Statement No. 10. Lifestyle factors, some systemic illnesses, several drugs, and physiological abnormalities such as slow colon transit and FED contribute to CC
Voting summary: accepted completely 23 (79.3%), accepted with some reservation 4 (13.8%), accepted with major reservation 1 (3%)
Level of evidence: II-2
Grade of recommendation: B
In epidemiological surveys, lifestyle factors reported to contribute to CC [
1] include insufficient dietary fiber and fluid intake, irregular and inadequate time in the toilet, sedentary life, prolonged bed rest, systemic illnesses, and chronic consumption of drugs causing CC [
39,
40]. Socio-demographic and lifestyle factors associated with constipation may differ in different regions [
41,
42]. A coastal eastern Indian study evaluating defecation frequency and predominant stool forms among 1200 apparently healthy subjects found that female gender, age > 35 years, non-vegetarianism, and sedentary lifestyle were associated with reduced defecation frequency [
14]. A community study from northern India found constipation to be more common among females, non-working people, non-vegetarians, and those with lesser fluid and green leafy vegetables/fruits/cereals intake, and poor physical activity [
7]. A recent multicenter study from India [
15] showed lifestyle factors associated with CC included physical inactivity, posture during defecation, smoking, intake of tea/coffee/alcohol, and animal protein intake. Common co-morbid diseases were hypertension, diabetes mellitus, and dyspepsia. Associated drug intake included antihypertensive and antidiabetic medications, antidepressants, and lipid-lowering drugs. Talley [
43] reported a list of drugs that carry a significant risk of constipation; this included antidepressants, antipsychotics, anticonvulsants, antispasmodics, antihistamines, opioid analgesics, diuretics, iron and calcium supplements, and aluminum antacids.
However, in patients with CC in tertiary care practice, slow colonic transit and FED often contribute to CC in addition to lifestyle factors [
1]. A study from a tertiary care center in West Bengal reported that 61.5% patients with CC had associated systemic co-morbidities such as diabetes mellitus (17.6%), hypothyroidism (10.5%), organic brain disease (19.8%), or combination of these diseases (13.6%) [
16]. Moreover, 37.7% of patients in this study were found to be regularly taking drugs known to cause constipation.
Physiological abnormalities (slow colonic transit, FED, or combination) have been reported in patients with CC from India. In a study from western India [
25], of 99 patients with primary constipation, 74 had functional constipation (FC) and 25 had IBS-C as per Rome III criteria. Pathophysiologic sub-types of primary constipation were normal transit constipation (NTC,
n = 46), slow transit constipation (STC,
n = 13), dyssynergic defecation (DD,
n = 38), and DD plus STC (
n = 2). Thus, 40% patients with primary constipation had FED and these patients were more likely to have a history of finger evacuation, straining, incomplete evacuation, and sensation of anorectal obstruction as compared to those having no DD. FC and IBS-C were clinically and pathophysiologically similar except for abdominal pain. In another study from northern India [
22], of a total of 249 consecutive patients with CC (Rome III), 86 (34%) had FED (abnormality in greater than or equal to two tests: balloon expulsion test, anorectal manometry, and defecography). Prolonged straining, incomplete evacuation, and squeeze anal sphincter pressure were significant predictors of FED on multivariate analysis. Manometry and defecography abnormalities were more common among the female FED patients. This is quite anticipated as obstetric trauma is one of the major factors causing FED among the females.
Statement No. 11. Obstetric trauma may contribute to the pelvic floor and anorectal abnormalities contributing to CC
Voting summary: accepted completely 19 (65.5%), accepted with some reservation 7 (24.1%), accepted with major reservation 1 (3%), rejected with reservation 1 (3%)
Level of evidence: II-2
Grade of recommendation: B
Defecation and continence require functional integration of the pelvic floor musculature. Damage to pelvic connective tissue, nerves, and muscles during childbirth contributes to the pathogenesis of pelvic floor dysfunction (PFD) [
44]. PFD in this setting may manifest as severe constipation, obstructed defecation, rectocele, hemorrhoids, rectal prolapse, or incontinence [
45]. Risk factors for PFD in females include older age, higher parity, and vaginal mode of delivery. [
46,
47]. Data from India on this issue are, however, limited.
A study on a female general population of Turkey [
37] reported a 67.5% prevalence of PFD of at least one major type. The prevalence of constipation and obstructed defecations were 33.2% and 26.8%, respectively. Age, vaginal delivery, and higher parity were found to be the risk factors associated with the development of PFD. A recent study on Lebanese women visiting clinics in a University Medical Center in Beirut [
48] reported a 34.6% prevalence of obstructed defecation. Pelvic Floor Bother Questionnaire (PFBQ) scores were found to be significantly higher in those who had ≥ 3 vaginal deliveries. Two studies from South Korea [
49,
50] reported a higher frequency of dyssynergic defecation in female constipated patients with prior vaginal delivery as compared to those without.
In a coastal eastern Indian study among 1200 healthy volunteers, the authors found that stool frequency reduced with age, more so in female than male, and such reduction started at the middle of the fourth decade; the authors suggested that this could be related to pelvic floor trauma due to childbirth. This issue requires further study [
14]. A recent study from northern India [
22] evaluated the frequency, spectrum, and factors associated with FED among patients with CC. This study found that female patients with FED more frequently had (a) abnormal defecography and (b) abnormalities on anorectal manometry. This issue requires further study [
14].
Statement No. 12. Indian toilet is more physiological than a western toilet for defecation
Voting summary: accepted completely 14 (48.3%), accepted with some reservation 10 (34.5%), accepted with major reservation 3 (10.3%), rejected completely 1 (3%)
Level of evidence: II-2
Grade of recommendation: B
Defecatory postures differ according to culture; squatting and sitting are the most common worldwide [
1]. Conventional Indian and Japanese toilets require squatting posture, but more people are gradually switching to western style toilets in urban areas in India. Western toilets need a sitting posture. Squatting is more physiological, ideal, and relaxed posture for defecation as it offers several advantages over “sitting”: (a) leads to better relaxation of puborectalis and hence widening of recto-anal angle; (b) faster, easier, and more complete evacuation; and (c) prevents excessive straining thereby protecting pelvic nerves from becoming stretched and damaged [
51,
52]. However, there is limited published literature supporting the advantages of squatting posture. In a study from Israel [
53] comparing three postures during defecation (squatting, sitting on standard height toilet seat, and sitting on low height toilet seat) showed that both the time needed for sensation of satisfactory bowel emptying and the degree of subjectively assessed straining were much lower in the squatting position as compared to both the sitting postures. In a recent study from Japan [
54] comparing three postures during defecation (squatting, sitting, and sitting with the hip flexed at 60° by placement of the feet on a height-adjustable step) showed that basal abdominal pressure before defecation was at lowest and recto-anal angle on defecation was at widest with squatting as compared to both the sitting postures.
Statement No. 13. Bristol stool form correlates with colon transit
Voting summary: accepted completely 19 (65.5%), accepted with some reservation 7 (24.1%), accepted with major reservation 1 (3%), rejected with reservation 2 (6.9%)
Level of evidence: II-2
Grade of recommendation: B
Stool form is often used as a clinical surrogate for colon transit in constipated patients. Bristol stool form scale (BSFS) has been in use in clinical practice for more than two decades [
55]. It has proved acceptable both to subjects in epidemiologic surveys and to patients attending gastroenterology clinics. Reasonable correlations have been observed between BSFS and whole-gut transit time [
55‐
57]. The utility of BSFS has been duly endorsed by the Rome Foundation [
58].
The validity of BSFS was confirmed in a study from Mayo Clinic, USA [
12], which showed that total as well as segmental colonic transit were significantly slower in persons with harder stools (BSFS scores 1–3) than those with looser stools (BSFS scores 5–7). A recent multicenter study from the USA [
59] showed a moderate correlation of stool form score with whole-gut and colonic transit times (CTT) in patients with constipation and found that Bristol stool form value < 3 predicted delayed whole-gut and colonic transit with a sensitivity and specificity of more than 80%. A recent multicenter study from Thailand [
18] showed that average 5-day BSFS was independently associated with delayed CTT and also that optimal average 5-day BSFS of ≤ 3 provided 68.0% sensitivity, 69.7% specificity, and 69.4% accuracy for predicting delayed CTT. Unfortunately, there is no study on this issue from India.
Statement No. 14. Specific pathophysiological abnormalities at the molecular level (myopathic, neuropathic, others) have been shown in a subset of patients with CC
Voting summary: accepted completely 11 (37.9%), accepted with some reservation 14 (48.3%), accepted with major reservation 4 (13.8%), rejected completely 1 (3%)
Level of evidence: II-3
Grade of recommendation: C
A few recent studies suggested that a subset of patients with CC may have some organic basis [
60]. Demonstration of histological abnormalities in patients with CC is essentially limited to resected colon specimens [
61]. Hence, these results cannot be generalized to patients with CC as colonic resection may be needed only in a small subset of patients with severe CC. Moreover, published literature is limited with most series being small and primarily pertain to STC [
62]. Elucidation of histopathological and ultrastructural abnormalities require special techniques like immune-histochemistry (IHC), immunofluorescence, and transmission electron microscopy (TEM). The spectrum of histopathological abnormalities include hypoganglionosis, inflammatory neuronopathy, degenerative leiomyopathy, loss of interstitial cells of Cajal (ICC) or glial cells, decreased acetylcholinesterase activity, mast cell infiltration, and neuroendocrine cell abnormalities [
63‐
66]. There are a few studies published from different parts of the World demonstrating specific pathophysiological abnormalities at the molecular level in patients with CC (Table
4) [
62,
63,
67‐
76] including a few Asian studies [
77‐
79].
Table 4
Studies from outside India that reported molecular level pathophysiological abnormalities in patients with chronic constipation
Park et al. 1995 | Idiopathic CC: 14, non-CC controls: 17 | Higher number of PGP-9.5 immunoreactive nerve fibers in the muscularis propria [ 67] |
Sjolund et al. 1997 | STC: 18 | Colonic specimens showed an increased peptide YY and 5-HT containing cells and also increased content of VIP, galanin, substance P, and NPY [ 68] |
Faussone-Pellegrini et al. 1999 | STC: 7, non-CC controls: 5 | A lower total neuron density and VIP-immunoreactive neurons at the two enteric plexuses reduced NOS-immunoreactive neurons at the myenteric plexus but more NOS-immunoreactive neurons at the submucous plexus [ 69] |
Knowles et al. 2001 | STC: 36, controls: 80 | Increased frequency of smooth muscle inclusion bodies suggestive of myopathy [ 63] |
Wedel et al. 2002 | STC: 11, non-CC controls: 13 | Reduced number of ICC, myenteric plexus hypoganglionosis [ 62] |
Lee et al. 2005 | STC: 10, non-CC controls: 10 | Decreased densities of ICC and PGP 9.5 reactive neuronal structures [ 70] |
Bassotti and Villanacci 2006 | STC: 26, non-CC controls: 10 | Reduced density of enteric ganglia cells, glial cells, and interstitial cells of Cajal but more apoptotic enteric neurons [ 71] |
Wedel et al. 2006 | STC: 13, controls: 12 | Myenteric hypoganglionosis, deficiency of ICC, and reduced immunoreactivity to smooth muscle markers [ 72] |
Wang et al. 2008 | STC: 15, non-CC controls: 45 | Reduced number of ICC and enteric neurofilaments in muscularis propria [ 73] |
Bassotti et al. 2011 | STC: 29, non-CC controls: 20 | Higher number of mast cells in all colonic segments [ 66] |
Bassotti et al. 2012 | FED: 11, non-CC controls: 20 | Higher number of mast cells in all colonic segments [ 74] |
Bassotti et al. 2012 | FED: 17, non-CC controls: 10 | Fewer glial cells in the enteric plexus; and reduced estrogen receptors β in the glial cells [ 75] |
Chan et al. 2013 | STC: 61 | Reduction in smoothelin immunoreactivity in the muscularis propria [ 76] |
A Korean study [
77] evaluating 14 patients with severe idiopathic CC undergoing subtotal colectomy with 10 non-constipated controls revealed myenteric ganglion cells (MGC) and interstitial cells of Cajal (ICC) to be reduced in patients as compared to controls. A study from China [
78] evaluated histopathology of 12 patients with STC and 8 age-matched normal controls. ICC was identified with a monoclonal antibody to c-kit by an indirect immunofluorescence method. Patients with STC showed a reduced number of ICC in all four regions (myenteric plexus, submucosal border, circular and longitudinal muscle layers). A study from Japan [
79] evaluated rectal biopsy specimens from patients with CC and age-matched normal controls for a number of neuroendocrine cells (NEC) within mucosal crypts using immunohistochemistry with antibodies against chromogranin-A (Ch-A) and serotonin (5-HT). The authors found a number of NEC to be significantly higher in patients with CC compared to controls.
A recent study from Delhi [
80] evaluated histopathology of resected colonic specimens from patients with chronic intestinal pseudo-obstruction. Desmosis was seen in all 8 subjects (100%), while intestinal neuronal dysplasia (IND), mesenchymopathy, lymphocytic myenteric ganglionitis, and leiomyopathy were noted in 4, 2, 1, and 1 patients, respectively. One patient with IND also had visceral myopathy.
Statement No. 15. Excessive methane production slows gut transit and is associated with CC
Voting summary: accepted completely 15 (51.7%), accepted with some reservation 9 (31.0%), accepted with major reservation 3 (10.3%), rejected completely 1 (3%)
Level of evidence: II-2
Grade of recommendation: B
About 30% to 62% of healthy humans harbor methane-producing bacteria in their gut [
81]. In vitro and in vivo studies indicate that methane inhibits GI motility and hence its level may inversely correlate with stool form and frequency [
82,
83]. Moreover, the area under the curve (AUC) for breath methane has been shown to correlate with severity of constipation [
82]. Furthermore, treatment with antibiotics aimed at gut methanogens has been shown to improve intestinal transit and constipation. A recent meta-analysis [
84] found a significant association between methane on a breath test and constipation (odd’s ratio = 3.51) and also an association between methane and delayed transit. There is limited data from India and the rest of Asia on the role of methane in CC.
A recent experimental study from Korea [
85] found that infusion of methane significantly decreased peristaltic velocity and increased contraction amplitude of guinea pig ileum. Another study from Korea [
86] found breath methane positivity to be significantly more frequent in patients with slow transit constipation than those with normal transit constipation and healthy controls (58.8%, 13.3%, and 12.2%, respectively). The left and total CTT were significantly higher in breath methane positive than negative patients.
A recent Indian study [
87] found a higher copy number of
Methanobrevibacter smithii in fecal samples of patients with IBS (particularly IBS-C) compared to healthy controls. The copy number negatively correlated with the stool frequency and was higher among methane producers than non-producers. The AUC for breath methane correlated with the
M. smithii copy number among methane producers. A randomized controlled trial from this same center showed that reduction of breath methane using rifaximin shortens CTT and improves constipation [
88].
Statement No. 16. Psychological issues are common in patients with CC
Voting summary: accepted completely 18 (62.0%), accepted with some reservation 11 (38%)
Level of evidence: II-2
Grade of recommendation: B
Psychological disorders have been reported to be associated with various functional gastrointestinal disorders (FGID’s) including CC and IBS [
89]. Many patients with CC have evidence of current or previous psycho-affective disorder [
90]. Anxiety, depression, and insomnia are the more commonly reported disorders. Psychological co-morbidities further impair quality of life in patients with CC [
91]. Patients with dyssynergic defecation and normal transit constipation or IBS-C are more likely to report psychological distress as compared to STC [
92‐
94]. There is limited published literature from Asia in general and India in particular on frequency and spectrum of psychological co-morbidities in patients with CC.
A study from China [
95] reported the presence of anxiety, depression, and sleep disorders in 41.5%, 38.3%, and 43.8%, respectively. These co-morbidities were more common in severely constipated patients than those with mild and moderate constipation; psychological co-morbidities also resulted in more hospital visits. A recent study from Hong Kong [
96] showed significantly higher anxiety and depression scores in patients with FC as compared to healthy controls. Anxiety and depression scores were higher in female patients, whereas male patients tended to use more coping strategies, and a number of coping strategies used correlated inversely with anxiety scores.
The landmark pan-Indian study [
5] reported a 60% prevalence of anxiety or depression while 39% subjects reported disturbed sleep. A study from New Delhi reported a 79.9% prevalence of ≥ 1 psychological co-morbidity in patients with IBS [
97]. The psychiatric co-morbidities observed in this study included anxiety, depression, panic syndrome, and somatoform disorders. Moreover, patients with severe disease had higher psychiatric co-morbidity. A recent study that evaluated frequency and risk factors of FGIDs in a rural Indian population found depression, anxiety, and disturbed sleep to be more common in patients with IBS and dyspepsia as compared to those without FGID [
6].
Statement No. 17. Solitary rectal ulcer syndrome is associated with FED
Voting summary: accepted completely 21 (72.4%), accepted with some reservation 5 (17.2%), accepted with major reservation 1 (3%), rejected completely 1 (3%)
Level of evidence: II-1
Grade of recommendation: B
Solitary rectal ulcer syndrome (SRUS) is a chronic benign rectal disorder affecting all age groups and presents with rectal bleeding, mucorrhea, tenesmus, constipation, and feeling of incomplete evacuation [
98]. Etiopathogenesis of SRUS remains unclear. Mucosal hypoperfusion/ischemia was proposed to be the causative factor in the past [
99]. A few recent studies reported the role of FED in the pathogenesis of SRUS [
100,
101]. There is limited data from India on the frequency of FED in patients with SRUS.
A case-control study from Lucknow, India [
102] showed that (a) 90% of patients with SRUS had CC (as per ROME III criteria), (b) patients with SRUS more often had FED as compared to healthy controls (as documented by balloon expulsion test [BET] and impaired anal relaxation), (c) more than half of patients with SRUS had abnormal defecography, (d) more than 40% of patients had functional defecation disorders according to Rome III criteria, and (e) those with abnormal BET had thicker internal anal sphincter (on endoscopic ultrasound examination) than those without. Another recent case-control study from Varanasi, India [
103] showed a higher frequency of FED in patients with SRUS as compared to healthy controls as documented by the presence of abnormal BET and impaired anal relaxation (53% vs. 20%; and 44% vs. 15%, respectively).