Minimal hepatic encephalopathy (MHE) negatively affects the prognosis of cirrhosis, but treatment is not standard. Rifamycin SV MMX (RiVM) is a nonabsorbable rifampin derivative with colonic action.
...In a phase 2 placebo-controlled, double-blind randomized clinical trial patients with MHE were randomized to RiVM or placebo for 30 days with a 7-day follow-up. The primary endpoint was a change in stool cirrhosis dysbiosis ratio. Gut-brain (cognition, stool/salivary microbiome, ammonia, brain magnetic resonance spectroscopy), inflammation (stool calprotectin/serum cytokines), patient-reported outcomes (sickness impact profile: total/physical/psychosocial, high = worse), and sarcopenia (handgrip, bioelectric impedance) were secondary. Between/within groups and delta (post-pre) comparisons were performed.
Thirty patients (15/group) were randomized and completed the study without safety concerns. While cirrhosis dysbiosis ratio was statistically similar on repeated measures ANOVA (95% CI: -0.70 to 3.5), ammonia significantly reduced (95% CI: 4.4-29.6) in RiVM with changes in stool microbial α/β-diversity. MHE status was unchanged but only serial dotting (which tests motor strength) improved in RiVM-assigned patients. Delta physical sickness impact profile (95% CI: 0.33 = 8.5), lean mass (95% CI: -3.3 to -0.9), and handgrip strength (95% CI: -8.1 to -1.0) improved in RiVM versus placebo. Stool short-chain fatty acids (propionate, acetate, and butyrate) increased post-RiVM. Serum, urine, and stool bile acid profile changed to nontoxic bile acids (higher hyocholate/ursodeoxycholate and lower deoxycholate/lithocholate) post-RiVM. Serum IL-1β and stool calprotectin decreased while brain magnetic resonance spectroscopy showed higher glutathione concentrations in RiVM.
RiVM is well tolerated in patients with MHE with changes in stool microbial composition and function, ammonia, inflammation, brain oxidative stress, and sarcopenia-related parameters without improvement in cognition. RiVM modulates the gut-brain axis and gut-muscle axis in cirrhosis.
BACKGROUNDThere is evidence of brain recovery on brain MRI early postliver transplant(LT) but the longer-term impact is unclear. Aim of this study was to determine the change in brain MRI parameters, ...cognition and health-related quality of life (HRQOL) between 6 and 12 months post-LT.
METHODSListed cirrhotics underwent cognitive, HRQOL and brain MRI pre, 6 months (post-LT1) and 1-year (post-LT2) post-LT. Assessment of MRI changes between visits was performed for ammonia-associated metabolite changes using spectroscopy (MRS), white matter changes using Tract-based Spatial Statistics (TBSS) analysis on Diffusion Tensor Imaging (DTI) data and grey matter changes using Voxel-based morphometry (VBM) analysis on 3D high resolution T1-weighted images.
RESULTSForty-five patients were included of which, twenty-three were tested at all visits. Cognitive and HRQOL scores improved between all visits compared to pre-LT values. This trend continued on MRS with reduced glutamine+glutamate(Glx) and higher myoinositol(mI), Choline(Cho) between pre-LT/post-LT1 but lower degrees of improvement between post-LT1/post-LT2. On DTI, mean-diffusivity(MD), linear-diffusivity(LD) and mode of anisotropy(MO) continued to increase in the posterior internal capsule at both post-LT visits. On VBM, a continued increase was seen in basal ganglia grey matter between both post-LT visits was seen.
CONCLUSIONSHRQOL and cognition continue to improve compared to pre-LT values up to 1 year post-LT, although the rate of improvement slows down after 6 months. Grey matter increase is steady over time at 1 year although changes in ammonia-related metabolites and white matter integrity improve at a slower pace at 1 year post-LT.
The pathogenesis of hepatic encephalopathy(HE) is unclear. However gut flora changes, inflammation and neuro-glial injury have been implicated. The aim was to evaluate factors that were associated ...with HE recurrence after lactulose withdrawal by analyzing the clinical phenotype, stool microbiome and systemic metabolome longitudinally. HE patients on a standard diet who were adherent on lactulose underwent characterization of their phenotype cognition, inflammatory cytokines, in-vivo brain MR spectroscopy(MRS), gut microbiome (stool Multitag Pyrosequencing) and metabolome (urine/serum
ex-vivo
MRS) analysis while on lactulose and on days 2, 14 and 30 post-withdrawal. Patients whose HE recurred post-withdrawal were compared to those without recurrence. We included seven men (53 ± 8 years) who were adherent on lactulose after a precipitated HE episode were included. HE recurred in three men 32 ± 6 days post-withdrawal. In-vivo brain MRS showed increased glutamine+glutamate (Glx) and decreased myoinositol with a reduction in stool
Faecalibacterium
spp., post-withdrawal. HE recurrence was predicted by poor baseline inhibitory control and block design performance and was associated with a shift of choline metabolism from tri-methylamine oxide formation towards the development of di-methylglycine, glycine and creatinine. This was accompanied by a mixed effect on the immune response (suppressed IL-10 and Th1/Th2/Th17 response). The correlation network showed
Prevotella
to be linked to improved cognition and decreased inflammation in patients without HE recurrence. We conclude that lactulose withdrawal results in worsening cognition, mixed inflammatory response effect, lowered stool
Faecalibacterium
and increase in MR-measurable brain Glx. HE recurrence post-lactulose withdrawal can be predicted by baseline cognitive performance and is accompanied by disrupted choline metabolism.
Background & Aims Asymmetric dimethylarginine (ADMA) is an inhibitor of nitric oxide synthase that accumulates in liver disease and may contribute to hepatic encephalopathy (HE). We aimed at ...evaluating the association of ADMA with cognition and brain MR spectroscopy (MRS) in cirrhosis. Methods Cirrhotic patients with/without prior HE and non-cirrhotic controls underwent cognitive testing and ADMA determination. A subgroup underwent brain MRS glutamine/glutamate (Glx), myoinositol (mI), N -acetyl-aspartate (NAA) in parietal white, occipital gray, and anterior cingulated (ACC). Cognition and ADMA in a cirrhotic subgroup before and one month after transjugular intrahepatic portosystemic shunting (TIPS) were also tested. Cognition and MRS values were correlated with ADMA and compared between groups using multivariable regression. ADMA levels were compared between those who did/did not develop post-TIPS HE. Results Ninety cirrhotics (MELD 13, 54 prior HE) and 16 controls were included. Controls had better cognition and lower ADMA, Glx, and higher mI compared to cirrhotics. Prior HE patients had worse cognition, higher ADMA and Glx and lower mI compared to non-HE cirrhotics. ADMA was positively correlated with MELD (r = 0.58, p < 0.0001), abnormal cognitive test number (r = 0.66, p < 0.0001), and Glx and NAAA (white matter, ACC) and negatively with mI. On regression, ADMA predicted number of abnormal tests and mean Z-score independent of prior HE and MELD. Twelve patients underwent TIPS; 7 developed HE post-TIPS. ADMA increased post-TIPS in patients who developed HE ( p = 0.019) but not in others ( p = 0.89). Conclusions A strong association of ADMA with cognition and prior HE was found independent of the MELD score in cirrhosis.
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