Current Management of Hepatic Encephalopathy REVIEW ARTICLE · 2018-12-22 · gic medications prescribed for unclear reasons. Discontinuation should be done in consultation with the

see related editorial on page x

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© 2018 The American College of Gastroenterology The American Journal of GASTROENTEROLOGY

REVIEW ARTICLE

INTRODUCTION

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).

BASIC PRINCIPLES UNDERLYING THE MANAGEMENT

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.

Current Management of Hepatic Encephalopathy

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

1Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA.

Correspondence: J.S.B. (email: [email protected])

Received 20 December 2017; accepted 8 June 2018

mailto:[email protected]

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C. Acharya, J.S. Bajaj2

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

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

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

Table 1 Nomenclature of HE

Based on

underlying

disease

Based on Severity Based on

time course

Based on

precipitating

factorsBased on

WHC severity

scale

Based on

ISHEN

severity scale

A

B

C

MHECovert

EpisodicSpontaneous

Grade 1

Grade 2

Overt

Recurrent

Persistent

PrecipitatedGrade 3

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

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3Current Management of Hepatic Encephalopathy


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

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].

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

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

for 2–3 bowel movements a day orally. If

unable to administer orally, use a similar

dose via NG or 300 ml of enemas 3–4 per

day till clinical improvement is noted.

Diarrhea,

flatulence, and

bloating. Un-

pleasant taste

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

(in lieu of lactulose)

None clinically

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

titrated for 2–3 bowel movements a day

orally for low grades or use 300 ml of 3–4

per day enemas till clinical improvement

is noted.

Diarrhea,

flatulence, and

bloating. Un-

pleasant taste

Rifaximin 400–550 mg PO twice daily in conjunc-

tion with lactulose or as monotherapy for

lactulose-intolerant patients.

No major side

effects

Experimental (not approved by FDA) therapy for secondary prophylaxis

of OHE

Probiotics Dose dependent on the type of mixture

used

No major side

effects

FMT One small open-label randomized clinical

trial

Bloating and

diarrhea

PEG polyethylene glycol, LOLA L-Ornithine L-Aspartate, BCAA branched-chain

amino acids, GPB glycerol phenylbutyrate, FMT fecal microbiota transplant

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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

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

of hospitalization

Rifaximin+lactulose > lactulose for all

Lactulose+BCAAs vs. lactulose+maltodextrin [113] Prevention of recurrence of OHE Lactulose+BCAAs = lactulose+maltodextrin with no

decrease in recurrence

Lactulose+rifaximin vs. rifaximin [84] Reversal of OHE and improvement in

MELD score

Lactulose+rifaximin > rifaximin for all

Lactulose+GPB vs. lactulose+rifaximin+GPB vs.

standard of care+placebo [58]

Prevention of recurrence of OHE Lactulose+GPB and lactulose+rifaximin+GPB > standard

of care+placebo

Lactulose vs. lactulose+probiotics vs. probiotics [50] Reversal of CHE based on psychometric

tests

Lactulose+probiotic > lactulose > probiotics

Lactulose+albumin vs. lactulose [25] Reversal of OHE and length of hospitali-

zation

Lactulose plus albumin > lactulose alone for OHE reversal

Lactulose+IV LOLA vs. placebo [55] Reversal of OHE, venous ammonia, and

length of hospitalization

Lactulose+LOLA > placebo. Benefit is limited to days 1–4

for OHE reversal

LOLA L-Ornithine L-Aspartate, GPB glycerol phenylbutyrate, BCAAs branch-chained amino acids

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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.

NH3 Glutamine

Glutamine

NH3

+ Indoles

+ Inflammatory

mediators

NH3

+ Indoles

+ Inflammatory

mediators

Reduced in

cirrhosis with

sarcopenia

Intestinal microbiome

Lactulose

Rifaximin and antibiotics

FMT

GPB,SPB and

OPA

OPA,

BCAAs

LOLA

Flumazenil

OPA

LOLA

NH3 enters the astrocyte and gets converted to

glutamine by combining with glutamate.

Glutamine results in astrocytic edema and HE changes

Phenylacetylglutamine

excreted

NH3

NH3

NH3

NH3

Urea(Reduced in cirrhosis)

Increased in

cirrhosis due to

dysbiosis

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

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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.

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

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-

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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.

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

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

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Cirrhotic

with

AMS

Initiate

general

care

Evaluate for

alternative

etiologies

Identify

precipitating

factors

Initiate

treatment

empirically

for OHE

If patient able to protect airway admit to

floor. If not ICU level of care warranted.

Cirrhotic

without

AMS

Is patient

employed?

Is patient a

driver?

Is patients

QOL poor?

Obvious

cognitive

disabilities

noted by

family or

patient?

- Start oral lactulose 20 g every 2–4 hours

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.

General floor

Improves:

Discharge on

secondary

prophylaxis

Does not improve:

- Ensure correct diagnoses

- Add rifxamin 550 mg po BID

- Search for refractory etiologies

- Consider experimental therapies.

- Intubate patient if needed

- 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

Improves:

Discharge on

secondary

prophylaxis

Consider evaluation for CHE

based on institutional

availability

- Multi-center study: 2 testing strategies

- One-center study: locally validated one

strategy

- Real-world: Stroop EncephalApp, SIP

questionnaire

Negative:

Consider

retesting in

6 months

Positive: Consider a

trial of treatment with

lactulose 20 g/day and

reevaluate in 8 weeks.

Therapy for 6 months

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

• Infections• GI bleeding• Electrolyte disorder• Diuretic overdose• Unidentified

• Lactulose either orally or via NG tube or via enemas depending on mentation• Other therapies

• Drug screen• Psychiatric disorder• Neurological disorders• Dementia• Obstructive sleep apnea

• Stabilize airway, vital signs• Triage appropriately• Lab work• IV fluids, NG tube, antibiotics empirically if indicated

Initiate general care

Evaluate for alternatives

Identify precipitating factors and

reverse

Commence empirical therapy

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

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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

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

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

http://www.encephalapp.com

http://www.encephalapp.com

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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,

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

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

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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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https://doi.org/10.1016/j.jceh.2017.11.010

GASTROENTEROLOGY ARTICLE OF THE WEEK September 6, 2018

Acharya C, Bajaj JS. Current management of hepatic encephalopathy. Am J Gastroenterol https://doi.org/10.1038/s41395‐018‐0179‐4 1. Lactulose for HE a. main mechanism of action is trapping ammonium in the gut b. lowering the colon lumen pH allows for the beneficial growth of bacteria such as lactobacillus c. Is the drug of choice for initiation of therapy for HE d. Is not effective in the treatment of minimal or covert hepatic encephalopathy 2. Main sites responsible for ammonia detoxification and excretion include a. skeletal muscle b. liver c. Kidneys d. intestinal epithelium True or False 3. Rifaximin is similar to lactulose and superior to placebo in the treatment of covert hepatic encephalopathy 4. Patients with recurrent HE should not consume more than 1.0g protein/kg/day 5. Sodium benzoate therapy has been found to be equally effective to lactulose for the treatment of acute HE 6. Rifaximin + lactulose has been found to be superior to lactulose alone in reversing OHE, and decreasing length of hospitalization 7. Metronidazole is recommended for OHE patients who cannot afford rifaximin 8. Patients admitted with OHE should undergo a comprehensive evaluation to exclude or diagnose infections 9. Sarcopenia (loss of skeletal muscle) is a risk factor for hepatic encephalopathy 10. Rifaximin is currently approved by the FDA as first line therapy for hepatic encephalopathy 11. Patients with cover hepatic encephalopathy should be reported to the department of motor vehicles and should not drive 12. Probiotics have not been studied in acute OHE, but may reduce or delay overt encephalopathy recurrence 13. Zinc sulfate theoretically could help encephalopathy by increasing urea cycle clearance of ammonia, data regarding its efficacy is lacking 14. Lactulose plus rifaximin has been found to be superior to rifaximin alone for the prevention of recurrent OHE 15. Based on open label studies, lactulose and probiotics prevent or delay onset of OHE in patients with CHE; there is no data regarding rifaximin efficacy 16. Patients undergoing TIPS for refractory ascites should receive HE prophylactic therapy with lactulose and/or rifaximin

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