Should We Treat Minimal/Covert Hepatic Encephalopathy, and with What?
Phillip K. Henderson, DOa, Jorge L. Herrera, MDb,*
KEYWORDS
Encephalopathy Covert hepatic encephalopathy Overt encephalopathy Minimal hepatic encephalopathy
KEY POINTS
Despite its name, minimal hepatic encephalopathy significantly impacts quality of life and daily function.
Most patients with cirrhosis develop covert encephalopathy during the natural history of their disease.
Probiotics, nonabsorbable dissacharides, rifaximin, and L-ornithine-L-aspartate have all been studied for treatment of covert hepatic encephalopathy (CHE).
Because of lack of readily accessible testing strategies, detection and treatment of CHE remains suboptimal and dependent on regional resources and expertise.
INTRODUCTION
Hepatic encephalopathy (HE) is a heterogeneous class of neuropsychiatric changes seen in cirrhosis in the absence of other organic brain disorders.1 HE is a spectrum of neurocognitive impairments in cirrhosis that range from abnormal neuropsychiatric testing without clinical evidence of disease (minimal HE [MHE]) to varying degrees of overt clinical findings (overt HE [OHE]).1 The categories of OHE are broken down by their cause: acute liver failure (type A), bypass (type B), and cirrhosis (type C). The West Haven classification is used to discern the varying degrees of OHE.2 Much debate has centered on the term “minimal” in MHE because of the concern for trivialization of the neurocognitive impairment in this subgroup by patients and clinicians.2 The term covert HE (CHE) has been adopted and accepted by the International CHE is extremely common with up to 80% of patients with cirrhosis being affected.3
Because of the lack of clinically detectable changes in verbal skills or motor function, the diagnosis of CHE is difficult and requires specialized testing to discern the subtle changes in cognition. The tools currently available for the diagnosis of CHE have been reviewed elsewhere in this issue. Some of these specialized psychometric tests require advanced training to perform and are not readily available in clinical practice. A survey of 137 members of the American Association for the Study of Liver Disease showed only 40% of the respondents routinely tested their patients for CHE. The surveyed group reported that the time and resource allocation required for diagnosis was a major barrier.4 Because of the lack of an easily performed standardized screening tool and controversy over which patients should be screened CHE remains an underdiagnosed condition.
COVERT ENCEPHALOPATHY: IS IT IMPORTANT?
Deficits in attention and coordination that are seen in CHE affect multiple dimensions of life in a patient with cirrhosis despite not being clinically detectable. Quality of life (QOL) is impacted in patients with CHE and translated into lower QOL scores.5 Studies by Groeneweg and colleagues6 have shown significant impact on activities of daily living using the Sickness Impact Profile (SIP). The SIP, which has been validated across a broad range of chronic medical conditions, detects significant impacts on the QOL of patients with cirrhosis with CHE.1 The SIP uses physical, social, and psychological domains to grade the degree of QOL impairment. The study by Groeneweg and colleagues6 showed that patients with CHE have significantly reduced scores in all domains. The most affected areas were alertness, home management, work, recreational activities, and sleep.3
Falls are a significant burden to health care use and account for 90% of fracture visits in emergency departments.7 The subclinical visual-motor impairment in patients with CHE puts them at risk for falls.8 Falls have been shown to be more common in patients with cirrhosis with CHE than without. Patients taking concurrent psychotropic medications were further at risk for falls.9 The increased prevalence of decreased bone mineral density among patients with cirrhosis places them at increased risk for fracture with falls. In the study by Roman and colleagues9 one-third of patients with CHE who fell sustained a fracture and hospital stays were longer and more costly in patients with CHE compared with patients with cirrhosis without CHE and healthy control subjects. Of note, all patients who were hospitalized because of falls with CHE experienced hepatic decompensation, whereas no patients hospitalized without CHE experienced decompensation.9
The attention and coordination defects seen in CHE also affect the ability to work. Schomerus and Hamster10 demonstrated that employability is affected by CHE. Blue collar workers whose employment centers on repetitive motion or manual labor are most affected by covert encephalopathy.1 Direct financial impact comes when these patients are unable to maintain employment or perform at work. Fellow coworkers who may be injured by subclinically impaired patients and caretaker burden contribute to the indirect costs of CHE.
The subclinical impairments in attention and coordination seen in CHE also have significant impact on driving skills. Several studies have highlighted the effect CHE has on driving. Both on-road and simulator testing have consistently shown that driving performance is decreased in patients with CHE compared with patients with cirrhosis without CHE and healthy control subjects.11–13 CHE patients were found to have a 22% chance of future traffic accidents compared with 3% in non-CHE patients with cirrhosis.14
Not all patients with CHE are affected. Up to 50% retain adequate driving capabilities and there is controversy on the value of routine psychometric testing to predict driving ability.15 Several algorithms have been suggested to stratify driving risk; however, because of the lack of universally accepted testing the widespread application still remains difficult.15 Standard therapies for CHE have been investigated and data support that driving ability can be improved with treatment.16
TREATMENT
Treatment of CHE is justified based on the impact of CHE on everyday life activities. In addition, once CHE develops 50% develop OHE within 3 years, which portends a graver prognosis.17 After OHE develops cognitive impairment persists despite medical therapy or orthotopic liver transplantation.18,19 Given the effects on well-being and outcomes, effective treatments strategies for CHE need to be developed. Several treatment algorithms have been proposed; however, exact timing and duration of therapy remains controversial because of the lack of standardized testing. Our group typically seeks out features of CHE from history, such as extreme fatigue, history of falls, accidents, difficulty maintaining employment, and if present empiric therapy is strongly considered. In the absence of these features we recommend psychometric testing for all patients with cirrhosis. Fig. 1 shows a proposed algorithm for the detection and management of CHE.
Once CHE is diagnosed, there is no consensus as to the best therapeutic agent to use. Probiotics, nonabsorbable disaccharides, rifaximin, and L-ornithine L-asparatate (LOLA) have been the agents most studied to date. The data supporting the use of these agents are summarized in Table 1. The remainder of this article reviews the evidence to support specific agents in the treatment of CHE.
Probiotics
Ammonia production is often implicated in the development of HE. Probiotics help modulate ammonia production by decreasing urease activity of enteric bacteria and decreasing ammonia delivered to the portal venous system.20 Probiotics decrease intestinal pH and improve gut nutrition causing favorable outcomes in ammonia modulation.21 Several studies have investigated the use of probiotics in the treatment of CHE. A study by Liu and colleagues22 compared fiber, fiber in combination with probiotics, and placebo. Psychometric test, stool pH, stool bacteriology, blood ammonia, and blood endotoxin levels were compared. When compared with placebo the combination of probiotics and fiber reversed 50% of CHE versus 13% with placebo. Statistically significant decreases in endogenous endotoxin and ammonia levels were seen in the treatment group. Of interest, Child-Pugh scores were found to have a statistically significant improvement in this small cohort (N 5 20) in the combination group compared with placebo (P 5 .04).22
A study by Bajaj and colleagues23 compared the effect of probiotics versus placebo on psychometric testing and QOL scores after 60 days of therapy. In the treatment arm of the study 70% of the patients showed reversal of CHE, whereas 0% of the patients in the placebo arm showed reversal (P 5 .03). In this study health-related QOL (HRQOL) was investigated using the Short Form 36. Probiotics were not found to impact HRQOL; however, some argue that if more sophisticated testing, such as the SIP, were used a different outcome may have been reached.23 In the Bajaj and Liu studies, no patient in the active treatment group developed overt encephalopathy. In contrast, in the study by Bajaj, 25% of the placebo cohort developed OHE.22,23
To further support the use of probiotics, a recent prospective, randomized controlled study revealed that 50% fewer patients developed HE on probiotics compared with placebo.24 A recent study by Vlachogiannakos and colleagues25 presented in abstract form at the American Association for the Study of Liver Diseases meeting showed a 60% reduction in CHE in patients treated with Lactobacillus plantarum versus placebo. Meta-analysis has confirmed significant benefit of probiotics and a more favorable side effect profile compared with lactulose.26 In addition to their excellent side effect profile, probiotics are also available commercially in yogurt without a prescription, giving them an advantage to other CHE therapies.27 Given its favorable safety profile, accessibility, and beneficial effect on CHE reversal, probiotics are an attractive option for the management of CHE; however, the type and dose are unknown.
Lactulose
Nonabsorbable disaccharides have long been used in the treatment of OHE. Lactulose exerts multiple effects on ammonia metabolism including altering colonic pH affecting ammonia synthesis and absorption and glutamine uptake.28 Several studies have investigated the impact of lactulose on the reversal of CHE. Dhiman and colleagues29 used psychometric testing to compare lactulose with placebo. In their study, significant improvement was seen in psychometric testing with 57% of patients in the lactulose group showing resolution of CHE. A larger randomized controlled trial by Prasad and colleagues30 also revealed a statistically significant impact on psychometric testing with the use of lactulose. HRQOL scores measured by SIP were also found to be significantly better in the group treated with lactulose. In this study, CHE negatively impacted 11 out of the 12 scales on the SIP and treatment with lactulose showed statistically significant improvement in the SIP in these domains. Further support for the prevalence of CHE in the population with cirrhosis was garnered in this study with 67.7% of Prasad and colleagues30 outpatient population showing psychometric evidence of CHE. A recent study in patients with extrahepatic portal vein obstruction by Sharma and Sharma31 confirmed the findings of the previous studies with over half of the patients treated with lactulose improving in psychometric studies.
Although effective, the study by Sharma and Sharma31 also highlighted the substantial side effects of lactulose leading to a well-known dilemma in the use of lactulose (ie, is the benefit worth the cost). In Sharma’s study, 30% of his cohort experienced gastrointestinal side effects including diarrhea, bloating, and taste alteration. Dose reduction was needed in four patients but no participant discontinued therapy during the study interval.31 The findings of Prasad and colleagues30 correlated with Sharma in that no serious adverse events were reported.31 It is well established that the adverse events of lactulose are not trivial and have been shown to independently decrease QOL in patients undergoing treatment, which can affect long-term compliance.32 Despite the side effect profile, lactulose has proved efficacy and is cost-effective in the treatment of CHE.33
Rifaximin
Rifaximin is a gut-specific, poorly absorbed antibiotic that has been used in a variety of gastrointestinal conditions from traveler’s diarrhea to irritable bowel syndrome. Unlike traditional antimicrobial therapy, rifaximin is thought to modulate rather than eradicate bacteria. Complex studies of the metabolome of enteric bacteria during treatment with rifaximin show an alteration in bacterial function rather than number.34
Several studies have evaluated the efficacy of rifaximin in CHE. The 2011 study by Bajaj and colleagues16 evaluated 41 patients randomized to rifaximin or placebo for 8 weeks. Rifaximin showed an improvement across a variety of study end points. Cognition improved in 91% of patients treated with rifaximin versus 61% in patients treated with placebo using a battery of neuropsychiatric tests. The psychosocial component of HRQOL was improved in patients treated with rifaximin.16 This study also used driving simulators and found that rifaximin improved driving errors more effectively than placebo (76% vs 31%; P 5 .13).16 There were no changes in ammonia levels between the groups but a clinically significant increase in the anti-inflammatory cytokine interleukin-10 was observed in the treatment group versus placebo, supporting the hypothesis of the mechanism of action of rifaximin in this study.16
A study performed by Sidhu and colleagues35 with a slightly larger cohort (N 5 94) treated patients with rifaximin and a significantly higher proportion (75% vs 20%) of patients in the treatment arm showed reversal of CHE on neuropsychiatric testing. A significant number of the five neuropsychiatric tests used in this study were improved within 2 weeks of therapeutic intervention. Similarly to the study by Bajaj, HRQOL was improved. After 8 weeks of therapy with rifaximin, HRQOL was improved as measured by total HRQOL scores.35
Rifaximin has excellent tolerability with few adverse events. In the study by Bajaj equal amounts of patients in the treatment and placebo arm experienced nausea, vomiting, and diarrhea, whereas more patients in the placebo arm developed headaches.34 In the study by Sidhu and colleagues,35 excellent tolerability was also shown. Only two patients in the treatment arm experienced adverse events. No patients in either study required dose reduction or treatment discontinuation because of rifaximin.16,35 This tolerability represents a significant advantage over nonabsorbable disaccharides. The largest drawback to the routine use of rifaximin is cost. Investigators have looked at cost-effectiveness of rifaximin in comparison with other conventional treatments. Bajaj and colleagues33 compared empiric treatment with various test-and-treat strategies and found that lactulose therapy was cost-effective across all testing variables. The use of the inhibitory control test to detect CHE and treatment with lactulose if testing was positive was the most cost-effective strategy. Rifaximin was not shown to be cost-effective at current prices.33 Despite the cost constraints, rifaximin has excellent tolerability and efficacy in the treatment of CHE.
L-Ornithine-L-Aspartate
LOLA has been studied in oral and parenteral forms for the treatment of OHE with mixed results. LOLA is a peptide composed of ornithine and aspartate, two biologically active amino acids. These two amino acids enhance ammonia metabolism by activating enzymes in the urea cycle. It also acts as a substrate for glutamate synthesis to further detoxify ammonia.36
A recent study by Alvares-da-Silva and colleagues37 evaluated 63 patients with CHE and randomized them in a double-blind fashion to oral LOLA versus placebo. Baseline evaluation included psychometric testing, critical flicker frequency, quantitative electroencephalogram, arterial ammonia, liver disease QOL assessment, and the Beck depression and anxiety surveys. After 60 days of treatment there was no improvement in patients receiving LOLA compared with the placebo arm. In contrast to studies using lactulose an overall increase in arterial ammonia concentration was seen in the placebo and LOLA groups. Similarly there was no statistically significant difference in QOL scores, anxiety, or depression scores.37
Although the results in reversal of CHE during active therapy were disappointing, a surprising finding was noted on follow-up. At 6 months after discontinuation of therapy, all study participants were evaluated to see if they had developed OHE. A statistically significant decrease was seen in the intervention group compared with placebo (5% vs 37.9%; P 5 .016).37 In comparison with the placebo arm, the LOLA arm also had improvements in Child-Pugh and Model for End-Stage Liver Disease scores compared with the placebo arm. One theory behind the prevention of OHE is the ability of LOLA to modulate lipid and peptide metabolism. It is also theorized that ammonia metabolism is increased leading to increased glutamine production, which can stimulate hepatocyte growth factors.36 More studies are needed to confirm these findings and to determine if longer treatment duration improves psychometric function and if improvements in liver function are sustained off therapy.
SUMMARY
Most patients with cirrhosis develop CHE over the course of their disease, resulting in significant decrement in QOL. Beneficial outcomes related to cognition, QOL, driving ability, and decrease in falls can be achieved if CHE is identified and treated. Despite its ubiquitous nature and significant potential for morbidity, the appropriate timing of diagnosis and treatment remains to be fully elucidated. Prophylactic therapy and test-and-treat options have been proposed but until standardized diagnostic tools exist to guide therapeutic decisions, CHE remains an underdiagnosed entity.
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