Clinically significant portal hypertension (CSPH), defined by hepatic venous pressure gradient (HVPG) ≥10 mmHg, is the key driver of potentially life-threatening complications in patients with compensated advanced chronic liver disease (cACLD) [
1]. The PREDESCI study, which included HVPG measurements in its design, demonstrated that prophylactic carvedilol treatment upon CSPH diagnosis improves clinical outcome [
2], even in the absence of high-risk varices (HRV), for which primary prophylaxis to prevent variceal bleeding is well-established.
Historically, the presence of varices in upper gastrointestinal endoscopy was the only broadly evaluable indicator of CSPH. However, CSPH may be present despite the absence of varices [
1]. The advent of non-invasive tests (NITs) for CSPH, most importantly vibration-controlled transient elastography for liver stiffness measurement (LSM), marked a paradigm shift in the diagnosis and management of CSPH [
3]: The ‘Baveno VII criteria’ indicate that CSPH is ruled-out if LSM ≤15 kPa and platelet count (PLT) ≥150 G/L, while it is ruled-in if LSM ≥25 kPa [
1]. These criteria were further refined by the consideration of another promising NIT for CSPH, i.e., spleen stiffness measurement (SSM), which has shown high diagnostic utility [
4,
5]. Prior to the paradigm shift towards treatment of CSPH regardless of variceal status to prevent first hepatic decompensation, the recommendation was to apply LSM and PLT to avoid screening endoscopies in patients with a low probability of HRV (‘Baveno VI criteria’) [
6], i.e., those with LSM ≤20 kPa and PLT ≥150 G/L [
6].
In their study conducted in a large cohort of prospectively characterized patients with mostly suppressed HBV-related compensated cirrhosis who underwent characterization via LSM, SSM, PLT, and endoscopy, Wang, Liang, Zhou, Song, and colleagues [
7] investigated the prognostic value of CSPH-NITs (and endoscopy) for hepatic decompensation [
7]. The authors applied the Baveno VII recommendations alongside SSM (‘Baveno VII single / dual cut-off’ algorithms) as well as the dated Baveno VI criteria to their patients. The prognostic relevance of the 25 kPa cut-off for LSM, i.e., the rule-in criterion for CSPH by Baveno VII, was validated. However, half of the decompensation events occurred in patients with LSM <25 kPa but LSM ≥15 kPa and/or PLT <150 G/L (i.e., ‘grey zone’), corroborating previous observations in other contexts [
8,
9]. Meanwhile, the algorithms considering SSM in addition to Baveno VII criteria could accurately identify most/all patients at risk, which is in line with previous studies which additionally considered SSM [
10] or VITRO [
8].
Beyond these somewhat expected results, the present study provides several interesting findings that are worth commenting on. First, even among high-risk patients (LSM >25 kPa), the 2-year incidence of hepatic decompensation was only approximately 8%, underlining the profound disease-modifying effects of viral suppression in HBV-related cirrhosis [
11]. This resembles observations in cACLD patients achieving HCV-cure and a post-treatment LSM >25 kPa, in whom the 3-year probability of hepatic decompensation was 9.6%, while accounting for hepatocellular carcinoma (HCC) development as a competing event—thereby lowering the estimate of hepatic decompensation, which is often preceded/driven by HCC [
12]. In contrast, 2-year incidences of decompensation of up to 20% have been reported in patients with compensated cirrhosis alcohol-related liver disease [
9]. Of note, the present study included almost 10% of patients with compensated Child-Turcotte-Pugh stage B cirrhosis, who accounted for half of decompensation events, as hepatic function (in particular, serum albumin) is the second key determinant of decompensation risk, besides CSPH [
13]. Thus, the 2-year incidence of decompensation among virologically controlled HBV-related cirrhosis patients with Child-Turcotte-Pugh stage A, i.e., the primary target population for CSPH-NITs, may be even lower than 8%.
Second, the authors report an outstandingly low technical failure rate for SSM of less than 2%. Meanwhile, other studies repurposing the 50 Hz LSM probe for SSM have reported technical failure rates of up to 24% [
4]. The authors attributed the low failure to the low median body mass index (BMI) of the cohort (23.5 kg/m2), highlighting the adverse impact of obesity on the feasibility of SSM via VCTE. Of note, VCTE via SSM has recently been refined by the introduction of a dedicated probe operating at 100 Hz, showing encouraging technical success rates, despite higher BMI [
5].
Lastly, the study validates the prognostic value of CSPHNITs for use in treated HBV-related cACLD. NIT-based algorithms/models for CSPH have primarily been developed in cohorts comprising a substantial proportion of viraemic HCV-infected patients, who are rare in current clinical practice [
14]. While our understanding of the evolution of CSPH and non-invasive monitoring upon aetiological cure has improved significantly in recent years, this gain in knowledge was primarily driven by HCV, and thus, investigations on the generalizability of NIT-based risk prediction algorithms/models in HBV are highly valuable [
11]. Of note, the Baveno VII criteria have been slightly adapted for HCV-cure by lowering the cut-off from 15 to 12 kPa in order to exclude (i.e., ≈99%) rather than rule-out (i.e., ≈90%) CSPH [
1,
12], thereby allowing to permanently discharge these patients from portal hypertension surveillance in case of consistent improvements. From a clinical perspective, this may have been overly conservative, given the absence of hepatic decompensation in those meeting the Baveno VI criteria. In line with observations in cACLD subjects achieving HCV cure [
12], HCC development was more common than hepatic decompensation during follow-up in the current study. As we are currently witnessing a policy shift from a stage-dependent to a risk-based approach for indicating HCC surveillance, this cohort may provide the opportunity to develop/validate models for estimating HCC risk that encompass information obtained by NIT, in analogy to those for HCV cure [
15,
16].
Despite the study’s mentioned strengths, some aspects deserve critical appraisal. First, varices were present in two out of three patients included in the study, and one out of five (i.e., n=234) patients had HRV. Meanwhile, only 57 of the included patients received prophylactic carvedilol/NSBB and only one patient underwent endoscopic variceal ligation. Even though the study’s enrolment period ended before the paradigm shift towards initiating carvedilol/NSBB therapy in cACLD patients with CSPH to prevent hepatic decompensation, primary prophylaxis of variceal bleeding in patients with HRV was the standard-of-care globally throughout the study period [
6], as it decreases bleeding and mortality risk vs. no active intervention, or therapeutic nihilism, as propagated by the authors. The reluctance of the treating physicians to use prophylactic carvedilol/propranolol (or ligation)—despite level 1a evidence and strong recommendations—is explained in the Discussion section of their article, where the authors claim that ‘very little patients are able to adhere to NSBB therapy due to contraindications, poor compliance, or physician decision’. Needless to say, we strongly disagree with this statement, which is invalidated by numerous clinical trials [
17] and real-life studies investigating carvedilol/NSBB or banding and not in line with our own clinical experience. Although the comparatively low background risk in the context of cACLD and HBV suppression translates into a higher number needed to treat (NNT) for preventing variceal bleeding, as compared to trials establishing primary prophylaxis (absolute risk reduction: ≈13%; NNT ≈8) [
18], the decompensation risk among those with HRV was not negligible and may have been halved by carvedilol therapy (extrapolating from the PREDESCI trial [
2]). While the treating physician’s opinions/therapeutic nihilism may have withheld the benefits of known effective treatment, from a scientific perspective, the study provides estimates of risks that weren’t modified by selectively applying preventive strategies in those with more advanced disease, which is remarkable.
Moreover, the study’s focus on varices needs to be discussed. The prognostic relevance of varices upon removal/suppression of the aetiological control is uncertain, as they may persist despite the resolution of CPSH [
19]. Unfortunately, HVPG measurements were not conducted in the current study, which precludes further gains in knowledge on the potential dissociation between endoscopic findings and portal hypertension. Nevertheless, even among those with an unfavourable status based on NIT (i.e., with a high likelihood of CSPH), HRV were associated with a higher risk of hepatic decompensation, thereby supporting their prognostic significance.
Finally, the study included some longitudinal data on NITs, but the small number of events in those with available information did not allow for a meaningful analysis of the prognostic utility of changes in NITs/updated values for outcome prediction. Most patients showed consistent results or improvements in NITs as expected following suppression of the primary aetiological factor. We encourage the re-evaluation of NITs in yearly intervals in cACLD patients as suggested by the Baveno VII consensus [
1]. However, recently emerging evidence suggests that the most updated NIT values rather than dynamics over time may guide patient management [
20], but studies focusing on HBV-related compensated cirrhosis would be desirable to confirm the generalizability of this finding.
In conclusion, the authors validated CPSH-NITs for the prediction of hepatic decompensation in a large study conducted in HBV-related compensated cirrhosis. However, any diagnostic test/surrogate of risk is only as valuable, as the clinical consequences that are drawn from it. ‘Ignorance is bliss’ does not appear to be the author’s diagnostic mantra for patients achieving HBV suppression; at the same time, therapeutic nihilism regarding CSPH/HRV seems to be equally inopportune.
FOOTNOTES
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Authors’ contribution
Both authors contributed equally to conceptualization and writing of the editorial (M.J., M.M.).
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Acknowledgements
M.J. and M.M. receive financial support from “Clinical Research Group MOTION, Medical University of Vienna, Vienna, Austria – a project funded by the Clinical Research Groups Programme of the Ludwig Boltzmann Gesellschaft (Grant Nr: LBG_KFG_22_32) with funds from the Fonds Zukunft Österreich”.
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Conflicts of Interest
The authors declare no conflict of interest regarding this work. Outside the submitted work, the authors declare the following potential conflicts of interest:
M.J. served as a speaker and/or consultant for Gilead. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Echosens, Eli Lilly, Gilead, Ipsen, Takeda, and W. L. Gore & Associates and received travel support from AbbVie and Gilead.
Abbreviations
compensated advanced chronic liver disease
clinically significant portal hypertension
hepatic venous pressure gradient
liver stiffness measurement
spleen stiffness measurement
vibration-controlled transient elastography
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