Introduction Hepatic encephalopathy (HE) pathogenesis is related to gut microbial products, which lead to deranged cerebral bioenergetics. Biofluid MR spectroscopy (MRS) can be used to determine changes in bioenergetics, gut microbial products, amino acid and lipid metabolites. Lactulose is used as a first-line HE Rx despite a poor evidence basis.
Aim To evaluate the clinical and metabolic consequences of lactulose withdrawal in HE.
Method Patients with cirrhosis on lactulose for precipitated HE underwent cognitive testing with inhibitory control (ICT), urine and serum collection for MRS and inflammatory markers while on lactulose. Lactulose was then withdrawn and patients followed for 30 days with visits at day 2, 14 and 30; ICT, serum and urine testing were repeated at every visit. Relapse of HE was defined clinically. Multivariate analysis of urine and serum metabolites involved principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA). Univariate analysis was applied to hypothesis-driven metabolites, multivariate-driven metabolites and inflammatory marker concentrations.
Results 7 cirrhotic men (age 53±7 years, 5 HCV, 2 alcohol) on lactulose for 6±5 months for precipitated HE (5 GI bleed, 2 infections) were included. Three patients clinically relapsed 38±6 days post-withdrawal; all 3 had >15 ICT lures while on lactulose. None of those who scored <15 ICT lures on lactulose relapsed. Lure increase OR, 2.5 (CI: 1.7 to 3.6) predicted relapse. Using ICT lures >15 as a cut-off for HE relapse, MRS distinguished with a sensitivity and specificity of 70.0%/63.6% using urine and 100%/100% using serum on PLS-DA. Urine PLS-DA: In relapsers, urine TMAO was reduced indicating altered gut bacterial metabolism while malonic acid and citrate were higher demonstrating impaired energetics. Glycine and phenylalanine, associated with false neuro-transmitters, were also increased in relapsers along with creatinine. Serum PLS-DA: Relapsers had higher choline and its metabolite, dimethylglycine levels which is associated with extrusion of choline after astrocyte swelling in HE as well as higher levels of lipids. Univariate analysis confirmed that relapsers had lower TMAO (p=0.00280) and higher choline (p=0.0414), LDL (0.0265) and creatinine (p=0.00970). Inflammation was depressed in relapsers compared to others evidenced by decreased endotoxin (p=0.03), IFN-γ (p=0.045), IL-4 (0.0002) and TNF-α (p=0.0013) suggesting a compensatory anti-inflammatory response syndrome.
Conclusion HE relapse post-lactulose withdrawal is associated with derangements in bioenergetics, amino-acid, lipid and gut microbial metabolism as well as depression of the inflammatory response.
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