The Brain-Muscle Axis in Minimal Hepatic Encephalopathy (MHE): A Placebo-Controlled, Longitudinal Double-Blind Trial With l-Ornithine l-Aspartate (LOLA) – Preliminary Results

Background and Aim: LOLA promotes nitrogen elimination and experimentally, has been shown to reduce sarcopenia. We investigated effects of 12 weeks of oral LOLA in an outpatient series with compensated cirrhosis and mHE. Patients were pre-screened with PHES tests and included if they scored −4 or worse. Methods: 34 English-speakers were included; twelve randomised to 12 weeks of oral LOLA at 6 g tds, 22 randomised to an identical-looking placebo. At baseline, 4 and 12 weeks, subjects underwent psychometric testing using PHES and a multi-domain, computerised battery, CogstateTM, serial Stroop, WTAR and Short Form-36 health questionnaires. Markers of muscle function were recorded including handgrip strength, calliper-measured thickness of biceps, triceps and subscapular skin folds, and 6-minute-walk-test. Subjects underwent magnetic resonance imaging on a Siemens 3T magnet including standard T1 and T2 sequences, functional MRI (fMRI) sequences (tasks and resting states) and proton MR spectroscopy of anterior cingulate cortex (ACC). LC Model software was used for metabolite identification. Results: At baseline both groups of patients were matched for drug compliance, age, years of education, PHES, WTAR, Stroop tests and SF-36. 57% of subjects in LOLA arm reported better energy levels than placebo group 0.04% (P-value < 0.001). Better concentration was reported by 21% of subjects in treatment arm, compared with none (P = 0.05). 28% reported improved memory in the treatment group vs 0.04% with placebo. Sleep improvements were reported by 35% in treatment arm, compared to 0.09% of placebo (P = 0.05). In both groups, changes in PHES totals, based on English normative data, between baseline and visit3 and on Cogstate testing were non-significant. Sub-analysis of the Digit-Symbol revealed significant improvement in performance within the LOLA-treated group (P = 0.05). WTAR and Stroop test performance did not show group differences. Change-in-biceps skinfold thickness showed a mean gain of 1.5 mm in the LOLA group with a mean loss of 1.0 mm (P = 0.05) with placebo. No differences were found in other skinfolds, or hand-grip or 6-minute-walk-tests. Significant volume reduction was seen in several regions (see Table 1) fMRI tasks did not vary significantly between groups. Spectroscopy of ACC showed significant changes in glutamate concentration (rm P = 0.03), after LOLA treatment.Table 1Subcortical Regions Showing Significant Volume Reduction (mm3) With LOLA Treatment at 12 Weeks on Co-registered MRI.Subcortical brain volume regionP-valueLeft-lateral-ventricle0.014Right-cerebellum-cortex0.050right-pallidum0.021CC_Mid_Anterior0.049 Open table in a new tab Conclusion: After 12 weeks of LOLA, patients reported a highly significant improvement in energy levels, and significant improvements in concentration. A significant treatment-related improvement in digit-symbol PHES-subtest in those receiving LOLA was seen. Comparable to LOLA-animal studies, an increase was noted in biceps skin fold thickness, which may indicate improved nutrition. Certain areas demonstrated significant volume-reduction with treatment, an observation that has not previously been noted in imaging studies of patients receiving this drug. Unlike previous studies, no functional changes were seen, but significant changes were found on MR spectroscopy of the ACC, a region (part of the default mode network) known to be metabolically active in mHE. Disclosures/Financial Association: I would like to acknowledge and thank CogstateTM for providing an opportunity for collaboration and the use of their software and Merz, Frankfurt for providing funding for this Investigator-led study. The authors have none to declare.