Hepatic encephalopathy: Diagnosis and management

Dr. Lorenzo Ridola MD, PhD, 1 , Jessica Faccioli 1 , Silvia Nardelli 1 , Stefania Gioia 1 , and Oliviero Riggio 1
  • 1 Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome, Italy
Dr. Lorenzo Ridola
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  • Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome, Italy
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, Jessica Faccioli
  • Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome, Italy
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, Silvia Nardelli
  • Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome, Italy
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, Stefania Gioia
  • Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome, Italy
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and Oliviero Riggio
  • Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome, Italy
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Abstract

Type C hepatic encephalopathy (HE) is a brain dysfunction caused by severe hepatocellular failure or presence of portal-systemic shunts in patients with liver cirrhosis. In its subclinical form, called “minimal hepatic encephalopathy (MHE), only psychometric tests or electrophysiological evaluation can reveal alterations in attention, working memory, psychomotor speed and visuospatial ability, while clinical neurological signs are lacking. The term “covert” (CHE) has been recently used to unify MHE and Grade I HE in order to refer to a condition that is not unapparent but also non overt. “Overt” HE (OHE) is characterized by personality changes, progressive disorientation in time and space, acute confusional state, stupor and coma. Based on its time course, OHE can be divided in Episodic, Recurrent or Persistent. Episodic HE is generally triggered by one or more precipitant factors that should be found and treated. Unlike MHE, clinical examination and clinical decision are crucial for OHE diagnosis and West Haven criteria are widely used to assess the severity of neurological dysfunction. Primary prophylaxis of OHE is indicated only in the patient with gastrointestinal bleeding using non-absorbable antibiotics (Rifaximin) or non-absorbable disaccharides (Lactulose). Treatment of OHE is based on the identification and correction of precipitating factors and starting empirical ammonia-lowering treatment with Rifaximin and Lactulose (per os and enemas). The latter should be used for secondary prophylaxis, adding Rifaximin if HE becomes recurrent. In recurrent/persistent HE, the treatment options include fecal transplantation, TIPS revision and closure of eventual splenorenal shunts. Treatment of MHE should be individualized on a case-by-case basis.

Introduction

Type-C hepatic encephalopathy (HE) is a complex neurological syndrome typical of patients with cirrhosis as a consequence of severe hepatocellular failure or the presence of large portal-systemic shunts, which causes a wide spectrum of nonspecific neurological and psychiatric manifestations. This condition ranges from a subclinical entity (minimal hepatic encephalopathy, MHE) to a most severe form characterized by a complete alteration of consciousness (overt HE, OHE).

OHE occurs in 30%–40% of patients with liver cirrhosis during the natural history of their disease,[1] but the real epidemiology is not easy to estimate. Prevalence rates of HE may be much higher in transjugular intrahepatic portosystemic shunt (TIPS),[2] as well as in spontaneous[3, 4] or surgical shunting carriers.[5]

MHE is “apparently” lacking any clinical evidence, in fact it can be detected only through psychometric evaluations or electrophysiological and other functional brain tests. MHE prevalence is also still debated but is considered very frequent (20%–80% of patients). Nevertheless, MHE is clinically relevant because it is related to patients’ falls, fitness to drive, working ability, sarcopenia, prognosis[6, 7, 8] and worsening patients and caregivers lives by altering their quality of life and socioeconomic status.

Recently, the term “covert” has been coined to unify MHE and Grade I HE in order to refer to a condition that is not unapparent, but also not overt. Both MHE and CHE are considered strong risk factors for the development of OHE (5%–25% of patients develop OHE within 5 years after cirrhosis diagnosis).[910]

According to its time course, HE is subdivided into three types: episodic HE if precipitated, recurrent HE if denotes bouts of HE occurring with a time interval of 6 months or less and persistent HE when shows continuous neurological alterations interspersed with relapses of OHE.[1, 2, 3, 4, 5, 11]

Clinical presentation and diagnosis of hepatic encephalopathy

Type C OHE should be suspected in case of personality changes occurring in a cirrhotic patient, such as apathy, irritability, disinhibition or obvious alterations in consciousness and motor function. Moreover, asterixis, as well as alterations of sleep wake cycle with excessive daytime sleepiness, can be frequently observed in this condition. Patients with OHE can further develop progressive disorientation in time and space, inappropriate behavior, acute confusional state with agitation or somnolence, stupor and finally coma. This can occur as a progressive alteration of state of consciousness, from mildest to serious forms, or as a direct fall in deeper stage of HE.

Episodic HE is often characterized by the presence of one or more precipitating events, both new or superimposed, that should be found and treated. So, searching for them is mandatory in all patients with OHE. When multiple precipitating events coexist, failure to identify and correct all precipitating factors can worsen the management.[12] Most common precipitating factors are infections, constipation, dehydration, hypokalemia and/ or hyponatremia, gastrointestinal (GI) bleeding and use of psychoactive drugs (opioids or benzodiazepines). In addition, recent evidences suggest that low serum albumin level are significantly associated with the development of OHE in liver cirrhosis and that long-term albumin administration to patients with decompensated cirrhosis significantly reduces the incidence rate and severity of type C OHE (grade 3–4), while improves 18-months survival.[11, 13, 14, 15]

The differential diagnosis for patients not responding to standard pharmacological approach should exclude the presence of alcohol withdrawal, meningitis and encephalitis.[16]

Some patients may present chronic HE, which is refractory to conventional medical therapy and often lacks evident precipitating events. The presence of unrecognized large Spontaneous Portal-Systemic Shunts (SPSSs) can be responsible for chronic course of HE. In fact, 46–70% of cirrhotic patients with refractory HE shows SPSSs at radiological imaging.[3,4,17, 18, 19]

TIPS opens an artificial link between portal and hepatic veins, shifting blood from splanchnic circulation into systemic vascular system in order to avoid the major complications of portal hypertension. Polytetrafluoroethylene (PTFE)-covered stents significantly reduce the incidence of shunt insufficiency[20] but is unfortunately counterbalanced by the development of OHE.[21] Strategies of HE testing range from simple clinical scales to more complex psychometric and neurophysiological tools; however, the entire spectrum of HE, being the severity as a continuum, cannot be studied using only one test. Clinical examination and clinical decision are the cornerstone of OHE diagnosis, while clinical scales analyze its severity; West Haven criteria (WHC)[22] as reported in Table 1[1] are still widely adopted for this purpose, and more recently, a simple clinical scale has been proposed[11] as shown in Table 2.

Table 1

West Haven criteria and clinical description and ISHEN modifications[1]

West-Haven criteria including MHEISHENDescriptionSuggestive operative criteria
CovertAbnormal tests without clinical manifestations.
MinimalAlterations in psychometric or neuropsychological tests exploring attention, working memory, psychomotor speed, visuospatial ability and executive functions. No clinical neurological signs.
Grade IEuphoria or anxiety, shortened attention span, impairment of addition or subtraction, altered sleep rhythm and lack of awareness.Cognitive/behavioral decay with respect to his/her standard on clinical examination or to the caregivers.
OvertLethargy or apathy, disorientation for time,Disorientation for time (at least three of the following
Grade IIobvious personality changes, inappropriate behavior, dyspraxia, asterixis.are wrong: day of the month, day of the week, month and season or year) ± the other mentioned symptoms.
Grade IIISomnolence to semi-stupor but response to stimuli, confusion, gross disorientation, bizarre behavior.Disorientation also for space (at least three of the following are wrong: country, state or region, city or place) ± the other mentioned symptoms.
Grade IVComaLacking response to painful stimuli.
Table 2

Algorithm for OHE grading[11]

1. Animal Naming Test (ANT)
List all possible animals in a minute. Number of animals____________
Simplified ANT: if yrs. of instructions < 8, add 3 animals
if yrs. of instructions < 8 add and age > 80, add 6 animals
No HE: > 15 animals
Covert HE (MHE or grade I): 10–15 animals
Overt HE (grade II-IV): < 10 animals
2. Orientation in time
FALSECORRECT
What year are we?
What month are we?
Which day of the week is it?
What is today’s date?
3. Orientation in space
FALSECORRECT
Which country are we in?
Which region are we in?
Which city are we in?
Where are we now?
4. Glasgow Coma ScaleScores
Eye opening response
The patient does not open eyes1
The patient opens eyes in response to painful stimuli2
The patient opens eyes in response to voice3
The patient opens eyes spontaneously4
Verbal response
The patient makes no sounds1
The patient makes incomprehensible sounds2
The patient pronounces inappropriate words3
The conversation is confused, disoriented4
The patient is oriented and converses normally5
Motor response
The patient makes no movements1
Extension to painful stimuli (decerebrate response)2
Abnormal flexion to painful stimuli (decorticate response)3
Flexion/withdrawal to painful stimuli4
The patient localizes painful stimuli5
The patient obeys commands6
5. Overall assessment results
Staging
NO HE (grade 0)Oriented in time
Oriented in space
ANT > 15 animals
Covert HEOriented in time
Oriented in space
ANT 10–15 animals
Overt HE grade IIDisoriented in time
Oriented in space
Overt HE grade IIIDisoriented in time
Disoriented in space
GCS = 8–14
Overt HE grade IV (coma)Disoriented in time
Disoriented in space
GCS < 8

OHE still remains an exclusion diagnosis of other mental status abnormalities. Therefore, as clinically indicated, and as explained previously, exclusion of precipitants and other aetiologies by laboratory and radiological assessment is needed.[1, 11]

Diagnosis of minimal HE

MHE is the mildest form of HE and can affect up to 80% of patients with liver cirrhosis, depending on the population studied and the type of diagnostic tool used.[23]

Ideally, each patient at risk should be tested for this condition because it constitutes a significant health problem and, despite its minimum expression, it is associated with burden on caregiver, poor prognosis, increased risk of developing episodes of OHE, inability to drive, sleep disorders, falls and therefore poor quality of life.[24, 25]

The optimal measure for diagnosing MHE is still debated. In fact, none of the methods proposed cover the complexity and the heterogeneity characteristic of MHE cognitive impairment; moreover, appropriate norms are often needed and MHE is still ignored or underdiagnosed by most clinicians.[6, 7, 8]

Diagnosis of MHE can often be overlooked for several reasons:

  • MHE is difficult to diagnose with objective neurological examination, so specific neuropsychological and/or neurophysiological tests are necessary.[23]
  • Cognitive impairment involves the areas of overall performance and psychomotor activities, while verbal functioning is usually preserved.[23]
  • Some tests are time consuming, expensive and require highly specialized personnel and specific testing equipment.[23, 26]
  • Diagnostic criteria and normal distribution values corrected for age and educational level are missing.[26]
  • There is no single optimal method for assessing the presence of MHE because none of the tests proposed covers all the aspects of HE; in fact each method explores different brain functions.[6]

Diagnosis of MHE can be made with psychometric tests (computerized and non-computerized) and electrophysiological tests (Electroencephalogram [EEG], Event related potentials, [ERP]).

Electrophysiological tests suffer from methodological problems, require sophisticated equipment and analysis and have less sensitivity than psychometric tests.[27] For this reason, they could be used in patients with poor performance on screening tests.[28]

Computerized tests are generally based on repeating a large number of trials, and therefore, give more precise results than paper-pencil tests.[29]

A preferable strategy for MHE diagnosis is to screen cirrhotic patients with rapid and highly sensitive computerized psychometric tests, and then use PHES for further validation.[30]

Testing strategies for MHE, as summarized in Table 3, are:

Table 3

Summary of the most widely diagnostic tools used for MHE diagnosis

TestTested domainCopyrightDedicated (Europe-Asia/ USA)Time required for administration and interpretation (min)Comments
NCT-APsychomotor speedYesNo/No1–2Poor specificity
NCT-BPsychomotor speed, set shifting and divided attentionYesNo/No1–3Poor specificity
BDTVisuospatial reasoning, praxis and psychomotor speedYesNo/Yes10–20It can be used for dementia testing as well
DSTPsychomotor speed and attentionYesNo/Yes4Tends to be very sensitive and is an early indicator
LTTPsychomotor speed and visuomotor abilityYesNo/Yes2–4Outcomes are errors and time; tests balance between speed and accuracy
SDTPsychomotor speedYesNo/es1–2Only tests psychomotor speed but has a higher sensitivity than DST
PHESPsychomotor speed, set shifting, attention, visual perception, visuospatial orientation and visuomotor abilityYesNo/Not for all tests15Inexpensive, easy to administer, good external validity, prognostic value (predictive of survival and OHE development); performance influenced by age and educational level
R-BANSVerbal/visual/working memory; visuospatial, language and psychomotor speedYesNo/Yes25–35Primarily studied in dementia and brain injury. Limited HE experience
ANTSemantic fluency test and verbal retrieval and recallNoNo1Simple to administer; good sensitivity for screening of MHE; prognostic value (predictive of survival and OHE development); easy tool for caregivers for identify mental status alterations; useful for illiterate patients
ICTResponse inhibition, working memory, vigilance and attentionYesNo/No15–20Need highly functional patients and familiarity with computers
SCAN testWorking memory, vigilance and attentionYesNo/No15–20Prognostic value (predictive of mortality)
CRTMotor reaction speed, sustained attention and inhibitory controlNANA10Not affected by age and educational level; no learning effect; simple software are required
Stroop TestPsychomotor speed, cognitive flexibility, executive control and functioning of anterior attention systemNoNA5Simple to explain, administer and interpret; good sensitivity for screening of MHE; highly accessible by web (available in app-form); influenced by age, educational level and training
CFFMeasure of visual temporal resolutionNANA10Simple to administer and interpret; prognostic value (predictive of survival and OHE development); partially influenced by training, setting and etiology; requires specialized equipment
EEGGeneralized brain activityNoYes/Yes10–15Can be performed in comatose patients; alterations not specific for HE
VEPsInterval between visual stimulus and activityNoYes/YesMay varyHighly variable and poor overall results
BAEPsResponse in brain cortex after auditory click stimuliNoYes/YesMay varyInconsistent response with HE testing/prognostication
P300 Cognitive evoked potentialsAn infrequent stimulus embedded in irrelevant stimuli is studiedNoYes/YesDifferent rangesCorrelates with severity of hepatic encephalopathy (high latency and low amplitude of P300 waves)

ANT: animal naming test; BAEPs: brainstem auditory evoked potentials; BDT: block design test; CFF: critical flicker frequency; CRT: continuous reaction time; DST: digit symbol test; EEG: electroencephalogram; ICT: inhibitory control test; LTT: line tracing test; NCT-A: number connection test A; NCT-B: number connection test B; PHES: psychometric hepatic encephalopathy score; SDT: serial dotting test; VEPs: visual evoked potentials.

  • PHES (psychometric hepatic encephalopathy score): It consists of a battery of paper-pencil psychometric tests developed specifically for MHE and validated in this population group.[23] The subtests are: NCT-A (number connection test A), NCT-B (number connection test B), SDT (serial dotting test), LTT (line tracing test), DST (digit symbol test). It lasts for about 15 minutes. PHES score is calculated as the sum of all the subtests’ score, corrected for age and educational level.[6] A final score < -4 points is suggestive for MHE.[26]
  • This test evaluates psychomotor speed, set shifting, attention, visual perception, visuospatial orientation, visuomotor ability, concentration and memory.[23]
  • PHES is recommended as the gold standard for MHE diagnosis because it covers the spectrum of cognitive alterations involved in HE, it is inexpensive[26] and simple to administer;[6] moreover, it has good external validity and has prognostic value since it can predict OHE development and survival.[23]
  • However, it is not sensitive to early neurological changes in a cirrhotic patient, results are influenced by age and educational level and some subtests have learning effect.[30]
  • CFF (critical flicker frequency): Light pulses are presented in decreasing frequency (from 60 Hz downwards) and patient has to press a button as soon as the impression of fused light switch to oscillating light. After a training phase, the test is repeated 8 times and the mean value of this run is calculated as CFF, which is a measure of visual temporal resolution. The cut-off value is 38–39 Hz and it takes about 10 minutes.[31]

This test is based on the hypothesis that retinal gliopathy, a consequence of astrocyte swelling, is a marker of brain gliopathy in patients with HE; so the flicker fusion frequency analysis reflects not only the efficiency of visual apparatus, but also the functional efficiency of cerebral cortex.[27]

It is simple to administer and interpret and is highly reproducible. It is not influenced by age and educational level,[27] language, verbal fluency and numbering and is not subject to learning effect.[29] It can predict mortality and OHE development[29] and it correlates with severity of neurological deficit in cirrhotic patients. In fact, the CFF value decreases in parallel with mental and psychomotor impairment, and therefore, this test can be useful for the quantification of MHE and its evolution over time.[6]

CFF is partially influenced by training,[23] setting (color and brightness of the stimuli, distance and angle between light source and subject) and etiology of cirrhosis, since patients with alcoholic disease have lower CFF values.[32] Finally, this test requires intact binocular vision, absence of color blindness and specialized equipment.[6]

  • CRT (continuous reaction time test): The subject has to press a button in response to one-hundred 500 Hz tones presented at 90 dB in random intervals of 2 to 6 seconds via headphones.[31] CRT-Index is the variation coefficient of the reaction times during test; a high index denotes a low variability (normal) while a low index denotes a loss of stability (abnormal). CRT-index < 1,9 discriminates with good sensitivity and specificity between organic damage and HE, and this value is used as the cut-off.[33]
  • This test evaluates the ability to react adequately and for a long time period, so it assesses sustained attention and attention stability.
  • Compared to the patients with organic brain damage, those with HE have slower reaction times and increasing intrapersonal variability of reaction times. This increase in variability seems to occur before the appearance of clinical signs of worsening HE; so this test may be able to recognize MHE from loss of stability of reaction times.[33] Moreover, this test is not influenced by age; there is no learning/tiring effect and requires simple software for testing.[4]
  • However, it is susceptible to confounding factors such as external distractions, use of psychoactive drugs and sleep disturbances.[33]
  • ICT (inhibitory control test): Several letters are presented at 500 msec intervals, with X and Y interspersed within these letters. During the initial part of the training run, the subject has to respond to every X and Y; in the latter part of this, he has to respond only when X and Y are alterning (called targets) and to inhibit from responding when X and Y are non alterning (called lures). After the training run, 6 tests run are administered;[34] each test lasts approximately 2 minutes, so it takes about 14 minutes overall.[32] At the end of the test, lure and target response rate and lure and target reaction time are automatically calculated. A good psychomotor response in characterized by lower lure response, higher target response and shorter target and lure reaction time.[30]
  • This test evaluates working memory, vigilance, attention and inhibition, which are cognitive domains affected in patient with MHE.[34]
  • Errors of inhibition, identified by a higher number of lures response, can be responsible for serious wrong decisions in daily life (such as during driving); patients with MHE tend to respond to a higher number of lures than healthy subject or cirrhotic patients without MHE.
  • Errors of omission/attention are characterized by a lower target detection rate; errors of omission and longer lure and target reaction times, are associated with impairment of processing speed and visuomotor functions.[34]
  • The ICT has good external validity, has prognostic value because it can predict the development of OHE, it is simple to administer, has high sensitivity/specificity and appreciable test-retest reliability.[35] Results are influenced by therapy, TIPS implantation and educational level, but not by age and alcoholic etiology.[30, 34] However, performing this test requires highly functional patients and familiarity with computers.[6] Further studies are needed to determine its ability to predict survival.[30]
  • Stroop test: This test includes two components, ON and OFF state, based on concordance or discordance of the stimuli. In the OFF state, the subject sees a neutral stimulus and has to respond as soon as possible by touching the matching color of the stimulus to the color displayed at the bottom of the screen; if the subject makes a mistake, he has to start over and continue until five complete correct runs. In the ON phase, the subject sees discordant stimuli and has to touch the color of the word presented, which is the name of the color in discordant coloring. The patient has to continue until five complete correct runs. At the end of the test, the time and number of runs necessary to complete the five correct runs in both phases are automatically measured.
  • The Stroop test evaluates the anterior attention system, which modulates inhibitory responses (ON state) and executive control, psychomotor speed and cognitive flexibility (OFF state).[28]
  • This test is simple to explain, administer and interpret; it has good sensitivity for the screening of MHE and can predict OHE development.[30] However, it requires familiarity with smartphone and results are influenced by age, educational level and training; in fact, patients without previous episodes of OHE, improve in ON phase with repetition (but not in the OFF state).[28]
  • SCAN test: This test is performed by randomly displaying a series of 72 sorted pairs of numbers for 3 seconds on a computer screen. Patient has to press the appropriate number on a keyboard if he identifies a common digit in the sequence of numbers presented. At the end of the test, the mean reaction time and the percentage of errors are recorded, and results are evaluated using the reaction times weighted by the number of errors. This test takes about 15–20 minutes.
  • It evaluates working memory, vigilance and attention, and has prognostic value, because it can predict mortality at one year of follow-up.[30]
  • ANT (animal naming test): This test consists of listing as many animals as possible in a minute. Depending on the number of animals listed, two threshold values have been proposed; in this way, it is possible to identify three scores: 0 if ANT >= 15, 1 if ANT is between 10 and 15, and 2 if ANT < 10.
  • Adequate performance on the ANT requires adequate executive functions and memory, because patient has to keep track of responses already given.[36]
  • The ANT explores functions of pre-frontal and anterior cortex that influenced semantic fluency and verbal and retrieval recall[6] that are affected in the early stages of HE. Therefore, it can be a useful first-line test for diagnosis of MHE.
  • This test is simple to administer and well accepted; it has good sensitivity for screening of MHE and prognostic value since it can predict the risk of OHE development and mortality at one year of follow-up. Results are marginally influenced by age and educational level (< 8 years of education and > 80 years of age) but not by sex. Learning effect is minimal.[36]
  • RBANS (repeatable battery for the assessment of neuropsychological status): This test explores verbal, visual and working memory, visuospatial functions, language and psychomotor speed. It lasts about 25 minutes.[25]
  • In the United States, it has been used extensively for screening of various cognitive disorders such as stroke, Alzheimer, dementia and schizophrenia. So, its diagnostic value in MHE requires further validation.[32]
  • EEG (electroencephalogram): It is used to identify the changes in cortical activity even in uncooperative patients.[6]
  • In patients with OHE, EEG shows a progressive slowing of general activity, an initial increase and then decrease of the wave’s amplitude and the presence of three-phase waves, which however are not specific for HE (these are found in other types of metabolic encephalopathy or in drug intoxication). Delta waves appear in comatose patients.
  • In patients with MHE, the quantitative EEG (q-EEG) analysis shows an increase in the relative power of the theta band and a decrease in the MDF (mean dominant frequency) in the posterior derivations. These changes correlate with indices of hepatic dysfunction and predict OHE development and liver-related death.[37]
  • EEG study during sleep may be helpful in cirrhotic patients because changes in MDF during sleep represent an early marker of brain dysfunction in a subject with MHE. In this situation, q-EEG shows alterations in slow oscillatory activity, with an increase in frequency of dominant delta-rhythm.[23]
  • Evoked potentials: They are electrical signals generated through adequate stimulation of excitable tissues using light (visual evoked potentials, [VEPs]), acoustic signals (brainstem auditory evoked potentials [AEPs]) or electrical stimulation of somatosensory nerves.[38]
  • Generation of BAEPs is achieved by applying fast sequences of monaural acoustic stimuli (between 1000 and 2000 clicks). Activation of the acoustic nerve is followed by stimulation of several parts of the brainstem. In healthy subjects, seven positive and negative waves can be recorded. Patients with HE stages 0-I, have no significant prolongations of BAEP-peaks I-V or of the interpeak latency I-V. So, BAEPs present an inconsistent response with HE tests.[38]
  • VEPs assess the interval between visual stimulus and brain activity, but the results are variable. This variability may depend on the use of a later component (N3) for the assessment of subclinical HE instead of the P100-component commonly used in routine neurological examinations; moreover, clinical definition of subclinical HE varies between different studies, so comparison between these results is very difficult. Therefore, use of VEPs in patients with MHE appears to be of little diagnostic value.[39]
  • P300 wave is an endogenous visual component that is elicited in the decision-making process (ERP). Patients with MHE have high latency and low amplitude waves. This has been linked to the severity of the HE.[23]

Treatment of hepatic encephalopathy

General recommendations for the treatment of episodic OHE type C include the following:

  • Prompt start of care of hospitalized patients with altered mental status.
  • Identify and eventually treat alternative and co-existing causes.
  • Identify and correct precipitating factors.
  • Consider starting empirical ammonia-lowering treatment.

Moreover, subjects with high HE degree (III and IV)[22] are at risk or unable to protect their airways and should ideally be managed in an intensive care setting.

Common empirical pharmacological approaches are non-absorbable antibiotics (Rifaximin) and non-absorbable disaccharides (Lactulose or Lactitol per os and per enemas). Other agents (branched-chain amino acids-BCAAs, probiotics, other antibiotics or intravenous L-ornithine L-aspartate-LOLA) are available, but evidences supporting their efficacy remain lacking.[1, 11] Recent studies have demonstrated that albumin infusion might improve the severity of OHE and might be associated with reduced in-hospital mortality in cirrhotic patients with or without OHE.[14]

Precipitant induced HE benefits from both prompt recognition and elimination of precipitating agents and specific HE therapies. Unfortunately, in majority of cases, it is difficult to understand which of the different approaches has had the decisive role.

Primary prophylaxis of OHE is not generally recommended, except in the case of upper gastrointestinal bleeding adopting therapies able to remove blood from the gastrointestinal tract.[41, 42] Rifaximin has been shown to be as effective as lactulose in preventing OHE after upper gastrointestinal bleeding.[43]

Secondary prophylaxis should initiate using non-absorbable disaccharides,[1,11,44,45,46] but overuse of lactulose should be avoided since it can cause complications (dehydration), which can newly precipitate bouts of HE. In case of recurrent OHE, the addition of Rifaximin, a non-absorbable antibiotic, has been demonstrated useful and safe in maintaining remission.[47] To date, there is no evidence about the role of pharmacological prophylaxis of HE after TIPS;[48] the use of shunt with different diameter may be considered,[49, 50] but it deserves further studies for validation.

In case of Recurrent HE not associated with TIPS or SPSSs, a therapeutic option may be fecal microbiota transplantation (FMT).[51] Recurrent HE in TIPS carriers may benefit of shunt revision if a causal relationship between shunt and HE is supposed (i.e., if HE occurs in a short period after TIPS or when the procedure leads to a significant reduction of portal-systemic gradient). This decision requires caution due to a possible recurrence of complications of portal hypertension (ascites or varices) after shunt reduction.[21]

Recurrent or persistent HE is also more frequent in patients bearing splenorenal shunt. Therefore, CT scan for SPSSs detection in patients with advanced liver disease is recommended in order to prevent, treat or identify the causes of recurrent HE. Recently, new radiological techniques such as plug assisted retrograde transvenous obliteration (PARTO) or coil assisted retrograde transvenous obliteration (CARTO) have been proposed to manage recurrent or persistent HE.[51, 53]

Treatment of MHE

Despite a subclinical nature, MHE and CHE seriously impair daily life because of poor quality of life, impairment of cognitive function or of driving skills and work performance. Therefore, the indication to treat patients may be strong. A series of various treatments have been proposed, that is, non-absorbable disaccharides, low absorbable antibiotics, probiotics, but no convincing evidences on the effective role of those therapies on MHE have emerged.[1,6,7,11] In fact, because of various concerns on available data and on the design of RCTs on MHE treatment,[54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66] recently published guidelines state that the treatment of MHE and CHE is not routinely recommended apart from on a case-by-case basis.[1, 11]

Conflict of Interest

Conflict of Interests: None declared.

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  • 9

    Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999; 30: 890–5.

    • Crossref
    • PubMed
    • Export Citation
  • 10

    Hartmann IJ, Groeneweg M, Quero JC, Beijeman SJ, de Man RA, Hop WC, et al. The prognostic significance of subclinical hepatic encephalopathy. Am J Gastroenterol 2000; 95: 2029–34.

    • Crossref
    • PubMed
    • Export Citation
  • 11

    Montagnese S, Russo FP, Amodio P, Burra P, Gasbarrini A, Loguercio C, et al. Hepatic encephalopathy 2018: A clinical practice guideline by the Italian Association for the Study of the Liver (AISF). Dig Liver Dis 2019; 51: 190–205.

    • Crossref
    • Export Citation
  • 12

    Pantham G, Mullen KD. Practical issues in the management of overt hepatic encephalopathy. Gastroenterol Hepatol (N Y) 2017; 13: 659–65.

    • PubMed
    • Export Citation
  • 13

    Bai Z, Guo X, Tacke F, Li Y,Li H, Qi X. Association of serum albumin level with incidence and mortality of overt hepatic encephalopathy in cirrhosis during hospitalization. Therap Adv Gastroenterol 2019; 12: 1756284819881302.

    • PubMed
    • Export Citation
  • 14

    Bai Z, Bernardi M, Yoshida EM, Li H, Guo X, Méndez-Sánchez N, et al. Albumin infusion may decrease the incidence and severity of overt hepatic encephalopathy in liver cirrhosis. Aging (Albany NY) 2019; 11: 8502–25.

    • PubMed
    • Export Citation
  • 15

    Paolo Caraceni P, Oliviero Riggio O, Angeli P, Alessandria C, Neri S, Foschi FG, et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. Lancet 2018; 391: 2417–29.

    • Crossref
    • PubMed
    • Export Citation
  • 16

    Nardelli S, Ridola L, Gioia S, Riggio O. Management of Hepatic Encephalopathy Not Responsive to First-Line Treatments. Curr Treat Options Gastroenterol 2018; 16: 253–9.

    • Crossref
    • PubMed
    • Export Citation
  • 17

    Ohnishi K, Sato S, Saito M, Terabayashi H, Nakayama T, Saito M, et al. Clinical and hemodynamic features in cirrhotic patients having a large spontaneous splenorenal and/or gastrorenal shunt. Am J Gastroenterol 1986; 81: 450–5.

    • PubMed
    • Export Citation
  • 18

    Lam KC, Juttner HU, Reynold TB. Spontaneous portosystemic shunt: relationship to spontaneous encephalopathy and gastrointestinal hemorrhage. Dig Dis Sci 1981; 26: 346–52.

    • Crossref
    • PubMed
    • Export Citation
  • 19

    Nardelli S, Gioia S, Ridola L, Riggio O. Radiological Intervention for Shunt Related Encephalopathy. J Clin Exp Hepatol 2018; 8: 452–9.

    • Crossref
    • PubMed
    • Export Citation
  • 20

    Bureau C, Garcia-Pagan JC, Otal P, Pomier-Layrargues G, Chabbert V, Cortez C, et al. Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized study. Gastroenterology 2004; 126:469–75.

    • Crossref
    • PubMed
    • Export Citation
  • 21

    Riggio O, Nardelli S, Moscucci F, Pasquale C, Ridola L, Merli M. Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. Clin Liver Dis 2012; 16: 133–46.

    • Crossref
    • PubMed
    • Export Citation
  • 22

    Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A Double blind controlled trial. Gastroenterology 1977; 72: 573–83.

  • 23

    Nardone R, Taylor AC, Höller Y, Brigo F, Lochner P, Trinka E. Minimal hepatic encephalopathy: A review. Neurosci Res 2016; 111: 1–12.

    • Crossref
    • PubMed
    • Export Citation
  • 24

    Wein C, Koch H, Popp B, Oehler G, Schauder P. Minimal hepatic encephalopathy impairs fitness to drive. Hepatology 2004; 39:739–745.

    • Crossref
    • PubMed
    • Export Citation
  • 25

    Bajaj JS, Saeian K, Schubert CM, Hafeezullah M, Franco J, Varma RR, et al. Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test. Hepatology 2009; 50: 1175–83.

    • Crossref
    • PubMed
    • Export Citation
  • 26

    Romero-Gómez M, Córdoba J, Jover R, Del Olmo JA, Ramírez M, Rey R, et al. Value of the critical flicker frequency in patients with minimal hepatic encephalopathy. Hepatology 2007; 45: 879–85.

    • Crossref
    • PubMed
    • Export Citation
  • 27

    Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Häussinger D. Critical flicker frequency for quantification of low grade hepatic encephalopathy. Hepatology 2002; 35: 357–66.

    • Crossref
    • PubMed
    • Export Citation
  • 28

    Bajaj JS, Thacker LR, Heuman DM, Fuchs M, Sterling RK, Sanyal AJ, et al. The Stroop smartphone application is a short and valid method to screen for minimal hepatic encephalopathy. Hepatology 2013; 58: 1122–32.

    • Crossref
    • Export Citation
  • 29

    Amodio P, Ridola L, Schiff S, Montagnese S, Pasquale C, Nardelli S, et al. Improving the inhibitory control task to detect minimal hepatic encephalopathy. Gastroenterology 2010; 139: 510–8, 518.e1–e2.

    • Crossref
    • PubMed
    • Export Citation
  • 30

    Luo M, Ma P, Li L, Cao WK. Advances in psychometric tests for screening minimal hepatic encephalopathy: From paper-and-pencil to computer-aided assessment. Turk J Gastroenterol 2019; 30: 398-407.

    • Crossref
    • PubMed
    • Export Citation
  • 31

    Sharma P, Sharma BC, Puri V, Sarin SK. Critical flicker frequency: diagnostic tool for minimal hepatic encephalopathy. J Hepatol 2007; 47: 67–73.

    • Crossref
    • PubMed
    • Export Citation
  • 32

    Weissenborn K. Psychometric tests for diagnosing minimal hepatic encephalopathy. Metab Brain Dis 2013; 28: 227–9.

    • Crossref
    • PubMed
    • Export Citation
  • 33

    Lauridsen MM, Thiele M, Kimer N, Vilstrup H. The continuous reaction times method for diagnosing, grading, and monitoring minimal/covert hepatic encephalopathy. Metab Brain Dis 2013; 28: 231–4.

    • Crossref
    • PubMed
    • Export Citation
  • 34

    Bajaj JS, Hafeezullah M, Franco J, Varma RR, Hoffmann RJ, Knox JF et al. Inhibitory control test for the diagnosis of minimal hepatic encephalopathy. Gastroenterology 2008; 135: 1591–600.

    • Crossref
    • Export Citation
  • 35

    Bajaj JS, Saeian K, Verber MD, Hischke D, Hoffmann RG, Franco J, et al. Inhibitory control test is a simple method to diagnose minimal hepatic encephalopathy and predict development of overt hepatic encephalopathy. Am J Gastroenterol 2007; 102:754–60.

    • Crossref
    • PubMed
    • Export Citation
  • 36

    Campagna F, Montagnese S, Ridola L, Senzolo M, Schiff S, De Rui M, et al. The animal naming test: an easy tool for the assessment of hepatic encephalopathy. Hepatology 2017; 66: 198–208.

    • Crossref
    • PubMed
    • Export Citation
  • 37

    Guerit JM, Amantini A, Fischer C, Kaplan PW, Mecarelli O, Schnitzler A, et al. members of the ISHEN commission on Neurophysiological Investigations. Neurophysiological investigations of hepatic encephalopathy: ISHEN practice guidelines. Liver Int 2009; 29: 789–96.

  • 38

    Kullmann F, Hollerbach S, Holstege A, Schölmerich J. Subclinical hepatic encephalopathy: the diagnostic value of evoked potentials. J Hepatol 1995; 22: 101–10.

    • Crossref
    • PubMed
    • Export Citation
  • 39

    Saxena N, Bhatia M, Joshi YK, Garg PK, Dwivedi SN, Tandon RK. Electrophysiological and neuropsychological tests for the diagnosis of subclinical hepatic encephalopathy and prediction of overt encephalopathy. Liver 2002; 22: 190–7.

    • Crossref
    • Export Citation
  • 40

    Sharma P, Agrawal A, Sharma BC, Sarin SK. Prophylaxis of hepatic encephalopathy in acute variceal bleed: a randomized controlled trial of lactulose versus no lactulose. J Gastroenterol Hepatol 2011; 26: 996–1003.

    • Crossref
    • PubMed
    • Export Citation
  • 41

    Tromm A, Griga T, Greving I, Hilden H, Huppe D, Schwegler U, et al. Orthograde whole gut irrigation with mannite versus paromomycine + lactulose as prophylaxis of hepatic encephalopathy in patients with cirrhosis and upper gastrointestinal bleeding: results of a controlled randomized trial. Hepatogastroenterology 2000; 47: 473–7.

    • PubMed
    • Export Citation
  • 42

    Sharma P, Sharma BC, Agrawal A, Sarin SK. Primary prophylaxis of overt hepatic encephalopathy in patients with cirrhosis: an open labeled randomized controlled trial of lactulose versus no lactulose. J Gastroenterol Hepatol 2012; 27: 1329–35.

    • Crossref
    • PubMed
    • Export Citation
  • 43

    Maharshi S, Sharma BC, Srivastava S, Jindal A. Randomised controlled trial of lactulose versus rifaximin for prophylaxis of hepatic encephalopathy in patients with acute variceal bleed. Gut 2015; 64: 1341–2.

    • Crossref
    • PubMed
    • Export Citation
  • 44

    Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo. Gastroenterology 2009; 137: 885–91.

    • Crossref
    • PubMed
    • Export Citation
  • 45

    Les I, Doval E, García-Martínez R, Planas M, Cárdenas G, Gómez P, et al. Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study. Am J Gastroenterol 2011; 106: 1081–8.

    • Crossref
    • Export Citation
  • 46

    Varakanahalli S, Sharma BC, Srivastava S, Sachdeva S, Dahale AS. Secondary prophylaxis of hepatic encephalopathy in cirrhosis of liver: a double-blind randomized controlled trial of L-ornithine L-aspartate versus placebo. Eur J Gastroenterol Hepatol 2018; 30: 951–8.

    • Crossref
    • PubMed
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  • 47

    Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362: 1071–81.

    • Crossref
    • PubMed
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  • 48

    Riggio O, Masini A, Efrati C, Nicolao F, Angeloni S, Salvatori FM, et al. Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled study. J Hepatol 2005; 42: 674–9.

    • Crossref
    • PubMed
    • Export Citation
  • 49

    Riggio O, Ridola L, Angeloni S, Cerini F, Pasquale C, Attili AF, et al. Clinical efficacy of transjugular intrahepatic portosystemic shunt created with covered stents with different diameters: results of a randomized controlled trial. J Hepatol 2010; 53: 267–72.

    • Crossref
    • PubMed
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  • 50

    Schepis F, Vizzutti F, Garcia-Tsao G, Marzocchi G, Rega L, De Maria N, et al. Under-dilated TIPS Associate With Efficacy and Reduced Encephalopathy in a Prospective, Non-randomized Study of Patients With Cirrhosis. Clin Gastroenterol Hepatol 2018; 16: 1153–62.

    • Crossref
    • Export Citation
  • 51

    Bajaj JS, Kassam Z, Fagan A, Gavis EA, Liu E, Cox IJ, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial. Hepatology 2017; 66: 1727–38.

    • Crossref
    • PubMed
    • Export Citation
  • 52

    Nardelli S, Gioia S, Ridola L, Riggio O. Radiological Intervention for Shunt Related Encephalopathy. J Clin Exp Hepatol 2018; 8: 452–9.

    • Crossref
    • PubMed
    • Export Citation
  • 53

    Nardelli S, Riggio O, Gioia S, Puzzono M, Pelle G, Ridola L. Spontaneous porto-systemic shunts in liver cirrhosis: Clinical and therapeutical aspects. World J Gastroenterol 2020; 26: 1726–32.

    • Crossref
    • PubMed
    • Export Citation
  • 54

    Watanabe A , Sakai T, Sato S, Imai F, Ohto M, Arakawa Y, et al. Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy. Hepatology 1997; 26: 1410–4.

    • Crossref
    • PubMed
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  • 55

    Horsmans Y, Solbreux PM, Daenens C, Desager JP, Geubel AP. Lactulose improves psychometric testing in cirrhotic patients with subclinical encephalopathy. Aliment Pharmacol Ther 1997; 11: 165–70.

    • Crossref
    • PubMed
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  • 56

    Dhiman RK, Sawhney MS, Chawla YK, Das G, Ram S, Dilawari JB. Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy. Dig Dis Sci 2000; 45: 1549–52.

    • Crossref
    • PubMed
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  • 57

    Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology 2007; 45: 549–59.

    • Crossref
    • PubMed
    • Export Citation
  • 58

    Sharma P, Sharma BC, Puri V, Sarin SK. An open-label randomized controlled trial of lactulose and probiotics in the treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 2008; 20: 506–11.

    • Crossref
    • PubMed
    • Export Citation
  • 59

    Mittal VV, Sharma BC, Sharma P, Sarin SK. A randomized controlled trial comparing lactulose, probiotics, and L-ornithine L-aspartate in treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 2011; 23:725–32.

    • Crossref
    • PubMed
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  • 60

    Sidhu SS, Goyal O, Parker RA, Kishore H, Sood A. Rifaximin vs. lactulose in treatment of minimal hepatic encephalopathy. Liver Int. 2016; 36: 378–85.

  • 61

    Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS, Soni RK. Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME Trial). Am J Gastroenterol 2011; 106: 307–16.

    • Crossref
    • PubMed
    • Export Citation
  • 62

    Bajaj JS, Heuman DM, Wade JB, Gibson DP, Saeian K, Wegelin JA. Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology 2011; 140: 478–87.

    • Crossref
    • Export Citation
  • 63

    Bajaj JS, Saeian K, Christensen KM, Hafeezullah M, Varma RR, Franco J, et al. Probiotic yogurt for the treatment of minimal hepatic encephalopathy. Am J Gastroenterol 2008; 103: 1707-15.

    • Crossref
    • PubMed
    • Export Citation
  • 64

    Ridola L, Nardelli S, Gioia S, Riggio O. How to Design a Multicenter Clinical Trial in Hepatic Encephalopathy. J Clin Exp Hepatol 2019; 9: 137–45.

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    • PubMed
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  • 65

    Ridola L, Riggio O, Gioia S, Faccioli J, Nardelli S. Clinical management of type C hepatic encephalopathy. United European Gastroenterol J 2020; 8: 536–43.

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    • Export Citation
  • 66

    Dhiman RK, Thumburu KK, Verma N, Chopra M, Rathi S, Dutta U, et al. Comparative Efficacy of Treatment Options for Minimal Hepatic Encephalopathy: A Systematic Review and Network Meta-Analysis. Clin Gastroenterol Hepatol 2020; 18: 800–12.e25

    • Crossref
    • PubMed
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1

    Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology 2014; 60: 715–35.

    • Crossref
    • Export Citation
  • 2

    Bai M, Qi X, Yang Z, Yin Z, Nie Y, Yuan S, et al. Predictors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in cirrhotic patients: a systematic review. J Gastroenterol Hepatol 2011; 26: 943–51.

    • Crossref
    • PubMed
    • Export Citation
  • 3

    Riggio O, Efrati C, Catalano C, Pediconi F, Mecarelli O, Accornero N, et al. High prevalence of spontaneous portal-systemic shunts in persistent hepatic encephalopathy: a case-control study. Hepatology 2005; 42: 1158–65.

    • Crossref
    • PubMed
    • Export Citation
  • 4

    Simon-Talero M, Roccarina D, Martinez J, Lampichler K, Baiges A, Low G, et al. Association between portosystemic shunts and increased complications and mortality in patients with cirrhosis. Gastroenterology 2018; 154: 1694–705.e4.

    • Crossref
    • PubMed
    • Export Citation
  • 5

    Porcheron J, Balique JG. Physiopathology and surgical treatment of hepatic encephalopathy after porto-caval anastomosis. Ann Gastroenterol Hepatol (Paris) 1995; 31: 287–94.

    • PubMed
    • Export Citation
  • 6

    Ridola L, Cardinale V, Riggio O. The burden of minimal hepatic encephalopathy: from diagnosis to therapeutic strategies. Ann Gastroenterol 2018; 31: 151–64.

    • PubMed
    • Export Citation
  • 7

    Ridola L, Nardelli S, Gioia S, Riggio O. Quality of life in patients with minimal hepatic encephalopathy. World J Gastroenterol 2018; 24: 5446–53.

    • Crossref
    • PubMed
    • Export Citation
  • 8

    Nardelli S, Gioia S, Faccioli J, Riggio O, Ridola L. Sarcopenia and cognitive impairment in liver cirrhosis: A viewpoint on the clinical impact of minimal hepatic encephalopathy. World J Gastroenterol 2019; 25: 5257–65.

    • Crossref
    • PubMed
    • Export Citation
  • 9

    Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999; 30: 890–5.

    • Crossref
    • PubMed
    • Export Citation
  • 10

    Hartmann IJ, Groeneweg M, Quero JC, Beijeman SJ, de Man RA, Hop WC, et al. The prognostic significance of subclinical hepatic encephalopathy. Am J Gastroenterol 2000; 95: 2029–34.

    • Crossref
    • PubMed
    • Export Citation
  • 11

    Montagnese S, Russo FP, Amodio P, Burra P, Gasbarrini A, Loguercio C, et al. Hepatic encephalopathy 2018: A clinical practice guideline by the Italian Association for the Study of the Liver (AISF). Dig Liver Dis 2019; 51: 190–205.

    • Crossref
    • Export Citation
  • 12

    Pantham G, Mullen KD. Practical issues in the management of overt hepatic encephalopathy. Gastroenterol Hepatol (N Y) 2017; 13: 659–65.

    • PubMed
    • Export Citation
  • 13

    Bai Z, Guo X, Tacke F, Li Y,Li H, Qi X. Association of serum albumin level with incidence and mortality of overt hepatic encephalopathy in cirrhosis during hospitalization. Therap Adv Gastroenterol 2019; 12: 1756284819881302.

    • PubMed
    • Export Citation
  • 14

    Bai Z, Bernardi M, Yoshida EM, Li H, Guo X, Méndez-Sánchez N, et al. Albumin infusion may decrease the incidence and severity of overt hepatic encephalopathy in liver cirrhosis. Aging (Albany NY) 2019; 11: 8502–25.

    • PubMed
    • Export Citation
  • 15

    Paolo Caraceni P, Oliviero Riggio O, Angeli P, Alessandria C, Neri S, Foschi FG, et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. Lancet 2018; 391: 2417–29.

    • Crossref
    • PubMed
    • Export Citation
  • 16

    Nardelli S, Ridola L, Gioia S, Riggio O. Management of Hepatic Encephalopathy Not Responsive to First-Line Treatments. Curr Treat Options Gastroenterol 2018; 16: 253–9.

    • Crossref
    • PubMed
    • Export Citation
  • 17

    Ohnishi K, Sato S, Saito M, Terabayashi H, Nakayama T, Saito M, et al. Clinical and hemodynamic features in cirrhotic patients having a large spontaneous splenorenal and/or gastrorenal shunt. Am J Gastroenterol 1986; 81: 450–5.

    • PubMed
    • Export Citation
  • 18

    Lam KC, Juttner HU, Reynold TB. Spontaneous portosystemic shunt: relationship to spontaneous encephalopathy and gastrointestinal hemorrhage. Dig Dis Sci 1981; 26: 346–52.

    • Crossref
    • PubMed
    • Export Citation
  • 19

    Nardelli S, Gioia S, Ridola L, Riggio O. Radiological Intervention for Shunt Related Encephalopathy. J Clin Exp Hepatol 2018; 8: 452–9.

    • Crossref
    • PubMed
    • Export Citation
  • 20

    Bureau C, Garcia-Pagan JC, Otal P, Pomier-Layrargues G, Chabbert V, Cortez C, et al. Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized study. Gastroenterology 2004; 126:469–75.

    • Crossref
    • PubMed
    • Export Citation
  • 21

    Riggio O, Nardelli S, Moscucci F, Pasquale C, Ridola L, Merli M. Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. Clin Liver Dis 2012; 16: 133–46.

    • Crossref
    • PubMed
    • Export Citation
  • 22

    Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A Double blind controlled trial. Gastroenterology 1977; 72: 573–83.

  • 23

    Nardone R, Taylor AC, Höller Y, Brigo F, Lochner P, Trinka E. Minimal hepatic encephalopathy: A review. Neurosci Res 2016; 111: 1–12.

    • Crossref
    • PubMed
    • Export Citation
  • 24

    Wein C, Koch H, Popp B, Oehler G, Schauder P. Minimal hepatic encephalopathy impairs fitness to drive. Hepatology 2004; 39:739–745.

    • Crossref
    • PubMed
    • Export Citation
  • 25

    Bajaj JS, Saeian K, Schubert CM, Hafeezullah M, Franco J, Varma RR, et al. Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test. Hepatology 2009; 50: 1175–83.

    • Crossref
    • PubMed
    • Export Citation
  • 26

    Romero-Gómez M, Córdoba J, Jover R, Del Olmo JA, Ramírez M, Rey R, et al. Value of the critical flicker frequency in patients with minimal hepatic encephalopathy. Hepatology 2007; 45: 879–85.

    • Crossref
    • PubMed
    • Export Citation
  • 27

    Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Häussinger D. Critical flicker frequency for quantification of low grade hepatic encephalopathy. Hepatology 2002; 35: 357–66.

    • Crossref
    • PubMed
    • Export Citation
  • 28

    Bajaj JS, Thacker LR, Heuman DM, Fuchs M, Sterling RK, Sanyal AJ, et al. The Stroop smartphone application is a short and valid method to screen for minimal hepatic encephalopathy. Hepatology 2013; 58: 1122–32.

    • Crossref
    • Export Citation
  • 29

    Amodio P, Ridola L, Schiff S, Montagnese S, Pasquale C, Nardelli S, et al. Improving the inhibitory control task to detect minimal hepatic encephalopathy. Gastroenterology 2010; 139: 510–8, 518.e1–e2.

    • Crossref
    • PubMed
    • Export Citation
  • 30

    Luo M, Ma P, Li L, Cao WK. Advances in psychometric tests for screening minimal hepatic encephalopathy: From paper-and-pencil to computer-aided assessment. Turk J Gastroenterol 2019; 30: 398-407.

    • Crossref
    • PubMed
    • Export Citation
  • 31

    Sharma P, Sharma BC, Puri V, Sarin SK. Critical flicker frequency: diagnostic tool for minimal hepatic encephalopathy. J Hepatol 2007; 47: 67–73.

    • Crossref
    • PubMed
    • Export Citation
  • 32

    Weissenborn K. Psychometric tests for diagnosing minimal hepatic encephalopathy. Metab Brain Dis 2013; 28: 227–9.

    • Crossref
    • PubMed
    • Export Citation
  • 33

    Lauridsen MM, Thiele M, Kimer N, Vilstrup H. The continuous reaction times method for diagnosing, grading, and monitoring minimal/covert hepatic encephalopathy. Metab Brain Dis 2013; 28: 231–4.

    • Crossref
    • PubMed
    • Export Citation
  • 34

    Bajaj JS, Hafeezullah M, Franco J, Varma RR, Hoffmann RJ, Knox JF et al. Inhibitory control test for the diagnosis of minimal hepatic encephalopathy. Gastroenterology 2008; 135: 1591–600.

    • Crossref
    • Export Citation
  • 35

    Bajaj JS, Saeian K, Verber MD, Hischke D, Hoffmann RG, Franco J, et al. Inhibitory control test is a simple method to diagnose minimal hepatic encephalopathy and predict development of overt hepatic encephalopathy. Am J Gastroenterol 2007; 102:754–60.

    • Crossref
    • PubMed
    • Export Citation
  • 36

    Campagna F, Montagnese S, Ridola L, Senzolo M, Schiff S, De Rui M, et al. The animal naming test: an easy tool for the assessment of hepatic encephalopathy. Hepatology 2017; 66: 198–208.

    • Crossref
    • PubMed
    • Export Citation
  • 37

    Guerit JM, Amantini A, Fischer C, Kaplan PW, Mecarelli O, Schnitzler A, et al. members of the ISHEN commission on Neurophysiological Investigations. Neurophysiological investigations of hepatic encephalopathy: ISHEN practice guidelines. Liver Int 2009; 29: 789–96.

  • 38

    Kullmann F, Hollerbach S, Holstege A, Schölmerich J. Subclinical hepatic encephalopathy: the diagnostic value of evoked potentials. J Hepatol 1995; 22: 101–10.

    • Crossref
    • PubMed
    • Export Citation
  • 39

    Saxena N, Bhatia M, Joshi YK, Garg PK, Dwivedi SN, Tandon RK. Electrophysiological and neuropsychological tests for the diagnosis of subclinical hepatic encephalopathy and prediction of overt encephalopathy. Liver 2002; 22: 190–7.

    • Crossref
    • Export Citation
  • 40

    Sharma P, Agrawal A, Sharma BC, Sarin SK. Prophylaxis of hepatic encephalopathy in acute variceal bleed: a randomized controlled trial of lactulose versus no lactulose. J Gastroenterol Hepatol 2011; 26: 996–1003.

    • Crossref
    • PubMed
    • Export Citation
  • 41

    Tromm A, Griga T, Greving I, Hilden H, Huppe D, Schwegler U, et al. Orthograde whole gut irrigation with mannite versus paromomycine + lactulose as prophylaxis of hepatic encephalopathy in patients with cirrhosis and upper gastrointestinal bleeding: results of a controlled randomized trial. Hepatogastroenterology 2000; 47: 473–7.

    • PubMed
    • Export Citation
  • 42

    Sharma P, Sharma BC, Agrawal A, Sarin SK. Primary prophylaxis of overt hepatic encephalopathy in patients with cirrhosis: an open labeled randomized controlled trial of lactulose versus no lactulose. J Gastroenterol Hepatol 2012; 27: 1329–35.

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    Maharshi S, Sharma BC, Srivastava S, Jindal A. Randomised controlled trial of lactulose versus rifaximin for prophylaxis of hepatic encephalopathy in patients with acute variceal bleed. Gut 2015; 64: 1341–2.

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    Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo. Gastroenterology 2009; 137: 885–91.

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    Les I, Doval E, García-Martínez R, Planas M, Cárdenas G, Gómez P, et al. Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study. Am J Gastroenterol 2011; 106: 1081–8.

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    Varakanahalli S, Sharma BC, Srivastava S, Sachdeva S, Dahale AS. Secondary prophylaxis of hepatic encephalopathy in cirrhosis of liver: a double-blind randomized controlled trial of L-ornithine L-aspartate versus placebo. Eur J Gastroenterol Hepatol 2018; 30: 951–8.

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    Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362: 1071–81.

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    Riggio O, Ridola L, Angeloni S, Cerini F, Pasquale C, Attili AF, et al. Clinical efficacy of transjugular intrahepatic portosystemic shunt created with covered stents with different diameters: results of a randomized controlled trial. J Hepatol 2010; 53: 267–72.

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    Schepis F, Vizzutti F, Garcia-Tsao G, Marzocchi G, Rega L, De Maria N, et al. Under-dilated TIPS Associate With Efficacy and Reduced Encephalopathy in a Prospective, Non-randomized Study of Patients With Cirrhosis. Clin Gastroenterol Hepatol 2018; 16: 1153–62.

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    Bajaj JS, Kassam Z, Fagan A, Gavis EA, Liu E, Cox IJ, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial. Hepatology 2017; 66: 1727–38.

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    Nardelli S, Gioia S, Ridola L, Riggio O. Radiological Intervention for Shunt Related Encephalopathy. J Clin Exp Hepatol 2018; 8: 452–9.

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    Nardelli S, Riggio O, Gioia S, Puzzono M, Pelle G, Ridola L. Spontaneous porto-systemic shunts in liver cirrhosis: Clinical and therapeutical aspects. World J Gastroenterol 2020; 26: 1726–32.

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    Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology 2007; 45: 549–59.

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    Sharma P, Sharma BC, Puri V, Sarin SK. An open-label randomized controlled trial of lactulose and probiotics in the treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 2008; 20: 506–11.

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    Mittal VV, Sharma BC, Sharma P, Sarin SK. A randomized controlled trial comparing lactulose, probiotics, and L-ornithine L-aspartate in treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 2011; 23:725–32.

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    Sidhu SS, Goyal O, Parker RA, Kishore H, Sood A. Rifaximin vs. lactulose in treatment of minimal hepatic encephalopathy. Liver Int. 2016; 36: 378–85.

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    Bajaj JS, Heuman DM, Wade JB, Gibson DP, Saeian K, Wegelin JA. Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology 2011; 140: 478–87.

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    Bajaj JS, Saeian K, Christensen KM, Hafeezullah M, Varma RR, Franco J, et al. Probiotic yogurt for the treatment of minimal hepatic encephalopathy. Am J Gastroenterol 2008; 103: 1707-15.

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    Ridola L, Nardelli S, Gioia S, Riggio O. How to Design a Multicenter Clinical Trial in Hepatic Encephalopathy. J Clin Exp Hepatol 2019; 9: 137–45.

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    Ridola L, Riggio O, Gioia S, Faccioli J, Nardelli S. Clinical management of type C hepatic encephalopathy. United European Gastroenterol J 2020; 8: 536–43.

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    Dhiman RK, Thumburu KK, Verma N, Chopra M, Rathi S, Dutta U, et al. Comparative Efficacy of Treatment Options for Minimal Hepatic Encephalopathy: A Systematic Review and Network Meta-Analysis. Clin Gastroenterol Hepatol 2020; 18: 800–12.e25

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