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

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

ISHEN: International Society for Hepatic Encephalopathy and Nitrogen Metabolism; MHE: Minimal hepatic encephalopathy; OHE: Overt hepatic encephalopathy; WHC: West Haven Criteria.

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.

ANT: Animal naming test; CFF: Critical flicker frequency; CRT: Continuous reaction time; DST: Digit symbol test; EEG: Electroencephalogram; ICT: Inhibitory control test; LTT: Line tracing test; MHE: Minimal hepatic encephalopathy; MRI: Magnetic resonance imaging; NCT-A: Number connection test A; NCT-B: Number connection test B; PHES: Psychometric hepatic encephalopathy score; SDT: Serial dotting test.

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.

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 (n)	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

¹Studies in which the inclusion criteria comprise patients with clinical history to the overt hepatic encephalopathy events.

²Unblinded study.

³Washout period of 4-6 wk between treatments.

⁴Compliance to treatment was not measured in one or the different treatment groups.

⁵Diet was not standardized according to the suggested treatment.

⁶Secondary objectives within the study.

⁷Analysis was performed within the same group (before–after treatment) despite the experimental design.

⁸Minimal hepatic encephalopathy reversion not measured. BDT: Block design test; DCT: Digit copying test; DST: Digit symbol test; EEG: Electroencephalogram; FCT-A: Figure connection test A; FCT-B: Figure connection test B; ITT: Intention to treat; MHE: Minimal hepatic encephalopathy; NCT: Number connection test; NCT-A: Number connection test A; NCT-B: Number connection test B; NNT: Number needed to treat; OHE: Overt hepatic encephalopathy; PCT: Picture completion test; PPS: Per protocol analysis set; RTT: Race track test.

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%

¹Studies in which the inclusion criteria comprise patient with clinical history to the overt hepatic encephalopathy events.

²Unblinded study.

³Compliance to treatment was not measured in one or the different treatment groups.

⁴Diet was not standardized according to the suggested treatment.

⁵Secondary objectives within the study.

⁶Analysis was performed within the same group (before–after treatment) despite the experimental design.

⁷Minimal hepatic encephalopathy reversion not measured. BDT: Block design test; CFF: Critical flicker frequency; DST: Digit symbol test; FCT: Figure connection test; FCT-A: Figure connection test A; ICT: Inhibitory Control Test; ITT: Intention to treat: LTT: Line tracing test; MHE: Minimal hepatic encephalopathy; NCT: Number connection test; NCT-A: Number connection test A; NCT-B: Number connection test B; NNT: Number Needed to Treat; OHE: Overt hepatic encephalopathy; PCT: Picture completion test; SDT: Serial dotting test.