Beer7 proposed that diverticulitis was due to the impaction of faeces in the neck of the diverticulum.
Table 1. Historical review and the increased prevalence with time of colonic diverticulosis. Reported year
Author(s) {
1700 1849 1880 1899
Littre Cruveilhier5
1904
Beer7
1925 1927 1968 1972 1960±1980
Spriggs & Marxer9 Fi®eld11 Parks12 Petrie10 Painter et al8,13,14
{Cited
Graser6
in Finney, 1928.4
Reports and events First described as `saccular outpouchings of the colon' Appreciated the risk of infective sequelae Development of roller milling of ¯our Introduced the term `peridiverticulitis' and suggested the mucosal herniation through areas of penetration of the vasa recta as the pathogenesis Proposed that diverticulitis was due to impaction of faeces in the neck of the diverticulum 10% in 1000 barium enemas, UK 9% in more than 10 000 post mortem series 30% in 300 post mortems 29% in 1170 barium enemas, UK Proposed the hypothesis of ®bre de®ciency disease and elevated intraluminal pressure
Pathophysiology of diverticular disease 565
Figure 1. (A) The black arrow indicates one of the weak circular muscle points where the vessel branches pass through. This is the area where diverticulum develops (B) This diagram shows how the mucosal and submucosal layer herniates through the circular muscle layer, resulting in the formation of a diverticulum (black arrow) at its common site between the mesenteric and lateral longitudinal muscular bands. (C) A radiologically injected specimen demonstrates the circumferential vessels passing super®cially to two diverticula on the left side; small branches pass towards the lumen of the specimen in close relationship with the necks of the two diverticula (two white arrows). (D) A macroscopic picture shows mucosal and submucosal herniation through the muscle layer, resulting in diverticulosis (black arrow). (Figs 1(A) and 1(B) are reproduced from Drummond54 by kind permission. Fig. 1(C) is reproduced from Slack55 by kind permission).
The prevalence of diverticular disease appears to have increased considerably during the 20th century, as have its complications, which are associated with morbidity and mortality. There is substantial evidence that this disease is related to civilization, industrialization and Western lifestyle and diet, and it has been described as `a disease of Western civilization'.8 The incidence of this disease in barium enema series has risen from 10% in 19259 to 29% in 197010 in the UK, although the indications for radiological investigation and the nature of the cohort in each of these studies was poorly de®ned. Post mortem series are likely to be much more reliable in de®ning incidence. However, there may be an underestimate related to whether the bowel is properly examined, since small diverticula may be more likely to be detected radiologically than at post mortem. In a study published by Fi®eld in 192711 the incidence of large bowel diverticula in a consecutive series of more than 10 000 post mortems was 9% in adults over the age of 50. In a post mortem series by Parks, published in 196812, the incidence of colonic diverticula rose to approximately 30% at the age of 50 and 50% above the age of 80.
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During the 1960s and 1970s Painter and colleagues proposed that a de®ciency of dietary ®bre causes an elevation of intraluminal bowel pressure, leading to excessive segmentation of the colon.2,13,14 They speculated that the cause could be the change in diet related to the development of roller milling of ¯our in 1880. Geographical dierences Diverticular disease is common in Western countries, including Europe, North America and Australia. It is less common in Africa, the Middle East, India and the Far East including Japan. The epidemiology of this condition has been changing. There is a changing incidence within certain countries, when considering the whole population, both within distinct ethnic groups in certain populations within those countries and in dierent ethnic groups who move to new locations. Studies looking at changing migration patterns have suggested that environmental factors appear to in¯uence genetically determined patterns of expression of disease. In South Africa, where the black and white populations previously lived separately, the prevalence in the white community was 21% but was only 1% in the black community. Recently the incidence in the black population appears to be increasing.15 In Japan, the incidence in a barium enema series in 1992 was 19% in those over the age of 50.16 In contrast, the incidence of this disease amongst the Japanese community in Hawaii was 52% in 197317, which was signi®cantly greater than in Japanese mainland series. The changing pattern of diverticular disease in these Japanese populations provides important insights into the genetic and environmental mechanisms that underlie this condition. Japan has become very industrialized over the last 40 years, with the widespread adoption of a Western lifestyle and diet. This may account for the increase in incidence from 11±19% seen in the relatively short period from 1985±1992.16 The prevalence, however, is still lower than in the West, which may relate to some of the Japanese population eating a Western type diet while a part of the population maintains a traditional diet. Predominant site of the diverticulosis Japanese diverticular disease is predominantly right-sided (70%)18, while in the West it is nearly always left-sided (90%).12 Despite the high prevalence of diverticular disease in the Japanese Hawaiian community the dominant site has remained right-sided, as it has in the indigenous Japanese population.19 In 13 947 consecutive barium enemas at a regional hospital in Japan, the prevalence of right-sided and bilateral diverticulosis increased from 9.6% between 1982 and 1987 to 17.6% between 1993 and 1997, whilst that of the left-sided diverticula did not change considerably in the same periods, increasing from only 2.8% to 4.9%.20 Therefore, although environmental and dietary factors appear to be important in causation, genetic factors may also be important, at least in terms of the site of diverticula. A similar recent increase in prevalence and right-sided predominance has also been reported in Singapore and Hong Kong. In 1986, Lee21 reported that in a series of 1014 consecutive autopsies in Singapore, colonic diverticulosis was encountered in 194 patients (19%) and that the ascending colon was aected most frequently (74%), followed by the caecum (45%) and the sigmoid colon (23%). In a Hong Kong barium enema series of 858 consecutive examinations between 1995 and 1996, 215 patients (25.1%) were
Pathophysiology of diverticular disease 567
found to have colonic diverticulosis: 55% had only right-sided involvement, 33% bilateral involvement and only 12% had exclusively left hemicolon involvement.22 PATHOPHYSIOLOGY It is generally believed that ageing and low dietary ®bre are the two main pathogenic factors involved in this disease. Physiological studies have also demonstrated the higher intraluminal pressures in the large bowel of patients with diverticulae. The interrelationship of these factors remains to be well characterized (Figure 2). Ageing The signi®cant relationship between ageing and the incidence of this disease was demonstrated by Hughes23 and Parks12 in autopsy studies. This condition is uncommon under the age of 40, but its prevalence increases rapidly thereafter with approximately 60% of the population over 70 years old having this condition. This was con®rmed by Gear et al24 in a radiological study of 189 subjects without abdominal symptoms who were drawn randomly from the population. Their study found a strong association between age and colonic diverticulosis. Its prevalence was 12% in the 45±49 age bracket, increased steadily with age and reached 64% at the age of 70 or over. In contrast, Chan et al22 found the peak prevalence in the 50±79 year age group, with a lower prevalence in the older age groups. This study examined the barium enema performed in 858 patients during the 1990s in Hong Kong. The authors suggested that this age pattern of prevalence could be explained by a recent rapid rise in prevalence in the younger age groups. They postulated that this might relate to recent Western cultural in¯uences in diet and lifestyle. If true, the bowel wall changes associated with ageing may be less important than the duration of intake of the low
Ageing
Weakening of the colonic wall
Colonic diverticular disease
Low fibre diet
Segmentation of the colon
High intraluminal pressure
Figure 2. A diagram showing the traditional concept of the mechanisms involved in colonic diverticulosis. The ageing could be associated with the weakening of the colonic wall. The low ®bre diet may lead to a small amount of stool, resulting in colonic segmentation. The intraluminal pressure tends to be high in the segmented colon and causes mucosal and submucosal herniation through the weakened muscle layer, consequently colonic diverticulosis develops.
568 T. Mimura et al
®bre Westernized diet. Painter & Burkitt had previously raised this hypothesis in 1975 stating that `it is the environment of the colon that is important rather than age of the colon'.2 This statement is most easily understood if one considers the fact that this condition is still extremely rare even among the elderly in the African black population where the Western lifestyle and diet are not yet popular.15 Low dietary ®bre Dietary ®bre primarily comprises the storage and cell wall polysaccharides of plants that cannot be hydrated by human digestive enzymes. The dietary ®bre intake for adults recommended by the American Dietetic Association is 20±35 g/day, while the average intake in the USA population is 14±15 g/day.25 In the study by Gear et al24 healthy asymptomatic subjects ingested barium and had a plain abdominal radiograph 4±5 days later. The opaci®ed large bowel on the radiograph was examined for diverticula. The prevalence of diverticulosis was compared between vegetarians and non-vegetarians. Vegetarians had a signi®cantly higher ®bre intake than non-vegetarians (41.5 versus 21.4 g/day, respectively) and a lower prevalence of diverticulosis (12 versus 33% respectively) (Table 2). In a prospective cohort study of 43 881 USA male health professionals aged 40±75 years, Aldoori et al26 demonstrated that the intake of the insoluble component of ®bre was signi®cantly correlated with a decreased risk of symptomatic diverticular disease (relative risk (RR) 0.63, 95% con®dence interval (CI) 0.44±0.91 and P for trend 0.02) and that this inverse correlation was particularly strong for cellulose (RR 0.52, 95% CI 0.36±0.75 and P for trend 0.002). Lin et al27 reported a retrospective study of 3105 colonoscopies together with dietary habit interviews of the subjects. They found that the prevalence of right-sided diverticulosis was strongly positively correlated with past meat consumption, but not with vegetable or fruit consumption or supplemental ®bre intake. High intraluminal pressure As is shown in Table 3, physiological studies have demonstrated the higher intraluminal pressures in the large bowel in patients with diverticula. Painter & Truelove13 showed no dierence in the resting intraluminal large bowel pressure when comparing healthy subjects and patients with diverticular disease. However, patients showed a greater increase in intraluminal pressure after the injection of provocative agents such as morphine or prostigmine. Arfwidsson28 and Parks & Connell29 demonstrated higher resting intra-colonic pressures as well as a greater increase in colonic activity after a
Table 2. The relationship between ®bre intake and colonic diverticulosis.
Vegetarians Non-vegetarians
n
Fibre intake (g/day)
Prevalence of colonic diverticulosis in a barium follow-through study (%)
55 189
41.5 + 12.6 21.4 + 8.2
12 33
Source: Gear et al.24 Vegetarians had a signi®cantly higher ®bre intake and lower prevalence of diverticulosis than nonvegetarians.
Pathophysiology of diverticular disease 569 Table 3. Intraluminal pressure of the colon with diverticula. Reference
Intra-luminal pressure Under resting
Provocative study
No dierence
" Morphine
Arfwidsson (1964)28
"
" Post-prandial
Parks & Connell (1969)29 Sugihara et al (1983)30 Christopher et al (2000)31
" " "
" Post-prandial " Neostigmine " Post-prandial
Painter & Truelove (1964)13
" Prostigmine " Prostigmine
" , greater increase of colon activity in diverticulosis than in control.
meal or prostigmine injection. These manometric features are related to the site of diverticulosis. Sugihara et al30 demonstrated elevated luminal pressures in the right side of the colon in Japanese subjects after stimulation with prostigmine. Christopher et al31 reported the similar pattern of abnormally stronger pressure waves in the diverticular segment than in the adjacent segments or in the normal colon, especially after meals and waking. Although there is clearly an excessive contractile response to stimuli, both natural (meals) and pharmacological (which are probably mimicking extrinsic nerve activation), it is unknown whether this is a cause or result of the disease. Parks32 recorded abnormal resting and stimulated pressures in a group of patients who had undergone resection of sigmoid diverticular disease 6 months previously, suggesting that this functional abnormality may exist as a predisposing state for the development of diverticulosis. This study did not report on the dietary habits of these patients. Painter and colleagues2,14 have suggested that a lack of dietary ®bre results in slower gut transit, allowing greater water absorption with the production of smaller, ®rmer stools. This may facilitate excessive colonic segmentation, resulting in higher intraluminal pressure and, hence, the development of diverticula (Figure 3). Although the relationship between low dietary ®bre and longer colonic transit time, with
Figure 3. (A) Diagram showing how segmentation produces the pulsion force that distends colonic diverticula and probably causes the initial mucosal herniation. (Reproduced from Painter et al14 by kind permission). (B) A macroscopic picture showing marked hypertrophy of the colonic wall with diverticula. The colonic lumen appears to be segmented by the folding hypertrophic colonic muscle layer, resulting in the formation of outpouchings.
570 T. Mimura et al
smaller amounts of stool, has been well demonstrated33, the link to this pressure change has not been conclusively demonstrated. To date in the literature there are no experimental human studies reporting altered pressure activity in response to changes in dietary ®bre. There is one study in rabbits, from 1972 and reported only in an abstract form, by Hodgson.34 He measured colonic activity of rabbits, provoked by prostigmine, before and after they were placed on a free diet of low ®bre (white bread, butter, milk and sugar supplemented by vitamins). After 4 months on this diet the rabbits had put on weight, had become constipated, their general condition had deteriorated and their colon had contracted. The postdietary mean colonic motility index was 5 times greater than the pre-dietary index. Most interestingly, scattered intertaenial temporary diverticulae were observed during colonic contraction induced by prostigmine. Tjiang et al35 reported the potential role of nitric oxide in the pathogenesis of this disease, demonstrating that the compliance of circular muscle in patients with diverticulosis was lower than that of controls. Furthermore, a nitric oxide inhibitor did not aect the compliance of this disease, while inhibiting that of controls. Nitric oxide, a potent smooth muscle relaxant, might be responsible for the segmentation of the colonic wall with diverticulosis and this is certainly a subject for future study. Colonic wall mechanical properties and muscle thickening Dierences between the colonic wall in African and Western subjects may help to explain some of the aetiological factors in this condition. Watters et al36 compared the mechanical properties of the colon in autopsy series of patients from Edinburgh, UK and Kampala, Uganda. The Edinburgh cases consisted of 32 specimens, including ®ve with diverticulosis. None of the 20 specimens from Kampala exhibited diverticular disease, because of its rarity. Tensile strength, width, thickness and burst strength of the colonic wall were measured. For both populations the tensile strength declined with increasing age. When comparing left and right colon, the former was narrower, weaker, less expansile and had lower tensile strength than the right colon. When comparing specimens from the two countries, those from Kampala were stronger, wider in diameter and had thinner walls. These ®ndings suggest that the black African colon is stronger and, therefore, presumably more resistant to deformity, than the Western colon. No dierence was found within the Edinburgh group between the colons with and without diverticulosis in terms of mechanical properties. Regional dierences in colonic compliance have been shown in both in vivo and in vitro studies. Compliance is lowest in the sigmoid and descending colon and greatest in the transverse and ascending colon. Waldron et al37 studied the `normal' colons of six subjects awaiting closure of transverse colostomies after a previous resection of distal colon carcinoma as well as the intact colons from six post mortem specimens. They demonstrated that the compliance was signi®cantly greater in the ascending colon than in the descending colon. Ford et al38 examined both the tonic and phasic colonic motility and the compliance of the transverse and sigmoid colon using a combined barostat±manometry assembly in 22 healthy subjects. They found that the mean increase in phasic contractility was signi®cantly greater and the compliance was lower in the sigmoid compared to the transverse colon. This dierence in mechanical properties between the right and left side colon might partly account for the left-sided predominance of diverticulosis in Western countries. Colonic muscularis propria thickening and in¯ammation are both common features in diverticulosis. When Morson39 examined 173 specimens resected for `diverticulitis',
Pathophysiology of diverticular disease 571 Table 4. Changing concept of diverticular disease.
Site of diverticula Muscle abnormality Intraluminal pressure Connective tissue In¯ammatory complication Bleeding
Classic type (Caucasian type)
New type (Asian type)
Left-sided Remarkable Abnormally high Normal Often Rare
Bilateral Absent Normal Abnormal Unusual Common
Source: Ryan.40
65% had focal or extensive in¯ammation, while 32% showed no in¯ammation but had marked abnormal muscle thickening. The tensile strength of this thickened muscle has never been evaluated. Ryan40 suggested that there might be two kinds of diverticulosis: one with muscle thickening con®ned mainly to the left colon and associated with infectious complications, and the other with no muscle abnormality but with diverticula throughout the colon commonly associated with bleeding and possibly being due to a connectivetissue abnormality (Table 4). This concept may explain the dierence between Western and Asian countries; muscle abnormalities and in¯ammatory complications are uncommon in Japan. The right-sided diverticulosis in Japan often consists of a single or a few diverticula and develops at an earlier age than the left-sided disease.18,41 Extracellular matrix (collagen and elastin) From the evidence presented above, it would appear that rigidity and segmentation of the colonic wall, possibly related to a prolonged chronic low dietary ®bre habit and resultant high intraluminal pressure, lead to the formation of colonic diverticula. This appears to be the case at least in the classic left-sided type of diverticulosis, with associated muscle thickening, most commonly seen in Western countries. The extracelluar matrix, including collagen, elastin and proteoglycans, is likely to be important in maintaining the strength and integrity of the colonic wall.42 It is possible that damage and breakdown of mature collagen with the synthesis of new, initially immature, collagen may lead to a weakness of the colonic wall. Further consideration of these tissue factors is warranted. Whiteway & Morson43 studied 25 sigmoid colons resected for `painful' diverticular disease and 25 normal sigmoid colons resected for a non-obstructing rectal cancer. The thickening of longitudinal and circular muscle observed in diverticular diseasewas neither hyperplasia nor hypertrophy, but appeared to be related to a contractile state. An increase in the amount of elastic ®bres, namely elastosis, was observed in the longitudinal muscle only. It was suggested that elastosis of the longitudinal muscle was responsible for longitudinal contraction, with subsequent thickening of both muscle layers. Thompson et al44 reported that collagen ®brils in the left colon were smaller and more tightly packed than those in the right colon with increasing age, and that this dierence was accentuated in diverticular disease. Three studies by Wess and colleagues have examined the possible role of diet and parental dietary factors in causing changes in colonic wall collagen. In a necropsy study45, collagen cross-linking was measured by collagen solubility in weak acid in the colons of
572 T. Mimura et al
5 patients with diverticulosis and 20 patients without diverticulosis. Inter- and intramolecular linkage of collagen by lysine aldehyde or hydroxylysine aldehyde is a normal phenomenon that is essential for maintaining the structure of collagen. Excessive cross-linking is thought to lead to rigidity and loss of tensile strength. Although total collagen was constant with age, collagen cross-linking increased with age and was greater in diverticulosis. The nature of collagen cross-linking may therefore be important in maintaining the integrity of the colonic wall. In an animal experiment46, 20 rats were fed a ®bre-de®cient diet while 20 rats were fed a high ®bre diet for 18 months. In the post mortem examination, diverticula were found in 42% of ®bre-de®cient rats but none in ®bre-fed rats. Collagen cross-linking was signi®cantly higher in rats fed the ®bre-de®cient diet. The concentration of short chain fatty acids (SCFAs) particularly butyrate, was lower in the bowel of ®brede®cient rats. Dietary ®bre may therefore in¯uence the nature of collagen crosslinking in the bowel. Parental dietary factors may be important, in addition to an individual's own diet. Wess et al47 studied three groups of rats under dierent dietary circumstances. Seventeen rats were fed with a low ®bre diet for 16 months after birth from parents who had been fed a low ®bre diet for 1 month prior to mating, but not during pregnancy. This group was named familial low ®bre (FLF). Nineteen rats born from high ®bre diet fed parents were fed a low ®bre diet themselves: weaned low ®bre (WLF). Twenty rats born from high ®bre diet fed parents were fed a high ®bre diet: familial high ®bre (FHF). Diverticula were found in 42%, 21% and 0% of the ospring in FLF, WLF and FHF, respectively. Collagen cross-linking was signi®cantly higher in FLF and WLF rats compared to FHF rats, in that order. Caecal and colonic SCFA concentrations were signi®cantly lowest in the FLF and highest in the FHF rats. These ®ndings suggested that a parental high ®bre diet could protect their ospring on a low ®bre diet from developing diverticulosis. Diet has a major in¯uence on the content of colonic bacterial ¯ora, which varies between races and regions.48 Such ¯ora may have an important impact on colonic wall structure and function. SCFAs are the principal end products of microbial carbohydrate fermentation, in which ¯oral bacteria break down carbohydrates and other substrates to obtain energy for growth and to maintain colonic cellular function.49 The main substrate for the microbial fermentation is dietary ®bre and the SCFAs produced in¯uence colonic function by providing energy-yielding substrates to the colonic mucosa, increasing or modifying intestinal mucosal growth and raising colonic blood ¯ow. In the two animal studies by Wess et al46,47, the concentration of SCFAs, particularly butyrate, was signi®cantly lower in the colonic contents of the ®bre-de®cient fed rats than in those of the high ®bre fed rats. Their ®ndings suggest that a lower ®bre diet causes higher collagen cross-linking, possibly through a lower production of SCFAs, resulting in a higher incidence of diverticulosis. The three papers by Wess et al45±47 suggest that changes in the structure and nature of collagen may seem to play an important role in the pathogenesis of colonic diverticulosis. Few other studies have investigated the roles of collagen in diverticulosis, and Bode et al50 recently demonstrated the increased synthesis of type III collagen, but not type I collagen, in colonic diverticulosis, although the implications of this ®nding for the pathogenesis of diverticulosis are not clear. The process by which the collagen is altered in this condition also remains to be explored. Matrix metalloproteinases may be important in this process. This family of essential endopeptidases degrades all classes of extracelluar matrix such as collagens, elastin and glycoproteins. They are secreted from a variety of cells including macrophages, T-cells
Pathophysiology of diverticular disease 573
and myo®broblasts, after stimulation by cytokines and other factors. Such factors may include the bacterial ¯ora.51 Changes in metalloproteinase activity, and their inhibitors, may hold important clues in relation to the ®nal eector pathway by which dietary changes and alterations in enteric ¯ora result in altered colonic wall structure and function in this condition. Miscellaneous: physical activity, smoking and the intake of caeine and alcohol In a prospective cohort study of 47 678 men aged 40±75 years, in the USA, Aldoori et al examined the relationship between the risk of symptomatic diverticular disease and smoking, caeine and alcohol intake52 as well as physical activity.53 They documented 382 newly diagnosed cases of symptomatic diverticular disease during the 4 year followup, which was equal to an annual incidence of 20/10 000 in this population. The only variable that was correlated with the risk of development of symptomatic diverticular disease was overall physical activity, which was signi®cantly inversely correlated with the risk of symptomatic diverticular disease (for highest versus lowest extremes, RR 0.63, CI 0.45±0.88). Smoking and the intake of caeine and alcohol were not correlated with any substantially increased risk of symptomatic diverticular disease. SUMMARY The prevalence of colonic diverticulosis has rapidly increased during the 20th century, as the low ®bre diet has prevailed in Western civilized areas. The ®bre content of the
Colonic muscle layer hypertrophy associated with less compliant bowel wall Extracellular matrix alteration Elastosis, increased collagen cross-linking Collagen degeneration & regeneration? MMPS?; SCFAS?; Luminal bacterial floral alteration?
Prolonged low fibre diet
Colonic diverticular disease
Genetic and racial factors (predominant site)
Smaller & firmer stool Nitric oxide?
Segmentation of the colon
High intraluminal pressure
Figure 4. Diagram showing the current and future concepts of the pathophysiology of colonic diverticulosis. The prolonged habit of low ®bre diet leads to colonic muscle hypertrophy and colonic segmentation, which are associated with each other. These phenomena may be mediated by alteration in the extracellular matrix and nitric oxide activity. Genetic and racial factors seem to be important in terms of the predominant site of the diverticula. MMP. matrix metalloproteinase; SCFA. short chain fatty acid.
574 T. Mimura et al
Western diet has been especially reduced since the introduction of milled ¯our at around 1880. Latterly, some developed and developing countries in Asia are following this trend. The latest insights, current ideas and some suggestions for future work with regard to the pathophysiology of colonic diverticulosis are presented in Figure 4. Low dietary ®bre, ageing and intraluminal pressure changes are inextricably linked and appear to be associated with colonic diverticulosis. Low dietary ®bre has been proven to be strongly associated with this condition by both well-designed clinical studies and experimental animal models. Ageing correlates well with the incidence of this disease, but may simply re¯ect a longer intake of low dietary ®bre. Although there is clearly an excessive contractile response to stimuli, both natural (food) and pharmacological, it remains controversial whether this is a cause or result of this disease. There is some dierence in the aetiology as well as in clinical presentation between the left-sided diverticulosis commonly seen in the Caucasian and the right-sided predominantly observed in the Asian. Despite the apparent importance of environmental and dietary factors as causes for this condition, genetic factors may also be important, at least in terms of the site of diverticulae. Further exploration of the production of short chain fatty acids, alterations of colonic bacterial ¯ora and structural and biochemical changes in the colonic wall is needed. These questions form the basis of ongoing enquiry in the 21st century.
Practice points . the dietary habit of low ®bre intake over a long period of more than 40 years is highly likely to be associated with the pathogenesis of colonic diverticulosis . the apparent association between ageing and colonic diverticulosis seems to be an indirect phenomenon, merely re¯ecting the prolonged low dietary ®bre intake . although the contraction of the colon with diverticulosis is excessive both at rest and under natural or pharmacological stimulation, it remains controversial whether this is a cause or result of this condition . left-sided diverticulosis is the most common in the Caucasian, while right-sided is predominant in the Asian. Despite the apparent importance of environmental and dietary factors in causation, genetic factors may also be important, at least in terms of the site of diverticula
Research agenda . experimental studies to investigate the alteration of the intraluminal colonic pressure activity in response to changes in dietary ®bre intake are necessary . detailed histopathological and molecular biological studies are required to elucidate the mechanisms for the thickening of the muscular layer in the colon with diverticulosis in terms of the roles of extracellular matrix, matrix metalloproteinases and intraluminal bacteria
Pathophysiology of diverticular disease 575
REFERENCES * 1. Slack WW. The anatomy, pathology, and some clinical features of diverticulitis of the colon. British Journal of Surgery 1962; 50: 185±190. * 2. Painter NS & Burkitt DP. Diverticular disease of the colon, a 20th century problem. Clinical Gastroenterology 1975; 4: 3±22. 3. Schoetz DJ Jr. Diverticular disease of the colon: a century-old problem. Diseases of the Colon and Rectum 1999; 42: 703±709. 4. Finney JMT. Diverticulitis and its surgical treatment. Proceedings, Inter-State Post-Graduate Medical Assembly of North America 1928; 55: 57±65. 5. Cruveilhier J. Traite d' Anatomie Pathologique Generale, vol. 1 Paris. Bailliere, 1849. 6. Graser E. Das falsche Darmdivertikel. Archivs Klinische Chirurgie 1899; 59: 638±647. 7. Beer E. Some pathological and clinical aspects of acquired (false) diverticula of the intestine. American Journal of Medical Science 1904; 128: 135±145. * 8. Painter NS & Burkitt DP. Diverticular disease of the colon: a de®ciency disease of Western civilization. British Medical Journal 1971; 2: 450±454. 9. Spriggs EI & Marxer OA. Intestinal diverticula. Quarterly Journal of Medicine 1925; 19: 1±34. 10. Petrie JC, Needham CD & Gillanders LA. Survey of alimentary radiology ®ndings in the North East of Scotland region 1967±1970. British Medical Journal 1972; 2: 78±80. 11. Fi®eld LR. Diverticulitis. Lancet 1927; i: 277±281. 12. Parks TG. Post-mortem studies on the colon with special reference to diverticular disease of the colon: a review of 521 cases. Proceedings of the Royal Society of Medicine 1968; 61: 932±934. 13. Painter NS & Truelove SC. The intraluminal pressure patterns in diverticulosis of the colon. Gut 1964; 5: 365±369. *14. Painter NS, Truelove SC & Ardran GM. Segmentation and the localization of intraluminal pressures in the human colon, with special reference to the pathogenesis of colonic diverticula. Gastroenterology 1965; 49: 169±177. 15. Segal I, Solomon A & Hunt J. Emergence of diverticular disease in the urban South African black. Gastroenterology 1977; 72: 215±219. 16. Nakada I, Ubukata H, Goto Y et al. Diverticular disease of the colon at a regional general hospital in Japan. Diseases of the Colon and Rectum 1995; 38: 755±759. 17. Stemmermann G & Yanani R. Diverticulosis and polyps of the large intestine: a necropsy study of Hawai Japanese. Cancer 1973; 31: 1260±1270. 18. Sugihara K, Muto T, Morioka Y et al. Diverticular disease of the colon in Japan: a review of 615 cases. Diseases of the Colon and Rectum 1984; 27: 531±537. 19. Stemmermann G. Pattern of disease among Japanese living in Hawaii. Archives of Environmental Health 1970; 20: 266±273. 20. Miura S, Kodaira S, Shatari T et al. Recent trends in diverticulosis of the right colon in Japan: retrospective review in a regional hospital. Diseases of the Colon and Rectum 2000; 43: 1383±1389. 21. Lee Y-S. Diverticular disease of the large bowel in Singapore: an autopsy study. Diseases of the Colon and Rectum 1986; 29: 330±335. 22. Chan CC, Lo KK, Chung EC et al. Colonic diverticulosis in Hong Kong: distribution pattern and clinical signi®cance. Clinical Radiology 1998; 53: 842±844. 23. Hughes LE. Postmortem survey of diverticular disease of the colon. Gut 1969; 10: 336±351. *24. Gear J, Ware A, Fursdon P et al. Symptomless diverticular disease and intake of dietary ®bre. Lancet 1979; 1: 511±514. 25. Anonymous Position of the American Dietetic Association: health implications of dietary ®ber. Journal of the American Dietetic Association 1997; 97: 1157±1159. 26. Aldoori WH, Giovannucci EL, Rockett RR et al. A prospective study of dietary ®ber types and symptomatic diverticular disease in men. Journal of Nutrition 1998; 128: 714±719. 27. Lin OS, Soon MS, Wu SS et al. Dietary habits and right-sided colonic diverticulosis. Diseases of the Colon and Rectum 2000; 43: 1412±1418. 28. Arfwidsson S. Pathogenesis of multiple diverticula of the colon in diverticular disease. Acta Chirurgica Scandinavica 1964; 342 (supplement): 1±68. *29. Parks T & Connell A. Motility studies in diverticular disease of the colon. Gut 1969; 10: 538±542. 30. Sugihara K, Muto T & Morioka Y. Motility study in right sided diverticular disease of the colon. Gut 1983; 24: 1130±1134. 31. Christopher K, Sadeghi P & Rao S. Investigation of the pathophysiology of diverticular disease. Gastroenterology 2000; 118: A833.
576 T. Mimura et al 32. Parks T. Rectal and colonic studies after resection of the sigmoid for diverticular disease. Gut 1970; 11: 121±125. 33. Burkit DP, Walker ARP & Painter NS. Eect of dietary ®bre on stools and transit times, and its role in the causation of disease. Lancet 1972; ii: 1408±1411. *34. Hodgson I. An animal model to study diverticular disease. British Journal of Surgery 1972; 59: 315±315. 35. Tjiang E, Raja M, Hoyle C et al. The role of nitric oxide in colonic compliance in diverticular disease. Gut 1998; 42 (supplement 1): A95. 36. Watters D, Smith A, Eastwood MA et al. Mechanical properties of the colon: comparison of the features of the African and European colon in vitro. Gut 1985; 26: 384±392. 37. Waldron DJ, Gill RC & Bowes KL. Pressure response of human colon to intraluminal distension. Digestive Diseases and Sciences 1989; 34: 1163±1167. 38. Ford MJ, Camilleri M, Wiste JA et al. Dierences in colonic tone and phasic response to a meal in the transverse and sigmoid human colon. Gut 1995; 37: 264±269. 39. Morson BC. The muscle abnormality in diverticular disease of the colon. Proceedings of the Royal Society of Medicine 1963; 56: 798±803. *40. Ryan P. Changing concepts in diverticular disease. Diseases of the Colon and Rectum 1983; 26: 12±18. 41. Miura S, Kodaira S, Aoki H et al. Bilateral type diverticular disease of the colon. International Journal of Colorectal Disease 1996; 11: 71±75. 42. Thomson HJ, Busuttil A, Eastwood MA et al. The submucosa of the human colon. Journal of Ultrastructure and Molecular Structure Research 1986; 96: 22±30. 43. Whiteway J & Morson BC. Elastosis in diverticular disease of the sigmoid colon. Gut 1985; 26: 258±266. 44. Thomson HJ, Busuttil A, Eastwood MA et al. Submucosal collagen changes in the normal colon and in diverticular disease. International Journal of Colorectal Disease 1987; 2: 208±213. 45. Wess L, Eastwood MA, Wess TJ et al. Cross linking of collagen is increased in colonic diverticulosis. Gut 1995; 37: 91±94. *46. Wess L, Eastwood MA, Edwards CA et al. Collagen alteration in an animal model. Gut 1996; 38: 701±706. *47. Wess L, Eastwood M, Busuttil A et al. An association between maternal diet and colonic diverticulosis in an animal model. Gut 1996; 39: 423±427. 48. Bengmark S. Ecological control of the gastrointestinal tract. The role of probiotic ¯ora. Gut 1998; 42: 2±7. 49. Mortensen PB & Clausen MR. Short-chain fatty acids in the human colon: relation to gastrointestinal health and disease. Scandinavian Journal of Gastroenterology 1996; 216 (supplement): 132±148. 50. Bode MK, Karttunen TJ, Makela J et al. Type I and III collagens in human colon cancer and diverticulosis. Scandinavian Journal of Gastroenterology 2000; 35: 747±752. 51. MacDonald TT & Pender SLF. Proteolytic enzymes in in¯ammatory bowel disease. In¯ammatory Bowel Disease 1998; 4: 157±164. 52. Aldoori WH, Giovannucci EL, Rimm EB et al. A prospective study of alcohol, smoking, caeine, and the risk of symptomatic diverticular disease in men. Annals of Epidemiology 1995; 5: 221±228. 53. Aldoori WH, Giovannucci EL, Rimm EB et al. Prospective study of physical activity and the risk of symptomatic diverticular disease in men. Gut 1995; 36: 276±282. 54. Drummond H. Sacculi of the large intestine, with special reference of their relations to the blood-vessels of the bowel wall. British Journal of Surgery 1916; 4: 407±413. 55. Slack WW. Diverticula of the colon and their relation to muscle layers and blood vessels. Gastroenterology 1960; 39: 708±711.
doi:10.1053/bega.2002.0298, available online at http://www.idealibrary.com on
3 Pathophysiology of diverticular disease Toshiki Mimura
MD
Consultant Surgeon Department of Gastrointestinal Surgery, University of Tokyo, 7±3±1 Hongo, Bunkyo-ku, Tokyo, 113±8655 Japan
Anton Emanuel
MD, MRCP
Senior Lecturer, Consultant Gastroenterologist
Michael A. Kamm
MD, FRCP, FRACP
Professor of Gastroenterology St Mark's Hospital, London, UK
There is substantial evidence that colonic diverticulosis is related to civilization, industrialization and a `Western' lifestyle and diet, being described as `a disease of Western civilization'. Its increased incidence during the 20th century and the morbidity and mortality associated with complications, demand that this condition should receive greater attention in terms of aetiology, prevention and management. It is generally believed that low dietary ®bre and ageing are the two main pathogenic factors involved in this disease. Physiological studies have also demonstrated that there is a higher intraluminal pressure in the large bowel with diverticula. This chapter provides the evidence currently available for the pathophysiology of colonic diverticulosis and discusses its aetiological factors, including low dietary ®bre, ageing and intraluminal pressure as well as extracelluar matrix such as collagen and elastin. The dierence between the left-sided diverticulosis commonly seen in Caucasians and the right-sided predominantly observed in Asians is also presented. Key words: colonic diverticulosis; civilization; dietary ®bre; ageing; intraluminal pressure; collagen; elastin.
COLONIC DIVERTICULOSIS: A 20TH CENTURY AND A CENTURYOLD PROBLEM Colonic diverticulosis is, in general, most commonly an acquired disease, developing as mucosal and submucosal herniations through the circular muscle layer at vulnerable All correspondence to: Dr Toshiki Mimura. Tel: 81 (0)3 3815 5411 ext 35144; Fax: 81 (0)3 5800 9734; E-mail: [email protected] c 2002 Published by Elsevier Science Ltd. 1521±6918/02/$ - see front matter *
564 T. Mimura et al
points where it is penetrated by blood vessels (false- or pseudo-diverticulosis).1 Whilst there are a small number of apparently congenital cases, in which the diverticulum is covered with the muscle layer (true diverticulum), this chapter will concentrate on the pathophysiology of the pseudo-colonic diverticulosis that is most commonly encountered in our clinical practice. In 1975, Painter & Burkitt2 described diverticular disease as `a 20th century problem'. In 1999, the American Society of Colon and Rectal Surgeons celebrated its 100th anniversary. Schoetz3 reviewed this disease in one of the society's `Centennial articles' entitled `Diverticular disease of the colon. A century-old problem', published in Diseases of the Colon and Rectum. Since we have just welcomed the 21st century it might be prudent to recognize that we still have an incomplete understanding of the aetiology and pathophysiology of this common and clinically important condition.
EPIDEMIOLOGY: A DISEASE OF WESTERN CIVILIZATION Although the epidemiology of colonic diverticulosis has been reviewed in detail in Chapter 1 of this volume, some of the historical and geographical aspects of its epidemiology will also be addressed in this chapter, because the clinical evidence for the role of low dietary ®bre as its pathogenesis is largely derived from them. Historical review As is shown in Table 1, this condition was ®rst described as `saccular outpouchings of the colon' by Littre in 1700 (cited in Finney)4, and the risk of infective sequelae of this disease was subsequently appreciated by Cruveilhier in 1849 (see p 593).5 In 1899, 50 years later, Graser6 introduced the term `peridiverticulitis' and suggested that mucosal herniation through areas of penetration of the vasa recta was the probable pathogenesis of this disease (Figure 1). In 1904, Beer7 proposed that diverticulitis was due to the impaction of faeces in the neck of the diverticulum.
Table 1. Historical review and the increased prevalence with time of colonic diverticulosis. Reported year
Author(s) {
1700 1849 1880 1899
Littre Cruveilhier5
1904
Beer7
1925 1927 1968 1972 1960±1980
Spriggs & Marxer9 Fi®eld11 Parks12 Petrie10 Painter et al8,13,14
{Cited
Graser6
in Finney, 1928.4
Reports and events First described as `saccular outpouchings of the colon' Appreciated the risk of infective sequelae Development of roller milling of ¯our Introduced the term `peridiverticulitis' and suggested the mucosal herniation through areas of penetration of the vasa recta as the pathogenesis Proposed that diverticulitis was due to impaction of faeces in the neck of the diverticulum 10% in 1000 barium enemas, UK 9% in more than 10 000 post mortem series 30% in 300 post mortems 29% in 1170 barium enemas, UK Proposed the hypothesis of ®bre de®ciency disease and elevated intraluminal pressure
Pathophysiology of diverticular disease 565
Figure 1. (A) The black arrow indicates one of the weak circular muscle points where the vessel branches pass through. This is the area where diverticulum develops (B) This diagram shows how the mucosal and submucosal layer herniates through the circular muscle layer, resulting in the formation of a diverticulum (black arrow) at its common site between the mesenteric and lateral longitudinal muscular bands. (C) A radiologically injected specimen demonstrates the circumferential vessels passing super®cially to two diverticula on the left side; small branches pass towards the lumen of the specimen in close relationship with the necks of the two diverticula (two white arrows). (D) A macroscopic picture shows mucosal and submucosal herniation through the muscle layer, resulting in diverticulosis (black arrow). (Figs 1(A) and 1(B) are reproduced from Drummond54 by kind permission. Fig. 1(C) is reproduced from Slack55 by kind permission).
The prevalence of diverticular disease appears to have increased considerably during the 20th century, as have its complications, which are associated with morbidity and mortality. There is substantial evidence that this disease is related to civilization, industrialization and Western lifestyle and diet, and it has been described as `a disease of Western civilization'.8 The incidence of this disease in barium enema series has risen from 10% in 19259 to 29% in 197010 in the UK, although the indications for radiological investigation and the nature of the cohort in each of these studies was poorly de®ned. Post mortem series are likely to be much more reliable in de®ning incidence. However, there may be an underestimate related to whether the bowel is properly examined, since small diverticula may be more likely to be detected radiologically than at post mortem. In a study published by Fi®eld in 192711 the incidence of large bowel diverticula in a consecutive series of more than 10 000 post mortems was 9% in adults over the age of 50. In a post mortem series by Parks, published in 196812, the incidence of colonic diverticula rose to approximately 30% at the age of 50 and 50% above the age of 80.
566 T. Mimura et al
During the 1960s and 1970s Painter and colleagues proposed that a de®ciency of dietary ®bre causes an elevation of intraluminal bowel pressure, leading to excessive segmentation of the colon.2,13,14 They speculated that the cause could be the change in diet related to the development of roller milling of ¯our in 1880. Geographical dierences Diverticular disease is common in Western countries, including Europe, North America and Australia. It is less common in Africa, the Middle East, India and the Far East including Japan. The epidemiology of this condition has been changing. There is a changing incidence within certain countries, when considering the whole population, both within distinct ethnic groups in certain populations within those countries and in dierent ethnic groups who move to new locations. Studies looking at changing migration patterns have suggested that environmental factors appear to in¯uence genetically determined patterns of expression of disease. In South Africa, where the black and white populations previously lived separately, the prevalence in the white community was 21% but was only 1% in the black community. Recently the incidence in the black population appears to be increasing.15 In Japan, the incidence in a barium enema series in 1992 was 19% in those over the age of 50.16 In contrast, the incidence of this disease amongst the Japanese community in Hawaii was 52% in 197317, which was signi®cantly greater than in Japanese mainland series. The changing pattern of diverticular disease in these Japanese populations provides important insights into the genetic and environmental mechanisms that underlie this condition. Japan has become very industrialized over the last 40 years, with the widespread adoption of a Western lifestyle and diet. This may account for the increase in incidence from 11±19% seen in the relatively short period from 1985±1992.16 The prevalence, however, is still lower than in the West, which may relate to some of the Japanese population eating a Western type diet while a part of the population maintains a traditional diet. Predominant site of the diverticulosis Japanese diverticular disease is predominantly right-sided (70%)18, while in the West it is nearly always left-sided (90%).12 Despite the high prevalence of diverticular disease in the Japanese Hawaiian community the dominant site has remained right-sided, as it has in the indigenous Japanese population.19 In 13 947 consecutive barium enemas at a regional hospital in Japan, the prevalence of right-sided and bilateral diverticulosis increased from 9.6% between 1982 and 1987 to 17.6% between 1993 and 1997, whilst that of the left-sided diverticula did not change considerably in the same periods, increasing from only 2.8% to 4.9%.20 Therefore, although environmental and dietary factors appear to be important in causation, genetic factors may also be important, at least in terms of the site of diverticula. A similar recent increase in prevalence and right-sided predominance has also been reported in Singapore and Hong Kong. In 1986, Lee21 reported that in a series of 1014 consecutive autopsies in Singapore, colonic diverticulosis was encountered in 194 patients (19%) and that the ascending colon was aected most frequently (74%), followed by the caecum (45%) and the sigmoid colon (23%). In a Hong Kong barium enema series of 858 consecutive examinations between 1995 and 1996, 215 patients (25.1%) were
Pathophysiology of diverticular disease 567
found to have colonic diverticulosis: 55% had only right-sided involvement, 33% bilateral involvement and only 12% had exclusively left hemicolon involvement.22 PATHOPHYSIOLOGY It is generally believed that ageing and low dietary ®bre are the two main pathogenic factors involved in this disease. Physiological studies have also demonstrated the higher intraluminal pressures in the large bowel of patients with diverticulae. The interrelationship of these factors remains to be well characterized (Figure 2). Ageing The signi®cant relationship between ageing and the incidence of this disease was demonstrated by Hughes23 and Parks12 in autopsy studies. This condition is uncommon under the age of 40, but its prevalence increases rapidly thereafter with approximately 60% of the population over 70 years old having this condition. This was con®rmed by Gear et al24 in a radiological study of 189 subjects without abdominal symptoms who were drawn randomly from the population. Their study found a strong association between age and colonic diverticulosis. Its prevalence was 12% in the 45±49 age bracket, increased steadily with age and reached 64% at the age of 70 or over. In contrast, Chan et al22 found the peak prevalence in the 50±79 year age group, with a lower prevalence in the older age groups. This study examined the barium enema performed in 858 patients during the 1990s in Hong Kong. The authors suggested that this age pattern of prevalence could be explained by a recent rapid rise in prevalence in the younger age groups. They postulated that this might relate to recent Western cultural in¯uences in diet and lifestyle. If true, the bowel wall changes associated with ageing may be less important than the duration of intake of the low
Ageing
Weakening of the colonic wall
Colonic diverticular disease
Low fibre diet
Segmentation of the colon
High intraluminal pressure
Figure 2. A diagram showing the traditional concept of the mechanisms involved in colonic diverticulosis. The ageing could be associated with the weakening of the colonic wall. The low ®bre diet may lead to a small amount of stool, resulting in colonic segmentation. The intraluminal pressure tends to be high in the segmented colon and causes mucosal and submucosal herniation through the weakened muscle layer, consequently colonic diverticulosis develops.
568 T. Mimura et al
®bre Westernized diet. Painter & Burkitt had previously raised this hypothesis in 1975 stating that `it is the environment of the colon that is important rather than age of the colon'.2 This statement is most easily understood if one considers the fact that this condition is still extremely rare even among the elderly in the African black population where the Western lifestyle and diet are not yet popular.15 Low dietary ®bre Dietary ®bre primarily comprises the storage and cell wall polysaccharides of plants that cannot be hydrated by human digestive enzymes. The dietary ®bre intake for adults recommended by the American Dietetic Association is 20±35 g/day, while the average intake in the USA population is 14±15 g/day.25 In the study by Gear et al24 healthy asymptomatic subjects ingested barium and had a plain abdominal radiograph 4±5 days later. The opaci®ed large bowel on the radiograph was examined for diverticula. The prevalence of diverticulosis was compared between vegetarians and non-vegetarians. Vegetarians had a signi®cantly higher ®bre intake than non-vegetarians (41.5 versus 21.4 g/day, respectively) and a lower prevalence of diverticulosis (12 versus 33% respectively) (Table 2). In a prospective cohort study of 43 881 USA male health professionals aged 40±75 years, Aldoori et al26 demonstrated that the intake of the insoluble component of ®bre was signi®cantly correlated with a decreased risk of symptomatic diverticular disease (relative risk (RR) 0.63, 95% con®dence interval (CI) 0.44±0.91 and P for trend 0.02) and that this inverse correlation was particularly strong for cellulose (RR 0.52, 95% CI 0.36±0.75 and P for trend 0.002). Lin et al27 reported a retrospective study of 3105 colonoscopies together with dietary habit interviews of the subjects. They found that the prevalence of right-sided diverticulosis was strongly positively correlated with past meat consumption, but not with vegetable or fruit consumption or supplemental ®bre intake. High intraluminal pressure As is shown in Table 3, physiological studies have demonstrated the higher intraluminal pressures in the large bowel in patients with diverticula. Painter & Truelove13 showed no dierence in the resting intraluminal large bowel pressure when comparing healthy subjects and patients with diverticular disease. However, patients showed a greater increase in intraluminal pressure after the injection of provocative agents such as morphine or prostigmine. Arfwidsson28 and Parks & Connell29 demonstrated higher resting intra-colonic pressures as well as a greater increase in colonic activity after a
Table 2. The relationship between ®bre intake and colonic diverticulosis.
Vegetarians Non-vegetarians
n
Fibre intake (g/day)
Prevalence of colonic diverticulosis in a barium follow-through study (%)
55 189
41.5 + 12.6 21.4 + 8.2
12 33
Source: Gear et al.24 Vegetarians had a signi®cantly higher ®bre intake and lower prevalence of diverticulosis than nonvegetarians.
Pathophysiology of diverticular disease 569 Table 3. Intraluminal pressure of the colon with diverticula. Reference
Intra-luminal pressure Under resting
Provocative study
No dierence
" Morphine
Arfwidsson (1964)28
"
" Post-prandial
Parks & Connell (1969)29 Sugihara et al (1983)30 Christopher et al (2000)31
" " "
" Post-prandial " Neostigmine " Post-prandial
Painter & Truelove (1964)13
" Prostigmine " Prostigmine
" , greater increase of colon activity in diverticulosis than in control.
meal or prostigmine injection. These manometric features are related to the site of diverticulosis. Sugihara et al30 demonstrated elevated luminal pressures in the right side of the colon in Japanese subjects after stimulation with prostigmine. Christopher et al31 reported the similar pattern of abnormally stronger pressure waves in the diverticular segment than in the adjacent segments or in the normal colon, especially after meals and waking. Although there is clearly an excessive contractile response to stimuli, both natural (meals) and pharmacological (which are probably mimicking extrinsic nerve activation), it is unknown whether this is a cause or result of the disease. Parks32 recorded abnormal resting and stimulated pressures in a group of patients who had undergone resection of sigmoid diverticular disease 6 months previously, suggesting that this functional abnormality may exist as a predisposing state for the development of diverticulosis. This study did not report on the dietary habits of these patients. Painter and colleagues2,14 have suggested that a lack of dietary ®bre results in slower gut transit, allowing greater water absorption with the production of smaller, ®rmer stools. This may facilitate excessive colonic segmentation, resulting in higher intraluminal pressure and, hence, the development of diverticula (Figure 3). Although the relationship between low dietary ®bre and longer colonic transit time, with
Figure 3. (A) Diagram showing how segmentation produces the pulsion force that distends colonic diverticula and probably causes the initial mucosal herniation. (Reproduced from Painter et al14 by kind permission). (B) A macroscopic picture showing marked hypertrophy of the colonic wall with diverticula. The colonic lumen appears to be segmented by the folding hypertrophic colonic muscle layer, resulting in the formation of outpouchings.
570 T. Mimura et al
smaller amounts of stool, has been well demonstrated33, the link to this pressure change has not been conclusively demonstrated. To date in the literature there are no experimental human studies reporting altered pressure activity in response to changes in dietary ®bre. There is one study in rabbits, from 1972 and reported only in an abstract form, by Hodgson.34 He measured colonic activity of rabbits, provoked by prostigmine, before and after they were placed on a free diet of low ®bre (white bread, butter, milk and sugar supplemented by vitamins). After 4 months on this diet the rabbits had put on weight, had become constipated, their general condition had deteriorated and their colon had contracted. The postdietary mean colonic motility index was 5 times greater than the pre-dietary index. Most interestingly, scattered intertaenial temporary diverticulae were observed during colonic contraction induced by prostigmine. Tjiang et al35 reported the potential role of nitric oxide in the pathogenesis of this disease, demonstrating that the compliance of circular muscle in patients with diverticulosis was lower than that of controls. Furthermore, a nitric oxide inhibitor did not aect the compliance of this disease, while inhibiting that of controls. Nitric oxide, a potent smooth muscle relaxant, might be responsible for the segmentation of the colonic wall with diverticulosis and this is certainly a subject for future study. Colonic wall mechanical properties and muscle thickening Dierences between the colonic wall in African and Western subjects may help to explain some of the aetiological factors in this condition. Watters et al36 compared the mechanical properties of the colon in autopsy series of patients from Edinburgh, UK and Kampala, Uganda. The Edinburgh cases consisted of 32 specimens, including ®ve with diverticulosis. None of the 20 specimens from Kampala exhibited diverticular disease, because of its rarity. Tensile strength, width, thickness and burst strength of the colonic wall were measured. For both populations the tensile strength declined with increasing age. When comparing left and right colon, the former was narrower, weaker, less expansile and had lower tensile strength than the right colon. When comparing specimens from the two countries, those from Kampala were stronger, wider in diameter and had thinner walls. These ®ndings suggest that the black African colon is stronger and, therefore, presumably more resistant to deformity, than the Western colon. No dierence was found within the Edinburgh group between the colons with and without diverticulosis in terms of mechanical properties. Regional dierences in colonic compliance have been shown in both in vivo and in vitro studies. Compliance is lowest in the sigmoid and descending colon and greatest in the transverse and ascending colon. Waldron et al37 studied the `normal' colons of six subjects awaiting closure of transverse colostomies after a previous resection of distal colon carcinoma as well as the intact colons from six post mortem specimens. They demonstrated that the compliance was signi®cantly greater in the ascending colon than in the descending colon. Ford et al38 examined both the tonic and phasic colonic motility and the compliance of the transverse and sigmoid colon using a combined barostat±manometry assembly in 22 healthy subjects. They found that the mean increase in phasic contractility was signi®cantly greater and the compliance was lower in the sigmoid compared to the transverse colon. This dierence in mechanical properties between the right and left side colon might partly account for the left-sided predominance of diverticulosis in Western countries. Colonic muscularis propria thickening and in¯ammation are both common features in diverticulosis. When Morson39 examined 173 specimens resected for `diverticulitis',
Pathophysiology of diverticular disease 571 Table 4. Changing concept of diverticular disease.
Site of diverticula Muscle abnormality Intraluminal pressure Connective tissue In¯ammatory complication Bleeding
Classic type (Caucasian type)
New type (Asian type)
Left-sided Remarkable Abnormally high Normal Often Rare
Bilateral Absent Normal Abnormal Unusual Common
Source: Ryan.40
65% had focal or extensive in¯ammation, while 32% showed no in¯ammation but had marked abnormal muscle thickening. The tensile strength of this thickened muscle has never been evaluated. Ryan40 suggested that there might be two kinds of diverticulosis: one with muscle thickening con®ned mainly to the left colon and associated with infectious complications, and the other with no muscle abnormality but with diverticula throughout the colon commonly associated with bleeding and possibly being due to a connectivetissue abnormality (Table 4). This concept may explain the dierence between Western and Asian countries; muscle abnormalities and in¯ammatory complications are uncommon in Japan. The right-sided diverticulosis in Japan often consists of a single or a few diverticula and develops at an earlier age than the left-sided disease.18,41 Extracellular matrix (collagen and elastin) From the evidence presented above, it would appear that rigidity and segmentation of the colonic wall, possibly related to a prolonged chronic low dietary ®bre habit and resultant high intraluminal pressure, lead to the formation of colonic diverticula. This appears to be the case at least in the classic left-sided type of diverticulosis, with associated muscle thickening, most commonly seen in Western countries. The extracelluar matrix, including collagen, elastin and proteoglycans, is likely to be important in maintaining the strength and integrity of the colonic wall.42 It is possible that damage and breakdown of mature collagen with the synthesis of new, initially immature, collagen may lead to a weakness of the colonic wall. Further consideration of these tissue factors is warranted. Whiteway & Morson43 studied 25 sigmoid colons resected for `painful' diverticular disease and 25 normal sigmoid colons resected for a non-obstructing rectal cancer. The thickening of longitudinal and circular muscle observed in diverticular diseasewas neither hyperplasia nor hypertrophy, but appeared to be related to a contractile state. An increase in the amount of elastic ®bres, namely elastosis, was observed in the longitudinal muscle only. It was suggested that elastosis of the longitudinal muscle was responsible for longitudinal contraction, with subsequent thickening of both muscle layers. Thompson et al44 reported that collagen ®brils in the left colon were smaller and more tightly packed than those in the right colon with increasing age, and that this dierence was accentuated in diverticular disease. Three studies by Wess and colleagues have examined the possible role of diet and parental dietary factors in causing changes in colonic wall collagen. In a necropsy study45, collagen cross-linking was measured by collagen solubility in weak acid in the colons of
572 T. Mimura et al
5 patients with diverticulosis and 20 patients without diverticulosis. Inter- and intramolecular linkage of collagen by lysine aldehyde or hydroxylysine aldehyde is a normal phenomenon that is essential for maintaining the structure of collagen. Excessive cross-linking is thought to lead to rigidity and loss of tensile strength. Although total collagen was constant with age, collagen cross-linking increased with age and was greater in diverticulosis. The nature of collagen cross-linking may therefore be important in maintaining the integrity of the colonic wall. In an animal experiment46, 20 rats were fed a ®bre-de®cient diet while 20 rats were fed a high ®bre diet for 18 months. In the post mortem examination, diverticula were found in 42% of ®bre-de®cient rats but none in ®bre-fed rats. Collagen cross-linking was signi®cantly higher in rats fed the ®bre-de®cient diet. The concentration of short chain fatty acids (SCFAs) particularly butyrate, was lower in the bowel of ®brede®cient rats. Dietary ®bre may therefore in¯uence the nature of collagen crosslinking in the bowel. Parental dietary factors may be important, in addition to an individual's own diet. Wess et al47 studied three groups of rats under dierent dietary circumstances. Seventeen rats were fed with a low ®bre diet for 16 months after birth from parents who had been fed a low ®bre diet for 1 month prior to mating, but not during pregnancy. This group was named familial low ®bre (FLF). Nineteen rats born from high ®bre diet fed parents were fed a low ®bre diet themselves: weaned low ®bre (WLF). Twenty rats born from high ®bre diet fed parents were fed a high ®bre diet: familial high ®bre (FHF). Diverticula were found in 42%, 21% and 0% of the ospring in FLF, WLF and FHF, respectively. Collagen cross-linking was signi®cantly higher in FLF and WLF rats compared to FHF rats, in that order. Caecal and colonic SCFA concentrations were signi®cantly lowest in the FLF and highest in the FHF rats. These ®ndings suggested that a parental high ®bre diet could protect their ospring on a low ®bre diet from developing diverticulosis. Diet has a major in¯uence on the content of colonic bacterial ¯ora, which varies between races and regions.48 Such ¯ora may have an important impact on colonic wall structure and function. SCFAs are the principal end products of microbial carbohydrate fermentation, in which ¯oral bacteria break down carbohydrates and other substrates to obtain energy for growth and to maintain colonic cellular function.49 The main substrate for the microbial fermentation is dietary ®bre and the SCFAs produced in¯uence colonic function by providing energy-yielding substrates to the colonic mucosa, increasing or modifying intestinal mucosal growth and raising colonic blood ¯ow. In the two animal studies by Wess et al46,47, the concentration of SCFAs, particularly butyrate, was signi®cantly lower in the colonic contents of the ®bre-de®cient fed rats than in those of the high ®bre fed rats. Their ®ndings suggest that a lower ®bre diet causes higher collagen cross-linking, possibly through a lower production of SCFAs, resulting in a higher incidence of diverticulosis. The three papers by Wess et al45±47 suggest that changes in the structure and nature of collagen may seem to play an important role in the pathogenesis of colonic diverticulosis. Few other studies have investigated the roles of collagen in diverticulosis, and Bode et al50 recently demonstrated the increased synthesis of type III collagen, but not type I collagen, in colonic diverticulosis, although the implications of this ®nding for the pathogenesis of diverticulosis are not clear. The process by which the collagen is altered in this condition also remains to be explored. Matrix metalloproteinases may be important in this process. This family of essential endopeptidases degrades all classes of extracelluar matrix such as collagens, elastin and glycoproteins. They are secreted from a variety of cells including macrophages, T-cells
Pathophysiology of diverticular disease 573
and myo®broblasts, after stimulation by cytokines and other factors. Such factors may include the bacterial ¯ora.51 Changes in metalloproteinase activity, and their inhibitors, may hold important clues in relation to the ®nal eector pathway by which dietary changes and alterations in enteric ¯ora result in altered colonic wall structure and function in this condition. Miscellaneous: physical activity, smoking and the intake of caeine and alcohol In a prospective cohort study of 47 678 men aged 40±75 years, in the USA, Aldoori et al examined the relationship between the risk of symptomatic diverticular disease and smoking, caeine and alcohol intake52 as well as physical activity.53 They documented 382 newly diagnosed cases of symptomatic diverticular disease during the 4 year followup, which was equal to an annual incidence of 20/10 000 in this population. The only variable that was correlated with the risk of development of symptomatic diverticular disease was overall physical activity, which was signi®cantly inversely correlated with the risk of symptomatic diverticular disease (for highest versus lowest extremes, RR 0.63, CI 0.45±0.88). Smoking and the intake of caeine and alcohol were not correlated with any substantially increased risk of symptomatic diverticular disease. SUMMARY The prevalence of colonic diverticulosis has rapidly increased during the 20th century, as the low ®bre diet has prevailed in Western civilized areas. The ®bre content of the
Colonic muscle layer hypertrophy associated with less compliant bowel wall Extracellular matrix alteration Elastosis, increased collagen cross-linking Collagen degeneration & regeneration? MMPS?; SCFAS?; Luminal bacterial floral alteration?
Prolonged low fibre diet
Colonic diverticular disease
Genetic and racial factors (predominant site)
Smaller & firmer stool Nitric oxide?
Segmentation of the colon
High intraluminal pressure
Figure 4. Diagram showing the current and future concepts of the pathophysiology of colonic diverticulosis. The prolonged habit of low ®bre diet leads to colonic muscle hypertrophy and colonic segmentation, which are associated with each other. These phenomena may be mediated by alteration in the extracellular matrix and nitric oxide activity. Genetic and racial factors seem to be important in terms of the predominant site of the diverticula. MMP. matrix metalloproteinase; SCFA. short chain fatty acid.
574 T. Mimura et al
Western diet has been especially reduced since the introduction of milled ¯our at around 1880. Latterly, some developed and developing countries in Asia are following this trend. The latest insights, current ideas and some suggestions for future work with regard to the pathophysiology of colonic diverticulosis are presented in Figure 4. Low dietary ®bre, ageing and intraluminal pressure changes are inextricably linked and appear to be associated with colonic diverticulosis. Low dietary ®bre has been proven to be strongly associated with this condition by both well-designed clinical studies and experimental animal models. Ageing correlates well with the incidence of this disease, but may simply re¯ect a longer intake of low dietary ®bre. Although there is clearly an excessive contractile response to stimuli, both natural (food) and pharmacological, it remains controversial whether this is a cause or result of this disease. There is some dierence in the aetiology as well as in clinical presentation between the left-sided diverticulosis commonly seen in the Caucasian and the right-sided predominantly observed in the Asian. Despite the apparent importance of environmental and dietary factors as causes for this condition, genetic factors may also be important, at least in terms of the site of diverticulae. Further exploration of the production of short chain fatty acids, alterations of colonic bacterial ¯ora and structural and biochemical changes in the colonic wall is needed. These questions form the basis of ongoing enquiry in the 21st century.
Practice points . the dietary habit of low ®bre intake over a long period of more than 40 years is highly likely to be associated with the pathogenesis of colonic diverticulosis . the apparent association between ageing and colonic diverticulosis seems to be an indirect phenomenon, merely re¯ecting the prolonged low dietary ®bre intake . although the contraction of the colon with diverticulosis is excessive both at rest and under natural or pharmacological stimulation, it remains controversial whether this is a cause or result of this condition . left-sided diverticulosis is the most common in the Caucasian, while right-sided is predominant in the Asian. Despite the apparent importance of environmental and dietary factors in causation, genetic factors may also be important, at least in terms of the site of diverticula
Research agenda . experimental studies to investigate the alteration of the intraluminal colonic pressure activity in response to changes in dietary ®bre intake are necessary . detailed histopathological and molecular biological studies are required to elucidate the mechanisms for the thickening of the muscular layer in the colon with diverticulosis in terms of the roles of extracellular matrix, matrix metalloproteinases and intraluminal bacteria
Pathophysiology of diverticular disease 575
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