Hepatic encephalopathy (HE) reflects part of the spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other known brain diseases. The Working Party at the 11th World Congress of Gastroenterology, Vienna, under the Organisation Mondiale de Gastroentrologie, proposed a multiaxial definition of hepatic encephalopathy that defines both the type of hepatic abnormality (type A, B or C) and the duration/characteristics of neurological manifestations [episodic, persistent or minimal hepatic encephalopathy (MHE)] in chronic liver disease.(1) HE comprises several dimensions such as cognition, emotion, behavior, and biologic rhythms that may be measured with one index to summarise these neurological domains. MHE represents one of these elements, is the mildest form of hepatic encephalopathy, and may be diagnosed on the basis of a cut-off score. To perform such a study a large sample is required and until such a study is carried out, MHE can best be characterised by psychometric and neurophysiologic methods.(1,2,3) While patients with hepatic encephalopathy have impaired intellectual functioning, personality changes, altered levels of consciousness, and neuromuscular dysfunction, patients with MHE have no recognisable clinical symptoms of hepatic encephalopathy but have mild cognitive and psychomotor deficits. Standard neurological examination is not sufficient to recognise the subtle cognitive function abnormalities, which mainly affect attention, speed of information processing, and motor abilities and coordination.

The term subclinical or latent hepatic encephalopathy was proposed to identify patients with these subtle cognitive function abnormalities.(4,5) According to the recommendations of the World Congress of Gastroenterology, MHE is a better term because use of the term ‘subclinical’ in subclinical hepatic encephalopathy may be misleading and may signify a lack of clinical importance to this diagnosis or may imply a separate pathogenesis. The impact of MHE on the quality of life in patients with cirrhosis has received increasing recognition.(1,6)

1.  Who develops MHE?
MHE is currently considered to be one end of the clinical spectrum of hepatic encephalopathy. Thus MHE develops in patients with significant liver function impairment and/or with portosystemic shunts. The diagnosis has traditionally been linked to patients with cirrhosis of the liver. However, impairment of cognitive function has been demonstrated in patients with noncirrhotic portal fibrosis(7) and extrahepatic portal venous obstruction(8) and is related to portosytemic shunting. Cognitive impairment in chronic hepatitis, which is correlated with the degree of fibrosis, is not currently considered the equivalent of MHE.(9)

The prevalence of MHE varies between 30% and 84% in patients with liver cirrhosis.(10) The major difficulty in the diagnosis of MHE has been the lack of a precise definition of what constitutes its “gold standard”. This large variation in prevalence among different studies is related to the criteria used for diagnosis, and the patient population that has been studied. Various factors that may determine the presence of MHE have been studied and include prior episodes of overt hepatic encephalopathy,(11) presence of oesophageal varices,(11) severity of liver disease, age,(12) alcoholic aetiology,(11) transjugular intrahepatic porto-systemic shunt (TIPSS) and surgical portosystemic shunts.(4 )Patients who develop MHE are older, have more severe liver disease as quantified by the Child-Pugh score, and more often have oesophageal and gastric varices. The prevalence of MHE is lower in cirrhotic patients with good liver function (Child class A, 36%) than in those cirrhotics with poor liver function (Child class B, 45%, Child class C, 72%; p=0.056, chi square for trend).(13) These patients more often have alcohol abuse as an aetiological factor and a history of clinical overt encephalopathy in the past. In an earlier study we did not find any relation between the presence of MHE and age, sex, and presence of oesophageal and gastric varices.(14) 

2. MAKING A DIAGNOSIS OF MHE?

The prerequisite for the diagnosis of MHE is the careful exclusion of clinical symptoms by a more precise and complete approach and which would include the following assessment.(15)

i)      Inquiry into the activities of daily living, e.g. appetite, sleep, energy, and activity levels and the overall quality of life.

ii)     Inquiry into the mental state, e.g. memory, cognition, concentration, and consciousness.

iii)    An assessment of mental state utilising the West Haven criteria(1) or other test systems such as mini mental score test.(16)

iv)    A comprehensive neurological examination particularly for evidence of hypomimia, dysarthria, tone, ataxia, tendon reflex, abnormal movements (such as tremor/asterixis).

v)     Exclusion of concomitant neurological disorders e.g. subdural haematoma, Wernicke’s encephalopathy,

metabolic abnormalities e.g. diabetes, renal failure, intoxication with drugs and/or alcohol.

Various tools have been evaluated for the correct diagnosis of MHE and include psychological tests, neurophysiological tests, regional cerebral blood flow changes and magnetic resonance spectroscopy.  However, in the absence of a “gold standard” psychometric and neurophysiological methods have been the most trusted and widely used tests. No consensus on diagnostic criteria or diagnostic tests has been established. The Working Party recommended use of at least two of the following instruments: number connection test-A, number connection test-B, block design test and digit symbol test.(1) While cautioning that changes in EEG and P300 latency findings are not specific for hepatic encephalopathy, the Working Party also suggested that EEG recordings and P300 auditory evoked potentials (P300-AEP) might be useful for supplementing these psychometric tests.(1)

A standardised test battery including the number connection test-A (NCT-A) and B, the line-tracing test, the serial-dotting test, and the digit-symbol test [porto-systemic encephalopathy (PSE) test or psychometric hepatic encephalopathy score (PHES)] is also recommended.(1,17) The battery has been extensively validated in the Spanish and German populations and can be performed in 15 to 20 minutes.(17,18) We have recently validated this battery in the Indian population.(13) We modified it by replacing NCT-B with figure connection test-A (FCT-A) because some of our patients are illiterate and can perform FCT-A instead of NCT-B. In principle, the FCT is similar to the NCT, except that numbers are replaced by figures (motifs).(19) FCT is a universally applicable test for assessing the mental state, and transcends the barriers of illiteracy and linguistic differences. The clinical significance of these tests has been evaluated in a large number of healthy volunteers and patients with MHE.(19) The normal data also takes care of concerns about the effect of age and education in our population. This battery examines motor speed and accuracy, visual perception, visuo-spatial orientation, visual construction, concentration, attention and to a lesser extent memory.

Critical flicker frequency (CFF) has recently been added to the long list of tests for the diagnosis of MHE. Two recent studies evaluated its usefulness in the diagnosis of MHE.(18,20) Both studies demonstrated that it was simple, reliable, and accurate. It is not influenced by age or education and can predict the development of overt HE. We compared (3) techniques (PHES, CFF and P300-AEP) in the diagnosis of MHE in 100 cirrhotic patients without overt hepatic encephalopathy. (48) (48%) patients had MHE as evidenced by altered PHES; CFF was altered in 21% and P300-ERP in 32%. 17 of 21 (81%) patients with altered CFF also showed impaired PHES thus providing additional information in only 3 patients. P300-ERP did not correlate with PHES (r=-0.227, P=0.069), CFF (r=0.155, P=0.205), or CTP score (r=0.109, P=0.373), thus P300-ERP was not a reflection of MHE in our patients.  PHES correlated with the CTP (r=-0.272, P=0.006) and with CFF scores (r=0.408, P<0.0001). CFF correlated with the CTP score (r=0.346, P<0.001). Hence PHES appears to be an ideal assessment tool for the diagnosis of MHE; it covers the spectrum of cognitive aspects that are affected in hepatic encephalopathy. CFF provided little additional information.(13)

PHES or at least two of the following instruments - NCT-A, NCT-B (or FCT-A), block design test and digit symbol test should be used for the diagnosis of MHE. Spectral EEG or CFF can supplement these psychometric tests.

3. Clinical Significance
The clinical significance of MHE may be discussed in three parts: (i) Does MHE impair daily functioning or health-related quality of life (HRQOL)? (ii) What is its natural history? and (iii) Is it associated with a poor prognosis? 

Does MHE impair daily functioning or health-related  quality of life?
While many patients have no clinically overt signs of impaired cognition, others show a cognitive decline which is better perceived by the patient, a relative, a colleague or by an employer than by a physician. Groeneweg et al(11) have demonstrated that several cognitive complaints (statements) have predictive value for MHE. These statements include impaired psychomotor performance (‘I have difficulty doing handwork; I am not working at all.’), decreased attention (‘I am confused and start several actions at a time.’), sleep or rest (‘I spend much of the day lying down in order to rest.”) and poor memory (‘I forget a lot; for example, things that happened recently, where I put things, etc.’).

Increasing evidence suggests that MHE is an important disorder that impairs patients daily functioning and HRQOL.(21,22,23) While the basic activities of daily life, such as shopping, dressing, personal hygiene, etc are largely preserved; complex activities involving attention, information processing and psychomotor skills such as driving a car, planning a trip etc are mainly affected.  Groenweg et al(21) have demonstrated diminished levels of daily functioning more frequently related to alertness, social interactions, recreation or work in stable cirrhotic patients with MHE. We also observed that the patients with MHE suffered significant impairment in daily functioning compared with cirrhotic patients who did not have MHE.(22) The impairments were much more pronounced in social interaction, alertness, emotional behavior, sleep, work, home management, and recreation and pastimes.(22) The patients with MHE demonstrated impairment in perception, memory, learning, expression (language, constructive abilities, and voluntary motor control), mental activity (attention, mental speed) and executive function.(3,15) The attention, executive functions, speed of information processing and visual spatial functions are affected in these patients as assessed by neuropsychological tests, which may be responsible for impairment in several domains of the SIP questionnaire. Blue-collar workers suffering from cirrhosis with MHE are less likely to earn their wages than the white-collar workers; 60% of ‘blue collar’ workers were unfit to work, whereas 20% of ‘white collar’ workers were unfit to work.(23) The impact of MHE on daily life is further illustrated by the fact that 50% of patients with MHE do not have regular employment, compared to 15% of patients without MHE.(11) These negative effects on functioning in the workplace and ability to work have profound socio-economic implications.

Sleep disturbance is a classic sign of hepatic encephalopathy. Results from a quality of life questionnaire indicated that disturbance in sleep was significantly higher in cirrhotic patients with MHE.(11,22) Cordoba et al(24)showed that nearly half the cirrhotic patients without overt encephalopathy had abnormalities in their quality of sleep; unsatisfactory sleep was associated with reduced sleeping time, increased sleep latency, increased awakening episodes during night and increased daytime sleepiness and naps. They attributed these disturbances to circadian abnormalities, a manifestation of minor encephalopathy. But they did not find any difference in the results of neuropsychological tests between individuals with and without sleep complaints.

Defective memory has also been shown to be a feature of MHE. Weissenborn et al(25) have demonstrated that patients with MHE scored lower than controls in memory tasks that included short and long term memory tests requiring free recall or recognition. The impairment was predominantly related to deficits in attention and visual perception. The memory deficit of MHE seems to comprise short-term but not long-term memory impairment. This can be described as an encoding defect, in which memory recall (also known as retrieval) is intact.

Effect of MHE on driving
Schomerus et al(26) were the first to postulate that the psychomotor defects found in MHE could have a negative effect on fitness to drive. In their study (40) cirrhotics underwent a neuropsychological test battery. On the basis of the psychometric tests performance, 60% of the patients were considered unfit to drive. This study however did not describe the methodology applied to assess driving fitness; this made their conclusions less convincing. Watanabe et al(27) reported similar results. However, a pilot study which included a real road test,  involved 15 cirrhotics, nine with MHE, and failed to detect impaired driving performance.(28)

The results from these studies underline the importance of testing the driving ability in MHE patients. In a landmark study, using a standardised 90-minute on-the-road driving test Wein and colleagues(29) reported that fitness to drive is impaired in cirrhotic patients with MHE, while patients without MHE scored similar to controls. More importantly, the instructor had to intervene more frequently during the test to avoid accidents in patients with MHE (36%) than in patients without MHE (6%) and in controls (8%).(29) A decline in cognitive function increases the risk for automobile crashes.(30) The impairment of attention and speed of mental processing affects an individual’s ability to react to unexpected traffic conditions, such as an illegal incursion by another vehicle at an intersection. Bajaj et al(31) have reported a higher self-reported occurrence of violations and accidents in MHE patients when compared with controls. Presence of MHE is a strong predictor for violations and accidents.(31) Yet another study confirmed these results and stated that difficulty in navigation may pose additional driving problems, compounding the pre-existing attention deficits.(32) Navigation is a complex system needed for safe driving that requires a functional working memory and other domains, which are adversely affected by MHE. Patients positive for MHE have impaired navigation skills on a driving simulator, which is correlated with impairment in response inhibition and attention. The illegal turns and accidents on the simulator correlated mostly with abnormal performance on the inhibitory control test (ICT), which tests response inhibition and is a measure of executive control.

Results of these studies suggest that MHE should be considered a medical condition that warrants treatment to improve psychomotor impairment.

What is the natural history of MHE?
Patients with MHE may improve, remain the same or deteriorate and develop overt encephalopathy over long-term follow up. Among 116 patients with cirrhosis who were followed up for up to 49 months, episodes of overt hepatic encephalopathy were significantly more common in patients with MHE as compared to those without.(33)Child-Pugh score was superior to MHE in predicting episodes of clinical hepatic encephalopathy.(33) We found that, over a mean follow up of 5.4 months, MHE tended to persist or worsen in patients with Child-Pugh score exceeding 6.(14) Although other clinical complications like ascites, spontaneous bacterial peritonitis, and gastrointestinal bleed developed equally in patients with and without MHE, overt hepatic encephalopathy developed more commonly in patients who had MHE.(14)

MHE predicts the development of overt encephalopathy.(34) In one study,(4) three of nine cirrhotics with MHE developed overt hepatic encephalopathy during a one-year follow up. Yen et al(35) found that significantly more patients with abnormal NCT-A or somatosensory evoked potentials had hepatic encephalopathy than patients with normal tests, over a 6-month period.

Is MHE associated with a poor prognosis?
The key issue is whether the presence of MHE adversely or favourably affects the survival of patients with liver cirrhosis. Though a recent study(33) and our own study(14) did not find any relationship between the presence of MHE and long-term survival, Amodio et al(36) showed a negative effect of MHE on survival. They found that increased risk of death was associated with abnormalities in the Scan test or in the Choice-2 test. Hartman et al(33) found that survival was similar in patients with or without MHE and was determined mainly by the Child-Pugh score, rather than by the presence or absence of MHE. A pathological oral glutamine challenge response in patients with MHE also appears to be associated with the development of overt HE and poor survival.(37,38)

MHE, therefore, is a clinically significant disorder that impairs HRQOL, predicts the development of overt encephalopathy and is associated with poor prognosis.
 
4. Does MHE improve with treatment?
The pathogenesis of MHE is thought to be similar to that of overt HE and ammonia plays a key role.(8,39,40,41,42) Ammonia induced alteration in cerebral blood flow and glucose metabolism has shown that there is significant decrease in glucose utilisation in various cortical regions that correlates with the patient’s cognitive functions.(42) Various treatment modalities have been used to treat this condition e.g., dietary protein manipulation,(4,43) branched-chain amino acids,(44,45) lactulose,(22, 46,47,48,49,50 ,51,52,53,54) flumazenil,(55) L–ornithine L–aspartate,(56) and probiotics.(57,58) Most of these therapies were aimed to reduce ammonia levels and a majority of these studies have shown improvement in psychometry, ammonia level and in cerebral oedema.

Non-absorbable disaccharides
Lactulose is the most common agent used in the treatment of MHE.  Treatment with lactulose is of benefit in a majority of patients with MHE.(22,46,47,48,49 ,51,52,53,54) Watanabe et al(48) showed that MHE disappeared in 50% of patients treated with lactulose for 8 weeks but persisted in 85% of untreated patients. There was improvement in psychometric test outcome when we administered lactulose for 3 months.(22) Lactulose lowers the ammonia level by altering the gut flora, which leads to decreased production and absorption of ammonia. We performed a meta-analysis of randomised trials of lactulose versus placebo or no intervention in treatment of patients with MHE and found that the treatment with lactulose was associated with improvement in the psychometric (cognitive) performance (Figure 1).



A recent study has investigated the effect of treatment-related improvement in cognitive function on HRQOL.22 Psychometric performance was measured by NCT and FCT A and B, picture completion and block design tests, and HRQOL by Sickness Impact Profile  in 90 cirrhotic patients at inclusion into the study and 3 months thereafter. (61) (67.7%) patients had MHE. They were randomly assigned in a 1:1 ratio to receive treatment (lactulose) for 3 months (n=31) or no treatment (n=30) in a non-blinded design. The mean number of abnormal NP tests decreased significantly in patients in the treatment group compared with patients in the untreated group (MANOVA for time and treatment, p =.001). Intention to treat analysis showed that improvement following lactulose therapy was significant. While 20 out of 31 (64.5%) patients in the treatment group improved, only 2 of 30 (6.7%) patients did so in the untreated group (Fisher’s exact test; p < .0001).  Mean total SIP score improved among patients in the treatment group compared with patients in the untreated group (MANOVA for time and treatment, P=.002). Improvement in HRQOL was related to the improvement in psychometry. This study demonstrated that lactulose improves both cognitive functions and HRQOL in cirrhotic patients with MHE.

Probiotics and synbiotics
Treatment with synbiotics (probiotics and fermentable fibre) has been suggested but not assessed in controlled studies in the treatment of MHE.(59) Probiotics may be effective in the treatment of hepatic encephalopathy by: 1) Decreasing total ammonia in the portal blood by reducing bacterial urease activity, and ammonia absorption by decreasing the pH, and improving the nutritional status of gut epithelium and decreasing intestinal permeability. 2) Decreasing inflammation decreasing intestinal permeability. 2) Decreasing inflammation and oxidative stress in the hepatocyte leading to increased hepatic clearance of ammonia and other toxins. 3) Decreasing uptake or formation of other toxins, such as endozepines and oxiphenols, and 4) Decreasing systemic cytokine levels and thereby astrocyte dysfunction. These processes may be additive or synergistic in treating MHE.

Liu et al (57) used a novel approach in modulating the gut micro-ecology and acidifying the gut lumen for therapeutic benefit in cirrhotic patients with MHE by treatment with synbiotics. They screened 97 consecutive cirrhotic patients without overt hepatic encephalopathy for MHE using the NCT and measurement of P300-AEP. MHE, defined by abnormality of at least one test modality, was seen in (58) (60%) patients. (55) of them were randomised to receive a synbiotic preparation i.e., probiotic plus fermentable fibre (n=20), fermentable fibre (n=20), or placebo (n=15) for 30 days.  The probiotic compound consisted of 4 freeze-dried, non-urease-producing bacteria, namely Pediacoccus pentoseceus 5-33:3, Leuconostoc mesenteroides 32-77:1, Lactobacillus paracasei subspecies paracasei (19) and Lactobacillus plantarum 2592, each at a dose of 1010 colony forming units per sachet. Fermentable fibre consisted of beta glucan, 2.5 g, inulin 2.5 g, pectin 2.5 g, and resistant starch, 2.5 g. Placebo consisted of wheat-based nonfermentable fibre. Patients were evaluated with NCT and BAEP, and for serum ammonia and endotoxin levels, and stool quantitative bacteriological analysis was done, at study entry, after 1-month of treatment and again after 14 days. Cirrhotic patients with MHE had substantial derangements in the gut microecology, with significant faecal overgrowth of potentially pathogenic Escherichia coli and Staphylococcal species.  Synbiotic treatment significantly increased the faecal content of non-urease-producing Lactobacillus species at the expense of these other bacterial species. This effect persisted at reassessment 14 days after cessation of supplementation. Such modulation of gut flora was associated with a significant reduction in blood ammonia level and reversal of MHE in 50% of patients. Synbiotic treatment was also associated with a significant reduction in endotoxaemia. The Child-Pugh functional class improved in nearly half the patients. Similar benefit was observed with fermentable fibre alone in a substantial proportion of patients.  This study suggests that treatment with synbiotics or fermentable fibre may be an alternative to lactulose for management of MHE in patients with cirrhosis. The results from an animal study suggest that probiotics are as effective as lactulose.(60)

5.  Is it time to recognise MHE and treat it?
Accumulating evidence from recent clinical studies clearly indicates that MHE is associated with significant disability and poor HRQOL.(21,22,23) MHE also has a negative effect on fitness to drive.(29) There is a higher self-reported occurrence of violations and accidents when compared with controls. The presence of MHE is a strong predictor for violations and accidents.(31) Treatment not only results in improvement in cognitive and psychomotor deficits(22,46,47,48,49 ,51,52,53,54) but also in HRQOL.(22) Lactulose and L–ornithine L–aspartate are safe and may be used for treating such patients. Probiotics need further studies to define their ideal composition and dose in the treatment of MHE. We believe that this is the prime time to recognise and treat MHE.(61) A modified treatment algorithm for patients with MHE based on recommendations from a panel of experts from the United States and Europe is recommended to assist the treating physician (Figure 1).(62)

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