When should I repeat the endoscopy in my patient with compensated cirrhosis, whom I just scoped and who had no or small varices?

Guidance regarding repeat endoscopy in patients with compensated cirrhosis whose index endoscopy reveals no or only small varices are based mainly on expert opinion (1). The American Society for Gastrointestinal Endoscopy (ASGE) recommends repeat endoscopy every 2–3 years for patients with no varices (low risk) and every 1–2 years for patients with small varices (higher risk) (1). In order to refine these recommendations, we analyzed the subjects with no or small varices from the HALT-C cohort (n=195) for clinical outcomes over an average duration of follow-up of 5.3 years (2). This manuscript reports a retrospective, post hoc analysis of patient data that had been previously collected under an IRB-approved protocol (3,4). The HALT-C Trial’s Quantitative Liver Function Test (QLFT) ancillary study was a US multi-center study conducted according to the Declarations of Helsinki and Istanbul and was approved by the respective institutional review boards of the participating centers. All participants provided written informed consent to participate. For the present analysis, only fully deidentified data were used. In accordance with institutional policies and federal regulations, this secondary analysis did not require additional IRB review, as no identifiable private information was accessed and the analysis was not prespecified. All study procedures complied with applicable guidelines and regulations for research using deidentified data.

Timing for follow-up and repeat endoscopy was based on risk for clinical outcome. In the HALT-C cohort, clinical outcome was defined as variceal hemorrhage (n=2), ascites (n=12), encephalopathy (n=8), Child-Pugh score progression ≥2 (n=29), transplant (n=6), and death (n=28). In addition to clinical follow-up, the patients underwent the oral cholate challenge test (HepQuant DuO^®) (5-8) and determination of Disease Severity Index (DSI). The DSI correlates with risk for portal hypertension, varices, and clinical outcome (9,10). Categories of clinical risk based on DSI were defined as follows (10,11):

• DSI ≤18.3 (low risk);
• DSI ≤24 with platelet count >135 nL⁻¹ (low to moderate risk);
• DSI ≤24 with platelet count ≤135 nL⁻¹ (moderate to high risk);
• DSI >24 (high risk).

We applied these categories to predict risk for clinical outcome in the 195 patients who had no or small esophageal varices (3,4). Kaplan Meier plots demonstrated stepwise increased risk for clinical outcome according to the above categories (Figure 1A,1B). DSI >24 represented the highest risk for early clinical outcome and DSI ≤18.3 the lowest risk.

Figure 1 Clinical outcomes stratified by DSI cutoff in the 195 subjects with ongoing chronic hepatitis C who had no or small varices. Subjects were enrolled in the HALT-C Trial QLFT ancillary study and followed for a median of 5.8 years. Panels A and B show the time-dependent increase in probability for clinical outcome in subjects with no and small varices stratified by DSI cutoffs (A) and DSI and PLT cutoffs (B). Panels C and D show the percentage of subjects with no or small varices who experienced clinical outcome by DSI cutoffs 18.3 (C) and 24 (D). DSI, Disease Severity Index; HALT-C, Hepatitis C Anti-viral Long-term Treatment against Cirrhosis; PLT, platelet count; QLFT, Quantitative Liver Function Test.

In our cohort, DSI predicted risk for clinical outcomes independent of presence or absence of varices. Using the DSI cutoff of 18.3, in subjects with no varices, 9 of 82 patients with DSI ≤18.3 (11%) versus 21 of 61 patients with DSI >18.3 (34%) had clinical outcomes (Chi-squared test, P<0.001), and in subjects with small varices, 5 of 22 patients with DSI ≤18.3 (23%) versus 18 of 30 patients with DSI >18.3 (60%) had clinical outcomes (P=0.009) (Figure 1C). Similarly for the DSI cutoff of 24, in subjects with no varices, 21 of 129 patients with DSI ≤24 (16%) versus 9 of 14 patients with DSI >24 (64%) had clinical outcomes (P<0.001), and in subjects with small varices, 11 of 36 patients with DSI ≤24 (31%) versus 12 of 16 patients with DSI >24 (75%) had clinical outcomes (P=0.004) (Figure 1D). Additionally, in a logistic regression analysis including the variables of DSI and either no or small varices, DSI (P<0.0001) was a highly significant predictor of risk for clinical outcome while categories of no or small varices was non-significant (P=0.07). These findings demonstrate that DSI identifies the patients most at risk for clinical outcomes.

Given these findings, we recommend:

• Performance of the oral cholate challenge test and determination of DSI prior to or after an index endoscopy and modification of timing of repeat endoscopy based on DSI;
• Later endoscopy at 2–3 years and less intense clinical follow-up in the patients with DSI ≤18.3 or DSI 18.3–24 with platelet count >135 nL⁻¹ (low risk);
• Earlier endoscopy at 1–2 years and closer clinical follow-up in the patients with DSI >24 or DSI 18.3–24 with platelet count ≤135 nL⁻¹ (higher risk).

Another consideration is when to repeat DSI testing. Based on the Kaplan Meier plots (Figure 1B), we recommend the following:

• DSI ≤18.3: 2–3 years (low risk);
• DSI ≤24 with platelet count >135 nL⁻¹: 1.5–2 years (low-to-moderate risk);
• DSI ≤24 with platelet count ≤135 nL^-1: 1–1.5 years (moderate-to-higher risk);
• DSI >24: <1 year (highest risk).

The HALT-C cohort consisted of patients with active chronic hepatitis C. These subjects had a high prevalence of overweight body habitus (75%) and obesity (44%), diabetes mellitus (25%), and alcohol use (12). In addition, in the SHUNT-V study, the diagnostic performance for large esophageal varices was similar between MASH and non-MASH subjects (10). These findings suggest that the results in the HALT-C subjects may be generalizable to both metabolic dysfunction-associated steatohepatitis (MASH) and alcohol-associated liver disease (ALD). The DSI is a quantitative measure of flow-dependent hepatic uptake of cholate through the sinusoids—a process that is agnostic to liver disease etiology. The patients in this cohort had active liver disease affecting the liver’s uptake of cholate, and patients with ongoing and untreated MASH would be similarly affected. Additional work is needed to validate these models for other liver disease etiologies, including MASH and ALD.

Although DSI correlates with liver stiffness measurements (LSM) by vibration-controlled transient elastography (VCTE), the correlation is relatively weak (13). In the recent SHUNT-V study of 275 subjects with compensated advanced chronic liver disease (cACLD) of all etiologies (10), 86 subjects had LSM by VCTE performed. A post hoc analysis compared the diagnostic performance of DSI 20 versus LSM 20 kPa since these values had equivalent rates of endoscopy avoidance to check for varices (43%). The analysis demonstrated that DSI missed fewer varices of any size compared with LSM for any given platelet count cutoff used in the Baveno criteria (14). Similarly, the analysis also demonstrated that DSI 20 captured more endoscopic lesions of portal hypertension than LSM (i.e., higher sensitivity for any varices, treated varices, large gastric varices, varices with red wale signs, and severe portal hypertensive gastropathy). Results were similar for DSI versus LSM comparisons of 18 vs. 19 kPa, 20 vs. 20 kPa, and 23 vs. 25 kPa where EGD avoidance rates were equivalently 38%, 43%, and 55%, respectively.

Similarly, DSI correlates with Enhanced Liver Fibrosis (ELF) score—although weakly. In a decision memorandum [DEN190056, “Evaluation of Automatic Class III Designation for ADVIA Centaur Enhanced Liver Fibrosis (ELF^™)”] (15), the performance in predicting risk for decompensation in patients with compensated MASH cirrhosis (n=305) was 4.3% for ELF <9.8, 4.0% for ELF 9.8 to 11.3, and 21.0% for ELF >11.3. Although not head-to-head, the performance of DSI in predicting risk for decompensation in patients with cACLD (n=215) was 6.6% for DSI <18.3, 30.6% for DSI 18.3 to 24, and 59.5% for DSI >24 (2). These comparisons to LSM and ELF suggest that DSI is a valid noninvasive tool for assessment of clinical risk.

A commercial pilot of the HepQuant DuO^® test was recently completed (14), and the test is now gaining broader market adoption in liver centers across the United States. The test is scalable and simple to collect, involving an oral dose of isotope-labelled d4-cholate and two blood draws at 20 and 60 minutes. The two blood samples are processed by centrifugation before shipping ambient to the HepQuant Laboratory. In a recent cost-effectiveness analysis, we modeled the impact of using DSI to guide decisions about screening endoscopy, surveillance intensity, and resource prioritization (16). The model demonstrated that DSI-guided management was highly cost-effective relative to standard care within two years at a test price of $3,250, saving an estimated 2,740 lives over five years. The model also showed that DSI becomes cost-saving within two years at ≤$3,213 per test and within 5 years at ≤$4,100. These findings support the economic and clinical value of DSI-based decision-making in patients with cACLD suspected of having large esophageal varices, reducing unnecessary endoscopy, optimizing resource use, and prioritizing high-risk patients to help prevent unanticipated hepatic decompensation.

In summary, DSI may be a better indicator of risk for clinical outcome than the categories of no or small varices in patients with cACLD. Use of DSI could further refine timing of repeat endoscopy and clinical follow-up to improve clinical management and resource utilization.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-133/prf

Funding: The HALT-C Trial QLFT ancillary study was supported by the National Institute of Diabetes & Digestive & Kidney Diseases (contract numbers are listed below); additional support was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities and by General Clinical Research Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed below); additional funding supplied by Metabolic Solutions, Inc. and by Hoffmann-La Roche, Inc., through a Cooperative Research and Development Agreement with the National Institutes of Health; contract and grants supporting this study included: University of Colorado School of Medicine, Denver, CO: (Contract N01-DK-9-2327, Grant M01RR-00051), University of California - Irvine, Irvine, CA: (Contract N01-DK-9-2320, Grant M01RR-00827), Virginia Commonwealth University Health System, Richmond, VA: (Contract N01-DK-9-2322, Grant M01RR-00065), and New England Research Institutes, Watertown, MA: (Contract N01-DK-9-2328). HepQuant, LLC had no role in the HALT-C Trial QLFT ancillary study design, conduct, and interpretation of findings. The development of the oral cholate challenge test (HepQuant DuO) and this retrospective analysis was funded by HepQuant, LLC.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-133/coif). J.C.I. (CMO) is an equity member and employee of HepQuant, LLC. M.P.M. is a paid consultant for HepQuant, LLC and has pending patents related to the oral cholate challenge test (HepQuant DuO) and simplified versions of the SHUNT test. G.T.E. (CEO) is an equity member and employee of HepQuant, LLC. G.T.E., in conjunction with the University of Colorado Denver Anschutz Medical Campus, has patents, both issued and pending, related to the dual cholate shunt test (HepQuant SHUNT). G.T.E., in conjunction with HepQuant, LLC, has pending patents related to the oral cholate challenge test (HepQuant DuO) and simplified versions of the SHUNT test. Funding for the HALT-C QLFT study was provided by the National Institute of Diabetes & Digestive & Kidney Diseases, and additional funding supplied by Metabolic Solutions, Inc. and Hoffmann-La Roche, Inc. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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