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©The Author(s) 2021.
World J Gastroenterol. Jun 14, 2021; 27(22): 3050-3063
Published online Jun 14, 2021. doi: 10.3748/wjg.v27.i22.3050
Published online Jun 14, 2021. doi: 10.3748/wjg.v27.i22.3050
Table 1 Classification of the different stages of hepatic encephalopathy
Diagnostic criteria | Classification stages | |||||
ISHEN | Unimpaired | Covert hepatic encephalopathy | Overt hepatic encephalopathy | |||
WHC | MHE | Grade I | Grade II | Grade III | Grade IV | |
No encephalopathy, no history of OHE | Imperceptible cognitive alterations during routine clinical examination | Trivial lack of awareness; Euphoria or anxiety; Shortened attention span; Impairment of addition or subtraction; Altered sleep rhythm | Lethargy or apathy; Disorientation for time; Obvious personality change; Inappropriate behavior; Dyspraxia asterixis | Somnolence to semistupor; Responsive to stimuli; Confused; Gross disorientation; Bizarre behavior | Coma |
Table 2 Diagnostic tools for the diagnosis of minimal hepatic encephalopathy
Test type | Test approach to differentiate MHE form unimpaired subjects |
Formal neuropsychological; Assessment | No standard battery for MHE has been designed, but could include test of attention, executive function, psychomotor ability, and speed information processing to evaluate cognition, and mental activity. |
Neuropsychological | EEG: Detect changes in cortical cerebral activity; Evoked potentials: Measurement of firing patterns of single cells or cell clusters. |
Computerised | SCAN test: Measures speed and accuracy to perform a digit recognition memory task of increasing complexity; CFF: Degree of vigilance; CRT: Relies on the repeated registration of the motor reaction time to auditory stimuli. Measures the stability of the reaction time; Stroop test: Evaluates psychomotor speed and cognitive flexibility; ICT: Test of response inhibition and working memory. |
Imaging | MRI: Through mean kurtosis values, evaluates six regions of interest, and amplitude of low frequency fluctuation values, which correlate with PHES values. |
Short neuropsychological batteries | PHES: Evaluates cognitive/psychomotor processing speed and visuomotor coordination (NCT-A, NCT-B, SDT, LTT, DST); ANT: Cognitive function related to prefrontal anterior/cortex cortical areas. |
Table 3 Published studies using several options for minimal hepatic encephalopathy treatment: Diet, branched-chain amino acids or L-ornithine-L-aspartate supplementation, and probiotics/symbiotics
Ref. | Study type | Follow-up (wk) | MHE diagnosis | Active treatment (s) | Objectives | Patients (n) | Main results/impact measures |
No history of OHE1 | |||||||
Kato et al[37], 2012 | Quasi-experimental | 8 | NCT-A, NCT-B, BDT, DST | 30-35 Kcal + 1.0-1.5 g/kg of protein/d3,4 | Reversal of MHE | 19 | 11/19 (57.8%) recovered at 4 wk, and 13/19 (68.4%) at 8 wk8 |
Maharshi et al[33], 2016 | Randomized2 | 24 | NCT-A/FCT-A, NCT-B/FCT-B, DST, LTT, SDT | Nutritional education/no nutritional therapy3,5 | Reversal of MHE | 60/60 | 27/38 (71.1%) vs 8/35 (22.8%); 27/60 (45%) vs 8/60 (13.3%), when considering PPS and ITT analysis. |
Malaguarnera et al[64], 2008 | Randomized, double-blind | 13 | NCT-A, NCT-B, BDT, SDT, TMT, AVL, EGG | Acetyl-L-carnitine /placebo5 | Cognitive scores7 | 60/55 | Changes of mean values in at least 20.71% to 32.79% respect to basal values8 |
Bajaj et al[34], 2014 | Randomized, double-blind | 8 | NCT-A, NCT-B, DST/BDT | LGG/placebo | Psychometric scores7 | 18/19 | Improvement from 1.02% to 15.89% from baseline values |
Bajaj et al[44], 2008 | Randomized2 | 8 | NCT-A, BDT, DST | Probiotic yogurt/no treatment4,5 | Reversal of MHE | 17/8 | ITT analysis: Reversal in 12/17 (70.58%) vs 0/7 (0%) |
Mittal et al[39], 2011 | Randomized2 | 12 | NCT-A/FCT-A, NCT-B/FCT-B, BDT, PC | Lactulose/VSL#3, LOLA/no treatment | Reversal of MHE | 40/40/40/40 | ITT analysis: Reversal of 4 (10%) in no treatment group, 19 (47.5%), 14 (35%) and 14 (35%) |
Possible history of OHE1 | |||||||
Egberts et al[35], 1985 | Crossover, double blind | 6 | EGG, DST, MVT-B | BCAAs/placebo | Psychometry and EGG | 11/11 | Improvement in psychometric test from 0 to 13.63% respect to basal values in DST8 |
Ndraha et al[36], 2011 | Double blind, randomized | 2 | CFF | BCAAs + LOLA/BCAAs4 | CFF | 17/17 | Improvement in CFF 7.0% and 1.96% values (Hz), respect to baseline |
Kircheis et al[41], 1997 | Randomized, double-blind | 1 | NCT-A | LOLA infusion vs Placebo5 | Psychometry7 | 26/27 | Improvement in mean time to respond NCT-A from baseline (29% vs 9.73%) |
Liu et al[29], 2004 | Randomized2 | 4 | NCT, BAEP | Symbiotics + fermentable fibers/fermentable fibers/placebo4,5 | Reversal of MHE7 | 20/20/15 | Reversal of 50% in symbiotic group, 50% in fermentable fibers group and 13% in placebo. Not statistically significant until compression of treatment groups vs placebo (P = 0.03)9 |
Dhiman et al[65], 2014 | Double blind, randomized | 24 | NCT-A/FCT-A, NCT-B, SDT, DST, LTT | VSL#3/placebo | Psychometric scores7 | 16/13 | Mean psychometric scores before and after probiotics -9.9 (-13.3- to -6.5) vs -5.7 (-8.4 to 2.9) P = 0.014. Proportion of patients with scores < -5 did not change in either group10 |
Malaguarnera et al[45], 2007 | Randomized, double-blind | 17 | TMT-A, TMT-B, BDT, MMSE | Bifidobacterium longum + FOS/placebo5 | Psychometry | 30/30 | No statistical or clinical change was found respect to basal values at, 30, 60, 90 and 120 d |
Ziada et al[48], 2013 | Randomized2 | 4 | NCT-A, DST, SDT | Lactulose/L, acidophilus/control5,6 | Psychometry | 24/26/25 | Normalization of test occurred in 13/24 (54.2%), 14/26 (53.8%), and 3/25 (12%) |
Table 4 Published studies using non-absorbable disaccharides for minimal hepatic encephalopathy treatment
Ref. | Study type | Follow-up (wk) | MHE diagnosis | Active treatment (s) | Objectives | Patients | Main results/impact measures |
No history of OHE1 | |||||||
Prasad et al[47], 2007 | Randomized2 | 12 | NCT-A/FCT-A, NCT-B/FCT-B, PCT, BDT | Lactulose vs no treatment | Psychometry | 31/30 | ITT analysis: Improvement in 20/31 (64.5%) vs 2/30 (6.7%); NNT:2 |
Horsmans et al[55], 1997 | Randomized, double-blind | 2 | NCT, RTT. | Lactulose vs lactose as placebo4,5 | Psychometry | 7/7 | Improvement in time on Psychometric test on lactulose group respect to basal values.7 Rate of improvement NCT: 5/7 (71.42%) vs 1/7 (14.28%); NNT:2 |
Sharma et al[50], 2008 | Randomized2 | 4 | NCT-A/FCT-A, NCT-B/FCT-B, P300ERP | Lactulose, probiotics, and lactulose + probiotics5 | Psychometry, P300ERP6 | 35/35/35 | Normalization in 17/31 (54.8%), 16/31 (51.6%), and 17/30 (56.6%) of MHE patients |
Morgan et al[60], 1989 | Cross-over, randomized | 83 | EEG, NCT, DST, DCT | Lactulose vs lactitol4 | Psychometry | 14/14 | No differences between treatments in median change in psychometric time or scores |
Possible history of OHE1 | |||||||
Dhiman et al[51], 2000 | Randomized2 | 12 | NCT-A/FCT-A, NCT-B /FCT-B, PCT, BDT. | Lactulose vs no lactulose4 | MHE improvement | 14/12 | Improvement in 8/10 (80.0%) vs 0/8 (0.0%), P < 0.001)8 |
Wang et al[49], 2019 | Randomized2 | 8 | NCT-A, DST | Lactulose vs no lactulose | MHE reversal | 67/31 | ITT analysis: 43/67 (64.2%) vs 7/31 (22.6%); NNT: 3PPS: 41/59 (69.5%) vs 6/28 (21.4%); NNT: 2 |
Table 5 Published studies using antibiotics for minimal hepatic encephalopathy treatment
Ref. | Study type | Follow-up (wk) | MHE diagnosis | Active treatment (s) | Objectives | Patients (n) | Main results/impact measures |
No history of OHE1 | |||||||
Ahluwalia et al[66], 2014 | Quasi-experimental | 8 | NCT-A, NCT-B, DST, BDS, LTT, SDT, ICT | Rifaximin4 | fMRI, ICT, MRS5 | 20 | Changes in ICT, improvement of 12% respect to baseline, indicating a better cognition |
Bajaj et al[61], 2013 | Quasi-experimental | 8 | NCT-A, NCT-B, DST, BDT, LTT | Rifaximin4 | Psychometry5 | 20 | Improvement in NCT-A time (11.8%), NCT-B time (11.8%), DST raw score (9.1%), BDT raw score (0.0%), LTT time (20.7%), LTT errors (39.8%), SDT time (12.3%) from basal values |
Bajaj et al[67], 2011 | Randomized, single-blinded | 8 | NCT-A, DST, BDT, ICT | Rifaximin/placebo4 | Driving performance, psychometry scores | 21/21 | Decrease of 46.6% of total errors respect to baseline in rifaximin group (P < 0.001)6. Improvement in NCT-A 91% vs 61% (NNT: 4); NCT-B: 81% vs 33% (NNT: 2); and ICT lures: 76% vs 43% (NNT: 3)7 |
Sidhu et al[59], 2015 | Randomized, non-inferiority trial | 12 | NCT-A, FCT-A, DST, PCT, and BDT | Rifaximin/lactulose | Reversal of MHE | 57/55 | ITT analysis shows a reversal at 2 wk: lactulose 40.0% vs rifaximin 52.63% (NNT: 8). ITT analysis at 3 mo shows reversal in 69.1% and 73.7% of lactulose and rifaximin, (NNT: 22) |
Goyal et al[62], 2017 | Prospective cohort | 24 | NCT-A, FCT-A, DST, PCT, BDT | Previous intake of Rifaximin compared to lactulose3,4 | Maintenance of remission for MHE | 42/38 | Still free of MHE: Rifaximin 42.8% vs lactulose 50.0% (NNT: 14) |
Possible history of OHE1 | |||||||
Agrawal et al[24], 2011 | Quasi-experimental | 1 | NCT, FTC, LTT. | Clarithromycin, lansoprazole, tinidazole3,4 | Psychometric scores5 | 35 | Improvement in 12.7%, 13.3%, and 18.7% respect to basal mean time in NCT, FCT and LTT, respectively |
Zhang et al[27], 2015 | Quasi-experimental | 5 | NCT-A, NCT-B, DST | Rifaximin 1 wk3,4 | Reversal of MHE | 26 | After a week, reversal present in 11/26 (42.3%) |
Sidhu et al[56], 2011 | Double-blind, randomized | 8 | NCT-A/FCT-A, DST, PCT, BDT | Rifaximin/placebo | Reversal of MHE | 49/45 | Reversal at 2 wk: 57% vs 18% (NNT: 3)At 8 wk: Reversal of 75.5% vs 20% (NNT: 2) |
Sharma et al[40], 2014 | Randomized2 | 8 | NCT-A/FCT-A, DST and/ or CFF | LOLA/rifaximin/Probiotics/Placebo4 | Reversal of MHE5 | 31/31/32/30 | ITT analysis: Improvement in CFF values (Hz) from baseline in 11.42%, 6.5%, 8.68%, and 2.28% |
- Citation: Moran S, López-Sánchez M, Milke-García MDP, Rodríguez-Leal G. Current approach to treatment of minimal hepatic encephalopathy in patients with liver cirrhosis. World J Gastroenterol 2021; 27(22): 3050-3063
- URL: https://www.wjgnet.com/1007-9327/full/v27/i22/3050.htm
- DOI: https://dx.doi.org/10.3748/wjg.v27.i22.3050