Open access peer-reviewed chapter

Minimal Hepatic Encephalopathy: Silent Tragedy

Written By

Gamal Shiha and Nasser Mousa

Submitted: March 21st, 2019 Reviewed: June 26th, 2019 Published: September 23rd, 2019

DOI: 10.5772/intechopen.88231

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Abstract

Hepatic encephalopathy (HE) is brain dysfunction caused by both acute and chronic liver diseases that produces a spectrum of neuropsychiatric symptoms in the absence of other known brain diseases. Minimal hepatic encephalopathy (MHE) is the mildest form of this spectrum. MHE is defined as HE without symptoms on clinical or neurological examination, but with deficits in the performance of psychometric tests, working memory, psychomotor speed, and visuospatial ability. Minimal hepatic encephalopathy is associated with impaired driving skills and increased risk of motor vehicle accidents and has been associated with increased hospitalizations and death. Despite its clinical importance, a large number of clinicians had never investigated whether their cirrhotic patients might have MHE. Although, there is no single gold standard test for diagnosis of MHE, a combination of two neuropsychological tests or psychometric hepatic encephalopathy score battery test and/or neurophysiological test is standard for diagnosis of MHE. It was found that, treatment for MHE improves neuropsychiatric performance and quality of life and decreases the risk of developing overt HE (OHE). The agents used to treat OHE have been tested in patients with MHE. In particular, lactulose, rifaximin, probiotics and l-ornithine and l-aspartate (LOLA) have all been shown to be beneficial, with documented improvement in psychometric performance after treatment.

Keywords

  • liver cirrhosis
  • hepatic encephalopathy
  • minimal hepatic encephalopathy
  • ammonia
  • neuropsychological testing
  • motor vehicle accident
  • lactulose and rifaximin

1. Introduction

Hepatic encephalopathy (HE) is a serious clinical problem of portal hypertension and cirrhosis that is characterized by neurologic and neuropsychiatric abnormalities. It is manifested by personality changes, cognitive dysfunction, and altered level of consciousness [1, 2]. Based on the severity, HE is classified into two groups: overt HE (OHE) presents episodically or continuously with obvious and clinically detectable symptoms; in contrast, covert HE (CHE) combines the two lowest grades of HE (minimal HE (MHE) and HE grade 1) [3]. Therefore, under the new classification (Table 1), OHE starts with grade 2 or with evidence of asterixis and disorientation. MHE is characterized by subtle cognitive and psychomotor deficits in the absence of recognizable clinical symptoms and signs of HE and is documented by neuropsychometric (NP) tests and neurophysiological tests, but HE grade 1 is defined by the presence of mild clinical alterations like euphoria, anxiety, or a shortened attention span. Although the consequences are serious, mostly CHE is often unnoticed or even neglected in routine clinical practice due to only very mild symptoms associated with grade 1, or no diagnostics in case of MHE [4, 5].

ClassificationCovert HEOvert HE
MHEGrade IGrade IIGrade IIIGrade IV
Description* Absence of recognizable clinical symptoms and signs
* Impairments only measurable with psychometric tests (psychomotor speed/executive functions or neurophysiological alterations)
* Minor lack of awareness
* Euphoria or anxiety
* Shortened attention span
* Altered sleep rhythm
* Fatigue, apathy, or lethargy
* Slight disorientation for time and place
* Obvious personality change
* Inappropriate behavior
* Asterixis
* Somnolence to semi-stupor
* Confused
* Marked disorientation to time and place
*Aggression
* Coma
* Signs of increased intracranial pressure

Table 1.

New classification combining covert and overt HE.

Minimal hepatic encephalopathy may have a bad impact on quality of life, risk of road traffic accidents, and can progress to overt HE [6, 7]. Still, there are no current guidelines for the ascertained diagnosis of MHE. The Working Group on HE endorsed that, at least two of the following neuropsychologic tests should be used for diagnosing MHE: number connection test-A (NCT-A), NCT-B, block-design test (BDT), and the digit-symbol test (DST) [4]. The existing definition of MHE is built on psychometric test results that are two SDs more than normal on at least two psychometric tests [8]. Therapy for MHE is targeted toward the gut, due to the ammoniagenic role of the gut contents, which have been hypothesized to play a part in MHE pathogenesis. Guidelines for HE in chronic liver disease do not recommend routine treatment of MHE. However, they state that when a patient has clear cognitive impairment, or deterioration of quality of life (QoL), skills for driving, or ability to perform jobs that require manual labor or have high public risk, the patient should be treated [3, 9].

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2. Prevalence of MHE

MHE is considered as a part of wide spectrum of typical neurocognitive alterations in liver cirrhosis, mostly involving the areas of attention, alertness, response inhibition, and executive functions [10, 11]. Depending on the population studied, patient level of education, age of the patients, and the diagnostic tool used, MHE incidence varies from 20 to 80% of cirrhotic patients [12, 13, 14, 15].

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3. Physiopathology

The pathogenesis of MHE is nearly similar to that of OHE [16]. The ammonia toxicity remains the key factor, but recently there is increased evidence that, hyperammonemia acts synergistically with systemic inflammation, oxidative stress, and gut microbiota [17, 18]. Numerous investigators suggested that, hepatic encephalopathy is a disorder of astrocyte function that plays a role in the detoxification of ammonia [19].

3.1 The role of ammonia

Ammonia is a key intermediate product in the metabolism of proteins. It is manufactured by the bacterial metabolism of amino acids and purines that are consumed in the human diet [20]. Under physiological environment, about 90% of the ammonium is primarily cleared by the synthesis of urea in the liver (by the Krebs cycle) and subsequently cleared by the kidneys and to a lesser extent by the muscles (Figure 1). Ammonia is also consumed in the conversion of glutamate to glutamine, a reaction that depends upon the activity of glutamine synthetase [21]. In liver cirrhosis, there are two factors that contribute to hyperammonemia: the first is a decrease in the healthy hepatocytes, resulting in deficiency of NH3 detoxification; the second is the existence of porto-systemic shunting that results in shifting of NH3-rich portal blood to the systemic circulation without hepatic detoxification—subsequently, the extrahepatic metabolization of ammonia by the brain and skeletal muscle cells becomes more important [17, 22, 23]. The skeletal muscle plays a significant role in ammonia metabolism as it contains glutamine synthetase. However, the muscle wasting that is clear in advanced cirrhosis may increase hyperammonemia. The kidneys express glutaminase and, somewhat, play a role in ammonia production. Similarly, the kidneys express glutamine synthetase and play a key role in ammonia metabolism and excretion [20]. Ammonia crosses the blood-brain barrier and is metabolized in the astrocytes by glutamine synthetase, which converts NH3 and glutamate to glutamine [17]. Increasing glutamine in astrocytes produces an osmotic gradient (Figure 2), promotes water shift into astrocyte producing edema [23], and generation of reactive oxygen species, thereby contributing to the cerebral dysfunction seen in HE [17]. The high-energy consumption by this process leads to oxidative stress which is accompanied by cellular dysfunction and disruption of neurotransmission predominantly of glutamate and γ-aminobutyric acid [24]. In the brain, NH3 produces inactivation of neuronal chloride extrusion pumps; these processes result in inhibition of both axonal conduction and excitatory postsynaptic potentials, subsequently suppressing inhibitory postsynaptic potential formation and depolarizing neurons [25, 26].

Figure 1.

Ammonia is produced primarily in colon from breakdown of amino acids and urea by bacteria. The ammonia is taken up by hepatocytes and converted, in the urea cycle, to urea, which is passed into blood. Urea is primarily excreted in the kidneys (75%) and the intestine (around 25%).

Figure 2.

Pathogenesis of hepatic encephalopathy. In normal conditions, gut release of ammonia results in high portal vein ammonia levels. Microbiota is also responsible for the formation of ammonia, endotoxins. In liver cirrhosis, the liver extracts portal venous ammonia poorly. The subsequent increase of arterial ammonia levels leads to increased disposition of ammonia in other tissues. Both the brain and muscle lack a complete urea cycle and rely on the formation of glutamine. Thus, the brain and muscle become ammonia-uptake and glutamine-releasing organs. In the brain, astrocytes metabolize ammonia through glutamine synthetase, converting glutamate and ammonia to glutamine which is osmotically active and promotes water shift into the astrocyte, thus producing intracellular swelling and edema.

3.2 Inflammation

Studies demonstrated that, severity of MHE might not correlate with severity of liver disease or the level of ammonia, proposing the existence of other pathogenic stimuli. Inflammation is one such stimulus that may add to the advancement of MHE and its progression to overt HE [27]. The studies suggested that, inflammation plays a synergistic role with ammonia in producing and modulating MHE [27, 28, 29]. Studies in patients with cirrhosis have documented higher levels of proinflammatory cytokines like tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. This reflects the possibility of developing a systemic inflammatory response that alters the blood-brain barrier (BBB) permeability and allows diffusion of ammonia moreover [30, 31].

3.3 Microbiota

Studies suggested that, many interactions with gut microbiota can play an active role in MHE (Figure 2). Microbiota changes have been linked with impaired cognition, endotoxemia, and inflammation. With the progression of cirrhosis, there is dysbiosis (unfavorable change in the composition of the microbiome) with decreased levels of autochthonous taxa (native Firmicutes) bacteria and increased levels of other taxa (Bacteroidetes, Actinobacteria). The native bacteria are important for the harmony of the gastrointestinal flora and for the well-being of the entire body. The autochthonous bacteria produce short-chain fatty acids that feed the colonic mucosal cells and reduce local colonic inflammation, and produce anti-bacterial peptides [32]. In patients with minimal HE, stool microbiota studies demonstrated an increase in Streptococcus salivarius[33]. Zhang et al. found worse dysbiosis in all cirrhotic patients versus healthy controls and also found over-representation of two bacterial families, Streptococcaceae and Veillonellaceae, in cirrhotic patients with and without MHE as compared with controls. Moreover, patients with MHE had an overabundance of Streptococcus salivarius. This dysbiosis could increase ammonia production due to its urease activity, and its count positively correlated with ammonia levels and cognitive testing in patients with MHE [34]. The cirrhosis dysbiosis ratio (CDR) is the ratio of autochthonous to non-autochthonous taxa in cirrhosis. The lower the CDR the more the endotoxemia and more decompensated the cirrhosis [35].

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4. Natural history of MHE

The incidence of MHE increases with progression of liver disease. With time, MHE may improve or progress to OHE [36, 37]. The rate of progression to overt HE was much higher in patients with MHE and Child-Pugh score > 6 than in those with MHE and Child-Pugh score ≤ 6 [38]. Moreover, MHE in patients with large portal-systemic shunts had a better outcome due to preserved hepatocytes [39]. Real probability of OHE at 3 years was 56% in patients of liver cirrhosis in the presence of MHE and 8% for those without MHE [37]. In addition, existence of MHE in cirrhosis associated with shorter survival time and increased mortality rate compared to those without MHE [40, 41, 42, 43].

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5. Clinical significance

MHE has a significant impact on daily activities. It decreases patients’ quality of life (QoL) [43, 44] and driving impairment due to the attention and visuomotor coordination deficits [45, 46, 47]. The Sickness Impact Profile was studied in a group of patients with cirrhosis to evaluate QoL indicators such as sleep, rest, eating, work, home management, recreation, ambulation, daily care, movement, and emotional behavior. All scales were significantly decreased in patients with MHE compared with individuals without MHE [48]. Moreover, those patients suffer from falls [49] and have a high risk of development of episodic HE [2].

5.1 Health-related quality of life (HRQoL)

Quality of life is a multidimensional index that reports all aspects of human well-being, including physical and cognitive capabilities, functional behavior, emotional status, and psychosocial adjustment [50]. The American Association for the Study of Liver Diseases survey conducted in 2007 demonstrated that, most clinicians believe MHE to be a significant problem. However, only 50% of clinicians had examined whether their patients might have MHE, and 38% had never studied their patients with liver cirrhosis [51]. Several evidences show that, HRQoL may seem to be influenced by the coexistence of MHE [48, 52, 53, 54, 55, 56]. MHE increases the incidence of disability, and has a negative effect on daily activities. The impact of the perception of the disease, in the form of a “Sickness Impact Profile,” has been studied in cirrhotic patients to assess the indicators of QoL. Each profile was significantly reduced in patients with MHE compared to individuals without MHE [48]. In addition, in the presence of MHE, QoL indicators, such as the capacity to drive a car, and the incidence of sleep disorders were also negatively affected [57, 58].

5.2 MHE and falls

Minimal hepatic encephalopathy is significantly associated with high risk of falls explaining the increased healthcare and hospitalization rate in patients with MHE compared to cirrhotic patients without MHE [49, 59, 60]. The presence of cognitive impairment was the only independent factor predictive of a fall. The chance of a fall in 1 year was found to be significantly higher in patients with MHE compared to those without MHE. Urios et al. demonstrated that, MHE patients show impaired balance, mainly on an unstable surface with eyes open, with longer reaction and confinement times and lower success in stability test limits compared to patients without MHE [61].

5.3 Effect of MHE on driving

Traffic accidents are more common in patients with MHE compared to normal individuals, as the driving process in patients with MHE is affected by defects in many factors such as, defects in attention and information processing, slow reactions, improper estimation of traffic conditions, and lack of coordination [48, 62]. As many as 33% of MHE patients reported a traffic accident or violation within the past year [63]. Interestingly, treatment with lactulose could substantially reduce societal costs by preventing motor vehicle accidents [64].

5.4 Risk of overt HE

MHE has been found to predict the development of overt HE in cirrhotic patients [2]. A recent study demonstrated that, CHE and elevated blood NH3 levels contributed to OHE development in cirrhotic patients [65]. The results of Wang et al. showed that, solely serum albumin level < 30 g/L is the predictor for developing OHE in CHE patients [66]. In a study of Thomsen et al., that enrolled 106 clinically stable cirrhotic patients with no previous history of OHE and followed them for 230 ± 95 d, it was found that, 13.3% of CHE patients developed OHE [67]. In a multicenter study by Patidar et al., a total of 170 cirrhotic patients were followed for a mean of 13 months. They found that 30% of cirrhotic patients developed at least one OHE episode, and that CHE increased their risk of developing OHE, hospitalization, and death/transplant [36].

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6. Diagnosis of MHE and CHE

There is no single optimal measure for diagnosis of MHE because none of the diagnostic strategies covers all aspects of deficits that are present in MHE [68, 69]. Testing approaches can be divided into two major types: psychometric and neurophysiological [70, 71]. As MHE affects many elements of cognitive functioning, which may not be impaired to identical degrees, the International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) recommends the use of at least two tests, based on the local population norms and availability, and if possible, with one of the tests being more widely accepted to serve as a comparator [72].

6.1 Diseases associated with minimal hepatic encephalopathy

The diagnosis requires the indication of tests in subjects who appear normal, but may suffer from cirrhosis, as the physician usually does not observe MHE [73]. Further group of patients who are not cirrhotic and may develop MHE are those with porto-systemic shunts of inborn origin or secondary to portal thrombosis. The available data of the neuropsychological characteristics of these patients indicate that cognitive abnormalities are indistinguishable from MHE [74].

6.2 Indications for testing

There is no consensus on patients to test for MHE. Some physicians recommend screening of all cirrhotic patients. However, testing should be completed in patients at risk (Table 2) for MHE such as, cirrhosis or porto-systemic shunts [5]. Special attention should be given to active drivers, patients handling heavy machines or reporting decline in work performance [75, 76].

Patients at risk of accidents
  • Risks at work, e.g., machine worker

  • Driving accident within the past year

  • Unprovoked falls

Patients who complain of cognitive symptoms
  • Psychomotor performance: “I have difficulty in carrying out fine motor tasks.”

  • Decreased attention: “I am frequent feelig of confused.”

  • Poor memory: “I forget a lot”.

Patients with decline in work performance observed by relatives or colleagues
Patients with previous history of episodic HE

Table 2.

Patients with cirrhosis, portal vein thrombosis, or porto-systemic shunts who should undergo tests for MHE.

6.3 Neuropsychological (paper-and-pencil) tests

The American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver recommended neurophysiological and psychometric tests to diagnose MHE [3, 51]. Many tests are used for diagnosis of MHE (Table 3); however, the gold standard and the most frequently used psychometric test for MHE diagnosis is psychometric hepatic encephalopathy score (PHES) [3, 4, 42].

TestTested domainTime required (minuets)AdvantagesDisadvantagesImpact factor
NCT-APsychomotor speed1–2Gold standard for MHE diagnosis validated internationallyLearning effectsAge and culture
NCT-BPsychomotor speed, set shifting, divided attention1–3Validated internationallyLearning effectsAge and culture
DSTPsychomotor speed, attention4Very sensitive and is an early indicatorLearning effectsAge and culture
BDTVisuospatial reasoning, praxis, psychomotor speed10–20It can be used for dementia testing as wellLearning effectsAge and culture
SDTPsychomotor speed1–2Only tests psychomotor speed, a higher sensitivityLearning effects; only tests psychomotor speedAge and culture
LTTPsychomotor speed, visuomotor ability2–4Tests a balance between speed and accuracyLearning effects,
outcomes are errors and time
Age and culture
Animal-naming testSemantic fluency test, verbal retrieval and recall1Easy test that has the required characteristics of simplicity, speed, for illiterate patientsLess validated test
CFFVisual discrimination and general arousal10Easy administration, application by a non-specialist, and results are independent of literacy and age, test can be administered at bedsideNot suitable for red-green blindness and visual impairmentAge
ICTResponse inhibition, working memory, vigilance, attention15–20Simple administration, higher sensitivity/specificityNeed highly functional patients, not suitable for non-English-speaking patientsAge and education
Stroop testPsychomotor speed and cognitive alertness10Quick to explain to patients, and simple to score and evaluateShould be familiar with iPhone/iPadAge and education
The SCAN TestWorking memory, vigilance, attention15–20Simple administrationLearning effectsAge and education
CDR assessment batteryReaction time, memory, and recognition15Appreciable test-retest reliabilityLearning effectsAge, education, and culture
EEGGeneralized brain activity10–15Can be done in comatose patients, no need of patient cooperation or risk of a learning effectNonspecific and may be influenced by accompanying metabolic disturbancesRequires neurological expertise in evaluation

Table 3.

Psychometric tests recommended for diagnosing minimal hepatic encephalopathy.

6.3.1 Standard neuropsychological assessment

Neuropsychological testing is a useful methodology for quantifying cognitive impairment. These tests directly measure cognitive functions that are directly related to activities of daily living. These include the number connection test A (NCT-A), number connection test B (NCT-B), figure connection test (FCT A), figure connection test B (FCT B), digit symbol test (DST), and serial-dotting test (SDOT) [77].

6.3.1.1 Number connection tests

The NCT-A accesses the visual-spatial orientation and psychomotor speed. Twenty-five circles numbered from 1 to 25 are scattered randomly on a sheet of paper. The patients must connect the numbers in order in the shortest time possible without mistakes. If a mistake is made, the subject must stop, correct the error, and then continue without stopping the clock. The test score is the time needed to perform the test, including the time needed to correct all errors. Poorer performance is shown by a longer time for completion (Figure 3). In the NCT-B (Figure 4), the numbers from 1 to 13 and the letters from A to L were included in circles. The patient is asked to connect numbers and letters in alternating manner, that means go from 1-A-2-B-3-C and so on. Test outcome is the time needed by the patient to perform the test, including error correction time. Besides visuospatial orientation and psychomotor speed, this test is suitable to study the ability to shift attention [78].

Figure 3.

Number connection tests-A.

Figure 4.

Number connection tests-B.

According to the guidelines of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism [79], the results of NCT-A will be considered abnormal when the test scores are more than the mean + 2 standard deviations (SDs) from the age-matched normal values. A newly developed electronic number connection test (eNCT) was developed. This test flashes the numbers 1–25 on a screen and needs the participant to click them in order while being timed [80]. These tests are time-consuming, and their results are influenced by age and educational status. However, these tests are recommended for diagnosis of MHE [42, 81].

6.3.1.2 Digit symbol test DST

Nine fixed pairs of numbers and symbols are present at the top of the test sheet. The patient is given a series of double boxes with a number given in the upper part. The target is to draw a symbol related to this number into the lower part of the boxes. The test result is the number of boxes correctly filled in 90 s (Figure 5). Pathological test results indicate a deficit in visuoconstructive abilities. [82]. DST will be considered abnormal when the test scores are less than the mean − 2 SDs from the age-matched normal values [79].

Figure 5.

Digit symbol test.

6.3.1.3 Block design test

This test recorded speed and accuracy. The task is to take 6–9 blocks that have all white sides, all red sides, and red-and-white sides followed by arranging them according to a pattern formed by examiner or shown on a card [83].

6.3.1.4 Psychometric hepatic encephalopathy score (PHES)

It consists of five paper-pencil tests: NCT-A/B, line tracing time (LTT), digit symbol test, and serial-dotting test (SDOT). This battery measures psychomotor speed and precision, visual perception, visuospatial orientation, visual construction, concentration, attention, and memory and can be completed in less than 20 minutes [68]. The results of PHES can be affected by age and education status of patients. A score is defined as the number of standard deviations of the difference between the two values for each test. MHE was diagnosed with the sum of all scores less than or equal to −4 points. Score < −4 suggests the presence of MHE [1, 84]. A simplified form of PHES, developed using only three of the original five tests, can be as good as the PHES in diagnosing [84]. For illiterate patients, the figure connection test has been used as a subtest instead of the number connection test [1]. PHES has a prognostic value for the occurrence of attacks of overt HE and mortality in cirrhotic patients [42, 43].

6.3.1.5 The animal naming test (ANT)

The ANT (maximum number of animals listed in 1 minute) has recently been developed to predict OHE. ANT is an easy test that has all the required characteristics of simplicity, speed, no cost, and relationship with clinical events to be used routinely for rapid investigation of HE in patients with cirrhosis at the office and at the bedside [85].

6.3.2 Computer-aided psychometric tests

Numerous current studies have showed that, computerization of psychometric tests could lead to simplification and easy administration in the clinic within a few minutes [10, 86, 87].

6.3.2.1 The critical flicker frequency (CFF)

CFF test is a psychophysiological tool that studies the frequency at which a fused light (presented from 60 Hz downward) appears to be flickering to the observer. Similarly, the general arousal of the patient is measured. Earlier studies have shown a reduction in its performance with worsening cognition and improvement after therapy. The CFF test needs numerous trials, intact binocular vision, absence of red-green blindness, and specialized equipment [15]. CFF predicts the first episode of OHE in cirrhotic patients who had never experienced OHE, and predicts mortality risk [88]. CFF test has many advantages, for example, easy administration, application by a non-specialist personal, and results that are independent of numeracy, literacy, and age [89].

6.3.2.2 Continuous reaction time (CRT) test

This test assesses the motor reaction time by having the patient press a button in response to auditory stimuli (through headphones). The most important test result is the CRT index, which measures the stability of the reaction times. The test result can differentiate between organic and metabolic brain impairment. The test is not affected by the patient’s age, gender with no learning or tiring impact [90, 91].

6.3.2.3 The inhibitory control test (ICT)

It is a computerized test of response inhibition and working. The ICT requires highly functional patients (Figure 6). The ICT can be done using a laptop and is analyzed using an automatic computerized system that significantly improves the convenience and flexibility of using this test in the clinical situation [92]. It has been validated for the diagnosis and follow-up of MHE in the USA. It was found that the ICT is simple to administer and has higher sensitivity/specificity for screening MHE than the standard psychometric test (SPT). On the other side, Taneja et al. found that the ICT is not as useful as the PHES in diagnosing MHE in patients with cirrhosis [93].

Figure 6.

Inhibitory control test. A continuous sequence of letters is displayed on the computer screen every 500 ms. The patient is educated to respond only if an X is preceded by a Y, or a Y is preceded by an X, but responses must be inhibited if an X is followed by an X, or a Y is followed by a Y.

6.3.2.4 The Stroop test

In 2013, Bajaj et al. developed an application, the EncephalApp-Stroop App, for screening MHE that is operated by the iOS system on the iPhone and iPad. The core of this innovative application is the Stroop test, which assesses psychomotor speed and cognitive alertness by measuring the time required to correctly identify a series of symbols and printed words with different colors [86]. The Stroop test evaluates psychomotor speed and cognitive flexibility by the interference between recognition reaction time to a colored field and a written color name. [86]. In a multicenter study that compared the EncephalApp-Stroop App to the PHES and ICT, the EncephalApp-Stroop App had good sensitivity (70–80%) for MHE screening and was predictive of the progression to OHE [94].

6.3.2.5 The SCAN test

It is a computerized test that measures the patient’s speed and accuracy to perform a digit recognition memory task of increasing complexity [40, 95]. It is done by randomly displaying a series of 72 sorted pairs of numbers for 3 s on a computer screen. Patients are instructed to press the appropriate number on a keyboard if they identify a common digit in the sequence of numbers presented. The mean reaction times and the percentage of errors are recorded, and the results are evaluated using the reaction times weighted by the number of errors [96].

6.3.2.6 Cognitive drug research (CDR) assessment battery

It is a computerized battery of cognitive tests designed by the Cognitive Drug Research Ltd. (Goring-on-Thames, UK). The test contains five psychometric subsets that test attention power, attention continuity, speed of memory, and quality of episodic and working memory. It measures reaction time, memory, and recognition. The task stimuli are existing on a laptop, and patients provide the correct response using the “YES” and “NO” buttons on a two-button response box, which records both accuracy and reaction time. The sensitivity and specificity of the CDR assessment battery for screening MHE are 86.4 and 81%, respectively [10].

6.3.3 Electroencephalography examination (EEG)

EEG can discover changes in cortical cerebral activity across the spectrum of HE without patient cooperation or risk of a learning effect [97]. Newly, an-economy friendly device has been found to produce similar results compared with a standard EEG machine across the HE spectrum [97].

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7. Treatment

Treatment of minimal hepatic encephalopathy with lactulose, probiotics, or l-ornithine-l-aspartate was seen to be effective in reducing abnormal tests and delay or eradicating risky motor car accident [47, 98, 99, 100, 101, 102, 103]. It is therefore rational, especially if the patients or their family/caregivers report symptoms/signs compatible with MHE, to introduce treatment specially in patients who are at particular risk of the consequences of MHE, such as falls, impaired, and driving ability.

7.1 Rifaximin

Rifaximin is an orally administered, non-absorbable, semi-synthetic antibiotic with a broad spectrum of effect on both Gram-positive and Gram-negative bacteria [11,, 104]. It was found that patients with MHE treated with rifaximin for an 8-week period showed significantly greater improvements in driving and cognitive performance and in the psychosocial dimension of the Sickness Impact Profile than those given a placebo [67]. Recently, a randomized controlled trial compared the efficacy of rifaximin with lactulose in reversal of MHE and improvement in HRQoL in cirrhotic patients with MHE. The study concluded that both drugs improve HRQoL equally well, in cirrhotic patients with MHE [105].

7.2 Non-absorbable disaccharides

The recommended standard of care for people with hepatic encephalopathy includes use of the non-absorbable disaccharides (lactulose and lactitol) [106, 107]. It was found that cirrhotic patients with MHE had improvement in health-related quality of life and psychometric performance after lactulose therapy [108]. Lactulose and lactitol, both, have effects on gut flora and are regarded as intestinal prebiotics. Adding lactulose to food can produce a bifidogenic effect connected to a favorable effect on colonic ammonia metabolism [109]. However, a recent meta-analysis evaluating the role of non-absorbable disaccharides in patients with MHE failed to show clear evidence in improving cognitive function and HRQoL [110].

7.3 LOLA (l-ornithine-l-aspartate)

Ammonia scavengers, including l-ornithine-l-aspartate, are agents that reduce blood ammonia concentration by enhancing the metabolism of ammonia to glutamine [111, 112, 113]. Bai et al. assessed eight RCTs (646 total patients, 46% diagnosed with MHE), evaluating the efficacy of LOLA compared to placebo in patients with cirrhosis. He found that treatment with LOLA diminished serum ammonia levels [114]. Evidence of important benefit of LOLA was also described in RCTs of patients with MHE assessed by psychometric testing or critical flicker frequency analysis. The oral formulation of LOLA was determined to be particularly effective for the treatment of OHE or MHE [115].

7.4 Probiotics

Prebiotics are non-digestible food ingredients that selectively stimulate the growth and/or activity of the bacteria in the colon. Probiotics are live microbes that alter the intestinal balance of the microflora. The combination of prebiotics and probiotics is named synbiotics. The meta-analysis of nine studies showed substantial evidence for the efficacy of prebiotics, probiotics, and synbiotics in the treatment of MHE [116]. A Cochrane Review examining the use of probiotics in the treatment of HE included seven trials and presented an advantage of probiotics to no treatment in all-cause mortality, number of adverse events, and QoL. Findings included reduced plasma concentrations of ammonia [117].

7.5 Zinc

Zinc, considered as a cofactor of urea cycle enzymes, is deficient in patients with cirrhosis, especially with malnutrition or encephalopathy [118]. Zinc is essential for the synthesis of coenzymes that mediate biogenic amine synthesis and metabolism [14]. Zinc deficiency also leads to change of neurotransmitters like γ aminobutyric acid and norepinephrine [119]. A recent RCT revealed that zinc supplementation can improve MHE in patients with liver cirrhosis associated with significant improvement in neuropsychometric tests and significantly decreased arterial ammonia level [76].

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8. Conclusion

The prevalence of MHE is high in liver cirrhosis. MHE is characterized by subtle motor and cognitive deficits, and impairs health-related quality of life. Detection of MHE and subsequent treatment could substantially reduce societal costs by preventing motor vehicle accident.

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Conflict of interest

The authors declare that there is no conflict of interest.

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Funding

This research received no specific grant from any funding agency in the public, commercial, or not for-profit sectors.

References

  1. 1. Mullen KD, Prakash RK. New perspectives in hepatic encephalopathy. Clinics in Liver Disease. 2012;16:1-5
  2. 2. Romero-Gómez M, Boza F, García-Valdecasas MS, García E, Aguilar-Reina J. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. The American Journal of Gastroenterology. 2001;96:2718-2723
  3. 3. 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;60:715-735
  4. 4. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy definition, nomenclature, diagnosis, and quantification: Final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002;35:716-721
  5. 5. Labenz C, Worns MA, Schattenberg JM, Huber Y, Galle PR, Labenz J, et al. Epidemiology of hepatic encephalopathy in german hospitals—The EpHE study. Zeitschrift für Gastroenterologie. 2017;55:741-747
  6. 6. Dhiman RK, Chawla YK. Minimal hepatic encephalopathy. Indian Journal of Gastroenterology. 2009;28(1):5-16
  7. 7. Bajaj JS, Heuman DM, Bell DE, White M, Gilles H, Luketic VA, et al. Burden of cirrhosis and hepatic encephalopathy on patients and caregivers. Hepatology. 2010;410A:52
  8. 8. Das A, Dhiman RK, Saraswat VA, Verma M, Naik SR. Prevalence and natural history of subclinical hepatic encephalopathy in cirrhosis. Journal of Gastroenterology and Hepatology. 2001;16:531-535
  9. 9. Waghray A, Waghray N, Mullen K. Management of covert hepatic encephalopathy. Journal of Clinical and Experimental Hepatology. 2015;5:S75-S81
  10. 10. 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. The American Journal of Gastroenterology. 2007;102:754-760
  11. 11. Ford JM, Gray M, Whitfield SL, Turken AU, Glover G, Faustman WO, et al. Acquiring and inhibiting prepotent responses in schizophrenia: Event-related brain potentials and functional magnetic resonance imaging. Archives of General Psychiatry. 2004;61:119-129
  12. 12. Bajaj JS. Management options for minimal hepatic encephalopathy. Expert Review of Gastroenterology & Hepatology. 2008;2:785-790
  13. 13. Schomerus H, Hamster W. Quality of life in cirrhotic with minimal hepatic encephalopathy. Metabolic Brain Disease. 2001;16:37-41
  14. 14. Sharma P, Sharma BC, Puri V, Sarin SK. Critical flicker frequency: Diagnostic tool for minimal hepatic encephalopathy. Journal of Hepatology. 2007;47:67-73
  15. 15. 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;45:879-885
  16. 16. Cordoba J, Alonso J, Rovira A, Jacas C, Sanpedro F, Castells L, et al. The development of low-grade cerebral edema in cirrhosis is supported by the evolution of (1) H-magnetic resonance abnormalities after liver transplantation. Journal of Hepatology. 2001;35:598-604
  17. 17. Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: A physiology-driven approach to the treatment of hepatic encephalopathy. Mayo Clinic Proceedings. 2015;90:646-658
  18. 18. Patidar KR, Bajaj JS. Covert and overt hepatic encephalopathy: Diagnosis and management. Clinical Gastroenterology and Hepatology. 2015;13(12):2048-2061
  19. 19. Brusilow SW. Hyperammonemic encephalopathy. Medicine (Baltimore). 2002;81(3):240-249
  20. 20. Chatauret N, Butterworth RF. Effects of liver failure on inter-organ trafficking of ammonia: Implications for the treatment of hepatic encephalopathy. Journal of Gastroenterology and Hepatology. 2004;19:S219-S223
  21. 21. Cichoż-Lach H, Michalak A. Current pathogenetic aspects of hepatic encephalopathy and non cirrhotic hyperammonemic encephalopathy. World Journal of Gastroenterology. 2013;19:26-34
  22. 22. Cooper AJ, Plum F. Biochemistry and physiology of brain ammonia. Physiological Reviews. 1987;67:440-519
  23. 23. Wijdicks EF. Hepatic encephalopathy. The New England Journal of Medicine. 2016;375:1660-1670
  24. 24. Schomerus H, Hamster W. Neuropsychological aspects of portal-systemic encephalopathy. Metabolic Brain Disease. 1998;13:361-377
  25. 25. Szerb JC, Butterworth RF. Effect of ammonium ions on synaptic transmission in the mammalian central nervous system. Progress in Neurobiology. 1992;39:135-153
  26. 26. Luo M, Guo JY, Cao WK. Inflammation: A novel target of current therapies for hepatic encephalopathy in liver cirrhosis. World Journal of Gastroenterology. 2015;21(41):11815-11824
  27. 27. Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. Journal of Hepatology. 2004;40:247-254
  28. 28. Shawcross DL, Wright G, Olde Damink SW, Jalan R. Role of ammonia and inflammation in minimal hepatic encephalopathy. Metabolic Brain Disease. 2007;22:125-138
  29. 29. Aldridgea DR, Tranaha EJ, Shawcross DL. Pathogenesis of hepatic encephalopathy: Role of ammonia and systemic inflammation. Journal of Clinical and Experimental Hepatology. 2015;5:S7-S20
  30. 30. Seyan AS, Hughes RD, Shawcross DL. Changing face of hepatic encephalopathy: Role of inflammation and oxidative stress. World Journal of Gastroenterology. 2010;16:3347-3357
  31. 31. Bémeur C, Butterworth R. Liver-brain proinflammatory signalling in acute liver failure: Role in the pathogenesis of hepatic encephalopathy and brain edema. Metabolic Brain Disease. 2013;28:145-150
  32. 32. Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology. 2014;146(6):1513-1524
  33. 33. Bajaj JS, Betrapally NS, Hylemon PB, Heuman DM, Daita K, White MB, et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology. 2015;62(4):1260-1271
  34. 34. Zhang Z, Zhai H, Geng J, Yu R, Ren H, Fan H, et al. Large-scale survey of gut microbiota associated with MHE via 16S rRNA-based pyrosequencing. The American Journal of Gastroenterology. 2013;108:1601-1611
  35. 35. Bajaj JS, Heuman DM, Hylemon PB, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. Journal of Hepatology. 2014;60(5):940-947
  36. 36. Patidar KR, Thacker LR, Wade JB, et al. Covert hepatic encephalopathy is independently associated with poor survival and increased risk of hospitalization. The American Journal of Gastroenterology. 2014;109:1757-1763
  37. 37. Hartmann IJ, Groeneweg M, Quero JC, Beijeman SJ, de Man RA, Hop WC, et al. The prognostic significance of subclinical hepatic encephalopathy. The American Journal of Gastroenterology. 2000;95(8):2029-2034
  38. 38. Das A, Dhiman RK, Saraswat VA, Verma M, Naik SR. Prevalence and natural history of subclinical hepatic encephalopathy incirrhosis. Journal of Gastroenterology and Hepatology. 2001;16:531-533
  39. 39. Lockwood AH. “What’s in a name?” improving the care of cirrhotics. Journal of Hepatology. 2000;32:859-861
  40. 40. Amodio P, del Piccolo F, Marchetti P, Angeli P, Iemmolo R, Caregaro L, et al. Clinical features and survival of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests. Hepatology. 1999;29:1662-1667
  41. 41. Romero-Gómez M, Grande L, Camacho I, Benitez S, Irles JA, Castro M. Altered response to oral glutamine challenge as prognostic factor for overt episodes in patients with minimal hepatic encephalopathy. Journal of Hepatology. 2002;37(6):781-787
  42. 42. Dhiman RK, Kurmi R, Thumburu KK, Venkataramarao SH, Agarwal R, Duseja A, et al. Diagnosis and prognostic significance of minimal hepatic encephalopathy inpatients with cirrhosis of liver. Digestive Diseases and Sciences. 2010;55(8):2381-2390
  43. 43. Romero-Gómez M, Córdoba J, Jover R, et al. Value of the critica flicker frequency in patients with minimal hepatic encephalopathy. Hepatology. 2007;45:879-885
  44. 44. Wein C, Koch H, Popp B, Oehler G, Schauder P. Minimal hepatic encephalopathy impairs fitness to drive. Hepatology. 2004;39:739-745
  45. 45. Watanabe A, Tuchida T, Yata Y, Kuwabara Y. Evaluation of neuropsychological function inpatients with liver cirrhosis with special reference to their driving ability. Metabolic Brain Disease. 1995;10:239-248
  46. 46. Bajaj JS, Hafeezullah M, Hoffmann RG, Varma RR, Franco J, Binion DG, et al. Navigation skill impairment: Another dimension of the driving difficulties in minimal hepaticencephalopathy. Hepatology. 2008;47:596-604
  47. 47. Dhiman RK, Sawhney MS, Chawla YK, Das G, Ram S, Dilawari JB. Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy. Digestive Diseases and Sciences. 2000;45:1549-1552
  48. 48. Groeneweg M, Quero JC, De Bruijn I, Hartmann IJ, Essink-bot ML, Hop WC, et al. Subclinical hepatic encephalopathy impairs daily functioning. Hepatology. 1998;28:45-49
  49. 49. Roman E, Cordoba J, Torrens M, Torras X, Villanueva C, Vargas V, et al. Minimal hepatic encephalopathy is associated with falls. The American Journal of Gastroenterology. 2011;106:476-482.49
  50. 50. Zhou YQ , Chen SY, Jiang LD, Guo CY, Shen ZY, Huang PX, et al. Development and evaluation of the quality of life instrument in chronic liver disease patients with minimal hepatic encephalopathy. Journal of Gastroenterology and Hepatology. 2009;24:408-415
  51. 51. Bajaj JS, Etemadian A, Hafeezullah M, Saeian K. Testing for minimal hepatic encephalopathy in the United States: An AASLD survey. Hepatology. 2007;45:833-834
  52. 52. Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R. Lactulose improves cognitive functions and health-relatedquality of life in patients with cirrhosis who have minimal hepaticencephalopathy. Hepatology. 2007;45:549-559
  53. 53. Arguedas MR, DeLawrence TG, McGuire BM. Influence of hepatic encephalopathy on health-related quality of life in patients withcirrhosis. Digestive Diseases and Sciences. 2003;48:1622-1626
  54. 54. Bao ZJ, Qiu DK, Ma X, Fan ZP, Zhang GS, Huang YQ , et al. Assessment of health-related quality of life in Chinese patients with minimal hepatic encephalopathy. World Journal of Gastroenterology. 2007;13:3003-3008
  55. 55. Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS, Soni RK. Rifaximin improves psychometric performance and health-relatedquality of life in patients with minimal hepatic encephalopathy (the RIME Trial). The American Journal of Gastroenterology. 2011;106:307-316
  56. 56. Marchesini G, Bianchi G, Amodio P, Salerno F, Merli M, Panella C, et al. Italian Study Group for quality of life in cirrhosis. Factors associated with poor health-relatedquality of life of patients with cirrhosis. Gastroenterology. 2001;120:170-178
  57. 57. Arguedas MR, DeLawrence TG, McGuire BM. Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis. Digestive Diseases and Sciences. 2003;48:1622-1626
  58. 58. Kim WR, Brown RS Jr, Terrault NA, El-Serag H. Burden of liver disease in the United States: Summary of a workshop. Hepatology. 2002;36:227-242
  59. 59. Qadri AM, Ogunwale BO, Mullen KD. Can we ignore minimal hepatic encephalopathy any longer? Hepatology. 2007;45:547-548
  60. 60. Soriano G, Román E, Córdoba J, Torrens M, Poca M, Torras X, et al. Cognitive dysfunction in cirrhosis is associated with falls: A prospective study. Hepatology. 2012;55:1922-1930
  61. 61. Urios A, Mangas-Losada A, Gimenez-Garzó C, González-López O, Giner-Durán R, Serra MA, et al. Altered postural control and stability in cirrhotic patients with minimal hepatic encephalopathy correlate with cognitive deficits. Liver International. 2017;37:1013-1022
  62. 62. Yildirim M. Falls in patients with liver cirrhosis. Gastroenterology Nursing. 2017;40(4):306-310
  63. 63. Gad Y, Zaher A, Mousa N, El-desoky A, Al-Adarosy A. Screening for minimal hepatic encephalopathy in asymptomatic drivers with liver cirrhosis. Arab Journal of Gastroenterology. 2011;12(2):58-61
  64. 64. Bajaj JS, Pinkerton SD, Sanyal AJ, Heuman DM. Diagnosis and treatment of minimal hepatic encephalopathy to prevent motor vehicle accidents: A cost-effectiveness analysis. Hepatology. 2012;55:1164-1171
  65. 65. Iwasa M, Sugimoto R, Mifuji-Moroka R, Hara N, Yoshikawa K, Tanaka H. Factors contributing to the development of overt encephalopathy in liver cirrhosis patients. Metabolic Brain Disease. 2016;31:1151-1156
  66. 66. Wang AJ, Peng AP, Li BM, Gan N, Pei L, Zheng XL, et al. Natural history of covert hepatic encephalopathy: An observational study of 366 cirrhotic patients. World Journal of Gastroenterology. 2017;23(34):6321-6329
  67. 67. Thomsen KL, Macnaughtan J, Tritto G, Mookerjee RP, Jalan R. Clinical and pathophysiological characteristics of cirrhotic patients with grade 1 and minimal hepatic encephalopathy. PLoS One. 2016;11:e0146076
  68. 68. Weissenborn K, Ennen JC, Schomerus H, Ruckert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy. Journal of Hepatology. 2001;34:768-773
  69. 69. Weissenborn K, Giewekemeyer K, Heidenreich S, Bokemeyer M, Berding G, Ahl B. Attention, memory, and cognitive function in hepatic encephalopathy. Metabolic Brain Disease. 2005;20:359-367
  70. 70. Montagnese S, Amodio P, Morgan MY. Methods for diagnosing hepatic encephalopathy in patients with cirrhosis: A multidimensional approach. Metabolic Brain Disease. 2004;19:281-312
  71. 71. Prakash R, Mullen KD. Mechanisms, diagnosis and management of hepatic encephalopathy. Nature Reviews. Gastroenterology & Hepatology. 2010;7:515-525
  72. 72. Guerit JM, Amantini A, Fischer C, Kaplan PW, Mecarelli O, Schnitzler A, et al. Neurophysiological investigations of hepatic encephalopathy: ISHEN practice guidelines. Liver International. 2009;29:789-796
  73. 73. Hilsabeck RC, Perry W, Hassanein TI. Neuropsychological impairment in patients with chronic hepatitis C. Hepatology. 2002;35:440-446
  74. 74. Ortiz M, Cordoba J, Alonso J, Rovira A, Quiroga S, Jacas C, et al. Oral glutamine challenge and magnetic resonance spectroscopy in three patients with congenital portosystemic shunts. Journal of Hepatology. 2004;40:552-557
  75. 75. 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. European Journal of Gastroenterology & Hepatology. 2008;20:506-511
  76. 76. Mousa N, Abdel-Razik A, Zaher A, Hamed M, Shiha G, Effat N, et al. The role of antioxidants and zinc in minimal hepatic encephalopathy: A randomized trial. Therapeutic Advances in Gastroenterology. 2016;9(5):684-691
  77. 77. Dhiman RK, Saraswat VA, Verma M, Naik SR. Figure connection test: A modified number connection test for the objective assessment of mental state in illiterates. Journal of Gastroenterology and Hepatology. 1995;10:14-23
  78. 78. Schomerus H, Hamster W. Neuropsychological aspects of portalsystemic encephalopathy. Metabolic Brain Disease. 1998;13:361-377
  79. 79. Randolph C, Hilsabeck R, Kato A, Kharbanda P, Li YY, Mapelli D, et al. Neuropsychological assessment of hepatic encephalopathy: ISHEN practice guidelines. Liver International. 2009;29(5):629-635
  80. 80. Wuensch T, Ruether DF, Zöllner C, Mueller T, Jung T, Kaffarnik M, et al. Performance characterization of a novel electronic number connection test to detect minimal hepatic encephalopathy in cirrhotic patients. European Journal of Gastroenterology & Hepatology. 2017;29(4):456-463
  81. 81. Sharma P, Sharma BC, Puri V, Sarin SK. Natural history of minimal hepatic encephalopathy in patients with extrahepatic portal vein obstruction. The American Journal of Gastroenterology. 2009;104:885-890
  82. 82. Kügler CF, Petter J, Taghavy A, Lotterer E, Wensing G, Hahn EG, et al. Dynamics of cognitive brain dysfunction in patients with cirrhotic liver disease: An event-related P300 potential perspective. Electroencephalography and Clinical Neurophysiology. 1994;91:33-41
  83. 83. Meyer T, Eshelman A, Abouljoud M. Neuropsychological changes in a large sample of liver transplant candidates. Transplantation Proceedings. 2006;38:3559-3660
  84. 84. Riggio O, Ridola L, Pasquale C, Pentassuglio I, Nardelli S, Moscucci F, et al. A simplified psychometric evaluation for the diagnosis of minimal hepatic encephalopathy. Clinical Gastroenterology and Hepatology. 2011;9:613-616.e1
  85. 85. 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(1):198-208
  86. 86. Bajaj JS, Thacker LR, Heumann 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;58:1122-1132
  87. 87. Mardini H, Saxby BK, Record CO. Computerized psychometric testing in minimal encephalopathy and modulation by nitrogen challenge and liver transplant. Gastroenterology. 2008;135:1582-1590
  88. 88. Barone M, Shahini E, Iannone A, Viggiani MT, Corvace V, et al. Critical flicker frequency test predicts overt hepatic encephalopathy and survival in patients with liver cirrhosis. Digestive and Liver Disease. 2018;50(5):496-500
  89. 89. Coşkun B, Özen M. Critical flicker frequency test for diagnosing minimal hepatic encephalopathy in patients with cirrhosis. The Turkish Journal of Gastroenterology. 2017;28:191-196
  90. 90. Lauridsen MM, Gronbaek H, Naeser EB, Leth ST, Vilstrup H. Gender and age effects on the continuous reaction times method in volunteers and patients with cirrhosis. Metabolic Brain Disease. 2012;27:559-565
  91. 91. Lauridsen MM, Thiele M, Kimer N, Vilstrup H. The continuous reaction times method for diagnosing, grading, and monitoring minimal/covert hepatic encephalopathy. Metabolic Brain Disease. 2013;28:231-234
  92. 92. Bajaj JS, Hafeezullah M, Franco J, Varma RR, Hoffmann RG, Knox JF, et al. Inhibitory control test for the diagnosis of minimal hepatic encephalopathy. Gastroenterology. 2008;135:1591-1600.e1591
  93. 93. Taneja S, Dhiman RK, Khatri A, Goyal S, Thumbru K, Agarwal R, et al. Inhibitory control test for the detection of minimal hepatic encephalopathy in patients with cirrhosis of liver. Journal of Clinical and Experimental Hepatology. 2012;2:306-314
  94. 94. Allampati S, Duarte-Rojo A, Thacker LR, Patidar KR, White MB, Klair JS, et al. Diagnosis of minimal hepatic encephalopathy using Stroop EncephalApp: A multicenter US-based, norm-based study. The American Journal of Gastroenterology. 2015;111:78-86
  95. 95. Montagnese S, Schiff S, Turco M, Bonato CA, Ridola L, Gatta A, et al. Simple tools for complex syndromes: A three-level difficulty test for hepatic encephalopathy. Digestive and Liver Disease. 2012;44:957-960
  96. 96. Amodio P, Marchetti P, Del Piccolo F, Rizzo C, Iemmolo RM, Caregaro L, et al. Study on the Sternberg paradigm in cirrhotic patients without overt hepatic encephalopathy. Metabolic Brain Disease. 1998;13:159-172
  97. 97. Schiff S, Casa M, Di Caro V, Aprile D, Spinelli G, De Rui M, et al. A low-cost, user-friendly electroencephalographic recording system for the assessment of hepatic encephalopathy. Hepatology. 2016;63(5):1651-1659
  98. 98. Zucker DM, Redulla R. Lactulose management of minimal hepatic encephalopathy: A systematic review. Gastroenterology Nursing. 2019;42(1):84-94
  99. 99. 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(6):1410-1414
  100. 100. Cao Q , Yu CB, Yang SG, Cao HC, Chen P, Deng M, et al. Effect of probiotic treatment on cirrhotic patients with minimal hepatic encephalopathy: A meta-analysis. Hepatobiliary & Pancreatic Diseases International. 2018;17(1):9-16
  101. 101. Gluud LL, Dam G, Les I, Marchesini G, Borre M, Aagaard NK, et al. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database of Systematic Reviews. 2017;5:CD001939
  102. 102. Horsmans Y, Solbreux PM, Daenens C, Desager JP, Geubel AP. Lactulose improves psychometric testing in cirrhotic patients with subclinical encephalopathy. Alimentary Pharmacology & Therapeutics. 1997;11(1):165-170
  103. 103. Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS, Soni RK. Rifaxim improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME Trial). The American Journal of Gastroenterology. 2011;106(2):307-316
  104. 104. Kimer N, Krag A, Gluud LL. Safety, efficacy, and patient acceptability of rifaximin for hepatic encephalopathy. Patient Preference and Adherence. 2014;8:331
  105. 105. Sidhu SS, Goyal O, Parker RA, Kishore H, Sood A. Rifaximin vs. lactulose in treatment of minimal hepatic encephalopathy. Liver International. 2016;36:378-385
  106. 106. Johanson JF. Review of the treatment options for chronic constipation. Medscape General Medicine. 2007;9(2):25
  107. 107. Jain L, Sharma BC, Srivastava S, Puri SK, Sharma P, Sarin S. Serum endotoxin, inflammatory mediators, and magnetic resonance spectroscopy before and after treatment in patients with minimal hepatic encephalopathy. Journal of Gastroenterology and Hepatology. 2013;28:1187-1193
  108. 108. Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R, et al. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephallopathy. Hepatology. 2007;45(3):549-559
  109. 109. Bouhnik Y, Attar A, Joly FA, Riottot M, Dyard F, Flourié B, et al. Lactulose ingestion increases Faecal bifidobacterial counts: A randomised double-blind study in healthy humans. European Journal of Clinical Nutrition. 2004;58:462-466
  110. 110. Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database of Systematic Reviews. 2016;5:CD003044
  111. 111. Blanco Vela CI, Poo Ramirez JL. Efficacy of oral L-ornithine L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Annals of Hepatology. 2011;10(Suppl 2):S55-S59
  112. 112. Rahimi RS, Rockey DC. Hepatic encephalopathy: Pharmacological therapies targeting ammonia. Seminars in Liver Disease. 2016;36(1):48-55
  113. 113. De Las Heras J, Aldamiz-Echevarria L, Martinez-Chantar ML, Delgado TC. An update on the use of benzoate, phenylacetate and phenylbutyrate ammonia scavengers for interrogating and modifying liver nitrogen metabolism and its implications in urea cycle disorders and liver disease. Expert Opinion on Drug Metabolism & Toxicology. 2017;13(4):439-448
  114. 114. Bai M, Yang Z, Qi X, Fan D, Han G. L-ornithine-L-aspartate for hepatic encephalopathy in patients with cirrhosis: A meta-analysis of randomized controlled trials. Journal of Gastroenterology and Hepatology. 2013;28:783-792
  115. 115. Butterworth RF, McPhail MJW. L-ornithine L-aspartate (LOLA) for hepatic encephalopathy in cirrhosis: Results of randomized controlled trials and meta-analyses. Drugs. 2019;79(Suppl 1):31-37
  116. 116. Shukla S, Shukla A, Mehboob S, Guha S. Meta-analysis: The effects of gut flora modulation using prebiotics, probiotics andsynbiotics on inimal hepatic encephalopathy. Alimentary Pharmacology & Therapeutics. 2011;33:662-671
  117. 117. McGee RG, Bakens A, Wiley K, et al. Probiotics for patients with hepatic encephalopathy. Cochrane Database of Systematic Reviews. 2011;11:CD008716
  118. 118. Blei A, Córdoba J, Practice Parameters Committee of the American College of Gastroenterology. Hepatic encephalopathy. American Journal of Gastroenterology. 2001;96:1968-1976
  119. 119. Chetri K, Choudhuri G. Role of trace elements in hepatic encephalopathy: Zinc and manganese. Indian Journal of Gastroenterology. 2003;22(Suppl 2):S28-S30

Written By

Gamal Shiha and Nasser Mousa

Submitted: March 21st, 2019 Reviewed: June 26th, 2019 Published: September 23rd, 2019