Prediction and prevention of the first episode of overt hepatic encephalopathy in patients with cirrhosis

Hepatology Communications · 4 authors, 2 centres

AI SUMMARY

FIDELITY 100%

POPULATIONpatients with liver cirrhosis without a history of overt hepatic encephalopathy

INTERVENTIONlactulose (30–60 mL 2–3 times daily) or probiotic VSL#3 (1 capsule 3 times daily)

COMPARISONno treatment / placebo

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TL;DR

This narrative review summarizes tools for predicting a first episode of overt hepatic encephalopathy (OHE) in cirrhosis patients, including cognitive tests (PHES, CFF, Stroop EncephalApp, Animal Naming Test), blood-based biomarkers, composite scores, sarcopenia, and spontaneous portosystemic shunts. Only two open-label studies have investigated primary prophylaxis of a first OHE episode as a primary endpoint—one with lactulose (11% vs. 28% OHE incidence, p=0.02) and one with probiotics (8.8% vs. 20.3%, p<0.05)—but both had significant limitations. The authors conclude that a general recommendation for primary prophylaxis cannot be made and call for adequately powered, double-blind RCTs in well-defined high-risk populations.

Full summary

3,911 CHARS

**Background:** Hepatic encephalopathy (HE) is a devastating complication of liver cirrhosis, with overt HE (OHE) associated with poor prognosis and impaired quality of life. Identifying patients at high risk for a first OHE episode could justify primary prophylaxis, but evidence on prediction tools and preventive therapies is heterogeneous. This narrative review summarizes available evidence on prediction and prevention of a first OHE episode.

**Methods:** The authors conducted a narrative review of the literature covering cognitive tests, blood-based biomarkers, composite scores, sarcopenia, spontaneous portosystemic shunts (SPSS), gut microbiome, genetics, and pharmacological interventions for primary prophylaxis of OHE. Key studies are described with exact numbers.

**Key Results:** - **Cognitive tests:** Patients with pathological PHES results had 3.9-fold (German study, n=191) and 2.1-fold (US study, n=170) increased risk of first OHE. The Stroop EncephalApp, Animal Naming Test (ANT), and critical flicker frequency (CFF) also show predictive value, though cutoffs vary. - **Blood-based biomarkers:** Ammonia levels >1.5× upper limit of normal correlated with increased OHE risk. IL-6 >6 pg/mL identified patients with first OHE within 1 year with >90% sensitivity (single-center study, no external validation). - **Composite scores:** The BABS score stratifies patients into 3 risk groups (score ≤0: 6% annual OHE risk; score ≥1: 25% annual OHE risk). The MASQ-HE score had an AUROC of 0.82 for OHE at 12 months and 0.92 for HE-associated hospitalization. - **Sarcopenia:** Affects up to 37.5% of cirrhosis patients (meta-analysis). Associated with MHE and OHE development in a study of 64 patients, but no study has excluded prior OHE. - **SPSS:** Total cross-sectional SPSS area >83 mm² was associated with higher OHE frequency (33% vs. 47%, p<0.05) in an international multicentric study. - **Oral glutamine challenge:** In 198 patients without prior OHE, cumulative 12-month OHE incidence was 4.7% (low-risk), 9.9% (intermediate), and 21.9% (high-risk). - **Genetics:** A risk score combining 4 SNPs and the phosphate-activated glutaminase microsatellite yielded a C-index of 0.83 (internal) and 0.74 (external validation). - **Primary prophylaxis:** Only two studies had first OHE as primary endpoint. Lactulose (n=120, open-label): OHE incidence 11% vs. 28% (p=0.02, NNT=4.6). Probiotic VSL#3 (n=160, open-label): OHE incidence 8.8% vs. 20.3% (p<0.05, NNT for MHE patients=4.2, for non-MHE=12.8). Both studies were single-center, open-label, with heterogeneous cohorts. - **Rifaximin:** No study primarily designed for first OHE prevention. A subgroup analysis of a Chinese study suggested lower OHE frequency with low-dose rifaximin. An ongoing multicenter RCT (NCT05071716, n=466, expected completion January 2025) is investigating rifaximin SSD vs. placebo. - **LOLA:** One study found fewer OHE episodes with LOLA vs. placebo (5% vs. 37.9%, p=0.016) as a secondary endpoint, but the primary endpoint (MHE reversal) was not met. - **TIPS:** Rifaximin reduced post-TIPS OHE risk by 50% in a double-blind RCT. In a subgroup without prior OHE, the reduction was not significant (35% vs. 51%, p=0.070). - **Variceal bleeding:** Lactulose is recommended to prevent OHE after variceal bleeding, supported by meta-analyses, though without survival benefit.

**Clinical Implications:** Current EASL guidelines recommend treatment of covert HE with nonabsorbable disaccharides, but a general recommendation for primary prophylaxis of a first OHE episode cannot be made. The available evidence is limited to two open-label, single-center studies with heterogeneous populations. Future research should focus on identifying high-risk populations using validated prediction tools and conducting adequately powered, double-blind, randomized controlled trials of pharmacological interventions.

PICO

PPOPULATION

patients with liver cirrhosis without a history of overt hepatic encephalopathy

IINTERVENTION

lactulose (30–60 mL 2–3 times daily) or probiotic VSL#3 (1 capsule 3 times daily)

OOUTCOME

first episode of overt hepatic encephalopathy within follow-up (12 months for lactulose study; mean 38.6–40.3 weeks for probiotic study)

STUDY TYPE

narrative_review

SPECIALTY

hepatology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10027066

Prediction and prevention of the first episode of overt hepatic encephalopathy in patients with cirrhosis

Hepatology Communications

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ABSTRACT

Hepatic encephalopathy (HE) is one of the most important complications of patients with liver cirrhosis. In addition, HE is associated with a dismal prognosis and has detrimental effects on patients’ quality of life. Thus, it is of pivotal importance to identify patients at high risk for overt HE (OHE) in whom primary prophylaxis may be justified. In this narrative review, we aim to provide insight into predictors and prediction tools for a first-time episode of OHE and to scrutinize the current level of evidence of primary prophylaxis. In recent decades, several cognitive tests, composite scores, and blood-based biomarkers have been demonstrated to be predictive of a first-time episode of OHE. Among the best validated are the established tests for minimal HE, such as the Psychometric Hepatic Encephalopathy Score, determination of the critical flicker frequency, Stroop EncephalApp, or the Animal Naming Test. Individualized risk stratification using blood-based biomarkers and cross-sectional imaging (sarcopenia and spontaneous portosystemic shunts) is coming to the fore, but validation in larger multicenter cohorts is often lacking. On the basis of current evidence, a recommendation for primary prophylaxis of a first episode of OHE cannot be made in general. Only 2 studies have investigated the prevention of a first-time OHE episode as the primary endpoint. In this narrative review, we provide a concise overview of the current evidence levels on prediction tools and pharmacological prevention of a first episode of OHE. In addition, we give an outlook on future research targets to improve knowledge on this important topic.

CITATION EXPORT

Simon J. Gairing, Eva M. Schleicher, Peter R. Galle et al.. Prediction and prevention of the first episode of overt hepatic encephalopathy in patients with cirrhosis. Hepatology Communications. (2023). https://doi.org/10.1097/HC9.0000000000000096

AUTHORS

4 · 2 CENTRES

Simon J. Gairing, Eva M. Schleicher, Peter R. Galle, Christian Labenz

1Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
2Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany