Minimal Hepatic Encephalopathy (MHE)

1. Episodic (precipitant-induced) encephalopathy, commonly seen in the hospital setting, where a superimposed event is a key factor. 2. Persistent (chronic) encephalopathy, seen with extensive portal–systemic shunts and after portocaval shunt surgery or placement of transjugular intrahepatic portosystemic shunt (TIPS). 3. Minimal (subclinical) encephalopathy reflects alterations in cognitive function in patients who clinically exhibit a normal mental state.


Introduction
Hepatic encephalopathy (HE) reflects a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other known brain disease.
Classification of hepatic encephalopathy is based on the clinical setting in which symptoms occur (Table 1). 1 The encephalopathy of acute liver failure shares clinical characteristics with that of cirrhosis, but also exhibits unique features. In cirrhosis, three major syndromes can be present: 1. Episodic (precipitant-induced) encephalopathy, commonly seen in the hospital setting, where a superimposed event is a key factor. 2. Persistent (chronic) encephalopathy, seen with extensive portal-systemic shunts and after portocaval shunt surgery or placement of transjugular intrahepatic portosystemic shunt (TIPS). 3. Minimal (subclinical) encephalopathy reflects alterations in cognitive function in patients who clinically exhibit a normal mental state.

Ammonia
There are various explanations why liver dysfunction or portosystemic shunting might lead to encephalopathy. In healthy subjects, intestinal neurotoxins, such as ammonia, manganase and the benzodiazepine-GABA system generated by gut bacteria from food, are transported by the portal vein to the liver, where 80-90% is metabolized and/or excreted immediately. In all subtypes of hepatic encephalopathy this process is impaired, either because the hepatocytes are incapable of metabolizing the neurotoxins or because portal venous blood bypasses the liver through collateral circulation or a medically constructed shunt. Neurotoxins accumulate in the systemic circulation. Ammonia plays a key role in the pathogenesis of HE. The small molecules of ammonia cross the blood-brain barrier and are absorbed and metabolized by astrocytes, population of cells in the brain that constitutes 30% of the cerebral cortex. Alzheimer type II astrocytes are the only cells containing glutamine synthetase that metabolize ammonia. It is hypothesed that glutamine synthesis within the astrocytes causes brain swelling. 14,15 Astrocytes also provide physical and nutritional support for neurons, maintain the integrity of the blood-brain barrier and regulate cerebral blood flow. 16 Ammonia also modulates glutamate neurotransmission and induces neurosteroid production in neurons, leading to a positive modulatory effect on the gammaaminobutyric acid-A receptor. 17 The precise molecular mechanism(s) responsible for neurological alteration in HE are not known. HE is associated with alterations in the expression of astrocytic and neuronal genes that code for various proteins that play a critical role in central nervous system function including maintenance of cell volume and neurotransmission. 14 The pathogenesis of MHE is similar to that of HE. [18][19][20][21][22] An increase in brain glutamine and brain water is pathophysiological change associated with deterioration in neuropsychological performance. Alterations in cerebral blood flow and glucose metabolism induced by ammonia are associated with a significant decrease of glucose utilization by various cortical regions that are involved in cognitive functions. 21 The cerebral metabolic rate for ammonia and the permeability-surface area product for ammonia are significantly higher in patients with MHE. 21 The increased permeability-surface area product of the blood-brain barrier permits ammonia to diffuse across the blood-brain barrier into the brain more freely than normal. This may cause ammonia-induced encephalopathy even though arterial ammonia levels are normal or near normal.
Cognitive deficits observed in patients with noncirrhotic portal hypertension have also been linked to ammonia. 18 Patients with noncirrhotic portal hypertension, such as extrahepatic portal venous obstruction, exhibited abnormalities in the results of neuropsychological tests, oral glutamine challenge test, and magnetic resonance (MR) imaging and spectroscopy similar to those described in HE associated with cirrhosis. 22 Other waste products implicated in hepatic encephalopathy include mercaptans (substances containing a thiol group), short-chain fatty acids and phenol.23

Serotonin
Serotonin, a neurotransmitter with widespread distribution in the CNS, is important for the regulation of sleep, circadian rhythmicity and locomotion. Changes in the synthesis, metabolism, storage and release of neuronal serotonin in HE suggest a serotonergic synaptic www.intechopen.com Miscellanea on Encephalopathies -A Second Look 4 deficit. Serotonin metabolism is exquisitely and selectively sensitive to the degree of portosystemic shunting and hyperammonaemia, suggesting a role for serotonin in early neuropsychiatric symptoms of HE. 24

Branched-chain amino acids (BCAA) and false neurotransmitters
An imbalans between aromatic aminoacids (AAA) (phenylalanine, tryptophan and tyrosine) and branched-chain amino acids (BCAA)(leucine, isoleucine and valine) has been described in patients with severe liver dysfunction. AAA and BCAA share a common transport mechanism into the CNS. AS a consequence of increased concentration of AAA, neuronal levels may be raised leading to the production of false neurotransmitters (octopamide and phenylethanolamide) 25 with subsequent development of HE. 26

Zink
Zinc is a substrate of urea cycle enzymes. It may be depleted in patients with cirrhosis. Zinc supplementation increases the activity of ornithine transcarbamalyse increasing excretion of ammonia ions. There is conflicting clinical data regarding zinc supplementation in the management of HE. 27,28,29

Manganese
Manganese is a neurotoxin that accumulates in the brains of patients with cirrhosis and portosystemic shunts. 30,31 Levels of manganase correlate with hyperintensity of nucleus pallidus seen on MR brain scans of patients with cirrhosis. These patients may also demonstrate extrapyramidal signs, suggesting that altered homeostasis of manganese and other minerals could be responsible for the cognitive deficits associated with liver cirrhosis.

Systemic inflammatory response
Iinflammatory response may be important factor that may contribute to the development of MHE and its progression to OHE. Inflammation elsewhere in the body may precipitate encephalopathy through the action of cytokines and bacterial lipopolysaccharide on astrocytes. 32 A recent study reported that severity of MHE was independent of severity of liver disease and levels of blood ammonia but markers of inflammation (higher neutrophil counts, C-reactive protein levels, and interleukin-6 levels) were significantly higher in those with MHE compared to those without MHE. 33 Same authors showed that induced hyperammonemia resulted in significantly greater deterioration in psychometric tests in cirrhotic patients who had an ongoing infection compared with those in whom the infection had resolved. 34 These two studies suggest that inflammation plays a synergistic role with ammonia in producing and modulating MHE.

Intestinal flora
Intestinal flora and endotoxins are another link between inflamation, ammonia and MHE. Imbalance of intestinal flora among cirrhotics compared to normal healthy controls has been demonstrated in the study of Zhao et al. 35 They found increase in the counts of aerobes (such as Enterobacter and Enterococcus) and anaerobes (such as Clostridium) and a decrease in www.intechopen.com Minimal Hepatic Encephalopathy (MHE) 5 the count of Bifidobacterium. The severity of imbalance in intestinal flora matched the degree of liver dysfunction. Liu et al. 36 reported that cirrhotic patients with MHE had substantial derangements in the gut microecology, with significant fecal overgrowth of potentially pathogenic Escherichia coli and Staphylococcus species. Treatment with synbiotics significantly increased the fecal content of non-urease-producing Lactobacillus species at the expense of these other bacterial species. Such modulation of gut flora was associated with a significant reduction in blood ammonia levels and reversal of MHE in 50% of patients. Synbiotic treatment was also associated with a significant reduction in endotoxemia. The CTP functional class improved in nearly 50% of the patients.

Clinical characteristics
OHE is traditionally classified into four grades according to the West Haven criteria (   37 A higher frequency of sleep disturbance in cirrhotic patients with MHE has been confirmed in studies using HRQOL questionaires. 39,40 Sleep disturbance in cirrhosis is not associated with cognitive impairment; thus it may not truly be an MHE symptom. Unsatisfactory sleep is associated with higher scores for depression and anxiety, raising the possibility that the effects of chronic disease may underlie the pathogenesis of sleep disturbance. 41 Disturbances in cirrhotics may also be related to abnormalities of circadian rhythm.

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Defective memory may be a signe of MHE. Patients with MHE have impaired short-and long-term memory. 38 This impairment is predominantly related to deficits in attention and visual perception. 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 (or retrieval) is intact.
Several cognitive statements (i.e. complaints), have predictive value for MHE, including impaired psychomotor performance ('I have difficulty doing handwork; I am not working at all'); impaired sleep or rest ('I spend much of the day lying down in order to rest'); decreased attention ('I am confused and start several actions at a time'); and poor memory ('I forget a lot; for example, things that happened recently, where I put things, etc.'). 41

Effect of MHE on daily functioning
MHE adversely affects HRQOL. Cognitive impairment in MHE mainly affects complex activities involving attention, information processing and psychomotor skills such as driving a car, planning a trip, etc. whereas basic activities of daily life, such as shopping, dressing, personal hygiene, etc. are preserved. 39,42,43 Patients with MHE had a significant impairment of daily functioning, such as social interaction, alertness, emotional behavior, sleep, work, home management, recreation and pastimes compared with cirrhotic patients who did not have MHE. 39,42 Treatment with lactulose improved both cognitive functions and HRQOL; improvement in the latter was linked to improvement in cognitive function. 39

Effect of MHE on driving
MHE adversely affects driving skills. Patients with MHE have higher rates of traffic violations and motor vehicle accidents. 41 Schomerus et al. 44 were the first to demonstrate a negative effect of psychomotor deficits in patients with MHE on driving fitness. Similar results were reported by Watanabe et al. 45 Wein et al. 46 found that the fitness to drive a car was impaired in cirrhotic patients with MHE using a standarizad 90-minute on-road driving test. Increased risk of automobile accidents was related to a decline in cognitive function. 47 Impairment in attention and speed of mental processing adversely affects an individual's ability to react to unexpected traffic conditions. Patients with MHE have higher rates of traffic violations and motor vehicle accidents. [47][48][49][50] Patients with MHE also had impaired navigation skills. 51 Navigation, required for safe driving, is a complex process that depends on functioning working memory, attention, and speed of mental processing; impairment in navigation skills correlated with impairment in response inhibition and attention.

Diagnosis of MHE
The absence of clinical evidence of hepatic encephalopathy is key to the diagnosis of MHE and can only be determined by a detailed assessment of the patient history and a comprehensive neurological assessment of consciousness, cognitive, and motor function.
Various tools have been evaluated for the diagnosis of MHE and include the neuropsychological tests, computerized tests, short neuropsychological and computerized test batteries and neurophysiological tests. Regional cerebral blood flow changes, 52 and www.intechopen.com Minimal Hepatic Encephalopathy (MHE) 7 magnetic resonance imaging and spectroscopy, 53 though useful for understanding pathogenic mechanisms, are currently not considered of diagnostic value.

Neuropsychological tests
Neuropsychological testing is an established methodology for quantifying cognitive impairment due to various forms of encephalopathy, including low-grade or minimal hepatic encephalopathy. Neropsychological tests directly measure cognitive functions that are directly relevant to activities of daily living. They have been applied for the diagnosis of HE for more than 50 years. In the fifties, measures like the construction or reproduction of a fivepointed star (Fig.1.) or a coil and handwriting have been used for the diagnosis of HE. Someties even more complex figures were presented to the patients to be reproducted. Although all tests were able to depict an increase or decrease of the constructional ability of a patients it was extremely difficult to quantify the test result. In general, psychometric tests have to fulfill the following criteria: they have to be objective, reliable, valid and sensitive. 54

Fig. 1. Star construction test
The neuropsychological features of MHE point to a disorder of executive functioning, particularly selective attention, visuospatial abilities and fine motor skills . 4 Although these domains are most commonly implicated in MHE, impairments of memory have also been reported. 55,56 The  64,65 Fine motor skill impairments have been noted on measures such as the grooved pegboard task, 57,58 and on line tracing tasks (the latter also involve visuospatial abilities). 66,67 Psychometric test batteries that shall be used for the diagnosis of MHE ought to examine exactly the fields of cognition: visual perception, visuo-spatial orientation, visual construction, concentration, attention and memory. 29 The small number of neuropsychological tests represent the cerebral disfunction of MHE. The number connection test (NCT) is the most widely used test in the psychometric assessment of cirrhotic patients. It was found to be capable of detecting mild mental dysfunction in cirrhotic patients.
The NCT-A (Fig.2) is a test of visuo-spatial orientation and psychomotor speed. The subject is shown a sheet of paper with 25 numbered circles which are randomly spread over the paper. The task is to connect the circles from 1-25 as quick as possible. Test result is the time needed by the subject including error correction time. 68 The NCT-B (Fig.3) is quite similar.The circles include the numbers from 1-13 and the letters from A-L. The subjects are asked to connect numbers and letters in alternating manner, that means go from 1-A-2-B-3-C and so on. Test result is the time needed including error correction time. Besides visuo-spatial orientation and psychomotor speed this test is appropriate to study the ability to shift attention. 68 The Block Design Test (BDT) is a test of visuo-spatial and motor skills (Fig.4). The task is to take 6-9 blocks that have all white sides, all red sides, and red and white sides and arrange them according to a pattern formed by examiner or shown on a card. Scored for speed and accuracy. 69 www.intechopen.com The line drawing test (Fig. 6) is a test of motor speed and accuracy. The patients have to follow the route of this labyrinth without crossing or even touching the borderlines. 70 The circle dotting test (Fig.8) is the most simple test of the battery. It is a test of pure motor speed. The subjects are asked to put a dot in each of the 100 circles given on the sheet, after they have prepared by dotting the 20 circles at the top of the sheet, first. Test result is the time needed. In 2009, the Commission on Neuropsychological Assessment of Hepatic Encephalopathy concluded that neuropsychological test batteries aimed at measuring multiple domains of cognitive function are generally more reliable than single tests, and tend to be more strongly correlated with functional status. 71 Both the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 72 and PSE-Syndrom-Test 73 may be used for this purpose.
The PSE-Syndrom-Test, developed in Germany and validated in several other European countries, incorporates older assessment tools such as NCT-A and NCT-B, the line-tracing test (LTT), the serial-dotting test (SDT), and DST.
The psychometric hepatic encephalopathy score (PHES) is a standardized test battery including NCT-A and B, the line-tracing test for time (t) and error (e), the serial-dotting test, and the digit symbol test. This battery examines many of the abnormalities seen in patients with MHE, including motor speed and accuracy, visuo-spatial orientation, visual perception, visual construction, attention, concentration, and, to a lesser extent, memory. PHES has a prognostic value for the occurrence of overt HE and mortality in cirrhotic patients. 74,75 12 The RBANS contains measures of verbal and visual anterograde memory, working memory, cognitive processing speed, language (including semantic fluency) and visuospatial function (line orientation and figure copy). It is a portable pencil-and-paper test that requires a folding stimulus booklet and paper record form to administer. Administration time is approximately 20-25 min. 71 In the study of Sorrel et al. 76 RBANS scores were strongly correlated with liver disease as measured by the model for end-stage liver disease staging. Scores on the RBANS also predicted disability independently of liver disease severity in this study.
Use of either the RBANS or the PSE-Syndrom-Test is recommended for diagnosing and monitoring minimal hepatic encephalopathy. The choice of which battery to use should be based upon the availability of local translations and normative data. 71
Changes in EEG/evoked responses are non-specific.
The major finding on EEG is a general decrease in wave frequency and an increase in wave amplitude. First, socalled theta-waves with a frequency between 4 and 7 cps occur, then these theta waves predominate and are committed by delta waves with a frequency of 1-3 cps. Preterminally there is a loss of wave amplitude and a flattening of the curve. These abnormalities may be found even in cirrhotics without clinical signs of encephalopathy. There is no close correlation between the grade of HE and the degree of EEG abnormalities. 70 The sensitivity of the EEG for the diagnosis of subclinical HE is limited compared to psychometric tests. 70 The EEG is useful for follow-up examinations, predominantly.
Among EEG variations, the most sensitive test is computer-assisted analysis, including the mean dominant EEG frequency and the power of a particular rhythm. 77,78 Quantified-EEG has a prognostic value for occurrence of bouts of overt HE and mortality in cirrhotic patients. 78 Evoked potentials are subdivided into the group of exogenous evoked potentials and endogenous evoked potentials. The exogenous evoked potentials like the flash or checkerboard visual evoked potentials (VEP), brainstem auditory evoked potentials (BAEP) and somatosensory evoked potentials are used to examine the function of sensory pathways. The endogenous evoked potentials are measures of cognitive function. In the only study that compares the different exogenous evoked potentials for their diagnostic ensitivity in hepatic encephalopathy, the BAEP were the most sensitive measure for the diagnosis of HE. 79 Among evoked responses, the P300 peak obtained in an auditory oddball paradigm is the most sensitive test. [80][81][82][83] These tests can supplement neurological or neuropsychiatric examination. It has been demonstrated that there was a greater likelihood of development of overt HE in cirrhotic patients with abnormal P300 event-related potential latencies and NCT than in patients with no such abnormality. 80 www.intechopen.com

Minimal Hepatic Encephalopathy (MHE) 13
Neurophysiological tests can be used during follow up to demonstrate change in a patient's condition. Their major limitations are: (i) need for specialized equipment and technical expertise for evaluation and interpretation; and (ii) inability to perform these tests in an outpatient clinic. 41 The changes observed in cerebral blood flow and metabolism in SPET, PET, and 1 H and 31 P MRS studies reflect the pathogenic process that underlies the condition rather than providing diagnostic information. Similarly, the morphological brain abnormalities identified in this population, including mild brain oedema, hyperintensity of the globus pallidus and other subcortical nuclei observed in cerebral MR studies, and the central and cortical atrophy observed in neural imaging studies, are unlikely to have diagnostic utility. 4

Computerized tests
Computerized psychometric tests measuring both the reaction time and the accuracy of performing tasks requiring psychomotor speed, attention, short-term memory, or choice ability.
Critical flicker frequency (CFF) tests the ability of a patient to perceive flickering and its fusion threshold. The CFF threshold measures visual discrimination and general arousal. 84 CFF is a simple, reliable and accurate method for the diagnosis of MHE. The technique shows little dependence on age, education or training. 75,85 Inhibitory control test (ICT) is a computerized test of attention and response inhibition that has been used to characterize attention deficit disorder, schizophrenia and traumatic brain injury. ICT has been validated for the diagnosis of MHE in USA and found to be reliable and sensitive for detection as well as follow-up of patients with MHE. 86

Magnetic resonance imaging and spectroscopy
Magnetic resonance imaging (MRI) identified the morphological brain abnormalities in the population of patients with cirrhosis, including mild brain oedema, hyperintensity of the globus pallidus and other subcortical nuclei, and central and cortical atrophy. High-signal abnormalities on T1-weighted images in the globus pallidum have been observed in cirrhotic patients, even without clinical evidence of HE. Deposition of manganese is regarded as the most likely explanation of this high-signal abnormality. 87 There is no direct correlation between pallidal hyperintensity and grade of encephalopathy. 88 Basal ganglia T1-weighted signal intensity and manganese accumulation appear to be related to the underlying degree of portal-systemic shunting rather than directly to neuropsychiatric impairment. 90  Magnetic resonance spectroscopy (MRS) shows a decrease in myo-inositol/creatine and choline/creatine ratios in the white matter with an increase in the Glx (glutamine and glutamate) concentration in the basal ganglia in patients with MHE. 91,92 Liver transplantation as well as lactulose therapy have been shown to reverse these changes at 4 weeks and later after transplantation. 91 However, the ability of MRS to differentiate between cirrhotic patients without HE and those with MHE has not been conclusively shown. 41 Diffusion-weighted imaging allows assessment of intracellular and extracellular water content in the brain, which helps in differentiating cytotoxic from vasogenic edema. 93 Diffusion tensor imaging has revealed that mean diffusivity, a measure of water movement across cell membranes, is significantly higher in patients with MHE in the regions of the corpus callosum, internal capsules, caudate nuclei and occipital white matter. Increase in mean diffusivity indicates the presence of interstitial brain edema. Mean diffusivity values increase as the grade of HE increases, suggesting that brain edema present in patients with HE may contribute to its pathogenesis. 94 Mean diffusivity values decreased significantly and there was a corresponding improvement in neuropsychological test scores in patients with MHE after three weeks of lactulose therapy. 94 MR imaging techniques therefore complement neuropsychological evaluation of MHE. 41

Diagnostic criteria for MHE
The diagnostic criteria for MHE have not been standardized but rest on careful patient history and physical examination, normal mental status examination, demonstration of abnormalities in cognition and/or neurophysiological function, and exclusion of concomitant neurological disorders.
No consensus on diagnostic criteria or diagnostic tests has been established.

Development of overt hepatic encephalopathy
Patients with MHE may improve, remain unchanged or deteriorate and develop overt HE over a long-term follow-up.
The frequency of MHE increases as the severity of liver disease increases. 4,[13][14][15][16]18,22 In view of a high frequency of MHE in patients with liver disease, it is important to understand its impact on future clinical outcomes, such as occurrence of overt HE, quality of life and survival, and to determine whether treatment of MHE can induce improvements in these outcomes.
Several studies that looked at the frequency of development of overt HE in cirrhotic patients found that those with MHE developed overt HE more often during follow up than those without MHE (Table 4). 4,15,17,20,48,88,89 In addition, some studies have shown an increased risk of death in patients with liver cirrhosis and MHE compared to those without MHE (Table 4).20,22,88 However, patients with MHE had poorer liver function than those without MHE in these studies, making it difficult to ascribe the poor outcome to the presence of MHE. Das et al.4 studied the relationship of progression of MHE to overt HE in relation to the severity of liver dysfunction and found that the rate of progression to overt HE was much higher in patients with MHE and a CTP score 6 than in those with MHE and a CTP score _ 6. Amodio et al. 88 found that the presence of MHE and that of liver dysfunction were both associated with mortality on univariate analysis; however, on multivariate analysis, liver functional status was the only independent predictor of mortality. In another study, progression of MHE to overt HE was associated with abnormal response to oral glutamine challenge, which in turn was associated with poor liver function.90 Furthermore, MHE in patients with preserved liver function but large portalsystemic shunts (congenital shunts, non-cirrhotic portal hypertension and cirrhosis with preserved liver function) appears to have a good outcome, even though these data are based on a small number of patients. 10 Thus, it appears that the higher risk of overt HE or death in patients with MHE may not be related to MHE per se but to the poorer liver function in patients with MHE.

Survival
Current data suggest that patients with MHE tend to have more frequent episodes of overt HE and poorer survival than in those without MHE, and indicate that patients with MHE have a more advanced liver disease. Child-Turcotte-Pugh score and PHES were associated with a poor prognosis

Treatment
Ammonia plays a key role in the pathogenesis of MHE Empiric therapy is based on the principle of reducing the production and absorption of ammonia in the gut-a number of agents are beneficial for this purpose.

Nutritional interventions
The European Society for Parenteral and Enteral Nutrition recommended, in 2006, that patients with cirrhosis must eat at least 1.2 g/kg of protein daily. They also recommended that the diet of patients with cirrhosis should be supplemented with branched-chain amino acids (BCAAs) and vegetable protein once HE has developed. Vegetable-based protein is better tolerated by patients with cirrhosis than meat-based protein .

Pharmacological therapy
Non-absorbable disaccharides include lactulose and lactitol. Treatment for MHE may be initiated with lactulose; patients should receive 30-60 mL of lactulose in two or three divided doses so that they pass two to three semi-soft stools per day. Although the appropriate duration of therapy for MHE is unsettled, at least three studies suggest that treatment may be advised for 3-6 months. (3,67,95) Lactulose decreases blood ammonia levels, and improves psychometric performance and HRQOL ( Branched-chain amino acids, flumazenil, L-ornithine L-aspartate, acetyl L-carnitine, and probiotics/synbiotics. A majority of these attempts were aimed at reducing blood ammonia level, and most studies have shown improvement in psychometric measurements, ammonia levels, cerebral edema and health-related quality of life (HRQoL)

Prebiotics, probiotics or synbiotics
Prebiotics, probiotics or synbiotics (probiotics and fermentable fiber) are effective in treating patients with MHE,63-67 and can also be used as long-term therapy. Liu et al. 65 showed that modulation of gut microecology and acidification of gut lumen in patients with liver cirrhosis and MHE by treatment with synbiotics resulted in increased fecal content of nonurease-producing Lactobacillus species, whereas the number of urease-producing pathogenic Escherichia coli and Staphylococcal species decreased. This effect persisted for 14 days after cessation of supplementation. It was associated with a significant reduction in blood ammonia and endotoxin levels and reversal ofMHEin nearly 50% of the patients. The severity of liver disease, as assessed according to CTP class, also improved in nearly 50% of the patients. In a recent randomized control trial, supplementation with probiotic yogurt resulted in a significant reversal ofMHEin the group receiving yogurt compared to no treatment.63 Treatment with a probiotic preparation also improves HROQL.67 Prebiotics, probiotics or synbiotics are efficacious in the treatment of HE by decreasing bacterial urease activity, pH in the gut lumen, ammonia absorption and total ammonia in the portal blood, and by improving nutritional status of gut epithelium resulting in decreasing intestinal permeability. In addition, they help ameliorate the inflammation and oxidative stress in the hepatocytes, leading to increased hepatic clearance of ammonia.98 These mechanisms may be additive or synergistic in treating MHE. Probiotics may represent a safe, effective, long-term therapy for MHE and may be an alternative to lactulose.

L-ornithine-L-aspartate
Clinical studies evaluating the role of LOLA in the treatment of MHE did not show its effectiveness; however, these studies were small and underpowered. A recent study that compared lactulose, a probiotic and LOLA with no treatment, however, showed that LOLA is as effective as lactulose or a probiotic preparation in improving psychometric performance and HRQOL.67 Larger prospective studies are warranted to evaluate the role of LOLA before it can be recommended for the treatment of MHE.

Antibiotics
The role of antibiotics in MHE has not been evaluated. Prospective studies with poorly absorbed antibiotics are required to evaluate their efficacy in improving MHE.