Letter: Different Risk of Acute Variceal Bleeding According to the Liver Disease Aetiology in Decompensated Cirrhosis Patients Receiving Carvedilol‐Based Primary Prophylaxis—May Insulin Resistance Unloose This Gordian Knot?

Editors.

We enthusiastically read the brilliant research by Villanueva et al. which, by systematically reviewing randomised clinical trials (RCTs) comparing non-selective beta-blocker (NSBB) versus variceal band ligation (VBL) for primary acute variceal bleeding (AVB) prevention in cirrhotic patients presenting high-risk varices, revealed NSBBs significantly improved survival versus VBL, with no additional benefit noted of the combination strategy, exclusively in patients with compensated advanced chronic liver disease (cACLD), reporting, in contrast, a similar survival with both therapies in decompensated (dACLD) individuals [1]. These findings remarked on a crucial need for personalised AVB-primary prophylaxis by adapting treatment to the clinical stage of cirrhosis [1].

More recently, the “CAVARLY trial” has demonstrated the superiority of the combination therapy (VBL-NSBB) to either strategy alone in preventing the first AVB in dACLD patients with high-risk varices [2]. Interestingly, an elevated rate of events in the carvedilol arm (33.6%) was reported, and, notably, over half of the patients did not show a haemodynamic NSBB response [2].

Unlike previous historical research [3], in this trial, a significant proportion (~50%) of enrolled patients presented Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD)-related cirrhosis, providing an updated snapshot of the current chronic liver disease (CLD) epidemiology.

Relevantly, type 2 diabetes mellitus (T2DM) and obesity have already been demonstrated to impair the haemodynamic response to NSBB, thus predisposing to overall hepatic decompensation [4, 5]. However, the impact of CLD aetiology on first AVB remains unexplored in dACLD patients.

From July 2022 to April 2024, we consecutively enrolled and followed over 12 months, 76 (35 viral-related and 41 MASD-related) dACLD individuals presenting high-risk varices (IRB-prot0021377/i). Patients received carvedilol-based primary prophylaxis (32 MASLD; 28 viral-related), reserving VBL for NSBB-intolerant subjects (9 MASLD; 7 viral-related) [6]. As in “CAVARLY”, NSBB compliance was self-monitored by arterial pressure measurements and a diary.

A significantly higher rate of AVB was observed in MASLD compared to the viral-related group (HR: 2.806, p: 0.027), specifically in the carvedilol-receiving patients. Interestingly, the Cox regression analysis (adjusted for sex, age, Child-Pugh, BMI, and endoscopic varices features) revealed T2DM (aHR: 2.541, p: 0.001), Homeostasis Model Assessment for Insulin Resistance (aHR: 2.112, p < 0.0001), obesity (aHR: 1.781, p: 0.002), and C-reactive protein (aHR: 1.72, p: 0.001) as the variables significantly associated with this outcome (Figure 1).

FIGURE 1

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First acute variceal bleeding occurrence in dACLD patients with high-risk varices (i.e., large varices or small varices with red signs) undergoing primary prophylaxis, according to the received treatment strategy and disease aetiology, with the analysis of variables influencing this outcome in the MASLD-NSBB (NSBB: carvedilol) group. Cumulative incidence analysis (Log-Rank test); Multivariate Cox Regression Analysis model (adjusted for sex, age, BMI, Child-Pugh score, and endoscopic varices features); aHR, adjusted hazard ratio; AVB, acute variceal bleeding; BMI, body mass index; dACLD, decompensated advanced chronic liver disease; HOMA-IR, homeostasis Model Assessment for Insulin Resistance; MASLD, metabolic dysfunction-associated steatotic liver disease; NSBB, non-selective beta-blocker; VBL, variceal band ligation.

These pioneering results appear consistent with evidence supporting a “dysmetabolic-specific” portal hypertension (PH) [5, 7, 8]. While systemic inflammation represents a well-recognised PH mediator regardless of the aetiology [9], insulin resistance (IR) emerges as a discriminant, acting as a pathogenetic key driver specifically in MASLD, where it has been revealed to promote intrahepatic endothelial dysfunction and enhance splanchnic vasodilation, thus contributing to more severe PH, also potentially conditioning NSBB-haemodynamic response [5, 7, 8, 10].

In the era of Precision Medicine, considering MASLD is dramatically supplanting viral aetiologies, future research should focus on shedding light on crucial points: translationally, how urgent is it to redesign new RCTs properly enrolling MASLD patients? As for the clinical stage [1], is it time to adapt strategies also according to the disease aetiology? Pathophysiologically, is IR sufficient to unloose the “Gordian knot” of MASLD-specific PH?