Lactulose for Preventing Overt Hepatic Encephalopathy: Between Evidence and Unresolved Questions

To the Editor,

1.

We read with great interest the systematic review and meta‐analysis by Kasmikha et al. [1], which provides an updated and clinically relevant synthesis of randomized evidence on lactulose for the prevention and treatment of hepatic encephalopathy (HE). The authors should be commended for addressing an important unresolved issue: whether lactulose should be considered not only for treatment and secondary prophylaxis, but also for the primary prevention of overt HE in selected patients with cirrhosis.

The main finding is compelling. Lactulose significantly reduced the risk of overt HE compared with no lactulose, including in studies focused on primary prophylaxis. Importantly, this benefit was not accompanied by an increased risk of serious adverse events or treatment discontinuation. These results reinforce the central role of lactulose in HE management and may inform future updates of international guidance, particularly regarding primary prophylaxis in selected high‐risk patients [2, 3].

However, the study also highlights several areas that remain clinically unresolved and therefore challenging. First, the populations included in the primary prophylaxis analyses were heterogeneous, ranging from patients with portal hypertension or poor patient‐reported outcomes to those with minimal/covert HE or acute precipitating events such as gastrointestinal bleeding. Therefore, the key question is no longer simply whether lactulose prevents HE, but rather which patients derive the greatest net benefit.

Second, the potential mortality benefit remains uncertain. While Bayesian analyses suggest a high probability of benefit, conventional pooled estimates did not show a statistically significant reduction in mortality. This distinction is clinically relevant, as mortality in decompensated cirrhosis is multifactorial and may not be directly modified by HE prevention alone.

Third, the optimal duration, dose titration and stopping rules for primary prophylaxis remain undefined. Lactulose is effective, inexpensive and generally safe, but its real‐world use is limited by bloating, diarrhoea, dehydration risk and adherence challenges. These issues are particularly relevant in frail, sarcopenic or elderly patients.

Future studies should therefore aim to move beyond a uniform preventive strategy and define risk‐based, phenotype‐driven approaches to lactulose prophylaxis. High‐risk groups such as patients with covert HE, recurrent falls, sarcopenia, large spontaneous portosystemic shunts, prior TIPS, hyponatraemia or recent decompensation deserve dedicated evaluation [2, 4, 5]. Pragmatic trials incorporating patient‐centered outcomes such as falls, hospitalizations, caregiver burden, quality of life and cost‐effectiveness would be especially valuable.

In conclusion, Kasmikha et al. [1] offer timely and important evidence that lactulose reduces overt HE. Future efforts should focus on refining patient selection, treatment duration, and monitoring strategies to ensure that preventive therapy is both effective and clinically meaningful.

Author Contributions

Lorenzo Ridola: conceptualization and manuscript writing, critical revision for important intellectual content, final approval. Stefania Gioia, Silvia Nardelli: critical revision for important intellectual content, final approval.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Linked Articles

This article is linked to Kasmikha et al. papers. To view these articles, visit https://doi.org/10.1111/liv.70765.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.