Expanding Criteria for Slow Colonic Transit in Patients Being Evaluated for Chronic Constipation by Scintigraphy

Abstract

Background:

Colonic transit measurement [geometric center (GC) at 24 and 48 hours] identifies slow transit constipation (STC) in patients with chronic constipation.

Aim:

To evaluate the utility of the difference between GC24 and GC48 (Δ_48–24) to identify STC in adults with chronic constipation.

Methods:

We reviewed medical records of 250 patients, aged 18–75 years, who underwent colonic transit by scintigraphy during 1994–2019 for investigation of chronic constipation. Data collected included demographics, medical and surgical histories, and anorectal manometry. We used colonic transit from 220 healthy controls to identify the 5^th percentile for diagnosing STC: 1.3 at 24h, and 1.9 at 48h. In addition, the 5^th percentile for Δ_48–24 was 0.38 for females and 0.29 for males. Data are reported as median and IQR [Q1, Q3]).

Key Results:

Among the 250 patients [median age 42.5y (IQR 30.75, 56), 84% female], based on GC24 <1.3, 52 (20.8%) had STC (3 males, 49 females); and based on GC48 <1.9, 28(11.2%) had STC (3 males, 25 females). Colonic transit was normal in 74.8%. In the groups with normal GC24 and GC48, Δ_48–24 identified an additional 32(15.1%) of 212 female patients and 4 (10.5%) of 38 male patients with slow progression of colonic transit between 24 and 48 hours. Among these 36 patients with abnormal Δ_48–24, 13(36.1%) had evidence of rectal evacuation disorder.

Conclusions & Inferences:

Δ_48–24 measurement on scintigraphic colonic transit can identify an additional 9.2% of STC in patients with constipation without rectal evacuation disorder, and can help individualize treatment of chronic constipation.

Graphical Abstract

INTRODUCTION

Constipation was ranked sixth among all leading gastrointestinal indications for ambulatory visits and constituted the reason for a total of 1,597,769 office and emergency department visits in the U.S. in 2014 (1). Constipation is categorized into two groups based on its timing: acute or chronic. Chronic constipation is a common clinical problem with high prevalence in the community, between 2 to 27% in western countries. It is defined as constipation lasting more than four weeks. Primary chronic constipation is classified into three main categories: constipation with normal colonic transit measurement, slow transit constipation (STC), and rectal evacuation disorders (2). In the subset of patients with STC, emptying of the colon is prominently delayed. There is a need for the proper diagnosis of the type of chronic constipation in order to select the best treatment options for each subgroup (3). The STC group is particularly relevant, owing to the fact that there are several diagnostic methods available to detect this category of constipation, and there are also possible therapeutic or surgical interventions indicated to relieve the condition. For example, identifying patients with STC could prioritize the use of prokinetic agents (e.g., bisacodyl, tegaserod, prucalopride) to treat the condition (3).

Diagnostic tests to identify STC include radiopaque markers (4, 5) and wireless motility capsule (6, 7), which typically provide one overall measurement. Scintigraphic colonic transit measurement is available at few centers and facilitates assessment of transit at different times after radiotracer ingestion, or regional transit such as the ascending colon emptying time (8–10). There are two recognized methods for measuring colonic transit by scintigraphy. One employs a methacrylate-coated, delayed release capsule containing ¹¹¹In-activated charcoal (8) to deliver solid particles to the ileocolonic region for bolus transfer to the colon (11), and is followed over 48 hours. The other method involves using water radiolabeled with ¹¹¹In-DTPA administered with a meal and followed through its colonic transit over 72 hours (9). Both methods are recognized in a practice guideline issued by the Society of Nuclear Medicine and Molecular Imaging and the European Society of Nuclear Medicine (12), and by the American and European Neurogastroenterology and Motility Societies (13).

Another advantage of the scintigraphic method is that the study is conducted over 48 or 72 hours, in contrast to radiopaque marker methods that usually take 4, 5, or 7 days (8).

Colonic transit measurement can differentiate normal from slow transit constipation in patients with chronic constipation. Based on a prior study of 1411 patients (3), 61 (4.3%) patients had slow colonic transit based on geometric center at 24 hours (GC24) <1.7 or GC at 48 hours (GC48) <3; these cut-offs were derived from studies in 37 healthy controls (14). These data suggested that STC was a relatively rare form of chronic constipation; however, this appraisal was based on cut-offs derived from a relatively small healthy control group. Our hypothesis was that a group of patients with chronic constipation with normal values of GC24 and GC48 may manifest slow movement of the radiotracer through the colon between these two times, suggesting delayed transit. The objective of the current study was to evaluate the utility of GC24 and GC48 individually to identify STC, based on cut-offs from 220 healthy controls, as well as identify the additional STC cases based on the difference between GC24 and GC48 (Δ_48–24) in adult patients presenting with chronic constipation.

METHODS

Design

This review of medical records at Mayo Clinic, Rochester, Minnesota was approved by Mayo Clinic Institutional Review Board for the patients who had granted consent for further use of their medical records for research.

Study Population and Colonic Transit Measurement

A cohort of 250 consecutive patients, aged 18–75 years and both genders, was chosen for inclusion in the study. They had undergone colonic transit measurements by scintigraphy over 48 hours during 1994–2019 for investigation of chronic constipation. We excluded patients with previous history of colonic obstruction, structural diseases of the colon or ileus.

Scintigraphic colonic transit was performed using a well-validated and standardized method with imaging at 24 and 48 hours (3)(8). This method involves simple binding of ¹¹¹InCl₃ to activated charcoal particles, placing the dried slurry into a gelatin capsule and immersing the capsule in a solution of methacrylate for 3–6 minutes; the whole process (usually performed for a batch of capsules weekly) is accomplished by a trained technologist in 60–90 minutes. Ideally, this can be done at a central radiopharmacy and this would be a requirement for broader application of the scintigraphic colonic transit test. Patients were instructed to stop all medications with potential effects on gastrointestinal or colonic transit 48 hours before the start of the transit measurement. The capsule was ingested after overnight fast. Anterior and posterior gamma camera images were obtained for measurement of colonic transit at 4, 24 and 48 hours after capsule ingestion.

Data extraction included demographics, medical history, history of abdominal or pelvic surgery, constipation duration, rectal evacuation disorder based on anorectal manometry, medication list, history of malignancy, and scintigraphic colonic transit values for GC24 and GC48. Δ_48–24 was calculated for each patient by subtracting GC24 from GC48. Anorectal manometry was available in 196/250 patients and was based on high resolution manometry in recent years; rectal evacuation disorder was defined by the combination of findings from digital rectal examination and anorectal manometry, taking into account the normal values based on age and gender: high anal resting pressure, low percentage of anal relaxation, prolonged balloon expulsion time, and abnormal rectoanal pressure differential (15).

Healthy Control Values

We used colonic transit from 220 healthy controls (145 females, 75 males for GC24; and 136 females, 63 males for GC48) to identify the 5^th percentile for diagnosing slow transit; the cut-offs included were: GC 1.3 and 1.5 at 24h for female and male participants, respectively, and GC 1.9 and 2.1 at 48h for female and male participants, respectively (16). GC values of 1 and 5, respectively, meant all isotope was in the ascending colon and stool. In addition, the 5^th percentile for Δ_48–24 was 0.38 for females and 0.29 for males.

Data Analysis of Colon Transit by Scintigraphy

Colonic transit results were evaluated by calculation of the GC; that is, the weighted average of the radioactivity in the 4 regions of the colon [ascending (AC), transverse (TC), descending (DC), rectosigmoid (RS)] and stool (3):

$$\text{GC}\text{=}\frac{\left[\left(\%\text{AC}\times 1\right)+\left(\%\text{TC}\times 2\right)+\left(\%\text{DC}\times 3\right)+\left(\%\text{RS}\times 4\right)+\left(\%\text{stool}\times 5\right)\right]}{100}$$

Values for GC24 and GC48 were extracted for all of the eligible patients. Δ_48–24 was calculated for each patient by subtracting GC24 from GC48. All data were reported as median and IQR (Q1,Q3). Δ_48–24 was evaluated for female and male groups separately. The control data, as well as the patient data, did not control for phase of the menstrual cycle. In a study that evaluated effects of menstrual cycle, Hinds et al. found no significant differences in colonic transit between phases of the menstrual cycle, and colonic transit in women was slower than in men, but not statistically significantly different. They recommended that, in the clinical setting, colonic transit studies can be performed throughout the menstrual cycle or when taking oral contraceptives (17).

RESULTS

Demographics, Co-morbidities and Concomitant Medications

Among the 250 patients, 212 (84.8%) were female and 38 were male. Evidence of rectal evacuation disorder (based on at least two manometric criteria listed above) was present in 100 (40%) patients and absent in 96 (38.4%) patients; anorectal manometry was not tested in 54 (21.6%) patients in whom there were no clinical (history or rectal examination) findings to suggest rectal evacuation disorders.

Other co-morbidities and concomitant medications in the entire patient cohort are shown in Table 1. We noted that 32.8% (82 patients) were receiving selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors, 32.8 % (82 patients) were receiving benzodiazepines or gabapentin, 19.6% (49 patients) were receiving ondansetron, and 16.4% (41 patients) were on thyroid hormone replacement.

Table 1.

Cohort demographics, rectal evacuation disorder, medical history and medications for all patients and by each gender. Data represented as N (%) or median (IQR).

Demographics	Total	Male	Female
Age when transit was done, years	42.5 (30.75,56)	44(29,59.2)	42(31,55.7)
Gender	250	38(15.2%)	212(84.8%)
Body mass index, kg/m2	23.2 (20.74,28.15)	25.3(21.8,28.8)	23(20.5,27.9)
Colonic Transit
Geometric center at 24 hours (GC24)	1.7 (IQR 1.3, 2.0)	1.8(1.5,2.2)	1.65(1.3,1.9)
Geometric center at 48 hours (GC48)	2.5 (IQR 2.0, 3.6)	2.65(2.2,4.07)	2.5(2,3.4)
Delta GC48 - GC24	0.8 (IQR 0.5, 1.6)	0.85(0.3,1.8)	0.8(0.5,1.5)
Past Medical History or Co-morbidities
Depression or anxiety	87(34.8%)	11(28.9%)	76(35.8%)
Hypothyroidism	43 (17.2%)	1(2.6%)	42(19.8%)
Gastroparesis	41 (16.4%)	5(13.1%)	36(16.9%)
Malignancy history	24 (9.6%)	4(10.5%)	20(9.4%)
Irritable bowel syndrome-constipation	33(13.2%)	4(10.5%)	29(13.6%)
Diabetes mellitus type 1 or 2	17(6.8%)	7(18.4%)	10(4.7%)
Essential hypertension	22 (8.8%)	6(15.7%)	16(7.5%)
Syncope, POTS	20 (8.0%)	3(7.8%)	17(8%)
Systemic sclerosis	3 (1.2%)	1(2.6%)	2(0.9%)
Connective tissue diseases#	15 (6.0%)	2(5.2%)	13(6.1%)
Ehlers-Danlos syndrome (hypermobility)	11 (4.4%)	0	11(5.1%)
History of non-colonic abdominal or pelvic surgery	177(70.8%)	19(50%)	157(74.4%)
Rectal evacuation disorder	Positive test: 100 (40.0%) Negative test: 96(38.4%) N/A:54(21.6%)	16(42.1%) 13(34.2%) 9(23.6%)	84(39.6%) 83(39.1%) 45(21.2%)
Concomitant Medications
Anti-spasmodics	22 (8.8%)	2(5.2%)	20(9.45)
Selective serotonin or serotonin-norepinephrine reuptake inhibitor	82(32.8%)	9(23.6%)	73(34.4%)
Tricyclic antidepressants.	27 (10.8%)	4(10.5%)	23(10.8%)
Opioid agonist	38 (15.2%)	1(2.6%)	37(17.4%)
Benzodiazepine, gabapentin	82 (32.9%)	12(31.5%)	70(33.1%)
Ondansetron	49(19.6%)	2(5.2%)	47(22.1%)
Calcium channel blocker	15(6.0%)	0	15(7%)
Levothyroxine	41 (16.4%)	1(2.6%)	40(18.8%)
Iron supplements	18 (7.2%)	2(5.2%)	16(7.5%)
Calcium supplements	38 (15.2%)	4(10.5%)	34(16%)

^#Connective tissue diseases included: rheumatoid arthritis, lupus erythematous, ankylosing spondylitis and mixed connective tissue disease

Colonic Transit Geometric Centers at 24 and 48 Hours

Colonic transit data for the entire group are summarized in Table 1 and Figure 1. Table 2 shows slow transit constipation by different parameters. Among 38 male patients, median GC24 was 1.80 (IQR 1.57, 2.20), median GC48 was 2.65 (IQR 2.20, 4.07), and median Δ_48–24 was 0.85 (0.30, 1.82); thus, at least 75% of all transit data were normal. Among the 212 female patients, median GC24 was 1.65 (IQR 1.30, 1.90), median GC48 was 2.50 (IQR 2.0, 3.40), and median Δ_48–24 was 0.80 (IQR 0.50, 1.50), indicating that over 1 quartile had slow colonic transit (GC <1.5 and <2.1 at 24 and 48h, respectively).

Figure 1.

Data of entire patient cohort showing colonic geometric center at 24 and 48 hours, as well as the delta geometric center between 24 and 48 hours. The plot shows the median, interquartile range (grey box), 5th and 95th percentiles (horizontal lines at end of vertical bars above and below the IQR grey box) and outliers (individual dots). The dashed line indicates the lower limit of normal range.

Table 2.

Slow transit constipation defined by different parameters

Patients N (%)	Slow Transit Constipation, based on:				Number with normal values for GC24 (≥1.3) and GC48 (≥1.9), but Δ48–24 <0.38
	GC24	GC48	Both GC24 and GC48	Δ48–24 <0.38
					Total	Rectal Evacuation Disorder
					34 (13.6%)	Yes	No	N/A
Females 212 (84.8%)	GC24<1.3	GC48<1.9	GC24<1.3 AND GC48<1.9	32 (15.0%)	26 (12.2%)	9 (34.6%)	16 (61.5%)	1 (3.8%)
	49 (23.1%)	25 (11.7%)	19 (8.9%)
Males 38 (15.2%)	GC24<1.5	GC48<2.1	GC24<1.5 AND GC48<2.1	10 (26.3%)	8 (21.0%)	3 (37.5%)	3 (37.5%)	2 (25%)
	6 (15.7%)	5 (13.1%)	3 (7.8%)

Based on GC24 <1.3, 49 (23.1%) female patients had STC and, based on GC24 <1.5, 6 (15.7%) male patients had STC. In total, 55 (21.6%) patients in the cohort were diagnosed with STC based on GC24. Based on GC48 <1.9 for female patients and GC48 <2.1 for male patients, 25 (11.7%) female patients and 5 (13.1%) male patients had STC. In total, 30 (12%) patients in the cohort were diagnosed with STC based on GC48.

Based on the presence of both GC24 <1.3 and GC48 <1.9 for females, 19 (8.9%) female patients had STC. Based on the presence of both GC24 <1.5 and GC48 <2.1 for males, 3 (7.8%) male patients had STC.

Colonic Transit Geometric Center Δ_48–24

In the group that had normal values for both GC24 and GC48, we evaluated Δ_48–24 to determine how many additional patients had abnormal colonic transit (using cut-offs <0.29 for males and <0.38 for females) (Figure 2). This analysis identified an additional 32 (15.1% of the total 212) female patients. Among these female patients, 12 (37.5%) had a diagnosis of rectal evacuation disorder, 18 (56.2%) did not have rectal evacuation disorder, and 2 (6.2%) did not have anorectal manometry done. Among the male patients, 4 (10.5% of the total 38) had slow progression of colonic transit between 24 and 48 hours and, among these, 1(25%) patient had a diagnosis of rectal evacuation disorder and 3 patients did not have any anorectal manometry performed. In total, among these 36 patients (14.4% of all) with abnormal delta, 13 (36.1%) patients had evidence of a rectal evacuation disorder. Therefore, Δ_48–24 identified an addition 9.2% of STC in patients with constipation without rectal evacuation disorder.

Figure 2.

Colonic transit study results for 24 and 48 hours in the subset of constipated patients without evidence of rectal evacuation disorder who all had normal GC24 and 48 at face value. Lack of progression of radiotracer between 24 and 48 hours is indicative of STC identified by abnormal Δ_48–24, as illustrated in 4 separate patients in the figure.

DISCUSSION

Our study has shown that a group of patients with chronic constipation who had normal colonic transit values at 24 and 48 hours had reduced movement of the radiotracer between these two time points. Thus, in this subset of patients with constipation, Δ_48–24 measurement on scintigraphic colonic transit can identify an additional 14.4% with STC and, among these, approximately two-thirds (9.2% of the total cohort) had STC without evidence of rectal evacuation disorder. This analysis shows that, in addition to colonic transit GC24 and GC48 measurements, Δ_48–24 can identify slow transit constipation.

Limitations of this study include the need to replicate our findings in an independent cohort, and the fact that the scintigraphic measurement of colonic transit is relatively restricted to tertiary referral centers. Although the colon scintigraphic studies are now limited to subspecialty or tertiary referral practices, with the recent revisions to the AMA CPT codes, this method is approved to be a routine clinical diagnostic tool and will get easier reimbursement from insurances. Therefore, in the near future, it is anticipated that more diagnostic centers would use this method routinely. Ideally, the preparation of the capsule for colonic transit measurement can be done at a central radiopharmacy and this would be a requirement for broader application of the scintigraphic colonic transit test. Both scintigraphic methods involve radiation exposure and have limited availability in comparison to conventional methods which use radiopaque markers. Therefore, the additional value of Δ_48–24 in the methods using radiopaque markers requires further validation, as well as repeat radiographs which would automatically increase radiation exposure. Although the scintigraphic evaluation of colonic transit is currently limited to subspecialty gastroenterology or tertiary referral practices, it is endorsed by societies of nuclear medicine (12) as well as societies of neurogastroenterology and motility (13), and it still represents the method endorsed for total and regional colonic transit measurement (18). We perceive our validation of an additional endpoint of slow colonic transit is relevant to the identification of slow transit constipation in clinical practice and research. Nevertheless, further research is necessary to validate the utility of the delta measurement as an objective endpoint in diagnosing slow transit constipation, to explore the utility of an abnormal Δ_48–24 when the colonic GC24 is normal or fast, as well as to assess the effects of treatment for slow transit constipation on the delta value estimated from the measurements at 24 and 48 hours.