Abstract
Background and Aims
Primary sclerosing cholangitis (PSC) is an autoimmune chronic cholestatic liver disease causing inflammation, fibrosis, and increased risk of cholangitis, cirrhosis, and hepatobiliary cancers. How PSC affects patient-reported quality of life (QoL) is sparsely studied. We aimed to investigate the impact of PSC on QoL.
Methods
This cross-sectional study included 101 patients with PSC. We investigated QoL using the PSC-specific PSC patient-reported outcome (PRO) instrument, the generic health-related QoL questionnaire EQ-5D-5L, and the fatigue visual analog scale (VAS) score. We also investigated associations between QoL and noninvasive inflammation and fibrosis measures; the macrophage marker soluble (s)CD163, fibrosis-4 score, and transient elastography.
Results
The median age was 45 years, 65% were males, 10% had PSC with autoimmune hepatitis overlap disease, and 92% had inflammatory bowel disease. Eighty-five patients completed all QoL questionnaires and reported high QoL across all PSC PRO instrument items and EQ-5D-5L. sCD163 correlated modestly with PSC PRO total score (rho = 0.28) and fatigue VAS score (rho = 0.26) but not EQ-5D-5L. Patients with any previous episode of cholangitis reported lower QoL than cholangitis-naive patients on the PSC PRO score (21 vs 15, P = .04) and EQ-5D-5L VAS score (71 vs 86, P = .01). There was no association between noninvasive markers of liver fibrosis and QoL.
Conclusion
In this cohort, patients with PSC reported high QoL. The PSC PRO score correlated with sCD163 and was sensitive to cholangitis episodes, validating the instrument as a true PSC-specific QoL tool.
Keywords: Primary Sclerosing Cholangitis, Patient-Reported Outcomes, Quality of Life, Liver Inflammation, Liver Fibrosis
Introduction
Primary sclerosing cholangitis (PSC) is an autoimmune chronic cholestatic liver disease affecting the intrahepatic and extrahepatic bile ducts. The persistent inflammation in the biliary tracts triggers episodes of cholangitis and the development of hepatic fibrosis, ultimately leading to cirrhosis, often necessitating liver transplantation.1,2 In addition, PSC increases the risk of developing hepato-pancreato-biliary malignancies, which are associated with poor prognoses.3
PSC often affects young individuals with concomitant inflammatory bowel disease (IBD) and presents with fatigue, pruritus, jaundice, abdominal pain, weight loss, and fever, adversely impacting the quality of life (QoL).3, 4, 5 Current treatments are limited to symptom management and therapeutic biliary interventions, with uncertain effects on overall disease progression.6 These challenges emphasize the need for further research into PSC across the spectrum of disease pathophysiology, therapeutic measures, progression predictors, and impact on QoL.
Most previous studies investigating QoL in patients with PSC used generic QoL measures such as the health-related QoL questionnaires Short-Form-36 and EQ-5D-5L or questionnaires specific to chronic liver diseases.7, 8, 9, 10 Recently, a PSC-specific patient-reported outcome (PSC PRO) instrument was developed to improve the clinical management of patients with PSC.11 However, the association between QoL and liver fibrosis, and especially inflammation, is less investigated.
We intend to investigate patient-reported health-related QoL in patients with PSC7,8 and hypothesize that PSC-specific QoL measures are associated with noninvasive biomarkers and examinations of liver inflammation and fibrosis.12,13 Accordingly, we report the lineage-specific macrophage activation marker soluble (s)CD163, the fibrosis-4 (FIB-4) score, and transient elastography (TE).14, 15, 16, 17, 18 Furthermore, this study constitutes an external validation of the novel PSC PRO instrument.11
Materials and Methods
Study Population and Cohort Description
This cross-sectional study reports the baseline data from a newly established cohort of patients with PSC from a tertiary liver clinic. Patients ≥18 years with PSC19 followed at either the outpatient clinic or hospital ward at the Department of Hepatology and Gastroenterology at Aarhus University Hospital, Denmark, were eligible for inclusion. Patients with prior liver transplantation or uncured cancer, except hepatobiliary and colorectal cancers, were ineligible for inclusion. The inclusion ran from February 2022 to October 2024. All study data were managed using REDCap electronic data tools hosted by Aarhus University.20,21 The study was approved by the Danish Ethics Committee (study no. 1-10-72-346-21) and conducted in accordance with the Declaration of Helsinki.
Data Collection
Demographic, anthropometric, clinical, and biochemical data were collected on the day of inclusion after written consent. Retrospective data, for example, medicine history, radiological procedures, and IBD status were extracted from the patient’s electronic medical records. The baseline data included the noninvasive liver inflammation and fibrosis measures: sCD163, FIB-4 score, and TE.
Blood samples for sCD163 were centrifuged, and serum was recovered and frozen at −20 °C within 1 hour. The serum was thawed and analyzed for sCD163 using an in-house sandwich enzyme-linked immunosorbent assay, as previously described.22 The sCD163 reference interval was 0.69–3.86 mg/L.23
The liver stiffness was measured using FibroScan and performed by trained hospital personnel. Based on the TE-value, participants were divided into 3 groups according to their fibrosis stage.18 Patients with a TE-value <8.1 kPa were grouped as F0–F1 fibrosis, patients with a TE-value between 8.1 and 13.4 kPa were grouped as F2–F3 fibrosis, and patients with a TE-value >13.4 kPa were grouped as F4 fibrosis (cirrhosis).
Furthermore, all patients were asked to answer QoL questionnaires including the disease-specific PSC PRO instrument and the generic EQ-5D-5L questionnaire. Patients also reported severity of fatigue and pruritus with a recall period of 7 days on a visual analog scale (VAS).9,11 All patients answered the questionnaires electronically, and directly into REDCap, while in the waiting room or at home on the day of study inclusion. The PSC PRO instrument consists of 2 modules: the first focuses on acute PSC-related symptoms and the second scales the impact of these symptoms on the patient’s everyday life. The score of module 1 ranges from 0 (the best possible QoL) to 120 (worst possible QoL). The score of module 2 ranges from 5 (the best possible QoL) to 35 (worst possible QoL). A total score is calculated by adding the total scores from the 2 modules. The EQ-5D-5L measures health in 5 levels across the 5 dimensions mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and provides an overall health score (EQ-5D-5L VAS) ranging from 0 (worst possible QoL) to 100 (best possible QoL). The fatigue and pruritus VAS scores range from 0 (no fatigue) to 100 (extreme fatigue).
Statistical Analysis
Patient characteristics are reported as numbers with percentages or medians with interquartile ranges (IQRs). We used the chi-square test for ordinal data and nonparametric Kruskal-Wallis test and Wilcoxon rank test for comparisons between groups. We used the Spearman’s rank-based test for correlations. A P value < .05 was considered statistically significant. All data analyses were performed in RStudio.
Results
Background Characteristics
In total, 101 patients were included in the PSC cohort. The participants had a median age of 45 years, 65 were male, 10% had PSC with autoimmune hepatitis (AIH) overlap disease, and 83 had concomitant IBD, predominantly ulcerative colitis (Table 1). Inclusion occurred from the outpatient clinic in relation to regular control visits for 93 (92%) patients, while the remaining 8 (8%) patients were included from the ward during hospitalization. The median time since the diagnosis of PSC was 6 years, and the majority had their diagnosis confirmed by magnetic resonance cholangiopancreatography and liver histology (Table 1). Furthermore, 87 patients had abnormal cholestatic liver biochemistry at the time of diagnosis, while only 24 patients reported PSC characteristic symptoms. Next, for the current work’s investigations of QoL, we used a subcohort of 85 patients who completed all QoL questionnaires.
Table 1.
Baseline Characteristics of the Aarhus PSC Cohort
| Variables | Patients (n = 101) |
|---|---|
| Sex, male (%) | 65 (64) |
| Age, y | 45 (33–57) |
| Time since diagnosis, y | 6 (3–12) |
| Diagnostic procedures performed | |
| Liver biopsy (%) | 55 (54) |
| MRCP (%) | 87 (86) |
| ERCP (%) | 18 (18) |
| PSC type | |
| Classic PSC (%) | 83 (82) |
| Small duct PSC (%) | 8 (8) |
| AIH overlap syndrome (%) | 10 (10) |
| Concomitant IBD | |
| Ulcerative colitis (%) | 65 (64) |
| Crohn’s disease (%) | 16 (16) |
| Unclassified IBD (%) | 2 (2) |
| No IBD (%) | 18 (18) |
| Activity in IBD (%) | 22 (26) |
| Anthropometrics | |
| Height (cm) | 178 (172–184) |
| Weight (kg) | 80 (70–93) |
| BMI (kg/m2) | 25.1 (23.4–28.7) |
| Disease characteristics | |
| Cirrhosis at baseline (%) | 8 (8) |
| Ursodeoxycholic acid treatment (%) | 18 (18) |
| Treatment for hepatic pruritus (%) | 12 (12) |
| Hospitalizations with cholangitis (%) | 18 (18) |
| Blood biochemistry | |
| Alanine aminotransferase (U/L) | 67 (36–109) |
| Aspartate aminotransferase (U/L) | 46 (33–74) |
| Gamma-glutamyl transferase (U/L) | 243 (108–450) |
| Alkaline phosphatase (U/L) | 185 (107–312) |
| Total bilirubin (μmol/L) | 13 (9–20) |
| Plasma albumin (g/L) | 38 (36–41) |
| INR | 1.0 (1.0–1.1) |
| Immunoglobulin G (g/L) | 13.8 (11.3–16.7) |
| Cancer antigen 19–9 (kU/L) | 11 (6–25) |
| C-reactive protein (mg/L) | <4 (<4–<4) |
| Soluble CD163 (mg/L) | 2.9 (2.1–3.9) |
| Predictive models and scores | |
| MAYO risk score | 0.11 (−0.37–0.72) |
| Amsterdam Oxford model | 1.75 (1.40–2.17) |
| Noninvasive liver fibrosis measures | |
| FibroScan, TE (kPa) | 6.2 (4.9–9.2) |
| FibroScan, CAP (dB/m) | 210 (165–255) |
| FIB-4 score | 1.04 (0.78–1.83) |
Data are expressed as numbers (percentages) or medians (interquartiles). Treatments for hepatic pruritus included cholestyramine, rifampicin, fibrates, and naltrexone.
BMI, body mass index; CAP, controlled attenuation parameter; ERCP, endoscopic retrograde cholangiopancreatography; INR, international normalized ratio; MRCP, magnetic resonance cholangiopancreatography; TE, transient elastography.
Quality of Life
In general, the patients reported a high QoL expressed by a low median PSC PRO total score of 17 (IQR: 10–30), and low scores across all PSC PRO Module 2 subcategories and in Module 1 (Table 2 and Supplementary Figure 1). An overall high QoL was also evident from the EQ-5D-5L responses to the 5 dimensions (Table 2) and the median EQ-5D-5L VAS score of 84 (IQR: 70–90). However, some patients experienced fatigue, reported as a median fatigue VAS score of 21 (IQR: 2–56). We observed a strong correlation between the PSC PRO total score and the fatigue VAS score (rho = 0.79, P < .001). Overall, the level of pruritus was reported as low with a median VAS score of 2 (IQR: 0–15). Ten patients received antipruritic therapy at the time of inclusion, including cholestyramine (n = 5), rifampicin (n = 4) and colesevelam (n = 1). These patients reported a higher median pruritus VAS score of 23 (IQR: 0–80).
Table 2.
The Reported Quality of Life in the 85 Patients Who Completed the PSC PRO Instrument, EQ-5D-5L Questionnaire, the Fatigue VAS Score, and the Pruritus VAS Score
| Questionnaire | Responders (n = 85) |
|---|---|
| PSC PRO instrument | |
| Module 1 | 7 (2–17) |
| Module 2 | 8 (7–11) |
| Physical function | 1.0 (1.0–1.5) |
| Activities of daily living | 1.3 (1.0–1.8) |
| Work productivity | 1.0 (1.0–1.6) |
| Role function | 1.0 (1.0–1.3) |
| Emotional impact | 1.5 (1.0–2.3) |
| Social/leisure impact | 1.0 (1.0–1.3) |
| Quality of life | 1.0 (1.0–1.8) |
| Total score | 17 (10–30) |
| EQ-5D-5L | |
| VAS score | 84 (70–90) |
| Descriptive dimensions | |
| Mobility | 1 (1–1) |
| Self-care | 1 (1–1) |
| Usual activities | 1 (1–2) |
| Pain/discomfort | 1 (1–2) |
| Anxiety/depression | 1 (1–2) |
| Fatigue (VAS score) | 21 (2–56) |
| Pruritus (VAS score) | 2 (0–15) |
Data are expressed as medians (interquartiles).
The PSC PRO instrument score of module 1 ranges from 0 (the best possible QoL) to 120 (worst possible QoL) and the score of module 2 ranges from 5 (the best possible QoL) to 35 (worst possible QoL). The EQ-5D-5L VAS score ranges from 0 (worst possible QoL) to 100 (best possible QoL), and the descriptive dimensions are scored from 1 (no problem) to 5 (extreme problems). The fatigue and pruritus VAS scores range from 0 (no fatigue or pruritus) to 100 (extreme fatigue or pruritus).
Noninvasive Measures of Liver Fibrosis and Associations With QoL
Most patients had normal sCD163 levels, low FIB-4 scores, and low FibroScan TE-values at inclusion (Table 1). Consequently, no or insignificant weak correlations were found between the patient-reported QoL scores and the noninvasive fibrosis measures, except for the sCD163 and the PSC PRO total score (rho = 0.28, P = .01) and the sCD163 and the fatigue VAS score (rho = 0.26, P = .02) (Figure 1). The PSC PRO module 2 domains activity of daily living (rho = 0.31, P < .01), work productivity (rho = 0.27, P = .03), and social impact (rho = 0.22, P = .04) were the main drivers for the correlation between PSC PRO and sCD163 (Supplementary Table 1). Furthermore, the PSC PRO total score, EQ-5D-5L VAS score, and fatigue VAS score were similar regardless of the degree of liver fibrosis (Supplementary Figure 2). The patient-reported QoL scores did not correlate with the PSC-specific prognostic scores, including the MAYO risk score and the Amsterdam Oxford Model score.
Figure 1.
Spearman’s correlations between sCD163 and the QoL measures PSC PRO total score (A), EQ-5D-5L VAS score (B), and fatigue VAS score (C).
IBD Status and QoL
The patient-reported QoL was similar for patients with and without concomitant IBD, and even unaffected by the type of IBD. Furthermore, the QoL was similar for the patients who had IBD activity compared with the patients in IBD remission at the time of inclusion (Supplementary Figure 3).
Cholangitis Episodes’ Impact on QoL
Furthermore, we investigated if a history of any cholangitis episode requiring hospitalization impacted the patient-reported QoL (Figure 2). Fifteen patients had a history of cholangitis requiring hospitalization, and 10 of these patients had a history of multiple hospitalizations because of cholangitis. These 15 patients reported a significantly lower QoL compared with patients without previous cholangitis episodes evaluated by the PSC PRO total score (median 21 [IQR: 12–65] vs 15 [8–26], P = .04), the EQ-5D-5L VAS score (71 [56–82] vs 86 [76–91], P = .01), and the fatigue VAS score (55 [20–79] vs 19 [0–50], P = .01). They also reported a higher median pruritus VAS score of 20 (IQR: 0–41). The median time since the last hospitalization with cholangitis was 3 years (IQR: 1–4). Notably, the patients who had experienced any previous episode of cholangitis also had higher sCD163 levels than cholangitis-naïve patients (median 3.53 mg/L [IQR: 2.84–5.06] vs 2.67 [1.88–3.59], P = .03).
Figure 2.
The quality of life measures PSC PRO total score (A), EQ-5D-5L VAS score (B), and fatigue VAS score (C) in patients with PSC divided by a history with any cholangitis episode requiring hospitalization (n = 15) or not (n = 63).
Subgroup Analyses
We observed no differences in the background characteristics between the cohort participants who completed all QoL questionnaires and the participants who did not (Supplementary Table 2). In the above analyses, we included patients with all subtypes of PSC. Therefore, we performed subgroup analyses on patients with PSC/AIH overlap disease, as these patients might have a different disease phenotype compared with classic PSC. The 10 patients included with PSC/AIH overlap disease did not differ in terms of demographics, anthropometrics, or most noninvasive liver fibrosis measures. However, they had modestly higher levels of alanine aminotransferase (median 114 U/L [IQR: 68–157]), gamma-glutamyl transferase (median 510 U/L [IQR: 308–974]), alkaline phosphatase (ALP) (median 307 U/L [IQR: 236–462]), and sCD163 (median 3.78 mg/L [IQR: 3.55–4.34]). In addition, they scored slightly higher on the PSC PRO total score (median 23 [IQR: 10–45]) and the fatigue VAS score (median 35 [IQR: 4–58]), without differing on the EQ-5D-5L VAS score (median 79 [IQR: 68–91]) or the low level on the pruritus VAS score (median 0 [IQR: 0–5]). Among the 10 patients with PSC/AIH overlap disease, 80% received corticosteroids and 90% received other immunosuppressive treatments. Furthermore, we allowed the inclusion of patients with ongoing or previous hepatobiliary (n = 2) and colorectal cancers (n = 5). The QoL questionnaire responses were similar regardless of a cancer history. The median time since cancer diagnosis and study inclusion was 5.5 years (range 1 month to 33.5 years).
Sensitivity Analyses
Finally, we investigated the associations between ALP and health-related QoL. We observed no statistically significant associations between ALP and PSC PRO total score (rho = 0.19, P = .09) or EQ-5D-5L VAS score (rho = 0.01, P = .99), nor between gamma-glutamyl transferase and PSC PRO total score (rho = 0.13, P = .25) or EQ-5D-5L VAS score (rho = −0.04, P = .71). The PSC PRO total score tended to be higher in patients with ALP >2× the upper normal limit compared with those with ALP ≤2× (median 23 [IQR: 12–33] vs 13 [IQR: 8–30], P = .07), whereas the EQ-5D-5L VAS scores were similar (median 80 [70–91] vs 85 [70–70], P = .86).
Discussion
In this study, we report inclusion data from a newly established Danish cohort of patients with PSC at a tertiary university hospital liver center, providing a comprehensive collection of patient-reported QoL measures using both PSC-specific and generic questionnaires and scores. The main finding was an overall high patient-reported QoL among Danish patients with PSC, predominantly included at regular control visits in the outpatient clinic. Furthermore, most patients had normal noninvasive measures of liver inflammation and fibrosis. We observed significant, but modest, correlations between the PSC-specific PSC PRO instrument QoL score and sCD163, but not fibrosis. Moreover, patients with any previous event of cholangitis had significantly lower QoL, with both disease-specific and generic scores, and higher levels of sCD163 than patients without previous cholangitis episodes. Overall, the results suggest a role for patient-reported QoL in the clinical management of patients with PSC and a potential association between QoL and liver inflammation.
QoL and PROs in patients with chronic liver diseases have gained clinical interest during the past decades.5,10,24, 25, 26, 27 Most previous studies investigating QoL in patients with PSC used generic QoL measures such as the Short-Form-36 and EQ-5D-5L or questionnaires specific to chronic liver diseases and consistent with the present work reported high QoL.7, 8, 9 The EQ-5D-5L answers among patients with PSC in our PSC cohort were similar to those of the general Danish population.28 These findings align with data from a large Dutch PSC cohort study.10
In the present work, we further expanded the assessment of QoL with the inclusion and validation of the recently developed PSC-specific PSC PRO instrument.11 Overall, patients in this PSC cohort and the PSC PRO instrument development cohort reported similar answers despite being different in multiple clinical variables. Hence, in the present cohort, only 8% had established cirrhosis, compared to 39% in the original PSC PRO instrument cohort. Further, the PSC PRO instrument development cohort consisted of fewer patients with IBD, fewer males, and none with cancer. As such, the present work expands the applicability of the PSC PRO instrument to patients with a more diverse PSC phenotype. Accordingly, we included patients with PSC/AIH-overlap disease, further supporting the robustness of the PSC PRO instrument. Recently, the PSC PRO instrument was validated in 55 Australian patients with PSC and we confirm their primary findings with cholangitis impacting the PSC PRO total score and fatigue being a dominating PSC-related symptom.25
Accordingly, we report a strong correlation between the PSC PRO instrument total score and the fatigue VAS score but no association between the PSC PRO instrument total score and the EQ-5D-5L VAS score. Patients with and without IBD did not report different answers to the PSC PRO instrument. This suggests that the most invalidating symptom of PSC is fatigue and that the PSC PRO instrument is in fact measuring the disease-specific QoL. As such, the clinical use of the PSC PRO instrument provides a detailed exploration of which everyday tasks are impacted by impaired QoL, guiding the clinical management of patients with PSC.
The disease pathogenesis of PSC is believed to be multifactorial with the involvement of the adaptive immune system.29 Some macrophage types play key roles in fibrogenesis, and Kupffer cells are highly present in liver biopsies from patients with PSC.22,30,31 Therefore, the role of circulating sCD163, shed from liver macrophages upon activation, has received rising interest as a noninvasive biomarker for monitoring liver diseases, as it is associated with ongoing liver inflammation and fibrosis severity for multiple acute and chronic liver diseases.15 We recently reported an independent association between sCD163 and disease severity and prognosis in patients with PSC.16 The present study expands and nuances the knowledge of these associations by revealing a significant positive correlation between sCD163 and the disease-specific PSC PRO instrument. In particular, the QoL domains measuring activity of daily living, work productivity, and social impact were the main drivers for the overall positive correlation. In an outpatient setting, the complementary monitoring of these variables may help clinicians with the early identification of disease progression. Since the concomitantly measured plasma C-reactive protein level was low, the contribution from nonhepatic macrophage sCD163 shedding was considered less likely. Furthermore, patients with any previous hospitalizations with cholangitis had higher sCD163 and lower disease-specific QoL, suggesting that cholangitis may induce marked and persistent clinical imprints and supporting that liver inflammation affects the disease-specific QoL.
The present study has both strengths and limitations. A major strength of the study is the large cohort size and the ambitious and thorough collection of data from patients with PSC. Yet, the present work reports only inclusion data, and future follow-up studies investigating longitudinal data are needed for further insight into the course and prognostic ability of patient-reported QoL through the PSC disease trajectory.26,27 Nevertheless, the publication of cohort inclusion data is justified and may stimulate the identification of important directions and collaborations for future work with the upcoming longitudinal data. This also explains the broad inclusion criteria, which allowed enrollment of patients with PSC across the entire disease spectrum. As such, the cohort reflects real-word practice. At the same time, adjustments may be required when analyzing data across distinct phenotypes, such as PSC/AIH overlap disease, which often requires corticosteroids or other immunosuppressive therapies, or the generally milder small-duct PSC. A limitation is the QoL questionnaire response rate of 85%, although the nonrespondents to the questionnaires were not clinically different from the respondents (Supplementary Table 2). Also, the response rate was higher than the approximately 70% achieved in the recent Australian and Dutch studies.10,25 We carefully considered including additional validated questionnaires to capture more granular QoL responses, but ultimately chose the measures described above to balance the need for a high response rate with the desire to assess multiple aspects of QoL.32 Patients were recruited evenly throughout the calendar year, reducing the impact of seasonal variation on QoL responses. The transferability of the results is limited, as all patients were included from only one tertiary liver center in Denmark, and most patients were enrolled at regular control visits at the outpatient clinic. However, in Denmark, patients with PSC are followed in tertiary referral centers only due to the rarity and potential rapid and severe course of the disease.
Conclusion
This newly established PSC cohort provides comprehensive data on Danish patients with PSC, and the planned prospective data collection will add to our knowledge of this rare but serious disease. The participants, primarily included in an outpatient setting, overall reported high QoL using both the novel disease-specific PSC PRO instrument and generic QoL scores. Moreover, the PSC PRO instrument total score was not associated with liver fibrosis severity but significantly associated with the inflammation biomarker sCD163 and affected by PSC-driven cholangitis episodes. This may ultimately strengthen the validity of the PSC PRO instrument and justify its use in the clinical management of patients with PSC, helping to guide the prioritizing of patient follow-up for those with the most urgent needs.
Footnotes
Conflicts of Interest: These authors disclose the following: Henning Grønbæk received research grants from AbbVie, Intercept, ARLA Food for Health, and ADS AIPHIA Development Services AG; consulting fees from Ipsen, Novo Nordisk, and Pfizer; lectured for AstraZeneca, Novo Nordisk, and EISAI; and was in the Data Monitoring Committee for CAMURUS AB. Lars Bossen received a research grant from Helsefonden. Rasmus Hvidbjerg Gantzel received support for conference participation from AbbVie and Ipsen. Holger Jon Møller is a shareholder in Spica Therapeutics. The remaining authors disclose no conflicts.
Funding: The authors report no funding.
Ethical Statement: The study was approved by the Danish Ethics Committee (study no. 1-10-72-346-21) and conducted in accordance with the Declaration of Helsinki. All patients were enrolled after written informed consent.
Data Transparency Statement: Anonymized study data may be available upon request to the corresponding author.
Reporting Guidelines: Reporting Guidelines were not applicable for this article type.
Material associated with this article can be found, in the online version, at https://doi:10.1016/j.gastha.2026.100964.
Supplementary Materials
References
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