Management of hepatic encephalopathy
Hepatic encephalopathy is a debilitating complication of cirrhosis. It is defined as brain dysfunction caused by liver insufficiency and/or portosystemic shunting  and is associated with an greater risk of death than other significant hepatic decompensation events . Hepatic encephalopathy manifests as a wide spectrum of neuropsychiatric abnormalities, from mild subclinical changes (eg, inversion of sleep cycle) to marked disorientation, confusion, and coma (Table 1) . Overt hepatic encephalopathy may develop over a period of hours or days and can occur spontaneously or following an event, such as gastrointestinal bleeding, infection, dehydration, or constipation. Recurrent episodes are possible. Between episodes, affected individuals might return to their baseline status or may retain cognitive abnormalities. Overt hepatic encephalopathy affects 30–45% of patients with cirrhosis  and minimal hepatic encephalopathy is seen in 20–80% . The presence of hepatic encephalopathy has a significant detrimental effect on the performance of complex tasks such as driving.
Survival is reduced. In one study survival in people with cirrhosis who presented with hepatic encephalopathy was 36% at 1 year and 15% at 5 years . In another study, the survival probability after a first episode of hepatic encephalopathy was 42% at 1 year but only 23% at 3 years . Furthermore, health-related quality of life is reduced and overt hepatic encephalopathy imposes a substantial further burden on affected families and health-care systems.
Once conditions mimicking overt hepatic encephalopathy have been excluded (Figure 1), initial management involves identifying, treating, and avoiding precipitating factors. Nearly 90% of patients can be treated by this approach alone . Targets to treatment should include infection, gastrointestinal bleeding, overdiuresis or dehydration, electrolyte disturbance, and constipation. Avoiding the use of sedative or narcotic agents is important. Opiates are particularly problematic as they potentiate constipation and, therefore, must be used at the lowest possible dose with appropriate laxatives prescribed concomitantly.
Non-absorbable disaccharides, particularly lactulose, form the mainstay of first-line treatment. Efficacy is based around the ability to reduce intestinal production and absorption of ammonia, which is achieved by a combination of actions: laxative effect, increased bacterial uptake of ammonia (via intraluminal pH change), inhibition of glutaminase activity resulting in a reduction of intestinal ammonia production, and an effect on the gut microbiome . A Cochrane review found a clear preventive effect with non-absorbable disaccharides against development and recurrence of overt hepatic encephalopathy . As a result, lactulose remains standard medical therapy.
The recommended starting dose for lactulose is 25 mL every 12 h until at least two soft bowel motions are produced per day. Dose reduction should be performed as required, with titration to a level that maintains two to three bowel motions per day . Non-adherence can be a contributing factor to treatment failure. This may often result in excessive laxative effects, sweet taste, nausea, bloating, and/or flatulence. Therefore, patients and their carers should be given clear advice on how to titrate the lactulose dose to maximize efficacy and reduce side-effects. If individuals are intolerant of lactulose, they should use alternative laxatives or regular enemas, although these will have less impact on ammonia production than lactulose.
Rifaximin is a minimally absorbed oral antibiotic that alters the gut flora, leading to reduced ammonia production and absorption. It is concentrated in the gastrointestinal tract, and despite broad-spectrum activity against gram-positive and gram-negative enteric bacteria, it has a low risk of inducing bacterial resistance . Rifaximin maintained remission from hepatic encephalopathy in a landmark randomized controlled trial of 299 patients . This treatment also significantly reduced the risk of hospitalization for those with overt hepatic encephalopathy over 6 months. Of note, 273 (91.4%) of patients in this study were using concomitant lactulose. Another study demonstrated long-term safety with rifaximin and a sustained reduction in hepatic-encephalopathy-related and all-cause hospitalization . A later multicentre UK study found that treatment with rifaximin-α was associated with reductions in the numbers of all-cause and critical care hospitalizations, bed days, 30-day emergency readmissions, and emergency department attendances .
At present, rifaximin is recommended by the National Institute for Health and Care Excellence to prevent recurrence of over hepatic encephalopathy. In practice, treatment with rifaximin should be considered in patients with persistent symptoms of encephalopathy despite lactulose or in lactulose-intolerant patients, or in those who have had two or more episodes of over hepatic encephalopathy in the previous 6 months. Rifaximin and lactulose in combination controls hepatic encephalopathy in most patients.
Education of patients with overt hepatic encephalopathy and of their relatives or carers is paramount to reducing recurrence and hospital admissions. Understanding of hepatic encephalopathy is limited among many of those affected and their caregivers, leading to structured education tools being developed with promising initial results . Key education points include the effects of medication and potential side-effects, the importance of adherence, and early signs of recurrence and appropriate actions (eg, laxative administration or, if febrile, seeing a general practitioner or attending hospital).
Other therapies for hepatic encephalopathy are generally less robustly supported by the available evidence, but could be considered in patients with recurrent disease despite lactulose and rifaximin, particularly for those who do not have the option of liver transplantation.
L-ornithine-aspartate is a stable salt of the amino acids ornithine and aspartic acid that is thought to lower blood ammonia concentrations in patients with cirrhosis by stimulating urea and glutamine synthesis from hepatocytes and skeletal muscle respectively. It might also have a directly hepatoprotective effect . It can be administered orally or intravenously. A recent Cochrane review suggested that L-ornithine-aspartate has beneficial effects on mortality and hepatic encephalopathy, but the quality of evidence remains very low .
Supplementation with branched-chain amino acids is another potential option. Levels of these amino acids are reduced in patients with cirrhosis, which results in impaired conversion of ammonia to glutamine in skeletal muscle and reduces its detoxification. Oral supplementation is effective in treating overt hepatic encephalopathy compared with placebo or no intervention, but not compared to lactulose or neomycin . There are no trials examining the efficacy of this treatment in prevention of recurrent hepatic encephalopathy.
Some patients with recurrent severe hepatic encephalopathy have large dominant portosystemic shunts that increase the risk of this disease due to gut-derived toxins bypassing the liver and entering the systemic circulation. In carefully selected patients with preserved liver function, embolisation of a dominant portosystemic shunt might improve hepatic encephalopathy . However, patients should be referred to a transplant centre for further assessment when considering this treatment. Similarly, in patients with hepatic encephalopathy who have a trans-jugular intrahepatic portosystemic shunt, reduction of the shunt diameter can be effective, but increases the risks of portal-hypertension-related complications redeveloping.
Given the poor prognosis of patients with cirrhosis and hepatic encephalopathy, individuals with poor liver synthetic function (UKELD score >49) should be considered for liver transplantation, if possible. Individuals with recurrent overt hepatic encephalopathy and UKELD scores <49 can also be considered for liver transplantation if they have had two hospital admissions in the preceding 6 months.
Recurrent hepatic encephalopathy is a significant complication of cirrhosis that has a huge impact on patients’ quality of life. Most patients can be effectively managed by treatment with lactulose and rifaximin and good education. Liver transplantation should be considered for those who have recurrent hepatic encephalopathy and/or significant liver synthetic dysfunction, as this intervention is curative. Other options remain experimental, but might be considered in selected patients. A potential management algorithm for severe recurrent hepatic encephalopathy is shown in Figure 1.
Figure 1. Management of severe recurrent hepatic encephalopathy [1,15]
About the Authors
Dr Stuart McPherson is a Consultant Hepatologist and Honorary Clinical Senior Lecturer at the Liver Transplant unit, in Newcastle, UK. Stuart’s major clinical and research interests include viral hepatitis, fatty liver disease, and cirrhosis. Stuart is the Secretary of the British Society of Gastroenterology.
Dr Alexandra Thompson is an ST6 gastroenterology registrar in south-east Scotland, currently doing an advanced hepatology training post at the Freeman Hospital, Newcastle.
- Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol 2014;61:642–659.
- Jepsen P, Ott P, Andersen PK, Sørensen HT, Vilstrup H. Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study. Hepatology 2010;51:1675–1682.
- Amodio P, Del Piccolo F, Pettenò E, et al. Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients. J Hepatol 2001;35:37–45.
- Bustamante J, Rimola A, Ventura PJ et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999;30:890–895.
- 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.
- Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 2016;5:CD003044.
- Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010;362:1071–1081.
- 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 2014;12:1390–1397.e2.
- Hudson M, Radwan A, Di Maggio P, et al. The impact of rifaximin-α on the hospital resource use associated with the management of patients with hepatic encephalopathy: a retrospective observational study (IMPRESS). Frontline Gastroenterol 2017;8:243–251.
- Garrido M, Turco M, Formentin C, et al. An educational tool for the prophylaxis of hepatic encephalopathy. BMJ Open Gastroenterol 2017;4:e000161.
- Butterworth RF, Kircheis G, Hilger N, McPhail MJW. Efficacy of l-ornithine l-aspartate for the treatment of hepatic encephalopathy and hyperammonemia in cirrhosis: systematic review and meta-analysis of randomized controlled trials. J Clin Exp Hepatol 2018;8:301–313.
- Goh ET, Stokes CS, Sidhu SS, Vilstrup H, Gluud LL, Morgan MY. L-ornithine L-aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 2018;5:CD012410.
- Gluud LL, Dam G, Les I, et al. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev 2017;5:CD001939.
- Laleman W, Simon-Talero M, Maleux G, et al. Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy. Hepatology 2013;57:2448–2457.
- Shawcross DL, Dunk AA, Jalan R, et al. How to diagnose and manage hepatic encephalopathy: a consensus statement on roles and responsibilities beyond the liver specialist. Eur J Gastroenterol Hepatol 2016;28:146–152.