Search results
Bile Acid Diarrhoea (Bad)
3,173 citations were identified. Of these, 94 were potentially relevant and the full text of these citations were retrieved for full evaluation. 15 papers were included, 79 papers did not satisfy the eligibility criteria (Supplementary Fig. 1).
Nine studies reported the prevalence of BAD based upon an abnormal SeHCAT scan. Two studies used elevated faecal bile acids over 48 hours and one study used an elevated serum 7α-C4 level. The remaining three studies used two diagnostic tests (SeHCAT scan and 7α-C4 level, total 48-hour faecal bile acids and 7α-C4 level).
Prevalence of a positive SeHCAT scan in patients fulfilling IBS criteria
The ten studies that reported the prevalence of BAD based upon an abnormal SeHCAT study are shown in Supplementary Table 1. Across the ten studies, seven different 7-day SeHCAT retention cut-off values (i.e. <5%, < 10%, < 11%, < 11·7%, < 15%,) were used. The two studies which had reported values within 2% of the < 10% cut-off (i.e. <8% to < 12%) were included in the prevalence calculation of the 7-day SeHCAT < 10% subgroup. Six papers [33–38] demonstrated the change in their rates of positive scans by using different cut-off values but only one [36] assessed treatment response to cholestyramine by comparing with placebo. Nevertheless, a previous systematic review showed that the response rate to bile acid sequestrants was higher in patients with severe BAD than those with mild or moderate disease [24]. One study [38]evaluated and compared the prevalence of BAD with different SeHCAT retention values as a result of using the Rome III and Rome IV criteria, respectively, to define their patients.
7-day SeHCAT retention < 5% (severe BAD)
Six studies reported prevalence using a 7-day cut-off value of < 5%. If the Rome III criteria were used in the paper by Shiha et al., the crude pooled rate would be 10·7% (range 2·6–53·8%) out of 580 patients and the estimated pooled rate would be 11% (95% CI 5–17%, Supplementary Fig. 2) by the random effects model. If the Rome IV criteria were used instead, the crude pooled rate would be 11·1% (range 2·6–53·8%) out of 546 patients and the estimated pooled rate would be 12% (95% CI 5–18%, Fig. 1). There was significant heterogeneity in both effect sizes (Q-test X2 = 32·4, P < 0·0001; I2 = 84·5% and Q-test X2 = 33·2, P < 0·0001; I2 = 85·0%).
7-day SeHCAT retention < 10% (moderate and severe BAD)
Seven studies reported prevalence using a 7-day cut-off value of < 10%. Additionally, two studies reported the prevalence using < 11% and < 11·7% as the cut-off. If the Rome III criteria were used in the paper by Shiha et al., the crude pooled rate would be 27·2% (range 7·8–65·3%) out of 907 patients and the estimated pooled rate would be 30% (95% CI 20–40%, Supplementary Fig. 2) by the random effects model. If the Rome IV criteria were used instead, the crude pooled rate would be 27·7% (range 2·6–53·8%) out of 873 patients and the estimated pooled rate would be 30% (95% CI 20–41%, Fig. 1). There was significant heterogeneity in both effect sizes (Q-test X2 = 114·0, P < 0·0001; I2 = 93·0% and Q-test X2 = 112·7, P < 0·0001; I2 = 92·9%).
7-day SeHCAT retention < 15% (mild, moderate and severe BAD)
Seven studies reported prevalence using a 7-day cut-off value of < 15%. If the Rome III criteria were used in the paper by Shiha et al., the crude pooled rate would be 34·5% (range 23·7–84·6%) out of 597 patients and the estimated pooled rate would be 41% (95% CI 29–54%, Supplementary Fig. 2) by the random effects model. If the Rome IV criteria were used instead, the crude pooled rate would be 34·8% (range 2·6–53·8%) out of 563 patients and the estimated pooled rate would be 42% (95% CI 29–54%, Fig. 1). There was significant heterogeneity in both effect sizes (Q-test X2 = 63·2, P < 0·0001; I2 = 90·5% and Q-test X2 = 63·5, P < 0·0001; I2 = 90·6%).
Prevalence of elevated total 48-hour faecal bile acid level in patients fulfilling IBS criteria
Four studies including 1,077 patients used an elevated level of total faecal bile acids over 48 hours to make a diagnosis of BAD (Supplementary Table 7). In three studies, an elevated faecal bile acid concentration > 2,337 µmol per 48 hours was considered diagnostic. The remaining study used 2,619 µmol per 48 hours. The crude pooled rate was 10·6% (range 7·4–35·2%). The estimated pooled rate was 25% (95% CI 8–43%, Supplementary Fig. 5) by the random effects model. There was significant heterogeneity in effect sizes (Q-test X2 = 38·2, P < 0·0001; I2 = 92·2%).
Prevalence of elevated serum 7α-C4 in patients fulfilling IBS criteria
All four studies including 232 patients used different cut-off values of 7α-C4 to make a diagnosis (Supplementary Table 8). The crude pooled rate was 22·4% (range 13·3–33·3%). The estimated pooled rate was 22% (95% CI 16–27%, Supplementary Fig. 6) by the random effects model, with no heterogeneity in effect sizes (Q-test X2 = 3·0, P = 0·4; I2 = 0·0%). However, Dior et al. mentioned that none of their IBS patients would have had BAD if 47·1ng/mL was chosen as the cut-off value, the level used by Camilleri and colleagues in their study. This would have resulted a crude pooled rate of 20·3% (range 0–24·1%) and an estimated pooled rate of 16% (95% CI 7–26%, Q-test X2 = 9·0, P = 0·03; I2 = 66·5%).
Carbohydrate Malabsorption (Cm)
875 citations were identified. Of these, 97 appeared to be potentially relevant and the full texts of these citations were retrieved for full evaluation. 39 were included and 58 papers did not satisfy the eligibility criteria (Supplementary Fig. 7).
The carbohydrates studied included lactose, fructose, sorbitol and mannitol. Using hydrogen breath testing, 28 studies evaluated lactose malabsorption and/or intolerance; 12 examined fructose malabsorption and/or intolerance and six examined alterative or mixed forms of CM. Five groups utilised genotyping studies to identify lactase deficiency. Several of these studies reported prevalence of more than one form of CM.
Prevalence Of Lactose Malabsorption In Patients Fulfilling Ibs Criteria
The 26 studies, including 6,700 patients, reported the prevalence (Supplementary Table 9). Doses of lactose used in two studies [39, 40] were different, which resulted in a high variability in the rates of lactose malabsorption. The lowest and highest reported rates from these two studies gave respective crude pooled rates of 47·3% (range 4·1–87·3%) and 48·2% (range 4·1–93·3%) over the 26 studies. Similarly, the estimate pooled rates were 50% (95% CI 41–59%) and 54% (95% CI 44–64%), respectively (Fig. 2). There was significant heterogeneity in both effect sizes (Q-test X2 = 1,627·3, P < 0·0001; I2 = 98·5% and Q-test X2 = 1,871·6, P < 0·0001; I2 = 98·7%).
In addition to lactose malabsorption, nine of these 26 studies also evaluated the prevalence of lactose intolerance, which is generally defined as a positive breath test along with increased abdominal symptoms after ingestion of lactose. However, two other studies [41, 42] interpreted a positive breath test as lactose intolerance, even in the absence of abdominal symptoms. One of these 11 studies used different dosages of lactose for breath testing [40]. 3,303 patients with IBS were assessed in total. The lowest and highest crude pooled rates from these 11 studies were 38% (range 18·3–71·7%) and 39·2% (range 21·0–85·0%), respectively. The estimated pooled rates were 40% (95% CI 31–49%) and 46% (95% CI 35–57%), with significant heterogeneity in both effect sizes (Q-test X2 = 146·3, P < 0·0001; I2 = 93·2% and Q-test X2 = 231·1, P < 0·0001; I2 = 95·7%, Supplementary Fig. 11).
Five studies including 970 patients applied genotyping studies to identify the homozygous state of a genetic variant, C/C-13910, for adult-type hypolactasia, also known as lactose intolerance (Supplementary Table 10). Two of these studies also evaluated another genetic variant, G/G-22018, which has also been shown to be associated with lactase deficiency, leading to lactose intolerance. The crude pooled rate for lactose intolerance as a result of the C/C-13910 gene was 37·9% (range 15·1-100·0%). The estimated pooled rate was 62% (95% CI 27–91%, Supplementary Fig. 11) by the random effects model, with significant heterogeneity in the effect sizes (Q-test X2 = 412·2, P < 0·0001; I2 = 99·0%).
The crude rate of lactose intolerance with the G/G-22018 gene in 225 patients from the two studies was 60·4% (range 47·2–68·0%).
Prevalence Of Fructose Malabsorption In Patients Fulfilling Ibs Criteria
13 studies evaluated the prevalence of fructose malabsorption, including 3,415 patients, using breath testing (Supplementary Table 11). One of the studies [43] used two different dosages of fructose for breath testing, resulting in a difference in the reported rates. The lower and higher crude pooled rates from all 13 studies were 66·4% and 66·7%, respectively (range 3–76·1%). Using random effects models, the estimated pooled rates were 41% (95% CI 21–60%) and 43% (95% CI 23–62%), respectively (Fig. 3). Significant heterogeneity was noted in both effect sizes (Q-test X2 = 1,434·2, P < 0·0001; I2 = 99·2% and Q-test X2 = 1,401·4, P < 0·0001; I2 = 99·1%).
Four of these 12 studies, including 2,590 patients, also examined the prevalence of fructose intolerance, in addition to fructose malabsorption. The crude pooled rate was 60·9% (range 7·8–64·1%). Using the random effect model, the estimated pooled rate was 37% (95% CI 2–71%), with a significant heterogeneity in effect sizes (Q-test X2 = 376·3, P < 0·0001; I2 = 99·2%, Supplementary Fig. 16).
Prevalence of alternative or mixed forms of CM in patients fulfilling IBS criteria
Six studies shown (Supplementary Table 12) reported the rates of alternative or mixed forms of CM.
Three studies investigated sorbitol malabsorption in a total of 91 patients and gave a crude rate of 47·3% (range: 35·3–60·0%). The estimated prevalence was 48% (95% CI 34–62%), with homogeneity demonstrated between studies (Q-test X2 = 3·7, P = 0·15; I2 = 46·4%, Supplementary Fig. 17).
Two groups reported that 31·4% and 70·2% of their patients fulfilling IBS criteria had a positive breath test for combined fructose-sorbitol malabsorption. Another group concluded that 9·4% of patients had either lactose or combined fructose-sorbitol malabsorption. One of the groups also reported that 20% of patients also had mannitol malabsorption.
Microscopic Colitis (Mc)
The search identified 1,484 citations. Of these, 91 were potentially relevant and full texts of these citations were retrieved. 17 papers were included, 74 did not satisfy our eligibility criteria (Supplementary Fig. 18 and Table 13). Four of these 17 studies reported the prevalence of MC but did not specify the subtype, one study only reported patients with lymphocytic colitis. The remaining 12 studies reported the prevalence of both lymphocytic and collagenous colitis, defined by a confirmed histological diagnosis (> 15 or > 20 lymphocytes in 100 epithelial cells for lymphocytic colitis and > 10 µm or > 15 µm thickened sub-epithelial collagen band for collagenous colitis).
Prevalence Of Mc In Patients Fulfilling Ibs Criteria
5,068 patients were included. The overall crude pooled rate for MC, including both subtypes, lymphocytic and collagenous colitis, was 2·9% (range 0·6–36·7%). The overall estimated rate was 3% (95% CI 2–4%, Fig. 4). There was significant heterogeneity in effect sizes (Q-test X2 = 115·8, P < 0·0001; I2 = 86·2%). Three studies [44–46] were deemed to be of high risk of bias and after excluding them a repeat analysis estimated the prevalence of MC to be 4% (95% CI 2–5%), and the level of heterogeneity between studies remained unchanged (Q-test X2 = 107·0, P < 0·0001; I2 = 87·9%, Supplementary Fig. 19).
Crude pooled rates from the studies were 2·4% out of 3,927 patients (range 0–36·7%) for lymphocytic colitis and 0·5% out of 3,850 patients (range 0–7·2%) for collagenous colitis; estimated rates were 5% (95% CI 2–9%) and 0% (95% CI 0–1%), respectively (Fig. 4). Significant heterogeneity between studies was noted in both groups (Q-test X2 = 193·4, P < 0·0001; I2 = 93·8% and Q-test X2 = 37·6, P = 0·02; I2 = 70·8%).
Pancreatic Exocrine Insufficiency (Pei)
The search strategy identified 314 citations. Of these, 11 appeared to be potentially relevant and the full text of these citations were retrieved. Two papers were included, nine did not satisfy our eligibility criteria (Supplementary Fig. 24). Both papers utilised faecal elastase-1 to diagnose PEI.
Prevalence Of Pei In Patients Fulfilling Ibs Criteria
A meta-analysis was not performed due to the number of papers identified. The two papers gave a crude rate of 4·6% (22/478), ranging between 1·8% and 6·1% (Supplementary Table 14).
Small Intestinal Bacteria Overgrowth (Sibo)
The search strategy identified 1,674 citations. Of these, 114 appeared to be potentially relevant and the full text of these citations were retrieved. 59 papers were included, 55 did not satisfy our eligibility criteria (Supplementary Fig. 25).
55 studies evaluated the prevalence of SIBO within their IBS patient cohorts utilising breath testing with glucose and lactulose. Three of these studies, alongside an additional four studies, examined small bowel fluid from their patients to identify those with SIBO (Supplementary Table 15).
Prevalence Of Sibo In Patients Fulfilling Ibs Criteria
Lactulose was used in 36 studies including 4,630 patients as the substrate for breath testing. One group compared and demonstrated a wide variation in the prevalence of SIBO by using six different diagnostic criteria to define their breath tests as positive [47]. If the lowest and highest reported rates from this study were adopted, the overall crude pooled rates for SIBO diagnosed by lactulose breath testing would be 43·7% and 45·1% (range 0–83·8%), respectively. Similarly, the estimated pooled rates would be 46% (95% CI 37–55%) and 49% (95% CI 40–57%), with significant heterogeneity in both effect sizes (Q-test X2 = 1,199·3, P < 0·0001; I2 = 97·1% and Q-test X2 = 1,142·5, P < 0·0001; I2 = 96·9%, Fig. 5).
Glucose was utilised as the substrate for breath testing in 22 studies including 2,149 patients. The crude pooled rate was 24·9% (range 0–48·5%) and the estimated pooled rate was 19% (95% CI 13–27%, Fig. 6). There was significant heterogeneity in the effect sizes (Q-test X2 = 354·9, P < 0·0001; I2 = 94·1%).
Seven studies examined 608 patients’ small bowel fluid to diagnose SIBO. The overall crude pooled rate was 14·5% (range: 4·2–37·5%) and the estimated pooled rate was 13% (95% CI 4–25%, Supplementary Fig. 32). There was significant heterogeneity in the effect sizes (Q-test X2 = 77·3, P < 0·0001; I2 = 92·2%).