The development and hosting of this resource hub has been sponsored by Norgine Pharmaceuticals Ltd. This resource hub contains links to educational content and resources from Norgine Pharmaceuticals Ltd, some of which may be promotional in nature.

Information intended for healthcare professionals only. This supplement has been commissioned by Norgine Pharmaceuticals Limited. Please see bottom of page for full disclaimer.

Click here to view prescribing information.

Click here to download the supplement.

Management of overt hepatic encephalopathy: a focus on rifaximin-α and NICE TA337

Lynda Greenslade MSc, RGN, Clinical Nurse Specialist in Hepatology, Sheila Sherlock Liver Unit, Royal Free Hospital, London, UK



Key points 

  • Hepatic encephalopathy (HE) is a reversible neuropsychiatric disorder that is caused by an accumulation of toxins in the bloodstream, that are normally removed by the liver
  • The prevalence of HE has been estimated to be in excess of 12,000 people in England
  • Hepatic encephalopathy places a high burden on patients, caregivers and their family
  • The pathogenesis of HE is not fully understood and makes diagnosis difficult
  • Initial diagnosis is based on the exclusion of other causes of brain dysfunction and whether the patient has risk factors for liver disease
  • The identification and treatment of any precipitating factors that may have caused the initial episode of HE is the first step for the management of overt HE
  • The management of risk factors should also be considered, such as the use of brief interventions for alcohol misuse, and lifestyle advice for people who are obese
  • Management options include:
    • use of lactulose
    • add-on therapy with rifaximin-α
  • It is important to recognise when a second episode of HE occurs, GPs can seek specialist advice on using rifaximin-α to prevent further episodes of HE
  • Successful management of overt HE includes education of the individual with this disorder, his/her caregiver, and family to understand why HE occurs, and why adherence to treatment can help prevent recurrences of this disorder and greatly improve quality of life. 


Hepatic encephalopathy (HE) is a reversible neuropsychiatric disorder that is caused by an accumulation of toxins in the bloodstream, which are normally removed by the liver. The disorder includes a range of neuropsychiatric abnormalities seen in patients with established liver disease, and HE is most commonly associated with liver cirrhosis.1 Indeed, the risk for the first episode of overt HE is 5–25% within 5 years after a diagnosis of cirrhosis.1 HE is associated with a poor prognosis, and mortality can also be positively correlated with HE severity.2,3,4 Neuropsychiatric abnormalities including personality changes, such as apathy and irritability, disorientation, inappropriate behaviour, confusion, and asterixis (flapping tremor in the hands) are all associated with HE and patients may also experience disturbances of their sleep/waking pattern.5

Hepatic encephalopathy can be broadly classified as covert or overt depending on the severity of the clinical symptoms of mental deterioration.5

One of the gaps in our understanding of HE is the relative lack of data reporting on the epidemiology of HE and resulting hospital admissions. In the UK, the number of people with recurrent episodes of overt HE is uncertain. The results of a study in England reported that the prevalence of liver cirrhosis was estimated to be 76 people per 100,000 of the population in 2001, which corresponds to approximately 32,000 people.6 With evidence suggesting that 30–45% of people with liver cirrhosis experience overt HE,7 the prevalence of HE in England can be estimated to be in excess of 12,000 people.

HE has a profound impact on people’s daily activities and quality of life as well as on family and caregivers.8


Currently in the UK, there are no consensus or clinical guidelines for the diagnosis of overt HE. The pathogenesis of HE is not fully understood and this can complicate diagnosis and patient management. When patients present with overt HE, the initial diagnosis is made through the exclusion of other causes of brain dysfunction, and the identification of risk factors for liver disease (see Box 1). Infections, constipation, gastrointestinal bleeding, and altered electrolytes should also be investigated and treated appropriately (see Box 2). In the UK, overt HE is diagnosed by clinical criteria using the West Haven criteria. In individuals with significantly altered consciousness, the Glasgow Coma Scale is used.5

Box 1: Does your patient have risk factors for liver disease?*9,10

  • Abnormal liver function test
  • Diabetes
  • History of excessive alcohol intake
  • Hyperlipidaemia
  • Obesity
  • Recently moved from a high risk area of hepatitis to the UK
  • Viral hepatitis (Hepatitis B or C)

*Please do not forget other causes of liver disease such as autoimmune hepatitis, primary biliary cholangitis/cirrhosis (PBC), primary sclerosing cholangitis (PSC).

Box 2: Precipitating factors that may trigger an episode of hepatic encephalopathy5

  • Alcohol detoxification
  • Any other causes of confusion 
  • Constipation
  • Diuretic overdose
  • Dehydration
  • Electrolyte disorder
  • Gastrointestinal bleeding
  • Infections

Table 1: Possible symptoms of HE11

Symptom grade  Symptom description
Covert Minimal
  • psycometric or neuropsychological alterations on tests without clinical evidence of mental change
Grade 1
  • trivial lack of awareness
  • euphoria or anxiety
  • shortened attention span
  • impairment of addition and subtraction
  • altered sleep rhythm
Overt Grade 2
  • lethargy or apathy
  • disorientation
  • obvious personality change
  • inappropriate behaviour
  • dyspraxia
  • asterixis
Grade 3
  • somnolence to semi-stupor
  • impaired responsiveness to stimuli
  • confusion
  • gross disorientation
  • bizarre behaviour
Grade 4
  • coma

Management and treatment 

The management of HE in primary care is outlined in an algorithm (see Figure 1), which was developed by working party group of healthcare professionals.11 The first step in the management of overt HE is to identify and treat any precipitating factors that may have caused the initial episode of HE. For example, by stopping gastrointestinal bleeding, treating infections, addressing kidney failure, and treating electrolyte abnormalities. 

The aim of treatment is to improve the symptoms of overt HE and to reduce the risk of recurrences and subsequent hospitalisation. Lactulose is generally used as an initial treatment option for overt HE.5 It works by changing the acidity of the stools which helps to discourage the growth of some bacteria (for example, those which produce ammonia) that are present in the bowel. Lactulose draws fluid into the bowel, which makes stools softer and easier to pass; it can also cause more frequent bowel movements.13 For patients with overt HE, lactulose is initially administered as 30–45 ml, three times a day.13 Subsequently, the dose of lactulose should be titrated to maintain two to three soft stool bowel movements per day.13 Establishing the correct dosing regimen of lactulose with individual patients can facilitate treatment adherence and prevent recurrences of HE. Educating the HE patient and his/her caregiver on the important role lactulose plays in preventing episodes of HE can also ensure adherence to treatment. Common adverse reactions to lactulose include flatulence, abdominal pain, nausea, and vomiting. If the dose is too high, diarrhoea will occur.13

Rifaximin-α is an effective add-on therapy to lactulose for the reduction of recurrences of overt HE episodes5,14,15 and results from the RFHE3001 and RFHE3002 clinical studies have shown that it has an acceptable tolerability profile.14,15 Rifaximin-α decreases intestinal production and absorption of ammonia, which is thought to be responsible for the neurocognitive symptoms of HE, thereby reducing the recurrence of acute episodes of overt HE.16 Common adverse reactions to rifaximin-α are dizziness, headache, depression, dyspnoea, upper abdominal pain, abdominal distension, diarrhoea, nausea, vomiting, ascites, rashes, pruritus, muscle spasms, arthralgia, and peripheral oedema.17

NICE recommends rifaximin-α as a treatment option for reducing the recurrence of episodes of overt HE in people aged 18 years or older.16 The NICE Technology Appraisal 337 for rifaximin-α provides an opportunity for patients to benefit from a medication that is proven to work in patients having their second episode of overt HE, this can result in less hospital admissions and improved cognition. More importantly, patients and their families/caregivers may be able to face each day without the burden of the physical and neuropsychiatric changes that a patient with HE will experience (see Box 3). It is important to recognise when a patient has a second episode of HE as recurring episodes could potentially be missed. GPs can seek specialist advice on using rifaximin-α to prevent further episodes of HE. 

An episode of overt HE is a serious complication of liver cirrhosis and GPs may not feel they have the expertise to manage patients with overt HE. GPs can help improve health-related quality of life with the early identification of potentially treatable risk factors for HE—such as offering lifestyle advice for patients who are obese, and the use of brief interventions for alcohol misuse, particularly when excess alcohol consumption is suspected as the cause of the episode.9 In order to make sure that patients get quality care, GPs should be encouraged to refer patients to a hepatologist for up to date advice and management. Any patient diagnosed with overt HE should be seen in a hospital that has a hepatologist so that they can be monitored, screened, tested for HE and treated appropriately.18 An episode of overt HE has a high mortality rate and may be an indication for liver transplantation. Not all patients are under the care of a hepatologist are appropriately referred for consideration for liver transplantation.

Good communication between the patient’s medical team and primary care is also key. Patient education about HE, how to recognise developing HE, and how to treat it is important. Including HE diagnosis and management in liver education for GPs would be helpful.

Management of hepatic encephalopathy in primary care

*Summary of product characteristics can be found at
Grading of symptoms is detailed overleaf

Adapted from Clayton M et al.11

Figure 1: algorithm for the management of hepatic encephalopathy in primary care

Box 3: Case study on the use of lactulose and rifaximin-α for the management of overt HE 

A 62-year-old male first presented with alcoholic hepatitis in September 2011. He was admitted to hospital where he was treated with lactulose. The patient had a prolonged hospital stay and upon discharge he refused to be followed up. The patient continued drinking and two months later he presented again with alcoholic hepatitis and confusion. He was diagnosed with overt HE and he was treated again with lactulose. Due to the HE, it was probably difficult to engage with the patient as he would have had some personality changes. One month later, the patient was admitted to hospital again with confusion. The overt HE was treated with lactulose. The patient also started rifaximin-α therapy and since then he has had no further hospital admissions with HE. The patient also stopped drinking alcohol for the past two years. He had a supportive wife and once she was educated about HE, what to look for, and understand the treatment for HE, she was able to manage his condition at home. It is clear that the use of lactulose and rifaximin-α therapy together with a supportive caregiver, this patient has had a positive outcome with no further hospital admissions due to HE. 


Hepatic encephalopathy is the term used to describe a complex and variable reversible neuropsychiatric condition of patients with liver disease, more commonly associated with advanced cirrhosis. The pathogenesis of HE is not fully understood and this can make diagnosis and patient management difficult. However, the prevalence of HE has been estimated to be in excess of 12,000 people in England. The impact of HE is severe, affecting not only the lives of patients but also their families and caregivers.

The identification and treatment of any precipitating factors that may have caused the initial episode of HE is the first step for the management of overt HE. Following this the next treatment option for patients with overt HE within primary care is lactulose. Establishing the correct dose of lactulose for individual patients to maintain two to three bowel movements per day can help prevent the recurrence of HE episodes. For patients who experience a second episode of overt HE, rifaximin-α is recommended by NICE as an add-on treatment option for reducing the recurrence of episodes of overt HE in people aged 18 years or older. Good communication between the patient and his/her caregiver are also key to the management of overt HE.


  1. Guest J, Nanuwa K, Barden R. Utility values for specific hepatic encephalopathy health states elicited from the general public in the United Kingdom. Health Qual Life Outcomes 2014; 12: 89–97.
  2. Jepsen P, Ott P, Andersen P et al. Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study. Hepatology 2010; 51: 1675–1682.
  3. Cordoba J, Ventura-Cots M, Simon-Talero M et al. Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF). J Hepatol 2014; 60: 275–281.
  4. Stewart C, Malinchoc M, Kim W et al. Hepatic encephalopathy as a predictor of survival in patients with end-stage liver disease. Liver Transpl 2007; 13: 1366–1371.
  5. 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 (3): 642–659.
  6. Fleming K, Aithal G, Solaymani-Dodaran M et al. Incidence and prevalence of cirrhosis in the United Kingdom, 1992–2001: a general population-based study. J Hepatol 2008; 49 (5): 732–738.
  7. Poordad F. Review article: the burden of hepatic encephalopathy. Aliment Pharmacol Ther 2007; 25 (Suppl 1): 3–9.
  8. Montagnese S, Amato E, Schiff S et al. A patients’ and caregivers’ perspective on hepatic encephalopathy. Metab Brain Dis 2012; 27 (4): 567–572.
  9. Williams R, Aspinall R, Bellis M et al. Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis. Lancet 2014; 384 (9958): 1953–1997.
  10. Alba L & Lindor K. Review article: non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2003; 17: 977–986.
  11. Clayton M et al. Management of hepatic encephalopathy in primary care. Chesham: MGP Ltd; August 2016 (last updated 2020).
  12. DVLA. Drug or alcohol misuse or dependence: assessing  fitness to drive. DVLA, 2019. Available at 
  13. Intrapharm Laboratories Limited. LactugalSummary of Product Characteristics. Available at 
  14. Bass NM, Mullen KD, Sanyal A et al. Rifaximin-α treatment in hepatic encephalopathy. N Engl J Med 2010; 362 (12): 1071–1081.
  15. Mullen KD, Sanyal AJ, Bass NM et al. Rifaximin-α is safe and well tolerated for long-term maintenance of remission from overt hepatic encephalopathy. Clin Gastroenterol Hepatol 2014; 12 (8):1390–1397.
  16. NICE. Rifaximin-α for preventing episodes of overt hepatic encephalopathy. NICE Technology Appraisal 337. NICE, March 2015.  
  17. Norgine Pharmaceuticals Limited. Targaxan 550 mg film-coated tablets—­Summary of Product Characteristics. Available at 
  18. Shawcross D, Dunk A, 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 (2): 146–152.

Norgine Pharmaceuticals Limited suggested the topic and author, commented on the author brief, and funded production of the supplement. The content has also been checked for factual accuracy to ensure it is fair and balanced, and to ensure its compliance with the ABPI Code of Practice. The sponsorship fee included the honorarium for the author. Final editorial control of the supplement has remained with the author and Guidelines

For all medicines mentioned in this supplement, please refer to for further information

The views and opinions in this supplement are not necessarily those of Norgine Pharmaceuticals Limited or of Guidelines, its publisher, advisers, or advertisers.

The copyright of Guidelines (including the Guidelines brand, logo, and the design and format of the book) rests with MGP Ltd unless otherwise stated.

No part of this publication may be reproduced in any form without the permission of the publisher.



Date of preparation: February 2020

Best practice in liver care