REVIEW URRENT C OPINION
Hepatic encephalopathy: how to test and treat Robert S. Rahimi a and Don C. Rockey b
Purpose of review Hepatic encephalopathy causes significant cognitive impairment and morbidity in patients with cirrhosis; however, hepatic encephalopathy is considered a reversible syndrome once recognized clinically. Although hepatic encephalopathy is not a single clinical entity, the pathophysiology resulting in brain dysfunction is not fully understood, although it is believed that ammonia production is an important contributing factor. The purpose of this review is to highlight studies used to test for hepatic encephalopathy and those utilizing specific new treatments. Recent findings A ‘STROOP’ smartphone app has been developed to allow clinicians to test for covert hepatic encephalopathy (CHE). Lactulose therapy was effective for cirrhotic patients as primary prophylaxis to prevent overt hepatic encephalopathy (OHE) episodes. In patients without prior OHE, probiotics can be useful in preventing OHE. Lactulose, probiotics, L-ornithine-L-aspartate, and potassium-iron-phosphate-citrate have been studied in the treatment of CHE. Rifaximin was found to be safe and well tolerated in long-term maintenance of remission from OHE; however, compared to lactulose therapy in CHE, it is not costeffective. Summary Refinement in clinical management strategies for patients with cirrhosis and hepatic encephalopathy appears to continue to contribute to improved patient outcomes. Keywords altered mental status, cirrhosis, covert, overt, portosystemic encephalopathy, STROOP
INTRODUCTION In the United States, in 2008, a discharge diagnosis of chronic liver disease (CLD) or cirrhosis was estimated to occur in 101 000 individuals, with an overall mortality of 30 558, resulting in cirrhosis being the 12th leading cause of death [1]. In 2010, the overall mortality from cirrhosis in the United States rose and was the 11th leading cause of death [2], consistent with a progressive increase in complicated CLD. One of the most difficult-to-manage complications of CLD and cirrhosis is hepatic encephalopathy, also known as portosystemic encephalopathy (PSE). Hepatic encephalopathy is generally defined as a reversible neuropsychiatric impairment, ranging from mild cognitive deficiencies to coma, in patients with underlying cirrhosis [3]. The prevalence of hepatic encephalopathy continues to rise for several reasons. For one, patients with chronic hepatitis C, typically born between 1945 and 1965 [4], are now developing cirrhosis and its complications at a more rapid pace than ever before. Data from the Healthcare Cost and Utilization Project (HCUP), a national repository of patient-level
hospital care data, reveal that the number of discharges for hepatic encephalopathy has increased from 2003 to 2011 from 40 012 to 50 048, respectively [5]. Although HCUP data over the past 9 years likely underestimate hepatic encephalopathy discharge data since hepatic encephalopathy is not always a primary diagnosis on admission, these data point to the potential for substantial increase in hepatic encephalopathy admissions. Additionally, we are currently in the midst of a global obesity epidemic, which fuels the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) [6], and these patients are now presenting in larger numbers with complications of CLD such as hepatic a Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas and bDepartment of Internal Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
Correspondence to Robert S. Rahimi, MD, MSCR, Liver Consultants of Texas, Baylor University Medical Center, 3410 Worth Street, Suite 860, Dallas, TX 75246, USA. Tel: +1 214 820 8500; fax: +1 214 820 0993; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:265–271 DOI:10.1097/MOG.0000000000000066
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KEY POINTS The majority of cirrhotic patients admitted to the hospital with AMS do not have hepatic encephalopathy; other causes should be searched for. The prognosis of patients with cirrhosis and AMS due to hepatic encephalopathy is better than for other causes of AMS. Diagnosing CHE can be challenging and timeconsuming; the STROOP app test is available for download, allowing a quick and reliable tool in screening for CHE. Rifaximin maintained remission and decreased readmission rates when used over a 2-year period in patients with hepatic encephalopathy; however, it would become cost-effective in comparison to lactulose therapy, if the monthly price decreased to less than $353. Although rifaximin is not US FDA-approved for OHE, it was more effective when combined with lactulose compared to lactulose alone. Ammonia blood levels do not reliably detect hepatic encephalopathy and should not be used as a screening test; frequent misinterpretations can arise when using ammonia levels to diagnose hepatic encephalopathy in a cirrhotic patient in the emergency department.
encephalopathy. This review will highlight recent data on testing, treating and outcomes in patients with hepatic encephalopathy.
HEPATIC ENCEPHALOPATHY DEFINITION Hepatic encephalopathy is described as encompassing a spectrum of reversible neuropsychiatric abnormalities that range from normal cognitive function (‘grade 0’) to minimal hepatic encephalopathy (MHE) (within grade 0) to overt hepatic encephalopathy (OHE) (where grade 1 is characterized by mild lack of awareness, shortened attention span and mild asterixis or tremor; grade 2 is characterized by lethargy, disorientation and obvious asterixis; grade 3 consists of somnolence with arousability, gross disorientation with bizarre behavior and muscle rigidity with clonus and hyper-reflexia; whereas grade 4 consists of coma with decerebrate posturing in patients with cirrhosis, after exclusion of neurologic and/or metabolic abnormalities [7 ]). It should be noted that patients with cirrhosis who are admitted with altered mental status (AMS) are most often presumed to have hepatic encephalopathy simply because of their alteration in mentation. However, recent data demonstrated that caution is required in these patients. In a cohort study of 1218 inpatients with cirrhosis, AMS was &&
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evaluated [7 ]. AMS was defined a priori to be caused by hepatic encephalopathy [defined according to the International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN)], sepsis/ infectious, metabolic, exogenous drugs/toxins, structural lesions, or psychiatric abnormalities; all of these disorders were carefully defined according to commonly accepted clinical criteria. In this cohort, AMS was the cause of admission in 349 patients (approximately one-third of the cohort). Although the most common cause of AMS was hepatic encephalopathy, accounting for nearly half of all patients, other causes of AMS were prominent and included the following: sepsis/infection (23%), metabolic disorders (8%), drugs/toxins (7%), structural lesions (5%), psychiatric disorders (1%), or multiple causes (8%). Remarkably, mortality in patients with AMS was 35% compared to 16% in those with normal mental status (NMS) (P < 0.0001). Patients with sepsis/infection, structural lesions, or multiple disorders causing AMS had much higher mortality (ranging from 61 to 79%) than those with hepatic encephalopathy. These data emphasize the point that over 50% of patients with cirrhosis admitted with AMS have a disorder that does not meet the definition of hepatic encephalopathy. Thus, it is critical to search for multiple different causes of AMS in patients with cirrhosis. Of note, there has been a recent proposal for alternative terminology for hepatic encephalopathy – adopted by the ISHEN. The consensus conference describes the spectrum of neurocognitive impairment in cirrhosis (SONIC), with MHE and grade 1 hepatic encephalopathy, categorized as covert hepatic encephalopathy (CHE), whereas grade 2–4 hepatic encephalopathy represents OHE [8].
PATHOPHYSIOLOGY The underlying mechanism(s) causing hepatic encephalopathy remain(s) under investigation. Currently, it is believed that hepatic encephalopathy is a result of multiple putative processes that cause functional impairment of neuronal cells. One of the main factors involved in the pathophysiology of hepatic encephalopathy is thought to be ammonia. Additionally, inflammatory cytokines, benzodiazepine-like compounds such as gamma-aminobutyric acid and manganese have been reported to play a role in hepatic encephalopathy [9]. A number of potential neurotoxicity mechanisms for ammonia have been described. Initially, ammonia increases the resting membrane potential and inhibits both axonal conduction and excitatory postsynaptic potentials. Furthermore, ammonia inactivates neuronal chloride extrusion pumps, suppressing inhibitory postsynaptic potential Volume 30 Number 3 May 2014
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formation and depolarization of neurons. The total brain ammonia that accumulates after crossing the blood–brain barrier, resulting in astrocyte swelling and brain edema due to the accumulation of glutamine in hepatic encephalopathy, may not be in the order of magnitude required to alter these postsynaptic potentials, until advanced stages [10]. Although glutamine is the main amino acid involved in hepatic encephalopathy, glutaminase haplotypes have been linked to the risk of OHE, as well as increased mitochondrial ammonia, leading to reactive nitrogen and oxygen species, resulting in worsening brain edema [11–14]. Ammonia is produced by colonic bacteria catabolism of nitrogenous sources and enterocytes from glutamine, pointing to the gastrointestinal tract as an important element in the pathogenesis of hepatic encephalopathy. However, it should be emphasized that although cirrhotic patients with hepatic encephalopathy often have elevated ammonia levels, there is no absolute correlation between ammonia levels and grade of hepatic encephalopathy [15 ]. &
RBANS has proven effective in screening patients for CHE; however, it requires a fee for its implementation [22]. Although paper-and-pencil testing has clinical applicability, computerized testing offers greater control over task stimulation, standardization and data gathering. The inhibitory control test (ICT) has been previously described as an attention and response inhibition test. Two studies evaluated lure response rates in cirrhotic patients. Those who scored above 5 lures out of 40 attempts had CHE diagnosed with 88% sensitivity, high accuracy (c-statistic ¼ 0.9), and had worse driving simulator performance with more traffic accidents; however, it was recommended in the second study that adjustments be made by target accuracy, in order to increase the diagnostic accuracy of CHE [23,24]. The ICT is limited in that patients quickly adapt by learned responsiveness with frequent testing and it requires personnel to be trained in administering the test; however, it can be downloaded for free at www.hecme.tv. Most recently, an interesting study by Bajaj et al. [25 ] evaluated a smartphone application called the STROOP app test (EncephalApp_ STROOP) that is available for free download on iTunes, as a valid and reliable tool to screen for CHE. Details regarding the ease of administration, scoring and interpretation for age-specific populations can be viewed at www.chronicliverdisease. org. Another study evaluating CHE without specialized testing used prior sickness impact profile (SIP) tests with 136 questions on 12 quality-of-life (QoL) topics. The authors modified this time-consuming test to finally contain four SIP questions and combined them with sex and age of individual patients to come up with a formula to identify CHE patients, called SIP CHE score. Over the 1-year follow-up of 93 patients, baseline SIP CHE scores above 0 correctly identified patients with CHE with nearly 80% sensitivity and specificity, whereas the 6-month evaluation’s sensitivity in SIP CHE scoring increased the sensitivity to 88%; the 1-year result was close to the baseline level of near 80% sensitivity, with 32% of the patients having CHE [26]. Although the SIP CHE strategy does not include specialized testing, accuracy of detecting CHE with this method needs further investigation. Although computerized tests can allow specific cognitive processes to be assessed, neurophysiological tests such as the critical flicker frequency (CFF) test are tools that can be used to help diagnose hepatic encephalopathy. In CFF, patients are shown a light pulse at 60 Hz, and then decreased gradually by 0.1 Hz per second. Once the fused light begins to flicker in a patient’s eye, they are asked to notify the &
TESTING FOR HEPATIC ENCEPHALOPATHY Hepatic encephalopathy historically has been a clinical diagnosis; however, the use of the West Haven criteria (WHC) in combination with neuromotor dysfunction, neuropsychological testing with hepatic encephalopathy scoring algorithm (HESA), clinical hepatic encephalopathy staging scale (CHESS), and modified-orientation log (MO-log) helps grade OHE more accurately, but, the length of time it takes to implement these tests in clinical practice limits their use [16–19]. In the past decade, diagnosing CHE has become important as it prognosticates the development of OHE. Although diagnosing CHE clinically can be a challenge (i.e. patients have a normal clinical exam), many screening tools have been studied to help aid in making the diagnosis. The Psychometric Hepatic Encephalopathy score (PHES), developed in Europe, was previously considered to be the gold standard in diagnosing CHE; however, administration and scoring have to be done in an outpatient setting, and with lack of available testing material and copyright concerns, widespread acceptance in the United States is limited [20]. Current consensus [21] recommendations include the use of PHES or the repeatable battery for the assessment of neuropsychological status (RBANS) for diagnosing CHE. Both tests require about 25 min or less, and are paper-and-pencil tests. RBANS tests for delayed memory and language capability, which are usually normal in CHE; hence the applicability of using this test is limited. Therefore, a modified version of
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examiner. Frequencies below 39 Hz can diagnose CHE according to a recent meta-analysis, with a sensitivity of 61% [95% confidence interval (CI) 55–67], specificity 79% (95% CI 75–83) and diagnostic odds ratio of 10.9 (95% CI 4.2–28.3, heterogeneity ¼ 74%), with a receiver operator curve of 0.84 [27]. The authors suggest that CFF is simple to perform and interpret, is independent of education, sex, age, and literacy, but should be used as an adjunct, and not a replacement to, psychometric testing. The limitation of CFF is the expense of the equipment and the time required to perform testing is less than 15 min, hence limiting its clinical applicability. Another interesting study evaluated CFF and PHES in hepatic encephalopathy, distinguished between individuals with OHE; however, PHES had significant overlap between controls and patients with OHE, and concluded that neither CFF nor PHES, or the combination, could reliably distinguish cirrhotic patients with CHE from controls or those with OHE [28].
TREATMENT FOR HEPATIC ENCEPHALOPATHY Therapy aimed at reducing ammonia levels, enhancing elimination or decreasing its production, has resulted in improvement in hepatic encephalopathy. For example, the nonabsorbable disaccharides (i.e. lacitol and lactulose) and antibiotics (i.e. neomycin and rifaximin) have been the mainstay of therapy based on prior studies. However, educating patients on the proper use of these medications, especially with lactulose to achieve the correct number of bowel movements per day, is clinically important, so as to potentially prevent readmission for hepatic encephalopathy events. In one study of 402 cirrhotic patients, the overall readmission rate was 69%, with the 1-month readmission rate being 37%. Of the total readmissions, 22% were thought to be preventable if proper use of maintenance lactulose therapy and education was given at discharge [29 ]. Although lactulose (b-galactosidofructose) and lactitol (b-galactosidosorbitol) have demonstrated variable efficacy in clinical trials, subset analysis of high-quality studies in a meta-analysis demonstrated that nonabsorbable disaccharides had no effect on hepatic encephalopathy compared to placebo [30]. Despite these mixed results, lactulose is still the first-line treatment for OHE, while concurrently searching and treating the underlying precipitant causing hepatic encephalopathy. Whereas prior studies have evaluated the use of neomycin for OHE [31], the side-effect profile of nephrotoxicity and ototoxicity has limited neomycin’s current use; this is particularly true since the advent of rifaximin, which has few side effects. &
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Although rifaximin received US Food and Drug Administration (FDA) approval in 2010, its use was for secondary prevention of OHE. Further study has attempted to expand our understanding of the potential use of rifaximin. Over a 6-month period, rifaximin resulted in a decrease in hospital readmission rates and OHE events compared to placebo. An extension of this study evaluated rifaximin in a phase 3, open-label maintenance study to assess the safety and rate of hospitalization with long-term rifaximin use defined as greater than or equal to 2 years [32 ]. In the all-rifaximin arm (n ¼ 392), the median exposure was 427 days. Adverse events were similar to the original randomized controlled trial (RCT), specifically without an increase in rate of infections or development of antibiotic resistance. The overall rates of hepatic encephalopathy-related hospitalization rate remained low (all rifaximin ¼ 0.21, prior RCT ¼ 0.3) compared to the placebo group (0.72). Hence, long-term therapy with rifaximin appears to reduce the rate of hepatic encephalopathy-related hospitalizations with no significant adverse events. The greatest current controversy about the use of rifaximin appears to surround its cost and costeffectiveness. A cost-effectiveness analysis using Markov modeling designed to test lactulose or rifaximin in preventing motor vehicle accidents (MVAs) in patients with CHE revealed that lactulose, but not rifaximin, was cost-effective across all strategies when compared to patients without any history of MHE. Of note, it was estimated that rifaximin would become cost-saving if its cost was decreased to less than $353 per month [33 ]. ‘Off-label’ use of rifaximin for OHE with or without the use of lactulose has become increasingly common. A commonly encountered situation is that in which rifaximin is added to lactulose for treatment of OHE. In this regard, a timely randomized, double-blind, placebo-controlled trial evaluated 120 cirrhotic patients with OHE, comparing 63 patients receiving both lactulose þ rifaximin 1200 mg/day (group A) to 57 patients receiving lactulose þ placebo (group B) [34 ]. The primary endpoint was complete reversal of hepatic encephalopathy, which occurred in 48 (76%) patients in group A compared to 29 (51%) patients in group B (P < 0.004). Additionally, group A patients had a shorter length of stay compared to group B (5.8 3.4 vs. 8.2 4.6 days; P ¼ 0.001). The authors concluded that the combination of lactulose þ rifaximin was more effective than lactulose alone in treating OHE. However, there is not currently a US FDA indication for the use of rifaximin in OHE. In a study examining the use of lactulose only in OHE, 120 cirrhotic patients without previous OHE &&
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episodes were randomized to lactulose (n ¼ 60) or no lactulose (n ¼ 60) and were assessed for hepatic encephalopathy using psychometric testing at recruitment and 3 months, then were followed monthly for 12 months to determine whether OHE developed. At 1 year, a total of 20/105 (19%) patients developed OHE, of which 6/55 (11%) and 14/50 (28%) were in the lactulose versus control groups, respectively (P ¼ 0.02). There were no statistically significant differences in mortality among the two groups. At 3 months, those receiving lactulose had less evidence of MHE [11/57 (19%)] compared to control [31/56 (55%)] (P ¼ 0.001). Although there were no differences in baseline MHE between groups, those receiving lactulose for MHE improved in 21/32 (66%); of note, 9/36 (25%) patients not receiving lactulose therapy recovered from MHE spontaneously. The overall number needed to treat (NNT) with lactulose to prevent an episode of hepatic encephalopathy in cirrhotic patients without any history of hepatic encephalopathy was 4 and 5.8 for those who developed MHE or OHE, respectively. The authors concluded that lactulose therapy was effective for cirrhotic patients as primary prophylaxis to prevent OHE episodes [35 ]. Another study focused on secondary prophylaxis for cirrhotic patients with hepatic encephalopathy. Over a 1-year period, 235 patients with a previous hepatic encephalopathy event who had recovered were randomized to receive either lactulose (30 ml three times a day, n ¼ 80), probiotics (three capsules daily containing 112.5 billion viable lyophilized bacteria per capsule, n ¼ 77), or no therapy (n ¼ 78). A total of 38 patients (16%) were lost to follow-up; 77 of 197 (39%) patients developed an episode of hepatic encephalopathy within 12 months. Using intention-to-treat analysis, including the initially enrolled patients, 30/80 (38%) receiving lactulose, 35/77 (45%) receiving probiotics, and 50/78 (64%) receiving no therapy, developed recurrent hepatic encephalopathy (P ¼ 0.003). Although the difference between lactulose and probiotic therapy as secondary prophylaxis for hepatic encephalopathy was statistically significantly different compared to using no therapy (P ¼ 0.001 and P ¼ 0.02, respectively), there was no significant difference found between lactulose and probiotic use (P ¼ 0.35). These data suggest that use of either lactulose or probiotics for secondary prophylaxis for hepatic encephalopathy seems reasonable (and equally effective) [36 ]. A RCT assessed the development of OHE using probiotics in patients with MHE (n ¼ 86; n ¼ 42 with MHE) with three times a day dosing of 1 108 colony forming units (CFU), and compared them to controls receiving no therapy (n ¼ 74; n ¼ 33 with &
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MHE) [37 ]. After psychometric, CFF and other testing ensued, a mean follow-up of nearly 40 þ 10 weeks for each arm resulted in a significant decrease in progression to OHE after receiving 3 months of probiotics; seven patients progressed to OHE, compared to controls; 14 patients developed OHE (P < 0.05). In patients without prior OHE, probiotics can be useful in preventing OHE; however, longer follow-up is needed to assess the efficacy of probiotic use. Another study presented at the American Association for the Study of Liver Diseases (AASLD) Annual Meeting, pending publication, studied cirrhotic patients admitted with OHE, randomizing them to receive either 4 l of polyethylene glycol 3350-electrolyte solution (PEG, n ¼ 25) or standardof-care lactulose (n ¼ 25) [38]. The primary outcome was the absolute difference in the HESA at 24 h, with an improvement in one HESA grade accounting for an overall response to either therapy. There were no differences in median admission ammonia levels, model for end-stage liver disease (MELD) scores, and baseline HESA grades between the two groups. Baseline and 24-h mean HESA scores improved from 2.3 0.8 to 1.6 0.9 in the lactulose group, and 2.3 0.9 to 0.9 1 in the PEG group (P ¼ 0.015). Median time for hepatic encephalopathy resolution was 2 days for lactulose and 1 day of PEG (P ¼ 0.01). The overall response within 24 h to lactulose and PEG was 52 and 91%, respectively (P ¼ 0.002), hence PEG improved hepatic encephalopathy over the first 24 h of hospitalization significantly faster than lactulose, suggesting that PEG may be superior to lactulose for treatment of patients hospitalized for OHE. A double-blind controlled trial investigated glycerol phenylbutyrate (GPB) in 178 patients (59 patients concurrently taking rifaximin) with cirrhosis who previously had two or more hepatic encephalopathy episodes in the prior 6 months. The mechanism of action of GPB is to lower ammonia via metabolism in an alternate pathway to urea for nitrogen excretion in the urine in the form of phenylacetylglutamine. Those taking 6 ml of GPB orally twice daily were found to have significantly reduced hepatic encephalopathy events (21 vs. 36%; P ¼ 0.02), total events (35 vs. 57; P ¼ 0.04) and time to first event (hazard ratio 0.56, P < 0.05). Patients not receiving rifaximin on enrollment showed more statistically significant improvements in all three categories stated above [39 ]. Plasma ammonia was significantly lower in patients receiving GPB. There were no differences in adverse events between the two groups. This study suggests that GPB has therapeutic potential in lowering ammonia and reducing hepatic encephalopathy events. Further studies are underway.
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An area that has received considerable attention is treatment of MHE, now considered CHE according to SONIC, as its prevalence ranges from 50 to 80% in patients with cirrhosis. A double-blind, placebo-controlled trial used an aqueous solution containing a potassium-iron-phosphate-citrate complex that is supposed to bind to intestinal ammonia and excrete it via the gastrointestinal tract. Investigators evaluated 51 patients with MHE, and treated them with either 4 weeks of potassium-iron-phosphate-citrate (n ¼ 25) or placebo (n ¼ 26), with 2 ml of solution, three times a day before a meal [40 ]. Overall, patients treated with potassium-iron-phosphate-citrate showed significantly more improvement in the PSE score (72%), compared to those treated with placebo (27%) (P ¼ 0.0014). Although seven patients (28%) reported 14 adverse events, most of which were mild or moderate gastrointestinal tract side effects when treated with potassium-iron-phosphate-citrate complex, four patients (15%) reported eight similar adverse events; therefore the investigational medication was well tolerated overall in the treatment option for MHE. Another study examined different therapies in MHE (also CHE), comparing no therapy (group A), lactulose 30–60 ml b.i.d. (group B), probiotics of 110 billion CFUs b.i.d. (group C) and L-ornithine-Laspartate 6 g t.i.d. (LOLA; group D) for 3 months to determine overall health-related quality of life (HRQoL) improvement, and outcomes in progressing to OHE [41 ]. Of the 322 cirrhotic patients, 160 (49.7%) were found to have MHE in which 40 patients were assigned to each of the four groups. Using neuropsychological assessment, recovery of MHE (i.e. NMS) was found in 10, 48, 35 and 35% of patients in groups A, B, C and D, respectively (P ¼ 0.006). There was no statistically significant difference in the rate of recovery from MHE or changes in ammonia level when comparing placebo to lactulose, probiotics or LOLA. Although no significant difference in OHE progression occurred over 3 months, a total of nine patients (6% overall) developed OHE. When comparing the SIP, which assesses the influence of disease and treatment on daily functioning (i.e. HRQoL), a statistically significant decrease in total SIP score was present in the treatment groups compared to no treatment (P < 0.001); again, no differences in SIP scores were found among treatment groups. The decrease in SIP scores correlated with an improvement in MHE on multivariate analysis; however, there was no correlation with the type of therapy offered. Overall, these results suggest that lactulose, probiotics and LOLA significantly improved MHE and HRQoL in cirrhotic patients compared with no therapy. Thus, practitioners should consider using any of these &&
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three treatments in those proven to have MHE based on neuropsychological testing, recognizing that LOLA is not available in the United States.
CONCLUSION Many recent studies have provided insight in the management of patients with cirrhosis and CHE or OHE. However, further research is still required, in particular, in assessing the most cost-effective, timely and ease of implementing testing for CHE. The best management strategy for treatment of CHE or OHE will require further studies, particularly with regard to the emergence of rifaximin and its cost-effectiveness. Induction and maintenance of therapy, along with educating primary care givers in patients presenting with OHE, is crucial in preventing readmission. Although there is clinical evidence to support the adjunctive use of rifaximin (i.e. with other therapies) for severe OHE, there is no current US FDA approval for this specific use. Acknowledgements None. Conflicts of interest D.C.R. received research support from Hyperion Therapeutics in 2011 and 2012. The authors have no conflicts of interest to report.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Heron M. Deaths: leading causes for 2008. Natl Vital Stat Rep 2012; 60:1– 94. 2. Heron M. Deaths: leading causes for 2010. Natl Vital Stat Rep 2013; 62:1– 97. 3. Ferenci P, Lockwood A, Mullen K, et al. 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. 4. Ward JW. The epidemiology of chronic hepatitis C and one-time hepatitis C virus testing of persons born during 1945 to 1965 in the United States. Clin Liver Dis 2013; 17:1–11. 5. Minino AM, Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2008. Natl Vital Stat Rep 2011; 59:1–126. 6. Rahimi RS, Landaverde C. Nonalcoholic fatty liver disease and the metabolic syndrome: clinical implications and treatment. Nutr Clin Pract 2013; 28:40–51. 7. Rahimi RS, Elliott AC, Rockey DC. Altered mental status in cirrhosis: etiol&& ogies and outcomes. J Investig Med 2013; 61:695–700. In a cohort of 1218 cirrhotic patients, of whom approximately one-third were admitted with AMS, nearly half of them had hepatic encephalopathy, whereas other causes of AMS were found to be from sepsis/infection (23%), metabolic disorders (8%), drugs/toxins (7%), structural lesions (5%), or multiple causes (8%). Patients admitted with AMS had a worse prognosis compared to NMS (35 vs. 16%; P < 0.0001), and patients with hepatic encephalopathy had lower mortality than in those with sepsis/infection, structural lesions, or multiple disorders (mortality 61, 68, and 79%, respectively). 8. Bajaj JS, Cordoba J, Mullen KD, et al. Review article: the design of clinical trials in hepatic encephalopathy: an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. Aliment Pharmacol Ther 2011; 33:739–747. 9. Williams ST. Pathophysiology of encephalopathy and delirium. J Clin Neurophysiol 2013; 30:435–437.
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Hepatic encephalopathy: how to test and treat Rahimi and Rockey 10. Szerb JC, Butterworth RF. Effect of ammonium ions on synaptic transmission in the mammalian central nervous system. Prog Neurobiol 1992; 39:135–153. 11. Romero-Gomez M, Jover M, Del Campo JA, et al. Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study. Ann Intern Med 2010; 153:281–288. 12. Albrecht J, Norenberg MD. Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology 2006; 44:788–794. 13. Jayakumar AR, Rama Rao KV, Schousboe A, Norenberg MD. Glutamineinduced free radical production in cultured astrocytes. Glia 2004; 46:296– 301. 14. Corbalan R, Hernandez-Viadel M, Llansola M, et al. Chronic hyperammonemia alters protein phosphorylation and glutamate receptor-associated signal transduction in brain. Neurochem Int 2002; 41:103–108. 15. Gundling F, Zelihic E, Seidl H, et al. How to diagnose hepatic encephalopathy & in the emergency department. Ann Hepatol 2013; 12:108–114. Fifty-nine patients with known cirrhosis were evaluated using the WHC and CFF for the presence of hepatic encephalopathy and correlations to ammonia levels were obtained. Using only ammonia levels, 41% of the time, a misdiagnosis of hepatic encephalopathy was seen in comparison to the WHC and 49% when compared with results of the CFF. Therefore, the authors concluded that ammonia blood levels do not reliably detect hepatic encephalopathy, and should not be used as a screening test; frequent misinterpretations can arise when using ammonia levels to indicate hepatic encephalopathy in a cirrhotic patient in the emergency department. 16. Simon-Talero M, Garcia-Martinez R, Torrens M, et al. Effects of intravenous albumin in patients with cirrhosis and episodic hepatic encephalopathy: a randomized double-blind study. J Hepatol 2013; 59:1184–1192. 17. Salam M, Matherly S, Farooq IS, et al. Modified-orientation log to assess hepatic encephalopathy. Aliment Pharmacol Ther 2012; 35:913–920. 18. Hassanein T, Blei AT, Perry W, et al. Performance of the hepatic encephalopathy scoring algorithm in a clinical trial of patients with cirrhosis and severe hepatic encephalopathy. Am J Gastroenterol 2009; 104:1392–1400. 19. Ortiz M, Cordoba J, Doval E, et al. Development of a clinical hepatic encephalopathy staging scale. Aliment Pharmacol Ther 2007; 26:859–867. 20. Prakash RK, Brown TA, Mullen KD. Minimal hepatic encephalopathy and driving: is the genie out of the bottle? Am J Gastroenterol 2011; 106:1415– 1416. 21. Randolph C, Hilsabeck R, Kato A, et al. Neuropsychological assessment of hepatic encephalopathy: ISHEN practice guidelines. Liver Int 2009; 29:629– 635. 22. Meyer T, Eshelman A, Abouljoud M. Neuropsychological changes in a large sample of liver transplant candidates. Transplant Proc 2006; 38:3559–3560. 23. Amodio P, Ridola L, Schiff S, et al. Improving the inhibitory control task to detect minimal hepatic encephalopathy. Gastroenterology 2010; 139:510– 518; e511-512. 24. Bajaj JS, Hafeezullah M, Franco J, et al. Inhibitory control test for the diagnosis of minimal hepatic encephalopathy. Gastroenterology 2008; 135:1591– 1600; e1591. 25. Bajaj JS, Thacker LR, Heuman DM, et al. The Stroop smartphone application & is a short and valid method to screen for minimal hepatic encephalopathy. Hepatology 2013; 58:1122–1132. One hundred and twenty-five cirrhotic patients (43 with previous OHE) and 134 controls were included in the original cohort. Stroop performance was significantly impaired in MHE, compared to those without MHE, according to SPTs, ICTs, and PHES (all P < 0.0001). Using a cut-off of more than 274.9 s (on-time and off-time) had a c-statistic of 0.89 in all patients and 0.84 in patients without previous OHE for MHE diagnosis using SPT as the gold standard. The validation cohort showed 78% sensitivity and 90% specificity with the above 274.9-s on-time and off-time cut-off, making the Stroop smartphone app a short, valid, and reliable tool for screening of MHE. 26. Nabi E, Thacker LR, Wade JB, et al. Diagnosis of covert hepatic encephalopathy without specialized tests. Clin Gastroenterol Hepatol 2013. [Epub ahead of print] 27. Torlot FJ, McPhail MJ, Taylor-Robinson SD. Meta-analysis: the diagnostic accuracy of critical flicker frequency in minimal hepatic encephalopathy. Aliment Pharmacol Ther 2013; 37:527–536. 28. Kircheis G, Hilger N, Haussinger D. Value of critical flicker frequency and psychometric hepatic encephalopathy score in diagnosis of low-grade hepatic encephalopathy. Gastroenterology 2013. [Epub ahead of print] 29. Volk ML, Tocco RS, Bazick J, et al. Hospital readmissions among patients with & decompensated cirrhosis. Am J Gastroenterol 2012; 107:247–252. Out of 402 cirrhotic patients, 276 (69%) had at least one nonelective readmission within a median time of 67 days. After 1 week and 1 month of discharge, 14 and 37% were readmitted, resulting in higher mortality. Predictors of time to first readmission included MELD score, serum sodium, and number of medications on discharge. About 22% of 1-month readmissions could be prevented if formal education were provided to patients regarding their medication regimen by more intensive outpatient monitoring. 30. Als-Nielsen B, Gluud LL, Gluud C. Nonabsorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. Br Med J 2004; 328:1046. 31. Strauss E, Tramote R, Silva EP, et al. Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepatogastroenterology 1992; 39:542–545.
32. Mullen KD, Sanyal AJ, Bass NM, et al. Rifaximin is safe and well tolerated for long-term maintenance of remission from overt hepatic encephalopathy. Clin Gastroenterol Hepatol 2013. [Epub ahead of print] A 2-year study regarding rifaximin’s safety and efficacy profile in preventing readmissions in patients with cirrhosis and hepatic encephalopathy was evaluated. A median exposure of 427 days of rifaximin 550 mg twice daily resulted in low readmission hepatic encephalopathy rates compared to placebo without any increase in adverse events including infections or antibiotic resistance. 33. Bajaj JS, Pinkerton SD, Sanyal AJ, Heuman DM. Diagnosis and treatment of & minimal hepatic encephalopathy to prevent motor vehicle accidents: a costeffectiveness analysis. Hepatology 2012; 55:1164–1171. Using a Markov model, five MHE management strategies were compared, all of which were assumed to reduce the MVA rate equivalent to an age matched noncirrhotic. The model included 1000 cirrhotic patients over a 5-year period, with the societal cost of a single MVA estimated to be $42 100. Lactulose was the most cost-effective strategy across all strategies (i.e. substantially reduced societal cost by preventing MVAs); however, rifaximin was not, and would become cost-effective if the monthly cost was below $353. 34. Sharma BC, Sharma P, Lunia MK, et al. A randomized, double-blind, controlled && trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol 2013; 108:1458–1463. One hundered and twenty patients with hepatic encephalopathy received either lactulose þ rifaximin (group A) or lactulose þ placebo (group B) in a randomized, double-blind fashion when admitted for OHE. Those in group A had a significant reversal of hepatic encephalopathy (P < 0.004), decrease in mortality (P < 0.05), and shorter length of stay (P ¼ 0.001) compared to cirrhotic patients in group B. Although more deaths were seen in group B, no differences in mortality were associated with gastrointestinal bleeding or hepatorenal syndrome between groups. 35. Sharma P, Sharma BC, Agrawal A, Sarin SK. Primary prophylaxis of overt & hepatic encephalopathy in patients with cirrhosis: an open labeled randomized controlled trial of lactulose versus no lactulose. J Gastroenterol Hepatol 2012; 27:1329–1335. One hundred and twenty cirrhotic patients without previous OHE were randomized to receive lactulose or placebo with the primary aim to evaluate the efficacy of lactulose for primary prophylaxis of overt and MHE. Those receiving lactulose developed less OHE (11 vs. 28%; P ¼ 0.02) with a NNT of 5.8 over 12 months compared to placebo. Lactulose also improved MHE in 66 vs. 25% of controls, with a NNT of 4. 36. Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary prophylaxis of hepatic & encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol 2012; 107:1043– 1050. Two hundred and thirty-five cirrhotic patients who recovered from hepatic encephalopathy were randomized to receive either lactulose, probiotics or placebo and were followed for 1 year and tested for development of OHE by psychometry and using the WHC. There were significant differences seen if lactulose or probiotics were given for secondary prophylaxis compared to placebo (P ¼ 0.001 and P ¼ 0.02); however, there were no differences when direct comparisons were made between lactulose and probiotics, respectively (P ¼ 0.349). 37. Lunia MK, Sharma BC, Sharma P, et al. Probiotics prevent hepatic encepha& lopathy in patients with cirrhosis: a randomized controlled trial. Clin Gastroenterol Hepatol 2013. [Epub ahead of print] One hundered and sixty patients with hepatic encephalopathy were randomly assigned to receive probiotics three times daily or no probiotics. Of the 86 patients (42 with MHE) receiving probiotics, seven developed OHE, compared to 74 patient (33 with MHE) controls, of which 14 developed OHE (P < 0.05) after psychometric testing was performed. There were no differences in overall mortality between the two groups. 38. Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. A Randomized trial comparing polyethylene glycol 3350-electrolyte solution (PEG) and lactulose in hospitalized patients with hepatic encephalopathy. Hepatology 2012; 56:; 191A-1144A. 39. Rockey DC, Vierling JM, Mantry P, et al. Randomized, double-blind, controlled && study of glycerol phenylbutyrate in hepatic encephalopathy. Hepatology 2014; 59:1073–1083. This phase 2 study evaluated 178 patients with cirrhosis, who received placebo or GPB for treatment of OHE. Overall, GPB decreased hepatic encephalopathy events significantly (P ¼ 0.02), time to first event (P < 0.05) and total events (P ¼ 0.04). There was an overal trend to fewer hospitalizations in patients receiving GPB (P ¼ 0.06).GPB appeared to be well tolerated. 40. Burkard T, Biedermann A, Herold C, et al. Treatment with a potassium-iron&& phosphate-citratecompleximprovesPSEscoresandqualityoflifeinpatientswith minimal hepatic encephalopathy: a multicenter, randomized, placebo-controlled, double-blind clinical trial. Eur J Gastroenterol Hepatol 2013; 25:352–358. This multicenter, double-blind, randomized placebo-controlled trial evaluated 51 patients with MHE. Those receiving 4 weeks of potassium-iron-phosphate-citrate solution showed significant improvements in PSE scores compared to placebo (72 vs. 27%; P ¼ 0.0014) as well as higher QoL scores (P ¼ 0.0036). 41. Mittal VV, Sharma BC, Sharma P, Sarin SK. A randomized controlled trial com& paring lactulose, probiotics, and L-ornithine L-aspartate in treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 2011; 23:725–732. This RCT compared lactulose, probiotics and LOLA to no therapy to evaluate HRQoL and progression to OHE in those with MHE. Any of the three therapies showed a significant improvement in HRQoL and reversal of MHE compared to no therapy; however, there were no significant differences between the therapies used. &&
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Hepatic encephalopathy: how to test and treat Robert S. Rahimi a and Don C. Rockey b
Purpose of review Hepatic encephalopathy causes significant cognitive impairment and morbidity in patients with cirrhosis; however, hepatic encephalopathy is considered a reversible syndrome once recognized clinically. Although hepatic encephalopathy is not a single clinical entity, the pathophysiology resulting in brain dysfunction is not fully understood, although it is believed that ammonia production is an important contributing factor. The purpose of this review is to highlight studies used to test for hepatic encephalopathy and those utilizing specific new treatments. Recent findings A ‘STROOP’ smartphone app has been developed to allow clinicians to test for covert hepatic encephalopathy (CHE). Lactulose therapy was effective for cirrhotic patients as primary prophylaxis to prevent overt hepatic encephalopathy (OHE) episodes. In patients without prior OHE, probiotics can be useful in preventing OHE. Lactulose, probiotics, L-ornithine-L-aspartate, and potassium-iron-phosphate-citrate have been studied in the treatment of CHE. Rifaximin was found to be safe and well tolerated in long-term maintenance of remission from OHE; however, compared to lactulose therapy in CHE, it is not costeffective. Summary Refinement in clinical management strategies for patients with cirrhosis and hepatic encephalopathy appears to continue to contribute to improved patient outcomes. Keywords altered mental status, cirrhosis, covert, overt, portosystemic encephalopathy, STROOP
INTRODUCTION In the United States, in 2008, a discharge diagnosis of chronic liver disease (CLD) or cirrhosis was estimated to occur in 101 000 individuals, with an overall mortality of 30 558, resulting in cirrhosis being the 12th leading cause of death [1]. In 2010, the overall mortality from cirrhosis in the United States rose and was the 11th leading cause of death [2], consistent with a progressive increase in complicated CLD. One of the most difficult-to-manage complications of CLD and cirrhosis is hepatic encephalopathy, also known as portosystemic encephalopathy (PSE). Hepatic encephalopathy is generally defined as a reversible neuropsychiatric impairment, ranging from mild cognitive deficiencies to coma, in patients with underlying cirrhosis [3]. The prevalence of hepatic encephalopathy continues to rise for several reasons. For one, patients with chronic hepatitis C, typically born between 1945 and 1965 [4], are now developing cirrhosis and its complications at a more rapid pace than ever before. Data from the Healthcare Cost and Utilization Project (HCUP), a national repository of patient-level
hospital care data, reveal that the number of discharges for hepatic encephalopathy has increased from 2003 to 2011 from 40 012 to 50 048, respectively [5]. Although HCUP data over the past 9 years likely underestimate hepatic encephalopathy discharge data since hepatic encephalopathy is not always a primary diagnosis on admission, these data point to the potential for substantial increase in hepatic encephalopathy admissions. Additionally, we are currently in the midst of a global obesity epidemic, which fuels the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) [6], and these patients are now presenting in larger numbers with complications of CLD such as hepatic a Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas and bDepartment of Internal Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
Correspondence to Robert S. Rahimi, MD, MSCR, Liver Consultants of Texas, Baylor University Medical Center, 3410 Worth Street, Suite 860, Dallas, TX 75246, USA. Tel: +1 214 820 8500; fax: +1 214 820 0993; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:265–271 DOI:10.1097/MOG.0000000000000066
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Liver &&
KEY POINTS The majority of cirrhotic patients admitted to the hospital with AMS do not have hepatic encephalopathy; other causes should be searched for. The prognosis of patients with cirrhosis and AMS due to hepatic encephalopathy is better than for other causes of AMS. Diagnosing CHE can be challenging and timeconsuming; the STROOP app test is available for download, allowing a quick and reliable tool in screening for CHE. Rifaximin maintained remission and decreased readmission rates when used over a 2-year period in patients with hepatic encephalopathy; however, it would become cost-effective in comparison to lactulose therapy, if the monthly price decreased to less than $353. Although rifaximin is not US FDA-approved for OHE, it was more effective when combined with lactulose compared to lactulose alone. Ammonia blood levels do not reliably detect hepatic encephalopathy and should not be used as a screening test; frequent misinterpretations can arise when using ammonia levels to diagnose hepatic encephalopathy in a cirrhotic patient in the emergency department.
encephalopathy. This review will highlight recent data on testing, treating and outcomes in patients with hepatic encephalopathy.
HEPATIC ENCEPHALOPATHY DEFINITION Hepatic encephalopathy is described as encompassing a spectrum of reversible neuropsychiatric abnormalities that range from normal cognitive function (‘grade 0’) to minimal hepatic encephalopathy (MHE) (within grade 0) to overt hepatic encephalopathy (OHE) (where grade 1 is characterized by mild lack of awareness, shortened attention span and mild asterixis or tremor; grade 2 is characterized by lethargy, disorientation and obvious asterixis; grade 3 consists of somnolence with arousability, gross disorientation with bizarre behavior and muscle rigidity with clonus and hyper-reflexia; whereas grade 4 consists of coma with decerebrate posturing in patients with cirrhosis, after exclusion of neurologic and/or metabolic abnormalities [7 ]). It should be noted that patients with cirrhosis who are admitted with altered mental status (AMS) are most often presumed to have hepatic encephalopathy simply because of their alteration in mentation. However, recent data demonstrated that caution is required in these patients. In a cohort study of 1218 inpatients with cirrhosis, AMS was &&
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evaluated [7 ]. AMS was defined a priori to be caused by hepatic encephalopathy [defined according to the International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN)], sepsis/ infectious, metabolic, exogenous drugs/toxins, structural lesions, or psychiatric abnormalities; all of these disorders were carefully defined according to commonly accepted clinical criteria. In this cohort, AMS was the cause of admission in 349 patients (approximately one-third of the cohort). Although the most common cause of AMS was hepatic encephalopathy, accounting for nearly half of all patients, other causes of AMS were prominent and included the following: sepsis/infection (23%), metabolic disorders (8%), drugs/toxins (7%), structural lesions (5%), psychiatric disorders (1%), or multiple causes (8%). Remarkably, mortality in patients with AMS was 35% compared to 16% in those with normal mental status (NMS) (P < 0.0001). Patients with sepsis/infection, structural lesions, or multiple disorders causing AMS had much higher mortality (ranging from 61 to 79%) than those with hepatic encephalopathy. These data emphasize the point that over 50% of patients with cirrhosis admitted with AMS have a disorder that does not meet the definition of hepatic encephalopathy. Thus, it is critical to search for multiple different causes of AMS in patients with cirrhosis. Of note, there has been a recent proposal for alternative terminology for hepatic encephalopathy – adopted by the ISHEN. The consensus conference describes the spectrum of neurocognitive impairment in cirrhosis (SONIC), with MHE and grade 1 hepatic encephalopathy, categorized as covert hepatic encephalopathy (CHE), whereas grade 2–4 hepatic encephalopathy represents OHE [8].
PATHOPHYSIOLOGY The underlying mechanism(s) causing hepatic encephalopathy remain(s) under investigation. Currently, it is believed that hepatic encephalopathy is a result of multiple putative processes that cause functional impairment of neuronal cells. One of the main factors involved in the pathophysiology of hepatic encephalopathy is thought to be ammonia. Additionally, inflammatory cytokines, benzodiazepine-like compounds such as gamma-aminobutyric acid and manganese have been reported to play a role in hepatic encephalopathy [9]. A number of potential neurotoxicity mechanisms for ammonia have been described. Initially, ammonia increases the resting membrane potential and inhibits both axonal conduction and excitatory postsynaptic potentials. Furthermore, ammonia inactivates neuronal chloride extrusion pumps, suppressing inhibitory postsynaptic potential Volume 30 Number 3 May 2014
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Hepatic encephalopathy: how to test and treat Rahimi and Rockey
formation and depolarization of neurons. The total brain ammonia that accumulates after crossing the blood–brain barrier, resulting in astrocyte swelling and brain edema due to the accumulation of glutamine in hepatic encephalopathy, may not be in the order of magnitude required to alter these postsynaptic potentials, until advanced stages [10]. Although glutamine is the main amino acid involved in hepatic encephalopathy, glutaminase haplotypes have been linked to the risk of OHE, as well as increased mitochondrial ammonia, leading to reactive nitrogen and oxygen species, resulting in worsening brain edema [11–14]. Ammonia is produced by colonic bacteria catabolism of nitrogenous sources and enterocytes from glutamine, pointing to the gastrointestinal tract as an important element in the pathogenesis of hepatic encephalopathy. However, it should be emphasized that although cirrhotic patients with hepatic encephalopathy often have elevated ammonia levels, there is no absolute correlation between ammonia levels and grade of hepatic encephalopathy [15 ]. &
RBANS has proven effective in screening patients for CHE; however, it requires a fee for its implementation [22]. Although paper-and-pencil testing has clinical applicability, computerized testing offers greater control over task stimulation, standardization and data gathering. The inhibitory control test (ICT) has been previously described as an attention and response inhibition test. Two studies evaluated lure response rates in cirrhotic patients. Those who scored above 5 lures out of 40 attempts had CHE diagnosed with 88% sensitivity, high accuracy (c-statistic ¼ 0.9), and had worse driving simulator performance with more traffic accidents; however, it was recommended in the second study that adjustments be made by target accuracy, in order to increase the diagnostic accuracy of CHE [23,24]. The ICT is limited in that patients quickly adapt by learned responsiveness with frequent testing and it requires personnel to be trained in administering the test; however, it can be downloaded for free at www.hecme.tv. Most recently, an interesting study by Bajaj et al. [25 ] evaluated a smartphone application called the STROOP app test (EncephalApp_ STROOP) that is available for free download on iTunes, as a valid and reliable tool to screen for CHE. Details regarding the ease of administration, scoring and interpretation for age-specific populations can be viewed at www.chronicliverdisease. org. Another study evaluating CHE without specialized testing used prior sickness impact profile (SIP) tests with 136 questions on 12 quality-of-life (QoL) topics. The authors modified this time-consuming test to finally contain four SIP questions and combined them with sex and age of individual patients to come up with a formula to identify CHE patients, called SIP CHE score. Over the 1-year follow-up of 93 patients, baseline SIP CHE scores above 0 correctly identified patients with CHE with nearly 80% sensitivity and specificity, whereas the 6-month evaluation’s sensitivity in SIP CHE scoring increased the sensitivity to 88%; the 1-year result was close to the baseline level of near 80% sensitivity, with 32% of the patients having CHE [26]. Although the SIP CHE strategy does not include specialized testing, accuracy of detecting CHE with this method needs further investigation. Although computerized tests can allow specific cognitive processes to be assessed, neurophysiological tests such as the critical flicker frequency (CFF) test are tools that can be used to help diagnose hepatic encephalopathy. In CFF, patients are shown a light pulse at 60 Hz, and then decreased gradually by 0.1 Hz per second. Once the fused light begins to flicker in a patient’s eye, they are asked to notify the &
TESTING FOR HEPATIC ENCEPHALOPATHY Hepatic encephalopathy historically has been a clinical diagnosis; however, the use of the West Haven criteria (WHC) in combination with neuromotor dysfunction, neuropsychological testing with hepatic encephalopathy scoring algorithm (HESA), clinical hepatic encephalopathy staging scale (CHESS), and modified-orientation log (MO-log) helps grade OHE more accurately, but, the length of time it takes to implement these tests in clinical practice limits their use [16–19]. In the past decade, diagnosing CHE has become important as it prognosticates the development of OHE. Although diagnosing CHE clinically can be a challenge (i.e. patients have a normal clinical exam), many screening tools have been studied to help aid in making the diagnosis. The Psychometric Hepatic Encephalopathy score (PHES), developed in Europe, was previously considered to be the gold standard in diagnosing CHE; however, administration and scoring have to be done in an outpatient setting, and with lack of available testing material and copyright concerns, widespread acceptance in the United States is limited [20]. Current consensus [21] recommendations include the use of PHES or the repeatable battery for the assessment of neuropsychological status (RBANS) for diagnosing CHE. Both tests require about 25 min or less, and are paper-and-pencil tests. RBANS tests for delayed memory and language capability, which are usually normal in CHE; hence the applicability of using this test is limited. Therefore, a modified version of
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examiner. Frequencies below 39 Hz can diagnose CHE according to a recent meta-analysis, with a sensitivity of 61% [95% confidence interval (CI) 55–67], specificity 79% (95% CI 75–83) and diagnostic odds ratio of 10.9 (95% CI 4.2–28.3, heterogeneity ¼ 74%), with a receiver operator curve of 0.84 [27]. The authors suggest that CFF is simple to perform and interpret, is independent of education, sex, age, and literacy, but should be used as an adjunct, and not a replacement to, psychometric testing. The limitation of CFF is the expense of the equipment and the time required to perform testing is less than 15 min, hence limiting its clinical applicability. Another interesting study evaluated CFF and PHES in hepatic encephalopathy, distinguished between individuals with OHE; however, PHES had significant overlap between controls and patients with OHE, and concluded that neither CFF nor PHES, or the combination, could reliably distinguish cirrhotic patients with CHE from controls or those with OHE [28].
TREATMENT FOR HEPATIC ENCEPHALOPATHY Therapy aimed at reducing ammonia levels, enhancing elimination or decreasing its production, has resulted in improvement in hepatic encephalopathy. For example, the nonabsorbable disaccharides (i.e. lacitol and lactulose) and antibiotics (i.e. neomycin and rifaximin) have been the mainstay of therapy based on prior studies. However, educating patients on the proper use of these medications, especially with lactulose to achieve the correct number of bowel movements per day, is clinically important, so as to potentially prevent readmission for hepatic encephalopathy events. In one study of 402 cirrhotic patients, the overall readmission rate was 69%, with the 1-month readmission rate being 37%. Of the total readmissions, 22% were thought to be preventable if proper use of maintenance lactulose therapy and education was given at discharge [29 ]. Although lactulose (b-galactosidofructose) and lactitol (b-galactosidosorbitol) have demonstrated variable efficacy in clinical trials, subset analysis of high-quality studies in a meta-analysis demonstrated that nonabsorbable disaccharides had no effect on hepatic encephalopathy compared to placebo [30]. Despite these mixed results, lactulose is still the first-line treatment for OHE, while concurrently searching and treating the underlying precipitant causing hepatic encephalopathy. Whereas prior studies have evaluated the use of neomycin for OHE [31], the side-effect profile of nephrotoxicity and ototoxicity has limited neomycin’s current use; this is particularly true since the advent of rifaximin, which has few side effects. &
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Although rifaximin received US Food and Drug Administration (FDA) approval in 2010, its use was for secondary prevention of OHE. Further study has attempted to expand our understanding of the potential use of rifaximin. Over a 6-month period, rifaximin resulted in a decrease in hospital readmission rates and OHE events compared to placebo. An extension of this study evaluated rifaximin in a phase 3, open-label maintenance study to assess the safety and rate of hospitalization with long-term rifaximin use defined as greater than or equal to 2 years [32 ]. In the all-rifaximin arm (n ¼ 392), the median exposure was 427 days. Adverse events were similar to the original randomized controlled trial (RCT), specifically without an increase in rate of infections or development of antibiotic resistance. The overall rates of hepatic encephalopathy-related hospitalization rate remained low (all rifaximin ¼ 0.21, prior RCT ¼ 0.3) compared to the placebo group (0.72). Hence, long-term therapy with rifaximin appears to reduce the rate of hepatic encephalopathy-related hospitalizations with no significant adverse events. The greatest current controversy about the use of rifaximin appears to surround its cost and costeffectiveness. A cost-effectiveness analysis using Markov modeling designed to test lactulose or rifaximin in preventing motor vehicle accidents (MVAs) in patients with CHE revealed that lactulose, but not rifaximin, was cost-effective across all strategies when compared to patients without any history of MHE. Of note, it was estimated that rifaximin would become cost-saving if its cost was decreased to less than $353 per month [33 ]. ‘Off-label’ use of rifaximin for OHE with or without the use of lactulose has become increasingly common. A commonly encountered situation is that in which rifaximin is added to lactulose for treatment of OHE. In this regard, a timely randomized, double-blind, placebo-controlled trial evaluated 120 cirrhotic patients with OHE, comparing 63 patients receiving both lactulose þ rifaximin 1200 mg/day (group A) to 57 patients receiving lactulose þ placebo (group B) [34 ]. The primary endpoint was complete reversal of hepatic encephalopathy, which occurred in 48 (76%) patients in group A compared to 29 (51%) patients in group B (P < 0.004). Additionally, group A patients had a shorter length of stay compared to group B (5.8 3.4 vs. 8.2 4.6 days; P ¼ 0.001). The authors concluded that the combination of lactulose þ rifaximin was more effective than lactulose alone in treating OHE. However, there is not currently a US FDA indication for the use of rifaximin in OHE. In a study examining the use of lactulose only in OHE, 120 cirrhotic patients without previous OHE &&
&
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episodes were randomized to lactulose (n ¼ 60) or no lactulose (n ¼ 60) and were assessed for hepatic encephalopathy using psychometric testing at recruitment and 3 months, then were followed monthly for 12 months to determine whether OHE developed. At 1 year, a total of 20/105 (19%) patients developed OHE, of which 6/55 (11%) and 14/50 (28%) were in the lactulose versus control groups, respectively (P ¼ 0.02). There were no statistically significant differences in mortality among the two groups. At 3 months, those receiving lactulose had less evidence of MHE [11/57 (19%)] compared to control [31/56 (55%)] (P ¼ 0.001). Although there were no differences in baseline MHE between groups, those receiving lactulose for MHE improved in 21/32 (66%); of note, 9/36 (25%) patients not receiving lactulose therapy recovered from MHE spontaneously. The overall number needed to treat (NNT) with lactulose to prevent an episode of hepatic encephalopathy in cirrhotic patients without any history of hepatic encephalopathy was 4 and 5.8 for those who developed MHE or OHE, respectively. The authors concluded that lactulose therapy was effective for cirrhotic patients as primary prophylaxis to prevent OHE episodes [35 ]. Another study focused on secondary prophylaxis for cirrhotic patients with hepatic encephalopathy. Over a 1-year period, 235 patients with a previous hepatic encephalopathy event who had recovered were randomized to receive either lactulose (30 ml three times a day, n ¼ 80), probiotics (three capsules daily containing 112.5 billion viable lyophilized bacteria per capsule, n ¼ 77), or no therapy (n ¼ 78). A total of 38 patients (16%) were lost to follow-up; 77 of 197 (39%) patients developed an episode of hepatic encephalopathy within 12 months. Using intention-to-treat analysis, including the initially enrolled patients, 30/80 (38%) receiving lactulose, 35/77 (45%) receiving probiotics, and 50/78 (64%) receiving no therapy, developed recurrent hepatic encephalopathy (P ¼ 0.003). Although the difference between lactulose and probiotic therapy as secondary prophylaxis for hepatic encephalopathy was statistically significantly different compared to using no therapy (P ¼ 0.001 and P ¼ 0.02, respectively), there was no significant difference found between lactulose and probiotic use (P ¼ 0.35). These data suggest that use of either lactulose or probiotics for secondary prophylaxis for hepatic encephalopathy seems reasonable (and equally effective) [36 ]. A RCT assessed the development of OHE using probiotics in patients with MHE (n ¼ 86; n ¼ 42 with MHE) with three times a day dosing of 1 108 colony forming units (CFU), and compared them to controls receiving no therapy (n ¼ 74; n ¼ 33 with &
&
&
MHE) [37 ]. After psychometric, CFF and other testing ensued, a mean follow-up of nearly 40 þ 10 weeks for each arm resulted in a significant decrease in progression to OHE after receiving 3 months of probiotics; seven patients progressed to OHE, compared to controls; 14 patients developed OHE (P < 0.05). In patients without prior OHE, probiotics can be useful in preventing OHE; however, longer follow-up is needed to assess the efficacy of probiotic use. Another study presented at the American Association for the Study of Liver Diseases (AASLD) Annual Meeting, pending publication, studied cirrhotic patients admitted with OHE, randomizing them to receive either 4 l of polyethylene glycol 3350-electrolyte solution (PEG, n ¼ 25) or standardof-care lactulose (n ¼ 25) [38]. The primary outcome was the absolute difference in the HESA at 24 h, with an improvement in one HESA grade accounting for an overall response to either therapy. There were no differences in median admission ammonia levels, model for end-stage liver disease (MELD) scores, and baseline HESA grades between the two groups. Baseline and 24-h mean HESA scores improved from 2.3 0.8 to 1.6 0.9 in the lactulose group, and 2.3 0.9 to 0.9 1 in the PEG group (P ¼ 0.015). Median time for hepatic encephalopathy resolution was 2 days for lactulose and 1 day of PEG (P ¼ 0.01). The overall response within 24 h to lactulose and PEG was 52 and 91%, respectively (P ¼ 0.002), hence PEG improved hepatic encephalopathy over the first 24 h of hospitalization significantly faster than lactulose, suggesting that PEG may be superior to lactulose for treatment of patients hospitalized for OHE. A double-blind controlled trial investigated glycerol phenylbutyrate (GPB) in 178 patients (59 patients concurrently taking rifaximin) with cirrhosis who previously had two or more hepatic encephalopathy episodes in the prior 6 months. The mechanism of action of GPB is to lower ammonia via metabolism in an alternate pathway to urea for nitrogen excretion in the urine in the form of phenylacetylglutamine. Those taking 6 ml of GPB orally twice daily were found to have significantly reduced hepatic encephalopathy events (21 vs. 36%; P ¼ 0.02), total events (35 vs. 57; P ¼ 0.04) and time to first event (hazard ratio 0.56, P < 0.05). Patients not receiving rifaximin on enrollment showed more statistically significant improvements in all three categories stated above [39 ]. Plasma ammonia was significantly lower in patients receiving GPB. There were no differences in adverse events between the two groups. This study suggests that GPB has therapeutic potential in lowering ammonia and reducing hepatic encephalopathy events. Further studies are underway.
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An area that has received considerable attention is treatment of MHE, now considered CHE according to SONIC, as its prevalence ranges from 50 to 80% in patients with cirrhosis. A double-blind, placebo-controlled trial used an aqueous solution containing a potassium-iron-phosphate-citrate complex that is supposed to bind to intestinal ammonia and excrete it via the gastrointestinal tract. Investigators evaluated 51 patients with MHE, and treated them with either 4 weeks of potassium-iron-phosphate-citrate (n ¼ 25) or placebo (n ¼ 26), with 2 ml of solution, three times a day before a meal [40 ]. Overall, patients treated with potassium-iron-phosphate-citrate showed significantly more improvement in the PSE score (72%), compared to those treated with placebo (27%) (P ¼ 0.0014). Although seven patients (28%) reported 14 adverse events, most of which were mild or moderate gastrointestinal tract side effects when treated with potassium-iron-phosphate-citrate complex, four patients (15%) reported eight similar adverse events; therefore the investigational medication was well tolerated overall in the treatment option for MHE. Another study examined different therapies in MHE (also CHE), comparing no therapy (group A), lactulose 30–60 ml b.i.d. (group B), probiotics of 110 billion CFUs b.i.d. (group C) and L-ornithine-Laspartate 6 g t.i.d. (LOLA; group D) for 3 months to determine overall health-related quality of life (HRQoL) improvement, and outcomes in progressing to OHE [41 ]. Of the 322 cirrhotic patients, 160 (49.7%) were found to have MHE in which 40 patients were assigned to each of the four groups. Using neuropsychological assessment, recovery of MHE (i.e. NMS) was found in 10, 48, 35 and 35% of patients in groups A, B, C and D, respectively (P ¼ 0.006). There was no statistically significant difference in the rate of recovery from MHE or changes in ammonia level when comparing placebo to lactulose, probiotics or LOLA. Although no significant difference in OHE progression occurred over 3 months, a total of nine patients (6% overall) developed OHE. When comparing the SIP, which assesses the influence of disease and treatment on daily functioning (i.e. HRQoL), a statistically significant decrease in total SIP score was present in the treatment groups compared to no treatment (P < 0.001); again, no differences in SIP scores were found among treatment groups. The decrease in SIP scores correlated with an improvement in MHE on multivariate analysis; however, there was no correlation with the type of therapy offered. Overall, these results suggest that lactulose, probiotics and LOLA significantly improved MHE and HRQoL in cirrhotic patients compared with no therapy. Thus, practitioners should consider using any of these &&
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three treatments in those proven to have MHE based on neuropsychological testing, recognizing that LOLA is not available in the United States.
CONCLUSION Many recent studies have provided insight in the management of patients with cirrhosis and CHE or OHE. However, further research is still required, in particular, in assessing the most cost-effective, timely and ease of implementing testing for CHE. The best management strategy for treatment of CHE or OHE will require further studies, particularly with regard to the emergence of rifaximin and its cost-effectiveness. Induction and maintenance of therapy, along with educating primary care givers in patients presenting with OHE, is crucial in preventing readmission. Although there is clinical evidence to support the adjunctive use of rifaximin (i.e. with other therapies) for severe OHE, there is no current US FDA approval for this specific use. Acknowledgements None. Conflicts of interest D.C.R. received research support from Hyperion Therapeutics in 2011 and 2012. The authors have no conflicts of interest to report.
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Hepatic encephalopathy: how to test and treat Rahimi and Rockey 10. Szerb JC, Butterworth RF. Effect of ammonium ions on synaptic transmission in the mammalian central nervous system. Prog Neurobiol 1992; 39:135–153. 11. Romero-Gomez M, Jover M, Del Campo JA, et al. Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study. Ann Intern Med 2010; 153:281–288. 12. Albrecht J, Norenberg MD. Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology 2006; 44:788–794. 13. Jayakumar AR, Rama Rao KV, Schousboe A, Norenberg MD. Glutamineinduced free radical production in cultured astrocytes. Glia 2004; 46:296– 301. 14. Corbalan R, Hernandez-Viadel M, Llansola M, et al. Chronic hyperammonemia alters protein phosphorylation and glutamate receptor-associated signal transduction in brain. Neurochem Int 2002; 41:103–108. 15. Gundling F, Zelihic E, Seidl H, et al. 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Improving the inhibitory control task to detect minimal hepatic encephalopathy. Gastroenterology 2010; 139:510– 518; e511-512. 24. Bajaj JS, Hafeezullah M, Franco J, et al. Inhibitory control test for the diagnosis of minimal hepatic encephalopathy. Gastroenterology 2008; 135:1591– 1600; e1591. 25. Bajaj JS, Thacker LR, Heuman DM, et al. The Stroop smartphone application & is a short and valid method to screen for minimal hepatic encephalopathy. Hepatology 2013; 58:1122–1132. One hundred and twenty-five cirrhotic patients (43 with previous OHE) and 134 controls were included in the original cohort. Stroop performance was significantly impaired in MHE, compared to those without MHE, according to SPTs, ICTs, and PHES (all P < 0.0001). Using a cut-off of more than 274.9 s (on-time and off-time) had a c-statistic of 0.89 in all patients and 0.84 in patients without previous OHE for MHE diagnosis using SPT as the gold standard. The validation cohort showed 78% sensitivity and 90% specificity with the above 274.9-s on-time and off-time cut-off, making the Stroop smartphone app a short, valid, and reliable tool for screening of MHE. 26. Nabi E, Thacker LR, Wade JB, et al. Diagnosis of covert hepatic encephalopathy without specialized tests. Clin Gastroenterol Hepatol 2013. [Epub ahead of print] 27. Torlot FJ, McPhail MJ, Taylor-Robinson SD. Meta-analysis: the diagnostic accuracy of critical flicker frequency in minimal hepatic encephalopathy. Aliment Pharmacol Ther 2013; 37:527–536. 28. Kircheis G, Hilger N, Haussinger D. Value of critical flicker frequency and psychometric hepatic encephalopathy score in diagnosis of low-grade hepatic encephalopathy. Gastroenterology 2013. [Epub ahead of print] 29. Volk ML, Tocco RS, Bazick J, et al. Hospital readmissions among patients with & decompensated cirrhosis. Am J Gastroenterol 2012; 107:247–252. 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32. Mullen KD, Sanyal AJ, Bass NM, et al. Rifaximin is safe and well tolerated for long-term maintenance of remission from overt hepatic encephalopathy. Clin Gastroenterol Hepatol 2013. [Epub ahead of print] A 2-year study regarding rifaximin’s safety and efficacy profile in preventing readmissions in patients with cirrhosis and hepatic encephalopathy was evaluated. A median exposure of 427 days of rifaximin 550 mg twice daily resulted in low readmission hepatic encephalopathy rates compared to placebo without any increase in adverse events including infections or antibiotic resistance. 33. Bajaj JS, Pinkerton SD, Sanyal AJ, Heuman DM. Diagnosis and treatment of & minimal hepatic encephalopathy to prevent motor vehicle accidents: a costeffectiveness analysis. Hepatology 2012; 55:1164–1171. Using a Markov model, five MHE management strategies were compared, all of which were assumed to reduce the MVA rate equivalent to an age matched noncirrhotic. The model included 1000 cirrhotic patients over a 5-year period, with the societal cost of a single MVA estimated to be $42 100. Lactulose was the most cost-effective strategy across all strategies (i.e. substantially reduced societal cost by preventing MVAs); however, rifaximin was not, and would become cost-effective if the monthly cost was below $353. 34. Sharma BC, Sharma P, Lunia MK, et al. A randomized, double-blind, controlled && trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol 2013; 108:1458–1463. One hundered and twenty patients with hepatic encephalopathy received either lactulose þ rifaximin (group A) or lactulose þ placebo (group B) in a randomized, double-blind fashion when admitted for OHE. Those in group A had a significant reversal of hepatic encephalopathy (P < 0.004), decrease in mortality (P < 0.05), and shorter length of stay (P ¼ 0.001) compared to cirrhotic patients in group B. Although more deaths were seen in group B, no differences in mortality were associated with gastrointestinal bleeding or hepatorenal syndrome between groups. 35. Sharma P, Sharma BC, Agrawal A, Sarin SK. Primary prophylaxis of overt & hepatic encephalopathy in patients with cirrhosis: an open labeled randomized controlled trial of lactulose versus no lactulose. J Gastroenterol Hepatol 2012; 27:1329–1335. One hundred and twenty cirrhotic patients without previous OHE were randomized to receive lactulose or placebo with the primary aim to evaluate the efficacy of lactulose for primary prophylaxis of overt and MHE. Those receiving lactulose developed less OHE (11 vs. 28%; P ¼ 0.02) with a NNT of 5.8 over 12 months compared to placebo. Lactulose also improved MHE in 66 vs. 25% of controls, with a NNT of 4. 36. Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary prophylaxis of hepatic & encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol 2012; 107:1043– 1050. Two hundred and thirty-five cirrhotic patients who recovered from hepatic encephalopathy were randomized to receive either lactulose, probiotics or placebo and were followed for 1 year and tested for development of OHE by psychometry and using the WHC. There were significant differences seen if lactulose or probiotics were given for secondary prophylaxis compared to placebo (P ¼ 0.001 and P ¼ 0.02); however, there were no differences when direct comparisons were made between lactulose and probiotics, respectively (P ¼ 0.349). 37. Lunia MK, Sharma BC, Sharma P, et al. Probiotics prevent hepatic encepha& lopathy in patients with cirrhosis: a randomized controlled trial. Clin Gastroenterol Hepatol 2013. [Epub ahead of print] One hundered and sixty patients with hepatic encephalopathy were randomly assigned to receive probiotics three times daily or no probiotics. Of the 86 patients (42 with MHE) receiving probiotics, seven developed OHE, compared to 74 patient (33 with MHE) controls, of which 14 developed OHE (P < 0.05) after psychometric testing was performed. There were no differences in overall mortality between the two groups. 38. Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. A Randomized trial comparing polyethylene glycol 3350-electrolyte solution (PEG) and lactulose in hospitalized patients with hepatic encephalopathy. Hepatology 2012; 56:; 191A-1144A. 39. Rockey DC, Vierling JM, Mantry P, et al. Randomized, double-blind, controlled && study of glycerol phenylbutyrate in hepatic encephalopathy. Hepatology 2014; 59:1073–1083. This phase 2 study evaluated 178 patients with cirrhosis, who received placebo or GPB for treatment of OHE. Overall, GPB decreased hepatic encephalopathy events significantly (P ¼ 0.02), time to first event (P < 0.05) and total events (P ¼ 0.04). There was an overal trend to fewer hospitalizations in patients receiving GPB (P ¼ 0.06).GPB appeared to be well tolerated. 40. Burkard T, Biedermann A, Herold C, et al. Treatment with a potassium-iron&& phosphate-citratecompleximprovesPSEscoresandqualityoflifeinpatientswith minimal hepatic encephalopathy: a multicenter, randomized, placebo-controlled, double-blind clinical trial. Eur J Gastroenterol Hepatol 2013; 25:352–358. This multicenter, double-blind, randomized placebo-controlled trial evaluated 51 patients with MHE. Those receiving 4 weeks of potassium-iron-phosphate-citrate solution showed significant improvements in PSE scores compared to placebo (72 vs. 27%; P ¼ 0.0014) as well as higher QoL scores (P ¼ 0.0036). 41. Mittal VV, Sharma BC, Sharma P, Sarin SK. A randomized controlled trial com& paring lactulose, probiotics, and L-ornithine L-aspartate in treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 2011; 23:725–732. This RCT compared lactulose, probiotics and LOLA to no therapy to evaluate HRQoL and progression to OHE in those with MHE. Any of the three therapies showed a significant improvement in HRQoL and reversal of MHE compared to no therapy; however, there were no significant differences between the therapies used. &&
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