Review Article 1

see related editorial on page x

Current Management of Hepatic Encephalopathy

Review Article
Chathur Acharya1 and Jasmohan S. Bajaj1

Hepatic encephalopathy is a state of brain dysfunction resulting from decompensation of cirrhosis. The mortality and
morbidity associated with the overt form of hepatic encephalopathy are high, and even the covert form associates
with poor outcomes and poor quality of life. We know that the dysfunction is not just an acute insult to the brain but
rather results in long-standing cognitive issues that get worse with each episode of HE. Hence, there is an urgency
to accurately diagnose these conditions, start appropriate therapy, and to maintain remission. Currently, we have two
mainstay pharmacological treatment options (lactulose and rifaximin), but the narrative is evolving with new therapies
under trial. Microbiome manipulation resulting in a favorable change to the gut microbiota seems to be a promising
new area of therapy.
Am J Gastroenterol https://doi.org/10.1038/s41395-018-0179-4

Introduction Basic Principles Underlying the Management

Hepatic encephalopathy (HE) is a serious complication of
decompensated cirrhosis with a significantly high mortality if
not managed appropriately and in a timely manner [1]. HE has a
high prevalence affecting up to 20% of decompensated cirrhotic
patients, and the first episode of overt HE (OHE) associates with
a poor prognosis [1–3].
HE clinical manifestations range from a mild loss of cognitive
abilities, to confusion and to coma. The AASLD and EASL have
classified HE as a continuum with OHE and covert HE (CHE) as
two distinct entities (Table  1) [4]. CHE is a new umbrella term
introduced in 2012, covering both minimal HE (MHE) and grade 1
HE due to the unreliability of the diagnosis of grade 1, normal, and
MHE on clinical examination [4–6]. In this review, CHE and MHE
will be used interchangeably. Though phenotypically different, the
underlying pathophysiology of CHE is like OHE and involves the
neurotoxic effects of ammonia and other toxic metabolites on
different regions of the brain in the setting of increased systemic
inflammation [7]. Clinically OHE, as the nomenclature suggests,
is noticeable to patients and caregivers, and involves significant
psychosocial stresses [8]. Despite optimal treatment, the risk for
recurrence of OHE is up to 40% within a month [9], making the
need for efficient reliable treatment options more relevant. CHE on
the other hand is not obvious but affects the patient’s health-related
quality of life (HRQOL), behavior, cognition, and can adversely
affect the driving skills [10, 11]. Hence, actively screening for HE
during clinic visits and looking for potential precipitating factors
should be the clinician’s prerogative. The treatment strategies, i.e.,
the pharmacological basis and clinical approach for these manifes-
tations of cerebral dysfunction in cirrhosis will be discussed here
(Tables 2 and 3).
of HE
All decompensated cirrhosis patients are at risk for HE given the
natural progression. MHE precedes OHE [12, 13], and hence in
recognized patients, extra care should be taken to monitor them
for preventable precipitants of OHE. Preventive strategies should
ideally be initiated for all cirrhotic patients irrespective of the HE
status.
An important preventive aspect to HE is the nutritional man-
agement of patients with cirrhosis (see Special topics). The cur-
rent recommendation is that patients with OHE should maintain
the same diet as other cirrhosis patients, as there is no evidence
that restricting dietary protein will prevent episodes of OHE [14].
Despite trying to maintain nutrition, certain patients with cirrho-
sis suffer from sarcopenia. There is mounting evidence to suggest
that sarcopenia is associated with HE [15, 16] presenting another
preventive opportunity in cirrhosis. Trying to improve nutritional
status and muscle mass with a high-protein diet and a before-bed-
time high-protein snack [17] will in theory help with prevention.
Branched-chain amino acids (BCAA), which are not readily avail-
able in the United States have been studied as a therapeutic drug
to alleviate sarcopenia in cirrhosis. BCAAs have also been studied
as a treatment option for OHE, but success in management of sar-
copenia and OHE has been limited [18–20]. Management of HE
should begin with non-pharmacological strategies before an offi-
cial diagnosis. Before labeling an episode as HE related, a thorough
review of medications must be done to eliminate or reduce opioids,
sedatives, sleep aids, psychoactive medications, and anticholiner-
gic medications prescribed for unclear reasons. Discontinuation
should be done in consultation with the prescribing provider to
prevent rebound phenomena that could alter mentation.

1
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA.
Correspondence: J.S.B. (email: jasmohan.bajaj@vcuhealth.org)
Received 20 December 2017; accepted 8 June 2018

© 2018 the american college of gastroenterology The American Journal of Gastroenterology

 2 c. Acharya, J.S. Bajaj
Table 1  Nomenclature of HE
Based on Based on Severity Based on Based on
underlying time course precipitating
Review Article
disease Based on Based on factors
WHC severity ISHEN
scale severity scale
MHE
A Episodic
Covert Spontaneous
Grade 1
B Grade 2 Recurrent
Grade 3 Overt Precipitated
C Persistent
Grade 4
Based on disease- A: Acute liver failure, B-Bypass/shunts, C- Cirrhosis; Based
on West Haven criteria (WHC)-MHE- minimal hepatic encephalopathy, not
clinically noticeable, Grade 1: Mild cognitive changes with no asterixis not easily
noticed in clinics, Grade 2: Confusion, disorientation to time, asterixis, Grade 3:
Disoriented to place and person, altered response to questions, Grade 4:
Comatose; Based on international society for hepatic encephalopathy and
nitrogen metabolism (ISHEN)- Covert Hepatic Encephalopathy: Combination of
MHE and Grade 1 OHE, OHE: All other clinically obvious grades of OHE on the
WHC; Based on time course- Episodic: 1 in 6 months, Recurrent: ≥2 episodes in
6 months, Persistent: constant with no reprieve: Based on precipitating etiology-
Precipitated- obvious etiology such as infection, noncompliance, Spontaneous-
no clear etiology
Despite our best efforts to understand its natural course, the
clinical course of decompensated cirrhosis, i.e., onset of OHE,
onset of ascites, development of variceal bleeding, etc. is often
unpredictable.
Pharmacological Approaches to HE
Treatment options for OHE work broadly on the principle of sys-
temic/gut ammonia reduction and intestinal microbial modula-
tion. Treatments are outlined below based on the mechanism of
action. Similar drugs are used for treatment of an acute episode
and prevention of recurrence. Table 2 provides a list of pharma-
cological options and Table 3 lists the studies with combination
therapies. Figure  1 shows the potential targets for the various
treatment options available. This section will cover acute, epi-
sodic, and recurrent OHE and CHE in detail.
Pharmacological therapies to modulate the gut milieu
As ammonia is a direct by-product of nitrogen metabolism, drugs
that help in reducing intestine luminal nitrogen by reducing pro-
duction and/or increasing excretion are our mainstay of therapy.
This is mainly due to easy availability and current evidence. Ther-
apies used for OHE and CHE are largely the same.
1. a. Non-absorbable disaccharides (lactulose and lactitol):
These drugs work by few mechanisms to improve outcomes.
The mechanisms could be related to a reduction of intestinal
pH by production of acetic and lactic acid (via bacterial deg-
radation of lactulose) that converts ammonia to ammonium
rendering it less absorbable, and then by an osmotic laxative
effect that flushes the ammonium ion out. Another potential
The American Journal of Gastroenterology
mechanism espoused during the pre-culture-independent
microbiota techniques era was a potential prebiotic action
where lactulose use was noted to result in an increase in the
fecal lactobacillus count [21]. However, recent evidence with
the use of culture-independent microbiota techniques has
not borne this out [22]. The most likely mechanism could
be related to its laxative action which unfortunately is a
major reason for noncompliance besides lactulose having an
unpleasant taste. On the other hand, lactitol is more tolerated
owing to less diarrhea and flatulence but it is not available in
United States. Given the low cost of lactulose, it is the drug of
choice for initiation of therapy for HE.
2. i. Non-absorbable disaccharides for OHE: Both drugs
(lactulose and lactitol) were studied before adequately pow-
ered randomized trials were required. These two medications
have been studied for acute episodes and for prevention of
recurrence of OHE. Uribe et al. studied lactulose as a 20%
enema vs. lactitol 20% enema vs. tap water enemas given 1 l
three times a day for up to 5 days in a RCT and noted that
there was similar improvement in mentation and ammonia
levels for lactitol and lactulose but both drugs were superior
to tap water enemas [23]. Morgan et al. compared oral lactitol
(26 ± 5 g/day) to oral lactulose (21 ± 5 g/day) for a duration of
5 days in acute OHE and noted significantly better perfor-
mance of lactitol for clinical improvement, psychometric
tests (number connection test A (NCT-A) and EEG), and the
portosystemic encephalopathy index (PSEI, P < 0.001) [24].
A randomized control trial (RCT) by Sharma et al. explored
the administration of albumin (1.5 g/kg/day IV) with lactulose
(30–60 ml oral/NG three times a day) vs. lactulose only for
acute OHE episodes for up to 10 days. Significantly improved
outcomes in terms of OHE recovery within 10 days (75% vs.
53.3%, P = 0.03), length of hospital stay (6.4 ± 3.4 vs. 8.6 ± 4.3
days, P = 0.01), and lower mortality (18.3% vs. 31.6%,
P < 0.05) during hospitalization in the albumin with lactulose
arm compared to lactulose-only arm were noted [25].
3. ii. Non-absorbable disaccharides for CHE: As with OHE,
multiple studies have been performed with lactulose, but
primarily for improvement in HRQOL and cognitive impair-
ment as measured by psychometric tests [26–28]. All these
studies showed that oral lactulose (20–30 g oral/NG three
times a day given for 8–12 weeks) was superior than placebo
in reversing the cognitive impairment noted pretreatment.
No studies specifically for lactitol have been done so far.
Due to the laxative action of lactulose, these trials have been
largely open-label in design.
4. a. Antibiotics (rifaximin, miscellaneous): Rifaximin is a
non-absorbable oral compound that has a complex mechanism
of action. Its functional impact is due to the effects that mitigate
the potentially pathogenic microbial taxa relatively sparing
the commensal bacteria. A recent review has summarized the
various potential mechanisms of action [29]. Rifaximin, 550 mg
www.nature.com/ajg

Table 2  List of current pharmacological options for management
of OHE
Drug Dose Undesirable
effects
First-line therapy for acute episodic OHE in the United States
Lactulose 20 g/30 ml—30 g/45 ml 3–4 per day titrated Diarrhea,
for 2–3 bowel movements a day orally. If flatulence, and
unable to administer orally, use a similar bloating. Un-
dose via NG or 300 ml of enemas 3–4 per pleasant taste
day till clinical improvement is noted.
Second-line therapy for acute episodic OHE in the United States (intol-
erant to lactulose)
Rifaximin 400–550 mg PO twice daily indefinitely No major side
effects
Third-line (not approved by FDA) therapy for acute episodic OHE
PEG 4 l of PO or via NG tube × 1 single dose None clinically
(in lieu of lactulose) in short-term
use
First-line therapy for prevention of recurrent OHE in the United States
Lactulose 20 g/30 ml—30 g/45 ml 3–4 per day Diarrhea,
titrated for 2–3 bowel movements a day flatulence, and
orally for low grades or use 300 ml of 3–4 bloating. Un-
per day enemas till clinical improvement pleasant taste
is noted.
Rifaximin 400–550 mg PO twice daily in conjunc- No major side
tion with lactulose or as monotherapy for effects
lactulose-intolerant patients.
Experimental (not approved by FDA) therapy for secondary prophylaxis
of OHE
Probiotics Dose dependent on the type of mixture No major side
used effects
FMT One small open-label randomized clinical Bloating and
trial diarrhea
PEG polyethylene glycol, LOLA L-Ornithine L-Aspartate, BCAA branched-chain
amino acids, GPB glycerol phenylbutyrate, FMT fecal microbiota transplant
oral twice daily is currently approved for use in conjunction
with lactulose as a second-line therapy for the first episode of
acute OHE or first-line therapy for OHE secondary prophylaxis
in patients who cannot tolerate lactulose in the United States.
5. i. Rifaximin for OHE: Rifaximin can only be adminis-
tered orally in the uncrushed form. Evidence for rifaximin
is strong and evolving. Rifaximin (1200 mg/day) has been
compared to lactulose (30 g/day oral/NG for 15 days) and
lactitol (60 g/day oral for 5–10 days) and has been shown to
be superior to lactulose and lactitol for improving mentation,
ammonia levels, and OHE clinical scores such as the PSE in
acute episodic OHE [30, 31]. Another RCT compared rifaxi-
min with lactulose against lactulose alone for acute episodic
OHE, and noted within a 10-day period significant improve-
ment in OHE symptoms (76% vs. 50.8%, P < 0.004), reduced
length of hospital stay (5.8 ± 3.4 vs. 8.2 ± 4.6 days, P = 0.001),
and reduction in mortality (23.8% vs. 49.1%, P < 0.05) at
© 2018 the american college of gastroenterology
current Management of Hepatic encephalopathy 3
the end of the study [32], in the combination arm. Under
investigation is a solid-state dispersible form of rifaximin
for primary prophylaxis of OHE, and preliminary data have
shown promising results for OHE prevention [33, 34].
Review Article
6. ii. Rifaximin for CHE: Only rifaximin has been stud-
ied (among the antibiotics). In an RCT, rifaximin (400 mg
three times a day) for 2 months was superior for reversal of
psychometric tests (number and figure connection tests A,
critical flicker frequency, and digit symbol test) compared
to placebo (P < 0.05) [30]. Other studies have shown rifaxi-
min (400 mg three times daily for 8 weeks) to be superior
to placebo (75.5% vs. 20%, P < 0.0001), and similar to
lactulose (30–120 ml/day for 3 months (73.7% vs. 69.1%))
for improvement in psychometric tests such as number and
figure connection tests, picture completion, digit symbol,
block design tests, and critical flicker frequency. Rifaximin
compared to placebo was superior in improving HRQOL
(mean sickness impact profile (SIP) score) from baseline
scores (11.67 vs. 6.45, P = 0.000 for rifaximin vs. 9.86 vs.
8.51, P = 0.82 for placebo) at the end of an 8-week trial
[35]. A study looking at cognition, HRQOL, and specifically
driving errors on a driving simulator, noted the superiority
of rifaximin (550 mg twice daily for 8 weeks) for rever-
sal of driving errors compared to placebo (76% vs. 31%,
P = 0.013) [36].
7. iii. Other antibiotics for OHE: Aminoglycosides, i.e.,
neomycin and ribostamycin, can be effective for acute OHE
management but are seldom used due to their systemic
toxicity (nephrotoxicity and ototoxicity) despite it being
FDA-approved [37, 38]. Other oral antibiotics studied but
not recommended for current use are vancomycin, paromo-
mycin, and metronidazole [39–41].
8. a. Miscellaneous laxatives (polyethylene glycol—PEG):
PEG, another osmotic laxative can be used for manage-
ment of acute OHE. Its postulated mechanism of action is a
flushing-out effect of ammonia from the gut-like lactulose. A
single RCT comparing PEG (4-l dose ×1 over 4 h orally/NG)
to lactulose only (20–30 g/day via oral/NG or 200 g/day rec-
tal) has proven it to be superior in terms of clinical improve-
ment over a 24-h period, documented by the HE scoring
algorithm (91% vs. 52%, P < 0.01), and by a shorter median
time to resolution (1 day vs. 2 days, P = 0.002) [42]. PEG has
not been FDA-approved for this indication but could be a
viable alternative to lactulose.
9. b. Probiotics: Probiotics are mixtures of beneficial bac-
teria that are hypothesized to help HE by modulating the
microbiome, which results in reduced systemic inflammation
but not necessarily in reduced ammonia [43–45]. Multiple
available mixtures have been explored, including VLS#3,
Lactobacillus GG, etc., but commercially available probiot-
ics may not have the recommended or claimed colony count
that the ones used in trials have. Therefore, the major reason
The American Journal of Gastroenterology
 4 c. Acharya, J.S. Bajaj

Table 3  Combination of drug studies done for OHE and CHE

Combination of drugs Study aim Results

Rifaximin+lactulose vs. lactulose [82] Reversal of OHE, mortality, and length Rifaximin+lactulose > lactulose for all
Review Article

Lactulose+BCAAs vs. lactulose+maltodextrin [113]
Lactulose+rifaximin vs. rifaximin [84]
Lactulose+GPB vs. lactulose+rifaximin+GPB vs.
standard of care+placebo [58]
Lactulose vs. lactulose+probiotics vs. probiotics [50]
Lactulose+albumin vs. lactulose [25]
Lactulose+IV LOLA vs. placebo [55]
LOLA L-Ornithine L-Aspartate, GPB glycerol phenylbutyrate, BCAAs branch-chained amino acids
of hospitalization
Prevention of recurrence of OHE
Reversal of OHE and improvement in
MELD score
Prevention of recurrence of OHE
Reversal of CHE based on psychometric
tests
Reversal of OHE and length of hospitali-
zation
Reversal of OHE, venous ammonia, and
length of hospitalization
Lactulose+BCAAs = lactulose+maltodextrin with no
decrease in recurrence
Lactulose+rifaximin > rifaximin for all
Lactulose+GPB and lactulose+rifaximin+GPB > standard
of care+placebo
Lactulose+probiotic > lactulose > probiotics
Lactulose plus albumin > lactulose alone for OHE reversal
Lactulose+LOLA > placebo. Benefit is limited to days 1–4
for OHE reversal

for the poor uptake of probiotics for HE remains the lack of
pharmacological quality medications as well as the use of dif-
ferent formulations.
10. i. Probiotics for OHE: There is no current evidence for
probiotics use in acute OHE [46]. The two major studies for
use of probiotics in OHE were for secondary prophylaxis and
not for acute OHE treatment [44, 47]. In the RCT by Agrawal
et al., use of probiotics (three capsules a day, each capsule
containing 112.5 billion lyophilized bacterial mixture) was
compared to lactulose alone (30–60 ml/day), and placebo for
12 months, and was associated with a lesser rate of re-admis-
sion for OHE for those on probiotics (34.4%) and lactulose
(26.5%) compared to placebo (56.9%), but no difference
was noted between lactulose and probiotics (P = 0.349). The
other RCT by Dhiman et al. studied VLS#3 (9 × 1011 colony-
forming units per sachet, a mixture of four lactobacillus
species given once daily), compared to placebo (patients were
taken off lactulose/rifaximin and were placed on alternative
laxatives) and noted an improvement in the Child Turcotte
Pugh (CTP) score and reduced breakthrough OHE (34.8% vs.
51.6%, P = 0.12) with reduced hospitalization risk (9.7% vs.
42.2%, P = 0.02). Both the studies clearly showed that probiot-
ics delay future OHE episodes. A study for primary prophy-
laxis showed that a probiotic mixture (1 × 108 colony-forming
units) three times daily for 3 months prevented OHE episodes
[43] in those with and without CHE history.
11. ii. Probiotics for CHE: Studies in CHE have shown a reduc-
tion in serum ammonia, inflammatory markers, endotox-
emia, and improvement in cognitive abilities (as evaluated by
multiple validated tests) [43, 45, 48, 49]. The RCT by Mittal
et al. randomized 120 cirrhosis patients diagnosed to have
MHE by NCT-A and B (or figure connection tests A and B)
and/or neurophysiological test (P-300 auditory event-related
potential), to either lactulose 30–60 ml/day or probiotic (four
capsules of VSL#3; total of 450 billion CFU/day) for 2 months.
The probiotic group and lactulose group were similar in terms
of remission (69.7% vs. 62.5%, P = 0.07). The RCT by Bajaj
et al. examined the effects of Lactobacillus GG (lactobacil-
lus GG AT strain 53103, (LGG)) vs. placebo, given daily in
30 cirrhosis patients diagnosed to have MHE by PHES and
the block design test, and noted significantly reduced serum
inflammatory markers and endotoxemia in the LGG group
at the end of 8 weeks. There have also been multiple stud-
ies that have compared probiotics to placebo, to lactulose, to
LOLA, and even a combination of lactulose with probiotics
that have shown benefit, i.e., superiority or equal efficacy in
reversing CHE [48–50]. The RCT by Mittal et al. compared use
of lactulose 30–60 ml two times a day, probiotics 110 billion
colony-forming units two times a day, LOLA 6 g three times a
day for 3 months, and no treatment in 120 cirrhosis patients
with MHE, and noted significant improvement in all treat-
ment arms (P = 0.006). They also assessed HRQOL via the SIP
questionnaire and found improvement in all treatment groups
compared to no treatment (P = 0.001).
Pharmacological therapies to affect the nitrogen balance
Ammonia is generated in the intestines and is transported via
the portal vein to the liver for metabolism. The liver and skel-
etal muscle are the main detoxifiers of ammonia to urea via the
urea cycle and to glutamine via glutamine synthetase/glutami-
nase, respectively. Glutamine produced in the skeletal muscles
enters systemic circulation and gets converted back to ammonia
in the kidneys for excretion. In cirrhosis, the urea cycle is altered,
and the skeletal muscle mass can be reduced due to sarcopenia,
effectively resulting in a reduced detoxification of urea and other
nitrogen waste products. Hence, therapies focusing on rectifying

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 current Management of Hepatic encephalopathy 5

NH3 Glutamine NH3 enters the astrocyte and gets converted to

glutamine by combining with glutamate.
Glutamine results in astrocytic edema and HE changes

Flumazenil

Review Article
NH3
NH3 NH3
+ Indoles OPA,
+ Inflammatory BCAAs
mediators Glutamine LOLA
Urea(Reduced in cirrhosis) Reduced in
cirrhosis with
OPA sarcopenia
LOLA

NH3
GPB,SPB and
NH3 OPA
+ Indoles Increased in
+ Inflammatory NH3
cirrhosis due to
mediators dysbiosis

Phenylacetylglutamine
excreted

Lactulose
Rifaximin and antibiotics
FMT Intestinal microbiome

Fig. 1  Areas of action for different therapies in cirrhosis and HE. HE, Hepatic encephalopathy

the abnormal ammonia/nitrogen waste metabolism pathways
have been developed. None of the drugs in this section are
approved for first-line therapy for acute or recurrent OHE proph-
ylaxis yet in the United States.
12. a. L-Ornithine L-Aspartate (LOLA): Both the components
of LOLA are substrates for the urea cycle and therefore act in
the liver to help clear ammonia in HE and other hyperam-
monemic conditions. Peripherally, it acts on glutamine syn-
thetase and increases glutamine levels. LOLA has a potential
beneficial effect of alleviating sarcopenia by increasing muscle
substrate, i.e., glutamine [51, 52], but stoppage has resulted in
a mild rebound increase in ammonia. Though not available
in the United States, it is manufactured in an oral and
intravenous form.
13. i. LOLA for OHE: Most of the studies done thus far have
looked at IV and oral forms only for chronic grade 2 OHE
(not acute OHE or grade 3,4) and noted an improvement in
mentation and venous ammonia [51, 53, 54]. The evidence
for the IV form for acute HE episodes is new. A recent RCT
by Sidhu et al. on 193 cirrhosis patients with OHE (grade
2–4) studied IV LOLA 30 g/day vs. placebo on top of con-
tinued standard-of-care therapy, i.e., lactulose till clinical
improvement. The study showed a benefit of IV LOLA with
lactulose over lactulose only, with improvement in mentation
(early (day 1–4) but not at day 5), improved recovery time
(1.9 ± 0.93 vs. 2.5 ± 1.03 days, P = 0.002), and length of stay.
No difference in inflammatory markers was seen. All patients
were administered IV cephalosporins regardless of infection
[55] and none of the patients were on rifaximin. Therefore,
this needs to be replicated in other centers without the use of
broad-spectrum antibiotics.
14. ii. LOLA for CHE: Given its ammonia-reducing proper-
ties, LOLA has been examined in CHE in comparison with
placebo, lactulose, rifaximin, and probiotics [48, 51, 56, 57]
and has shown improvement in psychometric tests, ammo-
nia, HRQOL, and in prevention of OHE. An RCT by Kircheis
et al. showed reversal of certain psychometric tests in those
with MHE when given LOLA 20 g once daily as a 4-h infu-
sion IV compared to placebo. The RCT by Alvares-da-Silva
showed that in 63 cirrhosis patients with MHE, compared
to placebo, LOLA 5 g given three times a day for 60 days did
not treat the cognitive deficits but prevented future OHE
episodes at 6 months.

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 6 c. Acharya, J.S. Bajaj
15. a. Glycerol phenylbutyrate (GPB): GPB enhances excre-
tion of nitrogenous waste by binding with glutamine (formed
in the skeletal muscles, gut, and liver) to form phenylacetyl-
glutamine which gets excreted in the urine.
Review Article
16. i. GPB for OHE: Given this unique property, it has found
validity in preventing OHE recurrence in those already on
lactulose or rifaximin or both [58]. In the large phase-II RCT
by Rockey et al., 178 cirrhosis patients with a history of OHE
in the last 6 months, who were already on standard-of-care
lactulose/rifaximin were enrolled. GPB 6 ml twice daily for
16 weeks was given. The GPB group had a lower plasma
ammonia level and lower HE episodes overall (21% vs. 36%;
P = 0.02) compared to placebo. GPB is available only as an
oral solution. It has not been studied for acute OHE manage-
ment yet and due to regulatory and logistic issues it is not
available for HE patients.
17. ii. There have been no studies of GPB for CHE yet.
18. a. Ornithine phenylacetate (OPA): This drug was devel-
oped for scavenging ammonia and glutamine to aid in excre-
tion [59]. It enhances gut, skeletal muscle, and liver glutamine
synthetase activity by providing a substrate to produce
glutamine and then binds the glutamine with phenylacetate to
form phenylacetylglutamine for easy urinary excretion.
19. i. OPA for OHE: OPA has been studied for acute OHE
and in preventing OHE recurrence. In a preliminary analysis
of a large randomized trial, there was a trend toward a
reduction in hospital stay duration in patients randomized
to therapy. In patients who were confirmed to be hyperam-
monemic via a central laboratory this reduction became
significant. The duration of inpatient HE tended to reduce in
the active treatment arm, not in the placebo infusion group.
The trial did not meet its primary endpoint (www.clinicaltri-
als.gov—NCT01966419) even though ammonia levels were
reduced significantly. Further evidence is awaited.
20. ii. There have been no studies of OPA for CHE yet.
21. a. Branched-chain amino acids (BCAAs): Patients with
cirrhosis lack sufficient BCAAs such as valine, leucine, and
isoleucine. These BCAAs are essential for detoxification of
ammonia in skeletal muscles during the process of glutamine
synthesis. BCAAs when compared to standard high-protein
diet therapies in HE were noted to be similar in terms of
nitrogen balance and safety for HE precipitation [60]. They
are not available in the United States and evidence is largely
from Asian countries.
22. i. BCAAs for OHE: Oral and IV formulations have been
compared to lactulose/neomycin to treat OHE (clinical
improvement, ammonia levels, mortality, and recurrence),
but so far, only the oral formulations have shown limited
The American Journal of Gastroenterology
benefit for OHE symptoms and none for mortality and
adverse events [20, 61].
23. ii. BCAAS for CHE: Both formulations (oral/IV) have
been studied looking primarily at improvement in psy-
chometric scores and have not shown significant clinical
improvement [20].
24. a. Sodium benzoate: This drug binds ammonia to form
hippurate for excretion and results in reduction in ammonia,
and hence has been applied in acute HE and was found to be
equally efficacious to lactulose for reducing ammonia [62],
and for clinical symptoms resolution. It is available as an oral
preparation (sodium benzoate and sodium phenylacetate
10%/10%) for use in patients with urea cycle disorders and
hyperammonemia but is not licensed for cirrhosis/HE in the
United States.
Pharmacological therapies to balance intracerebral
neurotransmitter chemicals
Brain neurotransmitter imbalance has been proposed as a mech-
anism for HE. There is evidence for this in animal models that
formed the basis for clinical trials. The drug in this category that
has been evaluated most is flumazenil, but it is not used currently
due to poor efficacy and predisposition to seizures [63, 64].
Pharmacological therapies to reduce systemic inflammation
Systemic inflammation is a major contributor too and an upregu-
lator of neuroinflammation, that is the main pathology in HE [7].
Probiotics and antibiotics act on the microbiome and help modu-
late this main driving force for inflammation. Studies have looked
at suppressing inflammation by using nonsteroidal drugs in animal
models [65, 66] but have not been looked at in humans. Albumin
is an important prognostic marker in chronic liver disease [67, 68],
has great anti-inflammatory properties and immunomodulatory
properties apart from being a strong oncotic agent, and has been
studied in acute OHE. Importantly, albumin infusions have shown
mortality benefit in infection-driven complications in decompen-
sated cirrhosis [69], and the evidence from the studies in this sec-
tion further adds to this.
25. i. Albumin for OHE: In an RCT by Simon-Talero et al.,
albumin use in acute OHE did not show improvement in
mentation but did show improvement in mortality at 90 days
(69.2% vs. saline: 40.0%; P = 0.02) compared to placebo (IV
normal saline). Albumin was given as IV 1.5 g/kg on day 1 and
1 g/kg on day 3, and patients were maintained on standard of
care for acute OHE. Majority of the patients in the study had
infections as precipitating etiology (53.8% in albumin vs. 36.7%
in saline groups). The study however had an unequal distribu-
tion of patients in both groups in terms of other complications
of portal hypertension [70]. A more recent study of the use of
lactulose with albumin showed that the combination is more
beneficial than lactulose only for OHE [25]. In this study as
well, the most common etiology for HE precipitation was infec-
www.nature.com/ajg

tions (35% vs. 32%). Apart from simple infusions, the Molecu-
lar Absorbent Recirculating System (MARS) with albumin has
been effective in management of OHE grade 3 and 4 [71].
26. ii. There have been no studies of albumin for CHE yet.
Miscellaneous therapies
a) Zinc sulfate: Cirrhotic patients with HE have been noted to have
low serum zinc levels [72]. Zinc is required in the urea cycle and
therefore for ammonia detoxification. Reding et al. randomized cir-
rhosis patients with chronic OHE (grade 1,2) to zinc acetate 600 mg/
day × 1 week vs. placebo and noted an improvement in NCT-A [73].
Brescri et al. in an RCT on OHE grade 1, 2 cirrhosis patients, using
the same dose of zinc acetate vs. standard of care for 6 months, noted
an improvement in NCT-A and the PSEI test at 6 months [74]. A
Cochrane analysis noted that there is insufficient data to use zinc
for improvement in OHE and for improvement of HRQOL [75].
In CHE, a single RCT comparing daily zinc gluconate with antioxi-
dants to lactulose for 3 months noted more improvement in psycho-
metric testing in zinc with the antioxidant arm [76].
b) l-Carnitine: This drug has interesting pharmacological
properties and works to remove ammonia via ureagenesis. The
RCT by Malaguarnera et al. showed a reduced ammonia level,
improvement in NCT-A, and clinical improvement in patients
with CHE and HE at the end of 90 days of l-carnitine (2 g twice
daily) compared to the placebo group [77]. The same authors
looked at acetyl-l-carnitine (ACL) and its role in improving
physical and mental fatigue and noted an improvement in the
treatment group compared to placebo [78, 79]. For MHE, the
same authors compared ACL to placebo for 90 days and noted
significant differences in improvement in the ACL group com-
pared to placebo [80].
Secondary prophylaxis for OHE
As after a single episode of OHE, the chance of having another
OHE episode increases, i.e., recurrence [81], and there is a strong
need for prophylaxis. Lactulose with rifaximin has been shown to
be superior than just lactulose in this regard (22.1% vs. 45.9% over
6 months) [82, 83] and superior to just rifaximin monotherapy
(13.9% vs. 24.8% over 6 months) [84]. Apart from HE medica-
tions, antibiotic prophylaxis with either norfloxacin or trimeth-
oprim/sulfamethoxazole daily for SBP must be considered for
prevention of recurrent SBP [85] which could precipitate OHE.
As norfloxacin is not available in the United States, many centers
use 250 mg of ciprofloxacin daily as first line and daily trimetho-
prim/sulfamethoxazole as second line due to the side effect profile
being better in fluoroquinolones. Interestingly, rifaximin prophy-
laxis for OHE may have an added benefit for SBP prophylaxis [86]
but using this in combination with another antibiotic for the pur-
pose of prophylaxis is not recommended yet.
Clinical Approach to HE (OHE and CHE)
We shall now discuss the real-world clinical management of OHE
and CHE by way of clinical cases.
© 2018 the american college of gastroenterology
current Management of Hepatic encephalopathy 7
Management of OHE
Case 1—OHE: A 59-year-old Caucasian man with chronic hepa-
titis C cirrhosis presents to the emergency room for confusion.
He was first seen in your clinic 2 years back for a new diagnosis of
Review Article
HCV cirrhosis based on abnormal low platelet counts that his pri-
mary care noticed. He at that time was found to be compensated.
In the emergency room, the patient is not very conversant and
appears confused. History is obtained primarily by his wife who
attests to this not being the first episode, and that the patient has
been on lactulose therapy with 3–4 bowel movements a day for the
past year.
Vital signs: Blood pressure––110/70, respiratory rate––14, heart
rate––66, and temperature––99.1 °F. On examination, he has jaun-
dice, anasarca, and considerable ascites with discomfort/rebound
tenderness on palpation. He is not oriented to time, place, or per-
son and is intermittently following commands. He has asterixis.
Neurological exam otherwise seems nonfocal. There is a concern
for OHE.
Management recommendations, i.e., the initial four-pronged
approach, continued management, and secondary prophylaxis
(Figs. 2 and 3) are specific to case 1.
Initiate care: Stabilization and triaging are the foremost. This
patient’s vital signs seem stable and he seems appropriate for
the general/step-down floor (based on institutional policy). The
patient obtains IV access, liver functions, the basic metabolic pro-
file, complete blood count, and venous ammonia levels on arrival.
Evaluate for alternatives: Serum/urine drug screen should be
obtained. The likelihood of this being an intracranial event is low
given that this is his second episode and he does not have focal
deficits; therefore, imaging may be lower down in the priority list.
Identify precipitating factors: A thorough evaluation of the
patient’s medication list, medication compliance, drug use includ-
ing alcohol use, and other psychoactive medications should be
discussed with the caregiver. Ascitic fluid for diagnosis of spon-
taneous bacterial peritonitis should be obtained. Given his tender
abdomen, consider starting ceftriaxone/cefotaxime intravenously
before culture data are back or if there is a delay in obtaining the
paracentesis. Consider chest X-ray, urinalysis/urine cultures, and
CT scan abdomen/pelvis for potential deep-seated infections, and
draw cultures for management of sepsis/infections, i.e., do a broad
workup for infectious etiologies. Screening the laboratory work for
electrolyte abnormalities and for acute kidney injury that could
manifest with altered mentation or precipitate OHE and correct-
ing them as appropriate will be of high value. Patients should get
blood work every 24 h or more frequently based on the underlying
electrolyte abnormalities.
Initiate empirical therapy: Empirical therapy with lactulose 30 g
or 45 ml/4–6 hourly titrated for at least 3–4 bowel movements a
day should be started via a nasogastric tube (NG) if there is any
doubt regarding safety of swallowing. Given this being his second
episode of OHE, he should be started on rifaximin 550 mg PO BID
once he can take medications orally.
Management past the four-pronged approach.  Course: The
patient’s blood laboratory work was found to be within normal
The American Journal of Gastroenterology
 8 c. Acharya, J.S. Bajaj

Initiate
general Is patient
care employed?
Review Article

Initiate Cirrhotic Evaluate for

Obvious
cognitive Cirrhotic
treatment
empirically with alternative disabilities
noted by without Is patient a
driver?
etiologies
for OHE
AMS family or AMS
patient?

Identify
precipitating Is patients
factors QOL poor?

If patient able to protect airway admit to Consider evaluation for CHE

General floor
floor. If not ICU level of care warranted. based on institutional
availability

- Intubate patient if needed - Start oral lactulose 20 g every 2–4 hours

- If intubated, insert NG tube and start oral
lactulose 30 g each hour until bowel
movements and clinical improvement.
- If not intubated, and patient cannot tolerate
oral lactulose, start rectal lactulose, 300 ml in
1000 ml every 2-4 hours until clinical
improvement. Switch to oral lactulose 20–30
gm every 2–4 hours once clinically improved
until BM or clinical improvement.
- If patient cannot tolerate oral
lactulose, start rectal lactulose, 300 ml
in 1000 ml every 2-4 hours until
clinical improvement.
- Multi-center study: 2 testing strategies
- One-center study: locally validated one
strategy
- Real-world: Stroop EncephalApp, SIP
questionnaire

Improves: Negative: Positive: Consider a

Discharge on Consider trial of treatment with
Does not improve: lactulose 20 g/day and
secondary retesting in
Improves: - Ensure correct diagnoses reevaluate in 8 weeks.
prophylaxis 6 months
Discharge on - Add rifxamin 550 mg po BID Therapy for 6 months
secondary - Search for refractory etiologies
prophylaxis - Consider experimental therapies.

Fig. 2  Schematic of the approach to a cirrhotic patient with/without AMS. AMS altered mental status

• Stabilize airway, vital • Drug screen

signs • Psychiatric disorder
• Triage appropriately • Neurological disorders
• Lab work • Dementia
• IV fluids, NG tube, • Obstructive sleep apnea
antibiotics empirically
if indicated

Initiate Evaluate for

general care alternatives

Identify
Commence
precipitating
empirical
factors and
therapy
reverse

• Lactulose either orally • Infections

or via NG tube or via • GI bleeding
enemas depending on • Electrolyte disorder
mentation • Diuretic overdose
• Other therapies • Unidentified

Fig. 3  Four guiding principles to approach a cirrhotic patient with altered mentation

The American Journal of Gastroenterology www.nature.com/ajg


limits, except for an elevated white blood cell count of 18,000
cells/dl with a left shift. His ascitic fluid sample shows a nucleated
count of 650 cells/mm3, and the cultures came back as positive for
E. coli management: the patient should be continued on IV cef-
triaxone till clinical improvement. Given the high nucleated cell
count, he could undergo a repeat diagnostic paracentesis on day 3
of antibiotics to check for improvement. As he improves clinically
to the baseline, he should be transitioned to PO ciprofloxacin and
be discharged to complete a 7-day course of antibiotics. He should
also get lactulose and rifaximin for secondary prophylaxis, and
PO ciprofloxacin 250 mg daily as prophylaxis for SBP to prevent
recurrent OHE after completion of his 7-day course of antibiotics.
The patient this time suffered from type 2, episodic, grade 2
OHE, precipitated by SBP, and further details regarding this clas-
sification can be found in the AASLD/EASL guidelines [4] and
Table 1.
Management of MHE/CHE
Given the current lack of routine clinical testing, the diagnosis of
MHE/CHE is often missed. The best approach is to optimize gen-
eral care in all patients, i.e., work on preventable causes of OHE
precipitation and closely monitor patients who test positive. Diag-
nosis is achieved with tests that examine psychometric and neu-
rophysiological properties of the brain. The commonly used tests
are the psychometric HE score (PHES), EncephalApp Stroop test,
inhibitory control test, and critical flicker frequency test [4]. Four
questions of the Sickness Impact Profile (SIP), an HRQOL ques-
tionnaire, have been shown to be efficacious in diagnosis of CHE
[87] as a potential “real-world” application. In a clinical single-
center setting, only one locally valid test is required for a diagnosis,
but in the research multicenter setting, two locally valid tests are
recommended. The caveat is that psychometric testing diagnoses
mild cognitive impairment from any etiology and hence the clini-
cal context is relevant. Patients who are on multiple psychoactive
medications for psychiatric conditions, were recently started on
new psychoactive medications, are actively consuming psychoac-
tive substances, or alcohol but then the results could be falsely
positive. Hence, the results must be interpreted with caution. In
situations of uncertainty, it is always good to seek the counseling
of a psychologist if available.
With regard to treatment of CHE, most studies so far have
looked at outcomes such as improvement in psychometric tests,
improvement in dysbiosis and inflammation, and HRQOL. Major-
ity of the studies did not look at prevention of hospitalization and
prevention of OHE as a primary endpoint in a double-blind man-
ner. Open-label studies and meta-analysis have concluded that
lactulose does prevent OHE development in CHE [88], and probi-
otics are effective in preventing OHE over a 3-month period [43].
Rifaximin has not been studied with the aim of preventing OHE in
patients with CHE/MHE.
Case 2/CHE: A 55-year-old African-American woman with
chronic hepatitis C cirrhosis presents to a clinic for a follow-up
visit. She was first seen in your clinic 2 years back for a new diag-
nosis of HCV cirrhosis, based on abnormal low platelet counts
that her primary care physician noticed. She subsequently started
© 2018 the american college of gastroenterology
current Management of Hepatic encephalopathy 9
on DAA therapy and achieved SVR in 12 weeks. She continued
to remain in SVR on follow-up visits, but over the last 1 year, she
started complaining of fatigue and not being herself. Clinical exam
and laboratory work that you obtain on the visit are normal. You
Review Article
obtain her annual liver US that shows cirrhosis but no other abnor-
malities.
Management of case 2.  The patient’s symptoms of fatigue
and not being her usual self, after being treated for HCV should
prompt further investigation. She should be questioned about any
new medications, use of psychoactive medications, and symptoms
of sleep apnea, i.e., other potential causes of fatigue/altered cogni-
tion. Another important aspect that needs to be kept in mind is
the presence of chronic HCV and whether it is being treated as
they associate with similar symptoms. The patient should be test-
ed/referred for testing to a center with expertise, or alternatively,
the EncephalApp Stroop can be used for a quick diagnosis. Upon
confirming a diagnosis, a trial of lactulose should be initiated and
appropriate follow-up scheduled (Fig. 2).
Ideally, it may be important to screen every cirrhotic patient
for CHE, but the groups to focus on are those with advanced
liver disease, who are currently employed and driving, and those
complaining of cognitive and quality-of-life issues. Screening for
CHE should be done in a location away from the routine clinical
areas by trained personnel. Real-world tests are the animal nam-
ing test [89], and four questions of the SIP [87] or EncephalApp
Stroop [90], all of which can be point-of-care. EncephalApp
results can be checked for CHE using http://www.encephalapp.
com, which is based on normative US data. If a nearby center or
a psychologist offers official testing, consider referring the patient
for an official diagnosis.
CHE treatment is not mandatory for those with positive official
testing but is on a case-by-case basis and done in conjunction with
patient discussion. First-line treatment could be a trial of lactu-
lose 20 g/day with an interim follow-up at 8 weeks. If the interim
check at 8 weeks shows no improvement, lactulose could probably
be stopped. The acceptance of lactulose varies between cohorts
in Eastern and Western countries [91] and this should be taken
into consideration, when considering lactulose or rifaximin. Given
the subtle nature of CHE, the significant implications, careful
counseling of patients, and their companions/caregivers regard-
ing the symptoms is important for early detection. Patients who
test positive irrespective of their decision to try lactulose should
be monitored closely as their risk for OHE is higher. Their car-
egivers should also be counseled about this since it will be the first
OHE episode.
Special Topics
Nutrition in HE
It is advised to have patients maintain a high-protein high-caloric
diet of 1.2–1.5 g/kg ideal body weight/day and 35–40 kcal/kg ideal
body weight/day, respectively [14]. This should be spaced out over
3–4 meals a day. Small frequent meals rather than large meals are
preferred [92]. For those with weight loss/sarcopenia, advise a
The American Journal of Gastroenterology
 10 c. Acharya, J.S. Bajaj
dietary supplement of a nightly high-protein snack. This could be
a liquid protein meal. Patients can also use peanut butter/Greek
yogurt etc. Although plant and dairy proteins are presumed to be
better regarding ammoniagenesis compared to animal proteins,
Review Article
the primary goal is to design diets that the patients will follow. We
should take care to avoid dehydration through diarrhea, excessive
activity, and concurrent diuretic use and not avoid fluids along
with salt, unless hyponatremic. In addition, patients should be
encouraged to maintain their physical activity to prevent muscle
mass loss. Moderate exercise in the gym (cycling and jogging) for
30–60 min three times a week could possibly help [93].
Liver transplantation (LT) for OHE
OHE is reversed post LT, but cognitive changes present pre-
LT can persist for up to 6 months post LT [94, 95]. A study by
Ahluwalia et al. noted that cognition and HRQOL continued to
improve 1 year post LT in all cirrhotic patients irrespective of the
OHE history [96]. Another recent study evaluating cognitive flex-
ibility based on the EncephalApp Stroop test noted the reversal of
OHE-related learning disability post LT [97]. More importantly,
studies have shown that having a pre-LT diagnosis of OHE does
not always predict recovery of cognitive functions post LT, rather
it is the presence of pre-LT cognitive impairment that is predic-
tive [94].
Currently, OHE (recurrent or persistent) is not an indication for
listing for LT unless associated with liver failure [4]. An interesting
study looked at incorporating a history of OHE into the MELD
score and noted that OHE-positive patients did have a higher
6-month post-LT mortality. However, the study also noted that
adding points to the MELD score for OHE predicted the mortal-
ity, and by not considering OHE in the MELD score, up to 29%
of patients were misclassified for LT [98]. Given the mounting
evidence of reversibility of cognitive deficits and HRQOL post
LT, there is a rise in the advocacy of considering pre-LT cognitive
impairment and OHE status while listing for LT.
Management of post TIPS OHE
There is limited evidence for prophylaxis of post TIPS OHE. Pre-
ventive strategies of ensuring that the patient has no identifiable
risk factors for post TIPS OHE are the first step. These risk factors
include patients without prior OHE, lower MELD score, sarcope-
nia, pre-TIPS cognitive impairment, and hyponatremia as risk fac-
tors that are noted to predict post TIPS OHE [99–101]. Lactulose
can be given if the patient develops OHE, but prophylaxis with
lactulose or rifaximin is not recommended [102]. In refractory
cases, the TIPS can be reversed or downsized but this can result in
increased portosystemic gradients (PSG) [103, 104]. A potential
preventive strategy or metric to guide and identify those at high
risk for post TIPS HE would be a low post TIPS PSG (<5 mmHg),
i.e., a post TIPS portosystemic gradient of >5 mmHg could pos-
sibly prevent HE [105].
Shunt closures for recurrent/persistent OHE
Recurrent OHE always has an underlying precipitating etiology. A
fervent search will often reveal a spontaneous portosystemic shunt
The American Journal of Gastroenterology
as the etiology in up to 70% of those with persistent OHE [106].
There are multiple options for shunt closure such as coil-assisted
retrograde transvenous occlusion (CARTO), plug-assisted ret-
rograde transvenous occlusion (PARTO), and balloon-occluded
retrograde transvenous occlusion (BRTO). Shunt closure by any
of these methods will prevent excessive gut-based products from
reaching the systemic circulation, and studies have shown that
despite closure and rise in portal hypertension complications are
not clinically significant [107, 108].
Driving and HE
Patients with CHE and OHE have a higher risk of road traffic
accidents and adverse outcomes related to the accidents [10, 109].
Most CHE patients are safe drivers and the presence of CHE does
not predict the inability to drive a motor vehicle [109]. Therefore,
from a medicolegal standpoint, it is not mandatory in the United
States (in any state) to report a driving impairment related to a
diagnosis of CHE to the DMV. However, if patients with cognitive
dysfunction purely related to CHE, have a higher rate of motor
vehicle crashes as gathered in questioning, they could possibly
have an official evaluation by the state’s department of motor vehi-
cles. At the very least, these patients should avoid driving long
distances, driving at night, and use GPS technology to prevent
navigation errors.
On the other hand, recent (<3 months) or current OHE, on
the other hand, does qualify as a reportable “lapses in conscious-
ness” diagnosis that requires reporting, and in some states requires
mandatory reporting [110]. It would be best practice to counsel
patients about the risks and to avoid driving in OHE if patients are
symptomatic and have recurrent OHE. This should be discussed
with patients and caregivers and documented in the chart.
Future Therapies
Fecal microbial transplant: Therapies focusing on modulation of
the microbiome are gaining more interest due to the increased
understanding of its role in HE. There have been a few studies
conducted in this field. The smallest study was on a single OHE
patient, and the intervention resulted in improved cognition and
favorable microbiome changes [111]. A larger trial involving
patients with recurrent OHE, showed that fecal enema transplants
resulted in an improvement in cognition and the fecal microbi-
ome profile with a reduced incidence of OHE post fecal transplant
[112]. Given the success of the initial trial, a more robust trial for
similar populations with oral fecal capsules is underway by the
same group (NCT03152188). Other newer therapies: Therapies
focusing on brain GABA receptors, altered E. coli, etc, are some of
the newer modalities that are being actively investigated in HE but
are not near clinical use now.
Conclusion
There are multiple factors that determine the risk and prognosis
for HE. Early recognition and correction of these factors in clinics
are essential to prevent morbidity. Acute OHE management is a
www.nature.com/ajg

complicated dynamic process where one needs to be cognizant of
precipitating factors and of the long-term effects of untreated HE.
In acute OHE, a wide net needs to be cast for recognizing precipi-
tating factors and empirical therapy started immediately. Our con-
ventional therapies are successful in the reversal of OHE but have
their own limitations. Newer therapies being studied for nitrogen
excretion and microbiome manipulation (fecal transplantation)
may be the future of adjunct therapy for recurrent OHE. CHE test-
ing and management are more controversial, but the consensus so
far is to screen, test, and treat on a case-by-case basis.
Conflicts of interest
Guarantor of the article: Jasmohan Bajaj.
Specific author contributions: CA and JSB wrote the paper.
Financial support: VA Merit Review I0CX001076 and
NIH R21TR020204.
Potential competing interests: JSB has served on Advisory Boards
for Norgine, Alfa-Sigma, Ocera, Synlogic, Kaleido, and Valeant
Pharmaceuticals. The other author declares no conflict of interest.
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