  cirrhosis of the liver  the only cure for which is liver transplant  is associated with several serious complications , including ascites , spontaneous bacterial peritonitis , variceal bleeding , and hepatic encephalopathy ( he ) .
guidelines established by the american association for the study of liver diseases currently recommend referring patients with cirrhosis for liver transplant when their model for end - stage liver disease ( meld ) score is 10 and their child - turcotte - pugh ( ctp ) score is 7 or when they experience their first major complication ( e.g. , he , ascites , or variceal bleeding ) .
however , the current united network for organ sharing allocation system only uses the meld score for prioritizing adults for liver transplant . the meld scoring system evaluates a patient 's short - term prognosis based on 3 common laboratory test results : serum bilirubin , international normalized ratio , and serum creatinine levels .
however , this scoring system does not take into account several serious complications of cirrhosis , such as he , when prioritizing patients for liver transplant .
this may have negative ramifications for patient care , as the development of he may be associated with substantial morbidity , mortality , and cost .  
he imposes a significant burden on patients , their families , and health care resources [ 5 , 6 ] .
he is characterized by alterations in behavior , cognitive abilities , consciousness , and neuromuscular function .
it negatively affects patient quality of life ( qol ) , and patients may be unable to drive , work , or adequately care for themselves because of its effects [ 811 ] .
patients may be less compliant with all prescribed medications , and hospitalizations related to he may increase patient exposure to opportunistic infections and be associated with substantial costs .
furthermore , he may be an independent predictor of mortality in patients with chronic liver disease .
he occurring before liver transplant can also have a substantial negative impact on posttransplant outcomes [ 1322 ] .
this paper will review the potential consequences of pretransplant he on posttransplant outcomes and therapeutic strategies for the pretransplant management of he .
he may occur in patients with acute liver failure ( type a he ) , in patients with portosystemic shunting but no intrinsic hepatocellular disease ( type b he ) , or , as in the majority of he cases , in patients with cirrhosis and cirrhosis - related portosystemic shunting ( type c he ) . because he is a progressive neuropsychiatric condition ,
he may be graded or scored based on the severity of the clinical manifestations , which may range from subtle neurologic abnormalities in mild cases to coma in severe cases .
minimal he ( sometimes referred to as covert he ) , which may occur in nearly 70% of patients with cirrhosis , is not associated with any clinical signs of brain dysfunction , but patients experience cognitive abnormalities that can lead to qol impairment [ 8 , 24 , 25 ] . unlike minimal he , overt he can manifest as a wide spectrum of symptoms that can be observed clinically , including those related to motor and neuropsychologic functions .
overt he has been shown to occur in nearly half of patients with cirrhosis   and , as with minimal he , also has a substantial negative impact on qol [ 710 ] .  
although research is ongoing , the pathogenesis of he is believed to primarily involve the exposure of the brain to elevated neurotoxin levels , particularly ammonia and other gut - derived toxins , leading to cellular morphologic changes ( e.g. , astrocyte swelling ) and the development of a variety of neurochemical , neurotransmitter , and neuroinflammatory changes [ 27 , 28 ] .
many factors that can precipitate he ( e.g. , hypokalemia , infection , and gastrointestinal bleeding ) serve to increase the production of ammonia or other gut - derived toxins or to reduce toxin metabolism by the liver ( e.g. , dehydration , anemia ) . although the exact pathophysiology of he is unclear , data are accumulating to suggest that the cascade of neuropsychiatric and neuromuscular sequelae of he may have a longer term or more permanent negative impact on patients with chronic liver disease than originally suspected .
  neurologic complications are common following liver transplant and may include alterations in mental status , seizures , and focal motor deficits .
the majority ( 75% ) of these complications are observed within the first month after liver transplant , suggesting a possible relationship between preoperative status and liver transplant rather than the effect of immunosuppression [ 13 , 19 , 31 ] .
however , neurologic complications may be observed in the long term , even 1 year after transplant [ 19 , 32 ] . of the neurologic complications ,
encephalopathy is most commonly observed , although the reported incidence has varied widely from 12% to 84% of patients at some point postoperatively [ 19 , 20 , 31 , 3336 ] .
a variety of factors may cause neurologic complications , including encephalopathy , infection ( e.g. , sepsis ) , perioperative complications , persistence of major portosystemic shunts , and immunosuppressant - associated toxicity .
neurologic complications have also been associated with a greater risk of patient mortality [ 13 , 37 ] .
thus , encephalopathy can be seen as a neurologic complication in itself and as a potential cause of neurologic complications .  
preoperative history of he is a significant predictor of posttransplant neurologic complications . in a prospective analysis of 84 patients with chronic liver disease
who had undergone a liver transplant , the presence of an abnormal neurologic exam suggestive of he before transplant was an independent risk factor for developing in - hospital central nervous system complications after transplant ( p = 0.007 ) . in a retrospective study of 101 patients who had undergone a liver transplant , a history of he
was strongly associated with neurologic complications after transplant ( univariate odds ratio ( or ) , 2.6 ; 95% confidence interval ( ci ) , 1.16.4 ; p = 0.03 ) .
furthermore , using a multivariate analysis , he in the immediate preoperative period was associated with posttransplant neurologic complications ( adjusted or , 10.7 ; 95% ci , 3.829.9 ; p < 0.013 ) .  
data continue to accumulate suggesting that even with resolution of prior episodes of overt he , patients may continue to have cognitive deficits after transplant .
patients who had undergone a liver transplant , on average 17 to 19 months previously , received a battery of cognitive tests ( e.g. , psychometric hepatic encephalopathy score ( phes ) and repeatable battery for the assessment of neuropsychological status ( rbans ; pearson education inc .
, san antonio , tx ) ) to determine if the presence of he before liver transplant was associated with more substantial neurocognitive abnormalities within about 1.5 years after transplant .
patients with a history of he before transplant ( n = 25 ) had significantly lower scores for 3 of 6 phes domains compared with healthy individuals ( n = 20 ) and for 2 of 6 phes domains ( attention domains ) compared with patients without he before transplant ( n = 14 ; figure 1 ) .
the investigators of this study did not determine the total phes score because of a lack of available normative values .
for rbans , patients with a history of he before transplant had significantly lower scores compared with healthy individuals in total rbans score and 4 of the 5 rbans subscores ( p < 0.05 ) . although the total rbans score , immediate memory , delayed memory , and attention subscores were lower for patients with he before transplant than for patients without he before transplant , no significant differences were observed .   in cross - sectional ( n = 226 ) and prospective assessments ( n = 59 ) of patients with cirrhosis , patients who had experienced overt he had greater cognitive dysfunction compared with patients without overt he . patients who had an episode of overt he had persistent impairment in cognitive function despite normalization of mental status on lactulose therapy , and the severity of impairment increased with the number of overt he episodes .
thus , patients who experience overt he may have persistent and cumulative deficits in working memory , response inhibitor , and learning that are chronic , cumulative , and not readily reversible ( i.e. , permanent ) .
although not studied in patients who had eventually undergone a liver transplant , persistent cognitive impairment after overt he was also supported by a study in 106 patients with cirrhosis currently without overt he who were examined on 2 occasions within a 3-day period for the presence of mild cognitive impairment ( phes ) . among 45 patients ( 42% ) without a history of overt he and 34 patients ( 32% ) without a history of overt he but with a current diagnosis of minimal he , phes results improved significantly from the first to the second exam ( p = 0.04 and p = 0.016 , resp . ) , suggesting a learning capacity for taking the tests involved in phes . however , there was no significant improvement in phes results at the second exam for the 27 patients ( 25% ) who had experienced at least 1 prior episode of overt he , indicating a lack of learning capacity in patients with a history of overt he .
therefore , patients with a history of overt he may have persistent cognitive impairment despite having a normal mental status and , in some cases , even in the presence of normal cognitive test results ( phes ) , which further supports the hypothesis that he is not a fully reversible condition .  
evidence also exists for the posttransplant persistence of cognitive dysfunction or radiologic abnormalities in patients exhibiting minimal he before transplant [ 1418 ] . in a small prospective study , 14 patients with minimal he underwent liver transplant and were assessed for visuomotor function ( average time of assessment , 21 months after transplant ) .
improvement of visuomotor and visuoconstructive skills ( e.g. , trail making tests , reconstruction of drawing , or picture ) was observed in some patients after transplant , but worsening was observed in others . of note , no significant improvement in posttransplant visuomotor and visuoconstructive performance was noted compared with pretreatment performance , with 50% of patients showing deterioration in performance . in addition ,
mean posttransplant results for the 14 patients with minimal he were significantly lower than for 22 age - matched healthy individuals ( p = 0.04 ) . in another study of patients with minimal he before transplant ( n = 23 ) , most assessed cognitive functions improved at 6 months after transplant , with some cognitive functions improving only 18 months after transplant ( e.g. , verbal short - term memory ) .  
data support the hypothesis that patients with a history of he before transplant can have more pronounced cognitive dysfunction after transplant than patients without a history of he .
however , results are confounded by some studies that suggest almost complete normalization of radiologic findings after transplant , including gradual normalization of glutamine / glutamate and choline signals in a majority of patients as measured by magnetic resonance spectroscopy [ 40 , 41 ] .
in addition , the mechanisms by which more pronounced posttransplant cognitive impairment occurs in patients with pretransplant histories of he are unclear , especially the lack of clearly defined variables that may play a role in short - term or long - term cognitive dysfunction . in a prospective study of 52 patients with cirrhosis who had a liver transplant ( 54% with minimal
he and 0% with overt he ) , cognitive function significantly improved from pretransplant values for memory , attention , executive function , motor function , and visuospatial domains of the battery of tests administered ( p < 0.05 ) . however , 13% of patients still had global cognitive impairment 6 to 12 months after transplant .
in addition , after liver transplant , cognitive function in patients with cirrhosis of alcoholic etiology , diabetes mellitus , and prior he was more severely impaired compared with patients without these factors .
posttransplant patients with alcohol - induced cirrhosis had memory decline , patients with diabetes mellitus exhibited attention impairment , and patients with histories of he had impaired motor function ( figure 2 ) .
a multivariate analysis indicated that prior he , diabetes mellitus , and cirrhosis of alcoholic etiology were considered risk factors for poor cognitive function that persists after transplant .
more research is necessary to gain a clearer understanding of the key demographics and disease characteristics that are involved to better identify patient subpopulations that are at the greatest risk for posttransplant neurologic complications .
the development of minimal or overt he before liver transplant may affect posttransplant outcomes , and he is a probable risk factor for neuropsychiatric symptoms after transplantation . therefore , although the cause of neuropsychiatric symptoms following a liver transplant is likely multifactorial , improving patient he status before transplant may improve posttransplant outcomes .
current pharmacologic therapies for he are primarily directed at reducing the systemic levels of ammonia and other toxins produced in the gastrointestinal tract , thereby reducing cerebral exposure .
patients may be treated for minimal he , overt he , or the prevention of he relapse
. however , most patients with minimal he do not currently receive treatment outside the context of clinical trials . in all of these cases , the mainstays of therapy are nonabsorbable disaccharides and antibiotics .
nonabsorbable disaccharides , such as lactulose and lactitol ( not available in the united states ) , are metabolized in the colon by intestinal bacteria , resulting in a reduction in colonic ph .
the acidic environment promotes uptake of ammonia by colonic bacteria , facilitates diffusion of ammonia from the blood into the intestine , and may reduce the survival of urease - producing bacteria .
nonabsorbable disaccharides also increase the osmotic pressure of the intestinal lumen , which induces catharsis and elimination of potential sources of gut - derived toxins from the body .
a 2004 meta - analysis of 22 randomized studies was conducted to evaluate the efficacy of nonabsorbable disaccharides compared with no treatment , placebo , or antibiotics in patients with acute , chronic , or minimal he .
nonabsorbable disaccharides appeared to improve he ( i.e. , reduced the risk of no improvement ) when compared with no intervention or placebo ( p = 0.002 ) .
however , when studies of poor methodologic quality were removed from the analysis , no significant effect was observed in the few high - quality trials that had been conducted . in addition
, nonabsorbable disaccharides had no significant effect on mortality compared with no treatment or placebo intervention .
the authors concluded that there was insufficient evidence to support or contest the use of lactulose or lactitol for the treatment of he .
a 2011 meta - analysis of 5 studies specifically evaluated nonabsorbable disaccharides for the treatment of minimal he and concluded that compared with placebo these agents significantly improved minimal he ( i.e. , reduced the risk of no improvement ) ( p < 0.0001 ) .
another 2011 meta - analysis of 9 studies evaluating lactulose for the treatment of minimal he confirmed that lactulose prevented the progression to overt he , compared with either placebo or no intervention .
subsequent to this analysis , an open - label randomized study concluded lactulose to be effective for the primary prophylaxis of overt he in patients with cirrhosis .
twenty ( 19% ) of 105 patients followed for 12 months developed an episode of overt he , six ( 11% ) in the lactulose group and 14 ( 28% ) in the nonlactulose treated group ( p = 0.02 ) .
however , consistent with other studies , no significant difference in mortality was observed ( p = 0.16 ) . in the 2004 meta - analysis ,
nonabsorbable disaccharides were significantly less effective than antibiotics in improving he ( i.e. , they were associated with a higher risk of no he improvement ; p = 0.03 ) and did not have a significantly different impact on mortality .
patients with he who received nonabsorbable disaccharides also had higher blood ammonia levels after treatment compared with patients who received antibiotics . however , a separate meta - analysis reported similar efficacy between antibiotics and nonabsorbable disaccharides in improving he .
in addition , a few studies have evaluated nonabsorbable disaccharides for the prevention of he recurrence ( i.e. , secondary prophylaxis ) [ 4851 ] . in 1 randomized , and unblinded , placebo - controlled study , 140 patients with cirrhosis who had recovered from a previous he episode were randomly assigned within 1 week of recovery to receive either lactulose 30 to 60  ml / d ( n = 70 ) or placebo ( n = 70 ) .
thirteen patients ( 9% ) were lost to follow - up ; 61 patients in the lactulose group and 64 patients in the placebo group were followed for a median of 14 months ( range , 120 months ) .
lactulose significantly reduced the percentage of patients who experienced overt he recurrence compared with placebo ( 20% versus 47% , resp . ;
however , no significant difference in the median time of he recurrence was observed ( 7.5 months ( range , 113 months ) versus 6.0 months ( range , 215 months ) , resp . ) .
in addition , no significant differences between the 2 groups were reported in admissions to the liver intensive care unit for conditions other than he or deaths during the study .  
adverse events ( aes ) associated with nonabsorbable disaccharides are commonly gastrointestinal - related and include abdominal pain , diarrhea , flatulence , and nausea .
diarrhea can also lead to secondary complications , including dehydration , hypokalemia , and hypernatremia .
anorexia and vomiting have also been reported as aes occurring with use of nonabsorbable disaccharides ( rate of 2% for each ) .
one additional concern with lactulose is that administration can cause abdominal distention , which may result in technical difficulties during liver transplant [ 54 , 55 ] .
nutritional status before liver transplant has also been shown to correlate with posttransplant survival   and is independently associated with the number of infection episodes after transplant .
malnutrition , assessed by a subjective global nutritional assessment exam , was found to be an independent risk factor for the length of stay in the intensive care unit and the total number of days spent in the hospital after transplant .
furthermore , alterations in specific laboratory measures ( e.g. , albumin , sodium , and potassium ) [ 5860 ] , which may be negatively impacted by gastrointestinal aes , have also been identified as risk factors for surgical complications in patients who received a liver transplant , and serum sodium levels are a prognostic factor for survival in patients awaiting liver transplant [ 61 , 62 ] .
thus , gastrointestinal aes may increase patient risk , particularly for patients who are prone to malnutrition because of various comorbid variables or conditions ( e.g. , dietary restrictions or gastroparesis ) .
it is possible that administration of nonabsorbable disaccharides such as lactulose may exacerbate pretransplant nutritional deficits , thereby contributing to poor posttransplant outcomes .  
antibiotics are administered to reduce systemic levels of ammonia and other gut - derived toxins by targeting gastrointestinal bacteria . because of the risk for systemic aes and bacterial antibiotic resistance with systemic antibiotics , nonsystemic antibiotics are preferred agents .
rifaximin is a nonsystemic gut - selective antibiotic and more than 20 studies have evaluated rifaximin for the treatment of overt he ( see review by lawrence and klee )   or minimal he [ 6668 ] . in 2010 , rifaximin was approved by the us food and drug administration for the maintenance of overt he remission in adults .   in a randomized , double - blind , phase 3 trial of rifaximin for the maintenance of he remission ,
patients in remission from he were treated with rifaximin 1100  mg / d ( n = 140 ) or placebo ( n = 159 ) for up to 6 months .
concomitant lactulose administration was permitted during the study : 91% of patients in each group received concomitant lactulose .
only 22% of patients in the rifaximin group experienced a breakthrough he episode compared with 46% of patients in the placebo group .
furthermore , rifaximin significantly reduced the risk of he breakthrough by 58% compared with placebo during the 6 months of treatment ( hazard ratio ( hr ) , 0.42 ; 95% ci , 0.280.64 ; p < 0.001 ; figure 4 ) .
data indicated that the number needed to treat ( nnt ) was 4 ( i.e. , for every 4 patients treated with rifaximin for 6 months , 1 episode of breakthrough he would be prevented ) .
in addition , 14% of patients in the rifaximin group reported an he - related hospitalization compared with 23% of patients in the placebo group .
rifaximin significantly ( p = 0.01 ) reduced the risk of he - related hospitalizations by 50% compared with placebo ( hr , 0.50 ; 95% ci , 0.290.87 ) .
data indicated that the nnt was 9 ( i.e. , for every 9 patients treated with rifaximin for 6 months , 1 episode of he - related hospitalization would be prevented ) .
health - related qol in the phase 3 trial was assessed using the chronic liver disease questionnaire ( cldq ) , which was administered every 4 weeks , and the time to he breakthrough recorded [ 70 , 71 ] .
a significant ( p = 0.0087 to 0.0436 ) improvement with rifaximin treatment was noted in the overall cldq scores and in each domain score compared with placebo treatment , and scores were significantly ( p < 0.0001 ) lower in patients who experienced he breakthrough compared with those who remained in remission .   in the phase 3 trial , rifaximin was well tolerated , with a similar incidence of aes reported in both groups .
the most common aes with rifaximin and placebo were nausea ( 14.3% versus 13.2% ) , diarrhea ( 10.7% versus 13.2% ) , fatigue
two cases of clostridium difficile infection ( cdi ) were reported during the double - blind portion of the trial , both in the rifaximin group .
the authors noted that these 2 patients had multiple risk factors for cdi , including repeated hospitalizations during which they received multiple courses of antibiotic therapy , advanced age , and pantoprazole use .
the impact of long - term rifaximin therapy on gut flora , including a risk of bacterial antibiotic resistance , is largely unknown .
however , the drug appeared to have a protective effect against infections within 90 days after transplant ( p = 0.026 ) in patients treated with rifaximin for he during liver transplant candidacy and was not associated with a higher risk of multidrug - resistant bacterial infections .
conventional antibiotics , neomycin and metronidazole , are also administered for the treatment of he . however , strong clinical data supporting their efficacy in the treatment of he are lacking .
one randomized , double - blind study failed to demonstrate a benefit with neomycin ( n = 20 ) compared with placebo ( n = 19 ) , with no significant differences observed for time to resolution of he symptoms or for 5-day , 30-day , or 12-month mortality . two small , randomized , double - blind studies ( n = 33 and n = 45 ) and 1 randomized , unblinded trial ( n = 173 ) have suggested that neomycin and lactulose may have similar efficacy in the treatment of he [ 7476 ] .
two randomized studies ( n = 35 and n = 49 ) have compared neomycin with rifaximin and suggested that they have similar efficacy in the treatment of he , although in one of the studies , patients who received rifaximin showed improvements sooner than those who received neomycin ( 3 versus 5 days , resp . ) [ 77 , 78 ] .
for metronidazole , 1 small study ( n = 18 ) comparing metronidazole with neomycin suggested that both antibiotics improved mental state , reduced asterixis , and improved electroencephalogram measures .
however , the risk of aes associated with neomycin and metronidazole may limit their use in patients with he and suggest that they might not be an ideal pretransplant choice of treatment .
intestinal malabsorption and diarrhea have been observed with neomycin therapy   and thus could impact pretransplant nutritional status of the patients .
although neomycin is poorly absorbed , prolonged administration may result in cumulative systemic concentrations sufficient to increase the risk of serious aes , such as ototoxicity and nephrotoxicity . because the meld scoring system includes
measures of renal dysfunction and neomycin may cause renal damage , neomycin may not be an ideal choice for patients , particularly those with high meld scores .
metronidazole has been associated with peripheral neurotoxicity and requires dosing adjustments in patients with severe liver disease because of impaired drug clearance .
metronidazole is a systemic antibiotic frequently administered for the treatment of cdi , and the potential risk of c. difficile resistance to metronidazole warrants judicious use of this agent .
compared with nonabsorbable disaccharides , neomycin , and metronidazole , rifaximin exhibits a more favorable safety and tolerability profile [ 47 , 65 , 82 ] .
rifaximin has not been associated with gastrointestinal aes such as diarrhea or nausea in clinical studies and would be unlikely to increase the risk of dehydration , weight loss , abdominal distention , malnutrition , or intestinal malabsorption in patients awaiting transplant , thereby minimizing the possible negative consequences of he therapy on patient nutritional status . a 2012 meta - analysis , incorporating data from 12 randomized controlled active comparator trials for the treatment of patients with he , assessed the efficacy and psychometric outcomes of rifaximin compared with other oral therapies ( including disaccharides and other antibiotics ) .
however , more favorable effects were observed with rifaximin with regard to psychometric parameters and serum ammonia levels .
a tolerability analysis , which included he prevention trial data , indicated that rifaximin was also associated with fewer adverse effects .
  he is a common complication of cirrhosis that substantially affects patient morbidity and mortality .
furthermore , he can have a detrimental impact on posttransplant outcomes , including patient survival .
data continue to emerge demonstrating the potential persistence of cognitive deficits associated with he , even after liver transplant
. therefore , prevention of he in patients with cirrhosis may improve pretransplant health status and thus improve posttransplant outcomes .
commonly prescribed therapies include nonabsorbable disaccharides ( e.g. , lactulose ) and nonsystemic antibiotics ( e.g. , rifaximin ) , and their various risks and benefits should be taken into consideration when deciding the most appropriate he management algorithm in patients awaiting liver transplant .
further studies to evaluate currently available therapies in preventing he and improving posttransplant outcomes are warranted .
 patients with cirrhosis commonly experience hepatic encephalopathy ( he ) , a condition associated with alterations in behavior , cognitive function , consciousness , and neuromuscular function of varying severity . 
 he occurring before liver transplant can have a substantial negative impact on posttransplant outcomes , and preoperative history of he may be a predictor of posttransplant neurologic complications . 
 even with resolution of previous episodes of overt or minimal he , some patients continue to experience cognitive deficits after transplant . because he is one of the most frequent pretransplant complications , improving patient he status before transplant may improve outcomes . 
 current pharmacologic therapies for he , whether for the treatment of minimal or overt he or for prevention of he relapse , are primarily directed at reducing cerebral exposure to systemic levels of gut - derived toxins ( e.g. , ammonia ) . 
 the current mainstays of he therapy are nonabsorbable disaccharides and antibiotics . 
 the various impacts of adverse effects ( such as diarrhea , abdominal distention , and dehydration ) on patient 's health and nutritional status should be taken into consideration when deciding the most appropriate he management strategy in patients awaiting liver transplant . 
 this paper reviews the potential consequences of pretransplant he on posttransplant outcomes and therapeutic strategies for the pretransplant management of he . 
1. Introduction
2. Consequences of Pretransplant HE on Posttransplant Outcomes
3. Neurologic Complications after Transplant
4. Treatment of HE in the Pretransplant Setting
5. Summary