Metabolic syndrome is associated with poor response to rifaximin in minimal hepatic encephalopathy

Abstract

Patients with cirrhosis may show minimal hepatic encephalopathy (MHE), for which rifaximin is effective. Metabolic syndrome may be associated with cognitive impairment. Our aims were to evaluate the influence of metabolic syndrome features on response to rifaximin for neurological and inflammatory alterations in MHE. A prospective cohort study was conducted in 63 cirrhotic patients and 30 controls from two tertiary centres recruited between 2015 and 2019. Metabolic syndrome was defined according to the Adult Treatment Panel-III. Patients were classified into 31 without and 32 with MHE according to the Psychometric Hepatic Encephalopathy Score (PHES). All participants performed specific psychometric tests, and inflammatory parameters were studied. Patients with MHE received rifaximin (400 mg/8 h). Response was evaluated by PHES at 3 and 6 months. Response according to metabolic syndrome manifestations was compared. The response rate was 66%. Older age (p = 0.012) and all metabolic syndrome diseases (p < 0.05) were associated with non-response, plus an increase in risk as the number of manifestations rose (p < 0.001). Patients with metabolic manifestations exhibited worse processing speed (p = 0.011), working memory (p = 0.005), visual coordination (p = 0.013) and lower proportion of activated CD4⁺ lymphocytes (p = 0.039) at baseline, as well as worse concentration (p = 0.030), bimanual coordination (p = 0.004) and higher levels of intermediate monocytes (p = 0.026), CX3CL1 (p < 0.05), IL-17 (p = 0.022), AHR (p = 0.010) and IgG (p < 0.05) at 3 and/or 6 months of rifaximin. Patients with clinical signs of metabolic syndrome have poor response to rifaximin for MHE, with a higher proportion of neurological alterations associated with a pro-inflammatory environment.

Figure 1

Performance of specific oral psychometric tests by controls, patients without MHE and patients with MHE according to presence of manifestations of metabolic syndrome at baseline. Oral SDMT: oral version of Symbol digit modalities test, expressed in correct pairings. Digit Span and Letter-Number sequencing test are expressed as right answers. Punctuation expressed as mean (SEM). *significant differences from controls (*p < 0.05; **p < 0.01; ***p < 0.001). ^αsignificant differences from no MHE (^αp < 0.05; ^ααp < 0.01; ^αααp < 0.001). ^significant differences from patients with MHE without metabolic syndrome manifestations (^p < 0.05; ^^p < 0.01; ^^^p < 0.001).

Figure 2

(a) Correlation between PHES and categorized number of metabolic manifestations at 3 months of rifaximin treatment. (b) Performance of Stroop test by controls, patients without MHE and patients with MHE according to presence of manifestations of metabolic syndrome at 3 months of rifaximin treatment. Stroop test: Congruent task: number of words read in 45 s; Neutral task: number of colours read in 45 s; Incongruent task: number of items completed in 45 s. Punctuation expressed as mean (SEM). *significant differences from controls (*p < 0.05; **p < 0.01; ***p < 0.001). α significant differences from no MHE (^αp < 0.05; ^ααp < 0.01; ^αααp < 0.001). ^significant differences from patients with MHE without metabolic syndrome manifestations (^p < 0.05; ^^p < 0.01; ^^^p < 0.001).

Figure 3

Inflammatory parameters at baseline and at 3 and 6 months of rifaximin treatment according to metabolic syndrome manifestations. *significant differences from controls (*p < 0.05; **p < 0.01; ***p < 0.001). ^αsignificant differences from no MHE (^αp < 0.05; ^ααp < 0.01; ^αααp < 0.001). ^βSignificant differences from patients without metabolic syndrome manifestations (^βp < 0.05; ^ββp < 0.01; ^βββp < 0.001). ^∂significant differences from baseline (^∂p < 0.05; ^∂∂p < 0.01; ^∂∂∂p < 0.001). Abbreviations: CTL: controls; MHE and NMHE: patients with or without minimal hepatic encephalopathy, respectively; MM: metabolic syndrome manifestations.