Managing Encephalopathy in the Outpatient Setting

Transcription

1 REVIEW Managing Encephalopathy in the Outpatient Setting Sahaj Rathi, M.D., and Radha K. Dhiman, M.D., D.M., F.A.M.S., F.A.C.G., F.R.C.P., F.A.A.S.L.D. Hepatic encephalopathy (HE) refers to brain dysfunction caused by liver insufficiency and/or portosystemic shunting, manifesting as a wide spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma. It has traditionally been classified according to severity into minimal hepatic encephalopathy (MHE) and HE grades I to IV. MHE includes patients with mild neurocognitive decline apparent only on specialized testing. Grade I HE includes subtle behavioral changes such as inattention, mood changes, and sleep disturbances, which are often difficult to detect on routine clinical evaluation. Therefore, the new classification includes both grade I HE and MHE into covert hepatic encephalopathy (CHE). 1 CHE is seen in 40% to 84% of patients with cirrhosis and is associated with poor quality of life (QOL), impaired driving skills, poor work performance, and reduced overall survival (Fig. 1). 2 DIAGNOSIS OF MHE The diagnosis of MHE requires specialized neurocognitive testing; however, these tests may be impaired in other causes of cognitive dysfunction as well. Only those with mini-mental state examination (MMSE) score greater than 24 may be considered for MHE testing. At least two different tests should be used depending on the local population norms, with one being a widely validated test. This would serve as a comparator for multicentre trials, as well as minimize missed cases (Table 1). 3 New biomarkers (S100b, an astrocytes protein, 3-nitrotyrosine, a reactive nitrogen intermediate) and imaging techniques (diffusion tensor imaging, voxel-based morphometry) have recently been described to characterize MHE and even predict survival. However, these need further evaluation and validation before they may be considered as diagnostic parameters. 4-6 TREATMENT OF HE IN THE OUTPATIENT SETTING According to the new nomenclature, CHE includes both MHE and grade I HE considering the difficulty in distinguishing between the two without specialized testing. However, a recent study demonstrated that patients Abbreviations: BCAA, branched-chain amino acid; CHE, covert hepatic encephalopathy; HE, hepatic encephalopathy; LOLA, L-ornithine-L-aspartate; MHE, minimal hepatic encephalopathy; MMSE, mini-mental state examination; OHE, overt hepatic encephalopathy; PHES, psychometric hepatic encephalopathy score; PSS, portosystemic shunt; QOL, quality of life; SIP, sickness impact profile. From the Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. Potential conflict of interest: Nothing to report. Received 15 August 2016; accepted 25 September 2016 View this article online at wileyonlinelibrary.com VC 2016 by the American Association for the Study of Liver Diseases 150 CLINICAL LIVER DISEASE, VOL 8, NO 6, DECEMBER 2016 An Official Learning Resource of AASLD

2 FIG 1 Consequences of CHE. with grade I HE had higher mortality and complication rates as compared with those with MHE. 7 In a barter between semantic accuracy and practical considerations of a busy outpatient setting, the treatment has been described in terms of CHE and is to include both MHE and grade I HE (Fig. 2). Treatment of HE depends on severity. Overt hepatic encephalopathy (OHE) is usually treated in-hospital, and on resolution, prophylaxis to prevent future episodes is recommended. There are no clear recommendations for treating CHE yet. However, CHE profoundly affects QOL, work productivity, and predicts a higher risk for development of OHE. Adding to this the increase in caregiver burden and the risk to society considering the possibility of accidents while driving and operating heavy machinery, treatment of CHE may well be justified. Nonabsorbable Disaccharides Lactulose forms the mainstay of treatment of HE. Dhiman and colleagues 8 have shown an improvement in CHE in 64% of patients with lactulose. It has also shown good results when used as primary as well as secondary prophylaxis for HE in cirrhosis. Use as primary prophylaxis is currently limited to only patients who have a high risk for development of OHE; however, the exact threshold is not yet defined. In our opinion, patients with decompensated cirrhosis may be considered for primary prophylaxis. Diarrhea, bloating, and nausea are common side effects. Antibiotics Rifaximin is the antibiotic of choice in the management of HE. It modulates the gut flora, improves gut dysbiosis, and has not been shown to induce resistance. Addition of rifaximin to lactulose therapy halves the chances of breakthrough HE in patients with one or more episodes of OHE. Monotherapy with rifaximin has also been shown to be effective in HE prophylaxis. 9 Probiotics Interest in the pathophysiology of the gut brain axis is rapidly emerging. Pathogenic gut bacteria play an important role in ammoniagenesis, and the improvement of gut dysbiosis by probiotics leads to improvement in HE. A recent meta-analysis suggested that probiotics led to improvement in CHE, reduced recurrence of OHE, and were well tolerated. Different strains have been used by studies, notably VSL#3, probiotic yogurt, and Bifidobacterium longum. VSL#3 has been found to be as effective as lactulose for secondary prophylaxis CLINICAL LIVER DISEASE, VOL 8, NO 6, DECEMBER 2016 An Official Learning Resource of AASLD

3 TABLE 1. TESTS FOR DIAGNOSIS OF MHE Test Description Reliability Advantages Disadvantages Paper-Pencil PHES 5 paper and pencil tests: Sensitivity: 96% Extensively validated Time-consuming number connection tests A and Specificity: 100% Requires psychologist B, digit symbol, line tracing and Learning effect serial dotting tests Requires good neuromuscular Adjusted for age, education control Repeatable Battery for the Paper or pencil battery testing --- Has US reference data Copyrighted Assessment of two domains, cortical and Requires psychologist Neuropsychological Status subcortical Language and memory not much impaired in CHE Computerized Inhibitory control test Presentation of letters at 500-ms Sensitivity: 87% Validated Requires highly functioning intervals Specificity: 77% Does not require patients Patients instructed to respond only a psychologist Requires a practice session when X and Y are alternating Cognitive Drug Research Psychometric battery presented on High degree of No need for prior computer Requires highly functioning computer with patients correlation with PHES knowledge patients responding via a two-button YES/NO response box Stroop EncephalApp Identification of the color of Sensitivity: >70% Easy to administer Cannot be performed in symbols or text presented, while Specificity: 90% Quick color-blind the word names a different color Reliable Freely available Scan test Computerized digit recognizing task Mortality Reliable, predicts mortality Need practice sessions, measuring the reaction times hazard ratio: knowledge of computer and errors 2.4 (95% confidence interval: ) Neurophysiological Electroencephalogram 6 Can detect changes in cerebral Sensitivity: % Independent of patient Requires interpretation by a evoked potentials activity across the spectrum of cooperation neurologist HE No learning effect Expensive and labor-intensive 152 CLINICAL LIVER DISEASE, VOL 8, NO 6, DECEMBER 2016 An Official Learning Resource of AASLD

4 TABLE 1. CONTINUED Test Description Reliability Advantages Disadvantages Critical flicker frequency Highest frequency at which the Sensitivity: % Simple Requires highly functioning flicker of a light source can be Specificity: 91% Reliable patients, binocular vision, absence of red-green color Not influenced by age, detected, above which light is blindness education perceived to be continuous --- Quick Requires good hearing Continuous reaction time Repeated registration of the motor reaction time to an auditory stimulus Rapid Screening Test SIP-CHE score Rapid screening method composed Sensitivity: 81-88% Quick Poor specificity of four questions Specificity: 24-37% No special training required Needs validation Abbreviations: PHES, psychometric hepatic encephalopathy score; SIP, sickness impact profile. Ammonia Scavengers L-Ornithine-L-aspartate (LOLA) has shown good results in treatment of OHE but showed no immediate improvement in patients with CHE. However, 6 months after administration, patients given LOLA were less likely to experience development of OHE, which may be caused by the modulation of lipid and peptide metabolism. Overall evidence on its use in CHE is still conflicting. Nutrition Detoxification of ammonia is impaired in liver disease, and ammonia metabolism shifts to the muscles and brain. Malnutrition and sarcopenia further divert ammonia to brain, worsening HE. A diet rich in protein ( g/kg) and energy (35-40 kcal/kg) is thus recommended. Vegetable and dairy protein should be preferred. Meals should be small, frequent, and evenly distributed. A late-night snack rich in complex carbohydrates mitigates a prolonged fasting state overnight. Branched-chain amino acids (BCAAs) may be given in patients who are unable to tolerate protein intake. Shunt Occlusion Patients who have recurrent or persistent OHE refractory to medical management should be screened for the presence of a spontaneous portosystemic shunt (PSS). Occlusion of shunts with balloon-occluded retrograde transvenous obliteration has shown rapid improvement in symptoms and better survival than those on medical management in patients with recurrent HE. Patients with transjugular intrahepatic PSSs may need a revision to reduce the shunting. CONCLUSION HE affects a majority of cirrhotic patients at some point in time. Although the overt form is self-evident, CHE is often neglected. Considering the accumulating evidence of its consequences, it would be prudent to test and treat for CHE. Disaccharides, antibiotics, and probiotics are effective options. Evidence with newer drugs is evolving and appears to be promising. CORRESPONDENCE Radha K. Dhiman, M.D., D.M., F.A.M.S., F.A.C.G., F.R.C.P., F.A.A.S.L.D., Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh , India. rkpsdhiman@hotmail.com 153 CLINICAL LIVER DISEASE, VOL 8, NO 6, DECEMBER 2016 An Official Learning Resource of AASLD

5 FIG 2 Algorithm for outpatient management of HE. TABLE 2. AGENTS USED IN OUTPATIENT TREATMENT OF HE Role Therapeutic Modality Mechanism CHE Secondary Prophylaxis of OHE Primary Prophylaxis of OHE Comments Lactulose Osmotic laxative Acidification of the colon # Urease-producing bacteria Improved cognitive function, driving performance Cost effective in preventing Most extensively studied. # Progression to OHE # Likelihood of OHE Mainstay of HE treatment and prophylaxis Cost effective # Ammonia production # Ammonia absorption accidents Rifaximin # Urease-producing bacteria # Ammonia production Improves cognitive function, QOL # Breakthrough HE, hospitalization Not studied Modulates flora Does not cause resistance Probiotics Improve dysbiosis Improvement in cognitive tests Improved QOL # Risk for hospitalization Not studied Well tolerated Available without prescription # Endotoxins BCAA Promote the synthesis of Unclear Improves Not studied No effect on overall mortality glutamine from ammonia in skeletal muscle recurrent HE LOLA Ammonia scavenging " Production of urea in hepatocytes, activating glutamine synthase in hepatocytes and skeletal muscle No improvement in CHE # Progression to OHE # Progression to OHE Not studied Evidence conflicting except in OHE, more studies needed Glycerol phenylbutyrate Zinc " Excretion of glutamine Not studied " Time to recurrence Not studied No benefit in patients on rifaximin If deficient, reduced urea Improvement in None Not studied No evidence on other cycle utilization of ammonia cognitive tests outcomes

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