Abstract
Background: Minimal Hepatic Encephalopathy (MHE) is a fluctuant cognitive deficit, and a common
complication of cirrhosis, with significant health and socioeconomic consequences. Oral L-Ornithine
L-Aspartate (LOLA) has been proposed to treat MHE but mechanism and efficacy are unknown. This
study hypothesises LOLA treatment will correlate with improvements in:
1) Cognitive function (primary endpoints)
2) Relation to Brain-muscle axis (secondary endpoints)
Design and methods: This double-blinded placebo-controlled trial included 34 patients (LOLA n=14,
placebo n=20) over 12 weeks. All underwent psychometric testing (PHES, CogstateTM, Stroop, Short
Form-36). Secondary endpoints included brain volume, white matter microstructure, brain function
(proton MR spectroscopy/ functional MRI); muscle power (handgrip strength, 6-minute-walk-test);
anthropometry (upper limb skinfold); muscle metabolome (lateral vastus muscle biopsy LC-MS
analysis).
Results: Significantly more patients receiving LOLA reported improved energy levels, specifically in
Vitality (SF36 subdomain). No differences in PHES, Cogstate and Stroop test performance occured.
Change-in-biceps skinfold thickness demonstrated significant gain with LOLA compared to placebo,
without differences in power. LC-MS experiments were not discriminatory. Whole Brain differences in
FA and RD suggested reduced brain oedema (subcortical volume reduction and global white matter
changes). No significant group differences in fMRI task/ resting activation were seen. Spectroscopy of
ACC showed significantly higher unresolved glutamine-glutamate (Glx) complex levels with LOLA, also
correlating with increased PPI use, and may represent LOLA-driven increased Krebs-cycling or a
function of altered gut microbiome.
Conclusion: No cognitive benefits were demonstrated. Improved quality of life measures maybe a
nutritional consequence also relating to increased biceps skinfold thickness with LOLA. Effects on brain
oedema are postulated. Future studies need higher powering to allow subanalysis by aetiology, and
smaller voxels at basal ganglia are recommended. Attempts to replicate rising ACC Glx with LOLA and
regions of interest identified on fMRI subanalysis may be fruitful.