| Background and Objective Irritable bowel syndrome(IBS)is a common kind of functional bowel disease,and IBS with predominant diarrhea(IBS-D)is the most common subtype in China.The diagnosis of IBS is based on Rome criteria.Abdominal pain and abdominal discomfort are the key symptoms of IBS in Rome Ⅲ diagnostic criteria.However,22.4～84.3%of Chinese IBS patients diagnosed with Rome Ⅲ criteria only have abdominal discomfort without abdominal pain.Thus,the fact that "abdominal discomfort" has been removed from the diagnostic criteria of Rome IV might lead to a certain impact on the diagnosis and treatment of IBS in China.So far,it is unclear whether there are essential differences between abdominal pain and discomfort.The purposes of this study are:a)to investigate the cognition of abdominal pain and abdominal discomfort in Chinese IBS-D patients through cognitive interview and compare the characteristics through clinical symptom analysis;b)to compare visceral hypersensitivity between patients with abdominal pain solely and those with discomfort solely;to compare the differences of mast cell(MC)and specific nerve fibers in colonic mucosa,and the differences of brain activity in resting state between groups,to explore the pathophysiological mechanisms of abdominal pain and discomfort in IBS-D patients from peripheral and central levels.Material and Methods IBS-D patients who met Rome Ⅲ criteria and had episodes of atleast one day per week were consecutively enrolled,and all subjects with obvious anxiety or depression were excluded.The cognition of abdominal pain and discomfort was investigated through cognitive interview,and according to the defecation-related symptoms confirmed after cognitive interview,the patients were divided into abdominal pain group,abdominal discomfort group,abdominal pain and discomfort group.After cognitive interview,questionnaires were administrated to investigate the characteristics of abdominal pain and discomfort,extra-intestinal symptoms,pain in other parts,and past medical care.The degree of abdominal pain and discomfort was indicated by the visual analogue scale(VAS).The IBS symptom severity scale(IBS-SSS)and main intestinal symptom score were used to assess the severity of IBS,and the IBS quality of life(IBS-QOL)was used to evaluate life aualitv.Further studies ahout the pathophysiological mechanisms of IBS-D were conducted in patients of abdominal pain group and abdominal discomfort group with moderate to severe symptom(VAS≥ 4).Rectal sensory thresholds were measured by rectal barostat test.In sigmoid colon mucosa biopsy samples,total MCs and activated MCs number was monitored by immunohistochemistry staining,the area of nerve fibers with anti-protein gene product 9.5(PGP9.5),anti-transient receptor potential vanilloid-1(TRPV1)and anti-substance P(SP)positive immunoreactivity(IR)was measured by double immunofluorescence staining,and their relative protein expression was detected by western blot assay.The activity of brain regions was assessed by resting-state functional magnetic resonance imaging(rs-fMRI),and analyzed by the amplitude of low frequency fluctuation(ALFF)method.Healthy subjects were matched as controls.Results A total of 80 patients with IBS-D were included for cognitive interview and questionnaires.Among them,60 patients self-reported defecation-related abdominal pain,and most(42/60,70%)described pain as abdominal spasm/cramping;45 patients self-reported defecation-related abdominal discomfort,and nearly half(22/45,48.9%)described discomfort as indescribable/unspeakable discomfort,and some patients described abdominal discomfort in a variety of ways.Of 13.3%patients considered discomfort to be pain or mild pain.All patients with self-reported abdominal pain confirmed the existence of abdominal pain,and 26.7%with self-reported abdominal discomfort confirmed there was no defecation-related abdominal discomfort after cognitive interview.Based on the symptoms confirmed after cognitive interview,patients were divided into abdominal pain group(47 cases),abdominal discomfort group(20 cases),abdominal pain and discomfort group(13 cases).The patients in abdominal discomfort group were mainly males(80%),and the degree of abdominal pain in abdominal pain group was severer than the degree of discomfort in abdominal discomfort group(4.9±1.3 vs 3.7±1.0,P=0.001).There were no significant differences in location,frequency,duration of abdominal pain/discomfort,IBS-SSS score,main intestinal symptom score,proportion of pain in other parts,IBS-QOL score and medical care between the two groups.A total of 26 IBS-D patients with moderate to severe symptoms(16 cases in abdominal pain group and 10 cases in abdominal discomfort group)and 12 healthy controls were ernrolled in the valid data analysis of pathophysiological studies(only 8 cases completed sigmoid colon mucosa biopsy tests in abdominal discomfort group).The rectal sensory thresholds of IBS-D patients were lower than healthy controls,and 50%(13/26)patients had visceral hypersensitivity.The ratio of visceral hypersensitivity in abdominal discomfort group was higher than abdominal pain group(90%vs 25%,P=0.001).The thresholds of initial and persistent sensation of defecation in abdominal discomfort group were lower than abdominal pain group(P=0.010 and P=0.046 respectively),and the threshold of initial sensation of defecation was negatively correlated with the duration of abdominal discomfort(r=-0.648,P=0.043).The total number of MCs in sigmoid colon mucosa in abdominal pain group was not significantly different from that of abdominal discomfort group or healthy controls,but the number and ratio of activated MCs were higher than healthy controls.The ratio of activated MCs was negatively correlated with the maximum tolerance threshold(r=-0.555,P=0.039).The area of anti-TRPV1-IR and anti-SP-IR positive nerve fibers and their relative protein expression in abdominal pain group were significantly higher than those in healthy controls,but not significantly different from abdominal discomfort group.In abdominal pain group,the area of anti-SP-IR positive nerve fibers was positively correlated with the degree of abdominal pain(r=0.499,P=0.049),and negatively correlated with the threshold of urging to defecate(r=-0.519,P=0.048).No significant correlation was found between the above indicators and clinical manifestations in abdominal discomfort group.In resting state,there were differences in the activity of brain regions among abdominal pain group,abdominal discomfort group and healthy controls,involving right medial temporal lobe,right occipital lobe,right middle temporal gyrus,right ventral lateral prefrontal cortex(RVLPFC)and dorsal anterior cingulate cortex(dACC).The activity of RVLPFC in abdominal pain group was higher(P=0.000)than that in abdominal discomfort group,and the mean ALFF(mALFF)of RVLPFC was positively correlated with patients’ maximum tolerance threshold(r=0.520,P=0.047).The activity of dACC and right middle temporal gyrus was higher in abdominal discomfort group than in abdominal pain group(P=0.005 and P=0.000,respectively).Conclusions IBS-D patients in China were able to accurately experience and report abdominal pain,and there were certain individual differences in the perception and description of abdominal discomfort.Abdominal pain and abdominal discomfort are two different symptoms,but have similar clinical characteristics.Visceral hypersensitivity was more prominent in IBS-D patients with abdominal discomfort solely,and was related to the occurrence and persistence of abdominal discomfort.The activation of MCs,the increase of pain-related nerve fibers in sigmoid colon mucosa,and their association with visceral hypersensitivity indicated that the intestinal mucosal inflammation-immune-nerve mechanism played an essential role in the generation of abdominal pain.Abdominal pain was also related to the increased activity of brain regions that regulate pain and relevant emotions(RVLPFC),while the occurrence of abdominal discomfort primarily related with the regions responsible for complex cognitive function and fear regulation(dACC). |
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