Can we rely on the orocecal transit time measured by the lactulose breath test? Simultaneous measurement of Tc99m colloid scintigraphy and lactulose breath hydrogen test in asymptomatic volunteers

doi:10.21203/rs.3.rs-4339707/v1

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Can we rely on the orocecal transit time measured by the lactulose breath test? Simultaneous measurement of Tc99m colloid scintigraphy and lactulose breath hydrogen test in asymptomatic volunteers

https://doi.org/10.21203/rs.3.rs-4339707/v1

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INTRODUCTION: The measurement of orofecal transit time (OCTT) has various challenges; its calculation through the detection of hydrogen in exhaled air with lactulose (H2 breath test), a non-invasive and widely used technique, is controversial and not validated in the local population.

AIM: To demonstrate the correlation between techniques for measuring OCTT through the simultaneous use of intestinal scintigraphy with radiolabeled colloid (OCTT-R) and lactulose breath hydrogen test (OCTT-H2).

METHOD: Healthy volunteers over 18 years old underwent a 12-hour fast, followed by oral administration of colloid sulfur mixed with lactulose. Simultaneously, abdominal images were obtained using a gamma camera, and breath samples were collected every 10 minutes for 180 minutes. The lactulose orocecal transit time (OCTT-H2) was considered when the curve elevation exceeded 20 ppm above the baseline value, after the first 60 minutes of the study. The orocecal transit time with radioisotopes (OCTT-R) corresponding to 50% activity of the tracer administered in the cecum was quantified.

RESULTS: Seventeen patients aged between 22 and 77 years (82% women) were included. OCTT-R varied between 73 and 180 minutes and OCTT-H2 between 60 and 130 minutes. OCTT-R with radioisotopes and OCTT-H2 showed a good correlation (r: 0.794; 95% CI: 0.508 - 0.923). Results of orocecal transit time with radioisotopes versus H2 did not have significant differences (p= 0.959).

CONCLUSION: OCTT-H2 is feasible to measure using lactulose as a substrate with a good correlation and no difference with isotopic technique.

The hydrogen breath test is based on the ability of the intestinal microbiota to ferment various types of orally administered sugars (such as lactose, glucose, or lactulose), producing short-chain fatty acids and the gases hydrogen (H2) and methane (CH4). These gases diffuse into the blood and pulmonary circulation, eventually being eliminated in exhaled air, making it possible to detect them using a gas chromatograph (1, 2). Measuring H2 in this way allows for the evaluation of malabsorption of certain nutrients such as lactose and fructose, as well as the presence of small intestinal bacterial overgrowth (SIBO) using substrates like glucose or lactulose. Additionally, it can provide a temporal approximation of sugar fermentation by the colonic microbiota, known as orocecal transit time (OCTT), for which the optimal non-invasive measurement method is not well defined. Global digestive tract transit can be calculated using a radio-opaque capsule without guides, which correlates well with radiopaque markers (3, 4). Radiopaque markers continue to be used to measure gastrointestinal transit (5).

In our setting, the most used method for detecting SIBO is through lactulose as a substrate, which is a non-absorbable carbohydrate. There are differences and controversies regarding the criteria for defining SIBO and OCTT; currently, the American and European consensus does not align in their definition, indicating that OCTT measurement is not recommended. The aim of our study is to determine the agreement between the hydrogen breath test with lactulose and the transit with radioisotopes in detecting OCTT, comparing the arrival of the radioisotope in the cecum (OCTT-R) and the rise in H2 levels corresponding to (OCTT-H2) following the oral administration of lactulose.

Descriptive, observational, cross-sectional, prospective study was conducted on asymptomatic volunteers over 18 years old. Pregnant women, patients with a history of other gastrointestinal disorders (such as liver cirrhosis, peptic ulcer, inflammatory bowel disease, irritable bowel syndrome), or other pathologies that could alter OCTT (such as diabetes mellitus, Parkinson's disease, and scleroderma, among others), abdominal surgery, recent or current use of medications that modify gastrointestinal transit (prokinetics and laxatives), antibiotic use in the last 15 days, and patients with a BMI > 35 kg/m2 were excluded. Patients with findings of small intestinal bacterial overgrowth (SIBO) were excluded from the analysis. Investigators from both the gastroenterology and nuclear medicine laboratories were blinded to the results of the other technique.

The OCTT-R was obtained using a GE Starcam2 gamma camera at the Nuclear Medicine. Simultaneously, the OCTT-H2 in exhaled air was determined using a QuinTron BreathTracker gas chromatograph (USA), which measures parts per million (ppm) of H2 and CH4. Participants followed a standard diet the day before the examination (low-fiber and carbohydrate-poor foods), and their last meal was at 8:00 PM. After fasting for 8 to 12 hours, a baseline sample of H2 in exhaled air was collected. Subsequently, 12 ml of 65% lactulose (equivalent to 10 grams) diluted in 200 ml of distilled water, along with 111 MBq (3 mCi) of Tc99m colloidal sulfur diluted in 120 ml, was orally administered. Immediately afterward, anterior-posterior, and posterior-anterior abdominal images were acquired for geometric mean calculation, after correcting for radioactive decay. Simultaneously, breath samples were collected serially every 10 minutes for 3 hours, following a standardized technique (2). OCTT-R was considered present when 50% of the radiopharmaceutical was observed in the cecum. OCTT with lactulose (OCTT-H2) was defined as a curve elevation exceeding 20 ppm above the baseline value after the first 60 minutes of the study.

The variables were described using frequencies (absolute and relative percentage) and measures of central tendency (median, interquartile range, mean, and standard deviation), according to the data distribution assessed by the Shapiro-Wilk test. Nominal and categorical variables will be analyzed using the chi-square test x2. Comparisons were made using the Wilcoxon test, and group correlations were assessed using Pearson correlation, considering a statistically significant result at p < 0.05. Statistical analysis was performed using SPSS software version 29.

This study was approved by the Scientific Ethics Committee and the Directorate of the Clinical Hospital of the University of Chile and follows the Declaration of Helsinsky. All patients signed informed consent before participating in the study. This study was framed within the project OAIC N°530/12.

Seventeen procedures were analyzed. The age of the participants ranged from 22 to 77 years (median 48 years). The majority (82%) were women and were in a normal nutritional state (53%). Table 1 presents the characteristics of the sample. The median of the initial observation of radiocolloid activity in the cecum was 60.0 minutes, with an interquartile range of 45.5 to 63.0 minutes. The average gastric emptying, it was 34 ± 6.4 minutes. OCTT-R 50% ranged from 73 to 180 minutes (mean 108 min) in the 17 procedures (OCTT-R-17). Regarding demographic variables, it was observed that age and nutritional status were not associated with OCTT-H2 or OCTT-R determined by expired air (p = ns). Gender trends could not be analyzed due to the low number of male cases. When evaluating the relationship of results between OCTT-R with radioisotopes and OCTT-H2, a high positive correlation (r: 0.794; 95% CI: 0.508–0.923) were observed (Fig. 1). Interestingly, when comparing the results of orocecal transit time with radioisotopes versus H2, no significant differences were observed between the evaluations (p = 0.959).

Table 1

Characteristics of the studied group and data obtained from radioisotope technique and lactulose breath test.
Characteristics	N	OCTT- R p value	OCTT- H2 p value
Total subject (n)	17
Sex		.258 ^§	.094 ^§
Male (n, %)	3 (17.6)
Female (n, %)	14 (82.4)
Age (years; mean ± SD)	48 ± 15.62	.096 ^§	.451 ^§
Nutritional Status (n, %)		.877 ^§	.352 ^§
Underweight	2 (11.8)
Normal range	9 (52.9)
Overweight	5 (29.4)
Obese	1 (5.9)
Cecum Visualization (minutes; median, IQR)	60 (45.5–60.0)	.244 ^§	.421 ^§
OCTT- R (minutes; mean ± SD)	108.1 ± 26.73	-	.959 ^†
OCTT- H2 (minutes; mean ± SD)	107.65 ± 30.11	.959 ^†	-
Note: Interquartile Range (IQR); Standard Deviation (SD). Adjusted time for 50% radioisotope presence in the cecum (OCTT- R); Orocecal Transit Time by H2 Breath Test with lactulose (OCTT- H2). § Chi-square test. † Wilcoxon test.

Despite the limited number of cases in our study, there was a good correlation in the measurement of orocecal transit time (OCTT) between both techniques (Fig. 2). The use of lactulose, a non-absorbable disaccharide, in hydrogen breath tests allows the evaluation of bacterial metabolism, and in the absence of bacterial overgrowth, an indicator of OCTT is the arrival of this sugar in the colon. There are various methods for measuring gastrointestinal transit with isotopes; however, In¹¹¹ is preferred over Tc^99m as a tracer for the intestine, especially in cases of constipation, due to its longer half-life. The technique is non-invasive, quantitative, and physiological, providing a low radiation dose and allowing the assessment of various gastrointestinal motility disorders (6). OCTT-R is not routinely measured in clinical practice; published values for gastrointestinal transit using radionuclides in adults vary depending on the technique used, diagnostic criteria, age, and gender. The reproducibility of scintigraphy for measuring colonic transit is good and allows evaluation of the stomach, small intestine, and large intestine, even in the pediatric population. It is useful for monitoring cases with intractable constipation using a technique with two radiopharmaceuticals with different half-lives; unfortunately, In¹¹¹ is not available in our setting (7).

Maurer et al. (2) presented a study in patients with Irritable Bowel Disease (IBS) using Tc99m and lactulose, like our experience. Their results revealed that subjects with an early rise in the H2 curve corresponded to variations in OCTT and not SIBO. Differences with our results may be influenced primarily by the methodology used, genotype, and the presence of a different intestinal flora. In terms of methodology, the authors used a test meal labeled with Tc99m, adding lactulose separately, while we mixed lactulose directly with radiolabeled colloidal sulfur. We chose this approach as we are uncertain about the impact of a meal in the H2 breath test, given that this examination is normally conducted after a fasting period of at least 12 hours.

In the retrospective study by Lin et al. (8), which included 139 patients, it was demonstrated that the H2 test with glucose had a high rate of false positives when compared to scintigraphy using DTPa-Tc99m up to 3 hours of observation; in this case, almost a third of the patients had undergone digestive surgery. Since glucose is absorbed in the proximal small intestine and rarely reaches the colon, we consider that studies with glucose are not truly comparable to those with lactulose.

Zhao et al. (9), in another Chinese study involving 94 patients and 13 controls, used the lactulose breath test and scintigraphy with DTPA-Tc99m to analyze the validity of the methodology for detecting SBI in IBS. They concluded that both tests combined are useful, and not independently.

The latest American consensus considers SIBO as values greater than 20 ppm above the baseline of H2 up to 90 minutes. In our experience, most patients show a sustained rise in the curve from 90 minutes onwards, persisting until the 180-minute mark, suggesting that lactulose has already reached the colon. Therefore, it would correspond to the presence of TTOC and not SBI. Considering an elevation of the curve up to 90 minutes as SBI, according to our experience, leads to overdiagnosis of SBI. In our group's research, in 3719 studies using our SBI criteria (elevation at least 2 times in the first 60 minutes), SBI was diagnosed in 41% of them (cohort of symptomatic patients), whereas using the American consensus of 90 minutes increased the SBI diagnosis to 77%. This could result in overtreatment of a significant number of patients (10).

Considering the existing controversies, is evident that more studies with a larger patient cohort are needed to determine the accuracy of OCTT study techniques. Considering the isotopic technique (OCTT-R) as the gold standard, our findings support the usefulness of OCTT-H2 obtained with lactulose, since its results are not significantly different and present high agreement with the arrival of the radiopharmaceutical to the colon.

Author Contribution

All authors contributed to the article and approved the submitted version. Christian von Muhlenbrock: Writing - original draft, Writing - review & editing.Ana Maria Madrid and Teresa Massardo: Conceptualization, Methodology, Formal analysis, Review & editing.Pablo Muñoz: Conceptualization and MethodologyGlauben Landskron and Karin Herrera: Formal analysis, Tables and Figures, Writing - review & editing.

Acknowledgments

Karin Hererra is grateful to the Excellence Program “Nutrición y Ciencias de los Alimentos” from the University of Granada.

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No competing interests reported.

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Can we rely on the orocecal transit time measured by the lactulose breath test? Simultaneous measurement of Tc99m colloid scintigraphy and lactulose breath hydrogen test in asymptomatic volunteers

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