Introduction

The physicochemical characteristics of the gastric contents in patients with gastroparesis and functional dyspepsia remains poorly understood. The application of swallowed telemetric capsules (gas-sensing and wireless motility capsules) provides unique information on CO₂ concentrations and pH within the stomach, and can identify gastric emptying [1]. Since gastric CO₂ is generated principally via chemical reactions between acid and bicarbonate, we hypothesised that changes in intragastric CO₂ concentrations might reflect episodes of duodeno-gastric reflux of bicarbonate.

Aims & Methods

The aim of the study was to describe the pattern of intragastric CO₂ concentrations and to compare with concomitant pH and symptoms in healthy subjects and patients previously diagnosed with gastroparesis or functional dyspepsia. Participants recruited from two Australian sites tandemly ingested the two devices in random order following an 8-hour fast, withholding usual prokinetics/laxatives and proton pump inhibitors for 72 hours prior and for the study duration. Habitual diet was resumed after a further 6 hours. Patients recorded dietary intake and symptoms. Gastric emptying was identified by capsule-specific criteria. When CO₂ concentrations stabilised after capsule swallowing, a baseline was identified upon which discrete CO₂ bursts were observed. The number of CO₂ bursts and area-under-the-curve (AUC) for those bursts was calculated. The association with changes in gastric pH and symptoms were evaluated.

Results

Thirty-three participants (n=4 healthy, n=24 gastroparesis, n=5 functional dyspepsia) completed the study and had an evaluable trace. Delayed gastric emptying (>5 h) was observed in 9 participants (n=8 gastroparesis, n=1 functional dyspepsia). There was a statistically significant correlation between gastric emptying time and diagnosis of gastroparesis (r=0.95, p<0.0001; Spearman test). Total AUC for CO₂ bursts was median 6.6 (IQR, 0.9-31) %.h in gastroparesis, compared with 1.8 (0.5-4.4) %.h in functional dyspepsia and 1.2 (0.2-2.2) %.h in healthy participants (p=0.2; Kruskal-Wallis test). Comparing those with normal gastric emptying time, subjects with delayed gastric emptying time had greater number of bursts (3 vs 2, p=0.01) and AUC CO₂ (28 [13–102] %.h vs 0.9 [0.4– 3.0] %.h, p=<0.0001; Mann-Whitney test) even when correcting for duration of gastric residence (1.4 [1.0-3.9] %.h vs 0.5 [0.2-1.1] %.h, p=0.0019). There was no consistent relationship between CO₂ peaks and exacerbation of symptoms or changes in intragastric pH.

Conclusion

Delayed gastric emptying, but not the clinical diagnosis, is associated with bursts of CO₂ production in the stomach, consistent with episodes of duodeno-gastric reflux (despite no changes to gastric pH). Further evaluation is required in larger cohorts to understand the physiological and clinical significance of these findings.

References

1. Zhou, J., K. Berean, H. Pedersen, P. Thwaites, P. Gibson, R. Burgell and V. Ho (2023). "Ingestible gas-sensing capsule for whole gut transit: prospective comparison with wireless pH-motility capsule (SmartPill) in gastroparesis and chronic constipation." Abstract accepted DDW.

Disclosure

PAT: Nil to declare.
JZ: Nil to declare.
CKY: Received research support from Atmo Biosciences for investigator-initiated studies.
KJB: Employee and shareholder of Atmo Biosciences.
PRG: Consultant or advisory board member for Anatara, Atmo Biosciences, Immunic Therapeutics, Novozymes, Novoviah and Comvita. He has received research grants for investigator‐driven studies from Atmo Biosciences. He holds shares in Atmo Biosciences. His Department financially benefits from the sales of a digital application, booklets and online courses on the FODMAP diet.
REB: Consultant or advisory board member for Allergan, Atmo Biosciences, Anatara. She has received speaking honoraria from Bayer.
VH: Nil to declare.

Introduction

Gastric emptying (GE) of liquids and solids is differentially regulated. GE of liquids follows an exponential kinetic and mainly depends on fundic tone, GE of solids requires trituration by antral contractions for passage through the adequately opened pylorus into the duodenum. Adler et al. showed that liquid GE was more often delayed in systemic sclerosis patients compared with GE of solids (Rheumatology 2022), but knowledge on the association between GE of solids and liquids in dyspeptic patients, in general, is limited.

Aims & Methods

To investigate this association and the correlation of GE times with symptoms, we compared results of breath tests using 13C-acetate (13C-ABT, GE-liquids) and 13C-octanoic acid (13C-OBT, GE-solids) in consecutive dyspeptic patients undergoing both tests (Keller et al. UEG J 2021). Normal ranges at our institution for 13C-ABT are 20-35 min (T lag-liquids), for 13C-OBT 50-150 min (T ½-solids). All patients additionally answered the gastroparesis cardinal symptom index questionnaire (GCSI, Revicki APT 2003).

Results

302 patients were included (230 women, age 45.9 (31.7-59.5) yrs, median(IQR)). Median T lag-liquids was 25 (20-35) min, median T ½-solids 78 (60-104) min. T lag-liquids and T ½-solids were weakly associated (R=0.165, p=0.002). Both were indirectly correlated with age (R=-0.280, p<0.0001 and R=-0.179, p=0.0009, resp), and similar in men and women. Concordant results for both tests were achieved in 172 subjects (57.6%): Both were normal in 161 (53.3%), both showed accelerated GE in 10 (3.3%) and both delayed GE in 3 (1%) subjects. Discrepant results were observed in 128 subjects (42.4%), in the vast majority of these, one of the tests was normal, but in 7 subjects (2.3%), GE was accelerated in one test, delayed in the other. 67 patients (22.2%) had delayed GE in at least one of the tests. Only in this subgroup, GE time correlated significantly with GCSI (R=0.242, p=0.024), in particular with the nausea/vomiting subscale (p=0.009).

Conclusion

In a large group of dyspeptic patients, more than 45% had disturbances of liquid and/or solid GE. In less than 5% of the total group both tests were found to be either accelerated or delayed in the same patient. Instead, measurements of liquid and solid GE often differred. In patients with delayed GE in at least one of the tests, severity of gastroparesis symptoms was associated with GE time. Thus, measurements of liquid and solid GE may be complementary and identify patients with different pathomechanism leading to GE disturbances and symptoms.

Introduction

Gastric emptying is controlled by phasic gastric contractions which occur at a frequency of ~3 cycles per minute (cpm) in phase with gastric slow waves. Tests to measure slow waves cannot directly detect abnormal contractions. The Atmo Capsule possesses an accelerometer that measures changes in capsule orientation and can thus detect gastric contractions. We analyzed accelerometer data to define its capability to characterize gastric contraction frequency and amplitude in patients with suspected dysmotility, and to assess if frequency or amplitude vary in relation to transit delay.

Aims & Methods

Gut transit was measured by the Atmo Capsule in 209 subjects: 48 with predominant upper GI (UGI) symptoms alone (suspected gastroparesis), 21 with lower GI (LGI) symptoms (suspected slow colon transit) alone, and 140 with combined UGI+LGI symptoms. This analysis utilized data from subjects recording valid gastric emptying time (GET) measures and did not incur protocol deviations affecting gastric transit. Delays in GET were categorized as: normal, <5 h; delayed, 5-10 h; severely delayed, ≥10 h. Fast Fourier Transformation (FFT) of the accelerometer data allows for the identification and analysis of the dominant gastric frequency and amplitude using 10-minute windows and a cutoff frequency of 4.5 cpm. Variability of frequency and amplitude measures were estimated by calculating interquartile range (IQR) and range (max-min) values and were analyzed in relation to presenting symptoms and gastric emptying delays.

Results

Gastric data from 190 subjects were suitable for analysis: gastric contractions with dominant frequencies of 3.30 cpm (IQR 0.47, range 1.47) and amplitudes of 0.10 arbitrary units (au) (IQR 0.04, range 0.14) were detected in 185 (97%) of subjects. Mean contraction frequency tended to be higher in those with delayed GET compared with no delay (p=0.016) and severe delay (p=0.005) (Table 1). Frequency IQR (p=0.002) and range (p=0.002) were higher for GET delay vs. no delay, while range was higher in severe GET delay vs no delay (p<0.001). Mean amplitude was higher in subjects with severe GET delay compared with normal delay (p=0.008) and normal transit (p=0.001). Amplitude IQR and range were both higher in those with severe GET delay compared with normal delay (p=0.002; p=0.001) and no delay (p<0.001 for both). Frequency metrics were similar irrespective of predominant symptoms. Amplitude means (p=0.022), IQR (p=0.030) and range (p=0.0004) were higher for UGI vs. LGI symptoms.

Table 1. Dominant gastric frequencies and amplitudes in relation to gastric emptying delays. Data shown as median (interquartile range) and analyzed via Kruskal-Wallis test.

Conclusion

The Atmo Capsule accelerometer reliably characterizes 3 cpm gastric contraction frequency and amplitude in subjects with proposed delays in gut transit. Increased variabilities in contraction frequency and amplitude were defined in those with severely delayed gastric emptying and increased amplitude variability was found for predominant upper GI symptoms. We propose these higher variations identified by accelerometry may reflect hypomotility or contractile dropout, suggesting additional clinical utility of the Atmo Capsule in suspected gastroparesis.

Disclosure

These authors disclose the following: Braden Kuo, Anthony J. Lembo, Eammon M.M. Quigley, Satish S.C. Rao, and William D. Chey serve on the Medical Advisory Board of Atmo Biosciences. Michael Cline and Baharak Moshiree served on the Medical Advisory Board of Atmo Biosciences. Braden Kuo has received funding from NIH, Vanda, Atmo Biosciences, and Takeda and has consulted for Evoke, Takeda, Ironwood, Novo Nordisk, Cindome, and Neurogastrx. Thomas Abell has received funding from Gastric Dysrhythmias, Neurogastrx, NIH GpCRC, and Vanda and has consulted for Enterra Medical, Novo Nordisk, Nuvaira, and Vanda. Anthony J. Lembo has received funding from Ardelyx, Biomerica, GSK, Ironwood, Takeda, and Vibrant and holds stock with Allurion, Bristol Myer Squibb, and J&J. Abigail Stocker has received funding from Cindome, Enterra Medical, and Vanda. William D. Chey has received funding from Atmo Biosciences, Commonwealth Diagnostics Intl, QOL Medical, and Salix; has consulted for AbbVie, Ardelyx, Biomerica, Comvita, Gemelli, Ironwood, Nestle, QOL Medical, Phathom, Redhill, Salix, Vibrant, and Takeda; has filed patents with My Nutrition Health, Digital Manometry, and Rectal Expulsion Device; and holds stock options with Coprata, Evinature, Food Marble, Kiwi Bioscience, and Modify Health. The remaining authors disclose no conflicts.

Introduction

Gastric emptying testing (GET) is used to assess gastric motility, however is non-specific and insensitive for neuromuscular disorders. Gastric Alimetry® is a new medical device combining non-invasive gastric electrophysiological mapping and validated symptom profiling.

Aims & Methods

This study aimed to assess patient-specific phenotyping using Gastric Alimetry with comparison to GET.
Patients with chronic gastroduodenal symptoms underwent simultaneous GET and Gastric Alimetry. Tests comprised a 30-minute baseline, ^99mTC-labelled egg meal, and 4-hour postprandial recording. Results were referenced to normative ranges^1,2. Symptoms were profiled in real-time during testing in the validated Gastric Alimetry App³, phenotyped with rule-based criteria, and compared to long-term symptom questionnaires of Rome IV criteria, Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM), Gastroparesis Cardinal Symptom Index (GCSI), Patient Assessment of Upper Gastrointestinal Disorders Quality of Life (PAGI-QoL), Patient Health Questionnaire-2 (PHQ-2), and State-Trait Anxiety Inventory-6 (STAI-6). Three Gastric Alimetry symptom profiles were phenotyped: i) continuous (symptoms do not correlate with meal or gastric activity); ii) gastric sensorimotor (symptoms increase within 30 minutes of the meal and decay as gastric activity decreases); and iii) Other (symptoms that do not fit the other two symptom profiles).

Results

75 patients with chronic gastroduodenal symptoms were assessed; 77% female, median age 43, median BMI 24.0. Motility abnormality detection rates were: GET 22.7% (14 delayed, 3 rapid); Gastric Alimetry spectral analysis 33.3% (14 dysrhythmic / low amplitude; 5 high amplitude; 6 abnormal frequency); combined yield 42.7%. In patients with normal spectral analysis, Gastric Alimetry symptom phenotypes included: gastric sensorimotor 17%; continuous 30%; other 53%. The sensorimotor phenotype correlated strongly with gastric amplitude (median r=0.61 vs r=0.08 and r=0.06 respectively; p=0.0002). Abnormal Gastric Alimetry phenotypes showed superior correlations with GCSI, PAGI-SYM, and STAI-6 anxiety scores (p<0.05), while Rome IV Criteria and delayed gastric emptying did not correlate (p>0.05). Delayed gastric emptying was not predictive of specific Gastric Alimetry phenotypes.

Conclusion

Gastric Alimetry generated a higher yield for motility abnormalities than GET in patients with chronic gastroduodenal symptoms. Gastric Alimetry also identified patient-specific symptom phenotypes, showing correlations with health psychology variables not observed with Rome IV and delayed gastric emptying. GET and Gastric Alimetry assess different aspects of gastric function, indicating these tests may have complementary roles.

References

1. Varghese C, Schamberg G, Calder S, et al. Normative values for body surface gastric mapping evaluations of gastric motility using gastric alimetry: Spectral analysis. American Journal of Gastroenterology 2022; Publish Ahead of Print. Epub ahead of print 2022. DOI: 10.14309/ajg.0000000000002077.
2. Abell TL, Camilleri M, Donohoe K, et al. Consensus recommendations for Gastric Emptying Scintigraphy: A joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Journal of Nuclear Medicine Technology; 36: 44–54.
3. Sebaratnam G, Karulkar N, Calder S, et al. Standardized system and app for continuous patient symptom logging in gastroduodenal disorders: Design, implementation, and validation. Neurogastroenterology & Motility 2022; 34. Epub ahead of print 2022. DOI: 10.1111/nmo.14331.

Disclosure

Greg O'Grady, Armen Gharibans and Peng Du hold intellectual property and grants in gastric electrophysiology and are Directors of University of Auckland spin-out companies (Greg O'Grady: Alimetry, Insides Company; Armen Gharibans: Alimetry; Peng Du: FlexiMap); Stefan Calder, Gabriel Schamberg, Stephen Waite, and Christopher N. Andrews are members of Alimetry. The remaining authors have no relevant conflicts of interest to declare.

Introduction

Gastroparesis (GP) is defined as symptomatic delayed gastric emptying. The most frequent etiologies are diabetes mellitus, after esophageal or gastric surgery and about a third of patients have idiopathic GP. The gastric emptying study by using a scintigraphy scintigraphy (GES) is considered as a principal diagnostic method. Endoscopic pyloromyotomy (G-POEM) is a method improving symptoms in about 60-70% of patients with GP. Its effect on gastric emptying remains controversial.

Aims & Methods

We performed a retrospective single-center analysis to assess the clinical efficicacy of G-POEM based on GES parameters. Between 2016 – 2024, a total of 72 patients with GP (confirmed by scintigraphy) underwent G-POEM and were later invited for clinical as well as scintigraphic assessment after 3, 12 and 36 months. Of these patients, 4 were excluded for missing data, incomplete follow-up data or non-standard testing meal. GES was always performed using the standardized 4 hours protocol with the standard testing meal mixed with 99Tc-DTPA. For this study, all GES were reanalyzed and the following parameters were established : residual activity after 2 hours, residual activity after 4 hours, biological halftimes of ingested activity and proximal-to-distal count ratio for time 0 (PDCR0).

Results

Mean value of GCSI before G-POEM was 3.1 and decreased to 1.6, 1.0 and 0.7 after 3, 12 and 36 months. Median value of GES after 2 hours was 60.2% before G-POEM and 38%, 32.6% and 24.2% after 3, 12 and 36 months. Median value of GES after 4 hours was 21.9% before G-POEM and 7.8%, 6.5% and 3.9% after 3, 12 and 36 months. Correlation index was weakly positive for GCSI and GES after 4 hours only for the first follow-up visit and negative for all remaining visits.
The residual activity after 2 hours and residual activity after 4 hours decreased after G-POEM during all follow-up visits (p<0,001). Mean decrease of residual activity after 4 hours was 12.89%, 15.13% and 6.7% after 3, 12 and 36 months.
Biological halftime also decreased after the procedure with statistically significant results with the mean halftime before G-POEM being 150 min and 86 min, 78.4 min and 65.8 min after 3, 12 and 36 months.
There was a difference between the diabetic and non-diabetic groups, with higher residual activity after 2 hours [median 29.6% before G-POEM, 9.0% after 3 months (p<0.001) and 11.0% after 12 months (p=0.005)] and 4 hours [median 64.8% before G-POEM, 39.4% after 3 months (p<0.001) and 37.7% after 12 months (p=0.012)] respectively in patients with diabetes.
The predictive value of PDCR0 for treatment success after G-POEM was only calculated for the first follow-up visit but was not statistically proved (p=0,712).

Conclusion

In our group of patients there is a weak correlation between the decrease of GCSI and GES early after G-POEM. The decrease in GES parameters tends to be lower in patients with diabetes compared to non-diabetic patients. Based on our data, predicting clinical success of G-POEM using PDCR0 cannot be recommended.

Introduction

STW5-II is a medicinal product composed by 6 herbal extracts that has been shown to relieve clinical symptoms in patients with dyspepsia. The mechanisms of action include selective effects on gastric tone, antro-pyloric activity
and visceral sensitivity. Patients with functional dyspepsia (FD) have a poor tolerance to gastric gas that has been related to a combination of several factors, including delayed gas transit and evacuation, visceral hypersensitivity and altered viscero-visceral reflexes.

Aims & Methods

The aim of the present study was to determine the effect of STW5-II on transit and tolerance of gastric gas in patients with FD. In 27 patients (26 female and 1 male, age range 22-70 years old) with FD and bloating (17 postprandial distress syndrome, 4 epigastric pain syndrome and 6 mixed type dyspepsia), a gas challenge test was performed after two weeks on STW5-II 20 drops t.i.d. or placebo, in a parallel, double blinded, controlled trial. The gas challenge test consisted in infusion of a mixture of gases into stomach through a nasogastric tube at 100 mL/min for 15 minutes (total volume infused 1500 mL) with concomitant gastric nutrient perfusion (Nutridrink 1.5 Kcal/ml, total 315 Kcal), mimicking a normal meal. Rectal gas evacuation, via a rectal tube connected to a barostat, and belching, by an esophageal multilumen impedance catheter, were continuously measured for 90 min from infusion start. Abdominal symptoms, using a 0-6 perception scale, and abdominal distension, using a tape measure, were quantified at 10-min intervals.

Results

Gastric gas infusion was followed by a progressive gas evacuation from the rectum, that was accelerated when patients were on STW5-II, compared to placebo. After 20 min from infusion start (when gas and nutrient perfusion was already finished) only 80±39 mL of gas had been expelled in studies on placebo, whereas 319±81 mL of gas were collected on STW5-II group (p=0.015). Thereafter, both groups continued to expel gas at similar rates, without differences between groups at the end of the study (837±180 mL and 1030±160 mL, saline and STW5-II, respectively; p=0.432). Gastric belches were exceptional in both groups (0.8±1.0 and 1.1±1.6 gastric belches in 90 min, saline and STW5, respectively; p=0.318).
Gastric gas infusion gas associated to a rapid rise in perception of abdominal symptoms, that was significantly lower in patients treated with STW5-II than those treated with placebo (score increment 3.0±0.4 vs 1.9±0.6, placebo and STW5-II, respectively; p=0.036). Following continuous rectal gas evacuation, perception decreased in both groups, however perception remained significantly greater at the end of the 90-min study period in patients on saline (score increment 1.4±0.6; p=0.018 vs infusion start), whereas it had returned to basal levels in patients treated with STW5-II (score increment -0.2±0.4; p=0.324 vs infusion start). There were no significant differences in abdominal girth increment between groups (max increment 16±2 mm and 13±2 mm placebo and STW5-II, respectively; p=0.224).

Conclusion

STW5-II is a medicinal product that improves tolerance to gastric gas in patients with functional dyspepsia, by acceleration of transit and rectal evacuation of gas, and reduction of the intensity of symptoms elicited by gas. Hence, this medicinal product could be beneficial for management of gas-related abdominal symptoms like bloating in patients with functional dyspepsia.
EudraCT: 2019-003976-38

Introduction

Functional Dyspepsia (FD), a common disorder of gut-brain interaction [1], is associated with alterations in gastric accommodation, gastric emptying, gastric sensitivity, gastroduodenal permeability, and the gut microbiome. Resilience, the ability to maintain function under personal or physical stress, may play a role in the development of FD, although no studies have evaluated this theory. We hypothesize that FD patients have lower resilience than the general population, which may lead to a new therapeutic target.

Aims & Methods

This prospective questionnaire study compared patients with FD (Rome IV criteria) with internal medicine clinic patients without dyspepsia at a tertiary referral center. Participants completed the FD symptom severity score [2], Brief Resilience Scale (BRS) [3], Connor-Davidson Resilience Scale (CDRS) [4], hospital anxiety and depression scale (HADS) [5], early childhood adverse life event questionnaire [6], and perceived stress score [7]. Questionnaires were distributed to clinic patients meeting inclusion/exclusion criteria.

Results

38 FD (mean age 43 years old, 87% female) and 31 control (mean age 57 years old, 39% female) patients completed the survey. FD patients exhibited lower resilience on the CDRS (96.83 vs. 90.26, P<0.04, CI -12.93 to -0.21) but not on the BRS (3.018 vs. 3.022, P<0.96, CI -0.15 to 0.13). FD patients and controls scored no different on the HADS anxiety index (17.05 vs. 18.38, P<0.064, CI -2.74 to 0.08) and depression scores (P<0.14, CI -0.21 to 1.5). The FD group reported "high" perceived psychological stress while the control group reported a “moderate” level (P<0.004, CI 2.002 to 9.827). In childhood, FD patients had significantly more adverse childhood events (29.3% vs. 15%, P<0.004, CI 0.05 to 0.25). FD patients were more likely to have been exposed to a household member suffering from a psychiatric illness compared to control patients (47% vs. 20%, P<0.049, CI 0.001 to 0.5). FD patients were also more likely to report psychological abuse in childhood (53% vs. 17%, P<0.03, CI 0.034 to 0.67). No other significant differences were found in types of early childhood trauma including physical abuse, familial substance abuse, witnessed maternal violence, or criminal behavior by a household member.

Conclusion

This novel, prospective questionnaire pilot study shows that FD patients have lower resilience compared to the general outpatient population on the CDRS. The long-term symptoms of FD may further decrease resilience. While anxiety and psychological stress are not strongly associated with FD, the significant exposure to childhood household members with a psychiatric diagnosis and significantly higher prevalence of self reported psychological abuse may explain the higher prevalence of antidepressant use in this population, especially considering the significantly higher level of self perceived psychological stress [8]. Otherwise, early childhood trauma appears similar between FD patients and patients without FD and is thus not likely to influence resilience markers. Understanding the contribution of resilience to development of FD may lead to therapies enhancing resilience, improving symptoms, and patient well-being.

References

1. El-Serag HB, Talley NJ. Systemic review: The prevalence and clinical course of functional dyspepsia. Aliment Pharmacol Ther. 2004;19:643-654.
2. Taylor F, Higgins S, Carson RT, et al. Development of a symptom-focused patient-reported outcome measure for functional dyspepsia: the functional dyspepsia symptom diary (FDSD). Am J Gastroenterol. 2018 Jan,113(1):39-48.
3. Smith BW, Dalen J, Wiggins K, et al. The brief resilience scale: assessing the ability to bounce back. Int J Behav Med. 2008;15(3):194-200
4. Connor KM & Davidson JR. 2003. Development of a new resilience scale: The Connor-Davidson Resilience Scale (CD-RISC). Depress. Anxiety, 18; 76-82
5. Zigmond AS & Snaith RP. 1983. The hospital anxiety and depression scale. Acta Psychiatrica Scandinavica, 67: 361-370
6. Felitti VJ, Andra RF, Nordenburg D, et al. Relationship of childhood abuse and household dysfunction to many of the causes of death in adults. The adverse childhood experiences (ACE) study. Am J Prev Med. 1998 May;14(4):245-58
7. Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav. 1983 Dec;24(4):385-96.
8. Esterita T, Dewi S, Suryatenggara FG, Glenardi G, et al. Association of Functional Dyspepsia with Depression and Anxiety: A Systematic Review. J Gastrointestin Liver Dis. 2021 Jun 18;30(2):259-266.