EDITORIAL

nature publishing group

317

Rifaximin and Minimal Hepatic Encephalopathy

Roger F. Butterworth, PhD, DSc1

Abstract: Minimal hepatic encephalopathy (MHE)

occurs in up to 70% of patients with cirrhosis and
has a clear impact on health-related quality of life
(HRQOL) in these patients. Antibiotics leading to
reductions in circulating ammonia have been used in
the past for the treatment of MHE. However, serious
adverse effects such as nephrotoxicity, ototoxicity,
and peripheral neuropathy limit their use to relatively
short time periods. In this issue of the American
Journal of Gastroenterology, an article by Sidhu
et al. demonstrates unequivocally that the antibiotic
rifaximin, a minimally absorbed antibiotic with
broad spectrum activity, improves psychometric
test performance scores and concomitantly
improves HRQOL in patients with MHE (the RIME
Trial). Rifaximin was well tolerated. Results of
the RIME Trial represent an important step in the
establishment of this antibiotic as an effective and
safe treatment for MHE.
Am J Gastroenterol 2011; 106:317318; doi:10.1038/ajg.2010.460

Minimal hepatic encephalopathy (MHE) is defined as a neuropsychiatric disorder of cirrhotic patients who, while clinically
(neurologically) free of symptoms, manifest abnormalities in central nervous system function when assessed using psychometric
tests or electrophysiological techniques. Significant impairment
of selective attention and executive function has been reported
in MHE, together with abnormalities in psychomotor speed,
visuomotor activity, response inhibition, slowing of the electroencephalogram, and prolongation of cognitive evoked potentials
(1). Working memory may also be impaired, a feature that has been
attributed to alterations of corticospinal synaptic plasticity.
MHE occurs in up to 70% of patients with cirrhosis and has a
clear impact on health-related quality of life (HRQOL) in these
patients. MHE may limit the patients ability to drive an automobile or to operate complex machinery. Moreover, it has been

demonstrated that the presence of MHE is an effective prognostic

indicator for the development of overt hepatic encephalopathy.
Diagnosis of MHE is currently based primarily on a combination of psychometric test procedures, including number connection tests (NCTs) A and B, the digit symbol test, and the block
design test. In addition, computerized psychometry and other
tests, such as the critical flicker frequency test, are increasingly
being employed for MHE diagnosis. The usefulness of these tests
as predictors of impaired ability to function in the performance
of every-day tasks was demonstrated recently in a study by Bajaj
et al. (2), who showed that poor performance on NCTs A and
B was associated with impaired navigational skills in cirrhotic
patients tested in a driving simulator. Moreover, better NCT-A
performance reflected strengths in visual scanning and psychomotor speed, whereas NCT-B testing placed additional demands
on cognitive flexibility and working memory in MHE patients.
Treatment of MHE is currently directed almost exclusively
toward reduction of gut-derived ammonia, and, with this in
mind, ammonia-lowering agents, including the non-absorbable
disaccharide lactulose (3) and probiotics (4), have been successfully used for the treatment of MHE. Antibiotics have been shown
to lead to reductions in circulating ammonia in patients with
cirrhosis. However, serious adverse effects such as nephrotoxicity and ototoxicity (in the case of the aminoglycosides neomycin
and paromomycin) and peripheral neuropathy (in the case of
vancomycin) have limited their use to relatively short time periods. Limits on the use of antibiotics may well change as a result
of the findings reported in this issue of the American Journal of
Gastroenterology in an article by Sidhu et al. (5), which show
unequivocally that the antibiotic rifaximin improves psychometric test performance scores and concomitantly improves HRQOL
in patients with MHE. This trial (the RIME Trial) was placebocontrolled, double blind, and adequately powered. Care was taken
to exclude neurological or psychiatric illnesses, as well as a wide
range of possible confounding factors. MHE was diagnosed using
well-validated psychometric tests, including NCT-A, a figure connection test (FCT) for assessment in the context of illiteracy, as
well as digit symbol and block design tests. Appropriately and
importantly, variations of the NCT-A and FCT tests were used for
serial evaluation in order to avoid the effects of learning, a feature

1
Department of Medicine, University of Montreal, Neuroscience Research Unit, Montreal, Quebec, Canada. Correspondence: Roger F. Butterworth, PhD, DSc,
Department of Medicine, University of Montreal, Neuroscience Research Unit, Montreal, Quebec, Canada H2X 3J4. E-mail: Roger.Butterworth@umontreal.ca
Received 22 September 2010; accepted 5 November 2010

2011 by the American College of Gastroenterology

The American Journal of GASTROENTEROLOGY

LIVER

see related article on page 307

LIVER

318

Butterworth

that has seriously limited the impact of some previous studies.

Intention-to-treat analysis revealed that the percentage of patients
showing reversal of MHE was significantly higher in the rifaximin
group compared with the control group after both 2 and 8 weeks
of treatment, and that HRQOL concomitantly improved after 8
weeks of rifaximin therapy. Rifaximin was well tolerated (5). A
current literature search reveals a second article that demonstrates
improved driving skills following rifaximin treatment in patients
with MHE (6). In this latter study, improvement in cognitive performance as well as improvement in the psychosocial dimension
of the SIP was also observed. These findings are in good general
agreement with those of the RIME Trial.
Rifaximin is a minimally absorbed antibiotic with broad spectrum activity against Gram-positive and Gram-negative aerobic and anaerobic enteric bacteria, and a low risk of bacterial
resistance (7). Rifaximin is more effective than lactulose in the
treatment of overt HE (8), and results of a large randomized double-blind placebo-controlled trial in 299 patients demonstrated
that rifaximin reduced the risk of an episode of overt HE over a
6-month period, with consequent reductions in the time to first
hospitalization and no serious adverse events (9). Results of the
RIME Trial demonstrate that the beneficial effects of rifaximin
extend to cirrhotic patients with MHE (5).
Much ambivalence remains as to the perception of the impact
of MHE, and a clear commitment to treatment is still lacking.
As an illustration of this point, results of a recent AASLD survey
showed that, although a majority of physician respondents were
of the opinion that MHE constitutes a significant medical problem in need of treatment, only half of them routinely did so (10).
Reasons for these inconsistencies no doubt relate to the impression that psychometric testing is time consuming, requiring
highly specialized personnel, to the lack of availability of agents
with appropriate efficacysafety characteristics, and to confusion
related to current terminology. Descriptors such as subclinical,
latent, and minimal may create the impression that the condition has limited impact on the well-being of patients. There is
also a great deal of confusion over what exactly constitutes MHE
and how it relates to other forms of encephalopathy. This is apparent even in the opening sentence in the article by Sidhu et al. (5),
who state that MHE is a part of the spectrum of overt hepatic

The American Journal of GASTROENTEROLOGY

encephalopathy (OHE). Of course, by definition it is not (11).

The future may provide a more appropriate term to describe this
condition. Irrespective of the name tag (subclinical, latent, minimal, or other), it is now abundantly clear that MHE has a major
impact on quality of life and should be promptly diagnosed and
treated. Results of the RIME Trial (5) represent an important step
in the establishment of rifaximin as an effective and safe treatment
for MHE.
CONFLICT OF INTEREST

Butterworth has served as consultant and has received speaker fees

and expenses from the following pharmaceutical companies: Astra
Zeneca (Canada), Merz (Germany), Ocera (USA), Otsuka (Japan),
Salix (USA), and Sigma-Tau (Italy).

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