Current approach to treatment of minimal hepatic encephalopathy in patients with liver cirrhosis

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%)

¹Studies in which the clinical history to the OHE events is specified or no is specified within the inclusion criteria.

²Unblinded study.

³The effect of other treatments for MHE was not studied.

⁴Treatment compliance was not assessed in one or different group of treatments.

⁵Diet was not standardized together with the suggested treatment.

⁶The treatment that the control group received was not specified.

⁷Secondary objectives within the study.

⁸The analysis was performed within the same group (before–after treatment) despite the study design.

⁹Addition of the effect of two maneuvers.

¹⁰MHE reversion was not measured. AVL: Auditory verbal learning test; BAEP: Brainstem auditory evoked potential; BCAAs: Branched-chain amino acids; BDT: Block design test; CFF: Critical flicker frequency; DST: Digit symbol test; EEG: Electroencephalogram; FCT-A: Figure connection test A; FCT-B: Figure connection test B; FOS: Fructooligosaccharides; ITT: Intention to treat; LOLA: L-ornithine-L-aspartate; LTT: Line tracing test; MHE: Minimal hepatic encephalopathy; MMSE: Mini mental state examination; MVT-B: Multiple choice vocabulary test B; NCT-A: Number connection test A; NCT-B: Number connection test B; PC: Picture completion; PPS: Per Protocol Analysis Set; SDT: Serial dotting test; TMT: Trail making test; TMT-A: Trail making test A; TMT-B: Trail making test B.