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Home , Cirrhosis, Hepatic encephalopathy

EDUCATION CLINICAL REVIEW

Hepatic due • Link to this article online for CPD/CME credits to

Mark A Ellul,1 Santosh A Gholkar,2 Timothy J Cross3

1 Overt affects approximately 20% Institute of and Global SOURCES AND SELECTION CRITERIA Health, University of Liverpool, of patients with liver cirrhosis each year.1 It is a patho­ We searched PubMed up to March 2015 (and updated Liverpool L69 7BE, UK gnomonic feature of and a common cause 2City Health Centre, Manchester June 2015) with the terms “hepatic encephalopathy” and M1 1PL, UK of admission to emergency departments. It affects the “minimal hepatic encephalopathy” targeting reviews and 2 3Department of , quality of life of both patient and relatives and signifies studies published in English since 1990. We searched the Royal Liverpool University Hospital, a poor prognostic indicator for patients with cirrhosis, references of identified articles as well as our own files. The Liverpool L7 8XP, UK with a survival of only 23% at three years from onset.3 selection of references was made based on our assessment Correspondence to: TJ Cross of relevance to the topic. [email protected] Treatments aimed at interrupting the pathogenesis of Cite this as: BMJ 2015;351:h4187 hepatic encephalopathy are known to reduce frequency doi: 10.1136/bmj.h4187 of hospital admissions and improve survival.4 motor slowing, which can only be detected on psychomet- Studies suggest that the prevalence of chronic liver dis- ric testing, using, for example, the psychometric hepatic thebmj.com ease in the United Kingdom is increasing, in part owing to encephalopathy score (PHES).8 Other neuropsychological Previous articles in this the increasing prevalence of non-alcoholic fatty liver dis- tests are outlined in table 1. There is no agreed “gold stand- series ease (NAFLD), related , and ard” test, and patients may score differently on each. The ЖЖCaring for sex workers C.5 6 Clinicians therefore need to be able to recognise signs tests therefore need to be used as part of a wider clinical (BMJ 2015;351:h4011) and symptoms of hepatic encephalopathy in patients who assessment. Which test is chosen depends on availability 4 ЖЖManagement of sharps might not have a diagnosis of . of equipment, training of examiner, and local preference. injuries in the healthcare This review aims to highlight the importance of recog- Psychomotor slowing may progress to subtle cognitive 14 setting nising hepatic encephalopathy in chronic liver failure and impairment and difficulties in concentration. Reversal (BMJ 2015;351:h3733) outlines a practical and evidence based approach to its of the sleep-wake cycle is an early sign in some patients. management, based on the framework of recent guidelines In addition, affective changes including depression and ЖЖAcute rheumatic fever from the European Association for the Study of the Liver occasionally personality changes are observed (such (BMJ 2015;351:h3443) 15 (EASL) and the American Association for the Study of Liver as irritability and inappropriate behaviour). Agitation ЖЖNormal lower limb Diseases (AASLD).4 Hepatic encephalopathy in acute liver and aggression can progress to acute confusion leading variants in children failure is managed differently, and will not be addressed. to progressive and . (also known (BMJ 2015;351:h3394) as a “liver flap”) constitutes an arrhythmic negative ЖЖDementia: timely What is hepatic encephalopathy and what are its signs and and loss of postural tone with a frequency of diagnosis and early symptoms? 3-5 Hz. This may be bilateral or asymmetric and is nor- intervention Hepatic encephalopathy constitutes a spectrum of neu- mally seen in the hands but can affect other parts of the (BMJ 2015;350:h3029) ropsychiatric abnormalities, beginning with subtle psy- body. It may be more easily felt than seen. chomotor changes and progressing to confusion with Hepatic encephalopathy must be distinguished from asterixis, , and then coma, arising in patients other causes associated with a change in cognition—such with impaired liver function or portosystemic shunting.7 as electrolyte disturbance, intoxication, cerebral hypo­ The first neuropsychological feature to emerge is psycho- perfusion, , and sepsis—as well as more chronic conditions such as . A for HOW PATIENTS WERE INVOLVED IN THE CREATION OF THIS ARTICLE hepatic encephalopathy is given in table 2. We consulted one of our patients who had experienced hepatic encephalopathy who kindly is often normal in stages 1-2 reviewed our manuscript and made suggestions about aspects of care that were especially of hepatic encephalopathy, but hyperreflexia and exten- important for patients with the condition sor posturing may develop later, together with a positive Babinski sign.16 THE BOTTOM LINE In liver cirrhosis are less common than in Hepatic encephalopathy is a sign of poor and correlates with (when they warn of developing cere- • 17 18 mortality in both in patients with acute liver failure and those with cirrhosis bral oedema) and suggest causes such as electrolyte associated with end stage liver disease derangement (for example, hypoglycaemia, hypomag- 19 • Patients without overt hepatic encephalopathy can have subtle cognitive nesaemia), alcohol withdrawal, , or . deficits affecting quality of life that may be responsive to treatment How is hepatic encephalopathy classified? • Hepatic encephalopathy is a clinical diagnosis that can be assisted by neuropsychology and neurophysiology There are several methods of classifying hepatic encepha- lopathy. The syndrome can be seen as comprising three • Evidence based treatments, such as and , influence both length and quality of life separate clinical entities: type A due to acute liver failure, type B due to portal venous bypass with portosystemic

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Table 1 | Psychometric tests for diagnosis of covert hepatic encephalopathy Test name Description Equipment required Problems Psychometric hepatic Six tests evaluating cognitive and psychomotor processing speed and Pencil and paper Vision must be intact encephalopathy score (PHES)8 visuo-motor coordination Stroop test9 Tests interference between a coloured field and a written colour name Computer, pencil and paper, or mobile phone app Vision must be intact Critical flicker frequency (CFF) test10 Assessment of ability to detect a light source flickering Specialised equipment Vision must be intact Continuous reaction time (CRT) test11 Motor reaction time to auditory stimuli Computer equipment and additional hardware Hearing must be intact SCAN test12 Computerised digit recognition task Computer equipment Vision must be intact Inhibitory control test (ICT)13 Test of attention and response inhibition to presented letters Computer equipment Requires patients to be familiar with computer use

shunting, and type C due to cirrhotic liver disease (table 2).7 and difficulty with activities of daily living that can Some authorities define hepatic encephalopathy as acute be detected on neuropsychological assessment (see or chronic; or as episodic, recurrent, or persistent; others table 1). It is not reliably detected by the clinician with- differentiate between non-precipitated and precipitated out investigations. Recent studies have demonstrated episodes. that covert hepatic encephalopathy affects up to 50% of Type B hepatic encephalopathy may develop acutely cirrhotic patients.8 Many patients develop covert hepatic after transjugular intrahepatic portosystemic shunting encephalopathy in a chronic manner, with subtle neu- (TIPS) procedures,20 in which an iatrogenic portosys- ropsychological changes that may have devastating temic is created. The likelihood of developing overt effects on the patient’s ability to function indepen- hepatic encephalopathy after TIPS varies from 15% to dently.24 Assessment for covert hepatic encephalopathy 48%,21 and is higher in older patients, those with previ- using psychometric tests may be particularly considered ous episodes of hepatic encephalopathy, and those with a in patients with known or suspected liver cirrhosis who higher Child-Pugh score.22 If covert hepatic encephalopa- complain of difficulties functioning in everyday life, thy is included the risk is higher. If hepatic encephalopa- whose relatives have noticed attentional difficulties, thy does develop, shunt size reduction or embolisation of or when employment is directly affected by cognitive portosystemic collaterals should be considered.­ 23 impairment.4 Covert hepatic encephalopathy also has The most common clinical classification used to a poor prognosis, with increased risk of hospitalisation describe the severity of hepatic encephalopathy is the and progression to overt hepatic encephalopathy or West Haven criteria (table 3).7 This describes the contin- mortality.25 uum of hepatic encephalopathy progressing through its four stages, from mild lack of awareness to coma. What causes hepatic encephalopathy? Covert hepatic encephalopathy refers to subtle Hepatic encephalopathy can develop due to liver failure neuropsychological problems, psychomotor slowing, from any cause. It is postulated that its pathogenesis is

Table 2 | Differentials differential diagnosis for hepatic encephalopathy Table 3 | West Haven criteria for grading severity of hepatic Category and diagnosis Distinguishing factors encephalopathy Grade Clinical features Metabolic: Diabetic ketoacidosis Covert hepatic encephalopathy Hypoglycaemia Hyperosmolar states Minimal hepatic Evidence of cognitive impairment on Patient’s history and results of blood and urine investigations will help to encephalopathy (MHE) neuropsychology Endocrine: exclude metabolic and endocrine causes Evidence of altered psychomotor speed or Hyponatraemia executive function Hypercalcaemia Requires psychometric tests to make the diagnosis Hypothyroidism Grade I Trivial lack of awareness Drugs and toxins: Alcohol withdrawal often causes , sweating, and prominent Euphoria or anxiety or withdrawal hallucinations. A collateral history of alcohol intake can be helpful Shortened attention span Wernicke’s encephalopathy Constricted pupils and depressed respiratory drive may indicate opiate Impairment of addition or subtraction (for Opioids toxicity example, serial 7s test) Altered sleep rhythm Infection: Look for prodromal personality change, fever, focal neurological signs, and Overt hepatic encephalopathy Encephalitis seizures as signs of encephalitis Sepsis related encephalopathy Evaluate carefully for a source of underlying sepsis: consider chest x ray and Grade II Lethargy or urine microscopy Disorientation for time Obvious personality change Vascular: Sudden onset focal neurological signs point to a cerebral vascular event Inappropriate behaviour Ischaemic stroke Cerebral hypoperfusion can occur secondary to cardiac failure or reduced Dyspraxia Intracranial haemorrhage circulating volume: consider echocardiography Asterixis Cerebral hypoperfusion Grade III Somnolence to semi-stupor Others: and brain imaging are vital if non-convulsive Response to stimuli Non-convulsive status or a space-occupying lesion are considered Confused Brain lesions Overnight oximetry and early morning arterial blood gas analysis can Gross disorientation Dementia point to obstructive sleep apnoea Bizarre behaviour Obstructive sleep apnoea Depression can cause psychomotor slowing and may coexist with other Psychiatric disorder pathologies: psychiatric evaluation may be warranted Grade IV Coma the bmj | 15 August 2015 27 EDUCATION CLINICAL REVIEW

related to the effects of nitrogenous waste products on the A PATIENT’S STORY brain, particularly and .26 Glutamine I will attempt to provide an account of the impact of HE by recounting actual occurrences. is normally metabolised by glutaminase in the small Most of these have a comic element which disguises the severe anxieties I experienced. intestine to ammonia and glutamate; ammonia is then In most cases I am paradoxically able to remember what was happening at the time, converted to in the liver.27 High levels of ammonia and, although I think I was aware of the distress I was causing to others, I was unable to change my behaviour until the effects wore off. in the serum lead to cerebral oedema, which acts syner- My episodes of hepatic encephalopathy usually started with the onset of confusion gistically with an inflammatory response in the central and a state of disorientation. I would start to shake, hold my head in my hands, and to cause complex cortical and subcortical become argumentative, unreasonable, and uncooperative. Bizarre behaviour usually dysfunction. In cirrhotic patients, - followed, such as: ing allows ammonia and other to bypass the liver and enter the systemic circulation, and this may • Dressing to go out to a dinner party, I presented downstairs with my trousers on back to also occur after transjugular intrahepatic portosystemic front. shunting. Hyponatraemia, common in cirrhosis, may also • Returning from buying a newspaper I stood in the dark on a freezing winter’s night trying exacerbate cerebral oedema and dysfunction.28 to unlock the back door without success until my partner returned home from shopping. Muscle volume depletion (sarcopenia) contributes to the • I once spent 20 minutes trying to figure out how to put on a pair of gardening clogs (no development of encephalopathy, since muscle represents laces). an alternative site of ammonia detoxification.29 Patients • I forgot how to brush my teeth despite having the brush loaded with paste put in my with a concomitant systemic inflammatory response syn- hand and the tap turned on. drome, such as from infection, are predisposed to devel- 30 31 • I went downstairs one morning to make my partner her cup of tea and returned oping hepatic encephalopathy. The inexplicably with a knife and no tea. has also been implicated in pathogenesis, and there is evidence for gut dysbiosis and small bowel overgrowth,32 • I didn’t recognise best friends whom my partner had called for help during one of my hence the possibility of therapies modulating microbiota, episodes. such as . • I offered my phone as payment in a shop. • I couldn’t work out how to read a book. Which investigations aid diagnosis? • I forgot how to use the computer There is no specific test for hepatic encephalopathy, • My handwriting became illegible. and the diagnosis should be made on clinical grounds through the exclusion of other conditions that can mimic Prior to my admission to hospital, I experienced a variety of attempts to diagnose or be confused with hepatic encephalopathy (see table 2). my condition. While I understand the need to cover every possibility before arriving at Testing of arterial or venous ammonia levels is commonly hepatic encephalopathy, greeting a confused and anxious patient with “Hello again, Mr performed, but levels correlate poorly with the grade of Crawford. Been again have we?” cannot help. Hepatic encephalopathy is an hepatic encephalopathy33 and should not be used alone awful experience for the patient and the carer. It is unpredictable and challenging and for establishing the diagnosis as they are not consistently mystifying in the early stages because it is usually impossible to ascribe the episodes to raised.34 any particular cause. Computed tomography or magnetic resonance imaging Generally, I was aware of what was happening and what I wanted to say, but I was should be performed in all patients in whom a diagnosis unable to make myself clear. This was especially frightening in hospital without my partner to help and decipher. I cannot overemphasise the importance of seeking the of hepatic encephalopathy is being considered, in order views and opinions of the patient’s carer in trying to assess the impact the condition has to exclude other conditions such as intracranial haem- on their lives. orrhage or space occupying lesions. Hyperintensity of I had many awful experiences alone on a ward. For example, when I was in bed and the basal ganglia on magnetic resonance imaging is sug- 35 wanted a blanket I resorted to miming to a nurse that I was cold because I couldn’t gestive of portosystemic shunting. Positron emission retrieve the necessary words. I remember hallucinating and developing irrational fears tomography has been used experimentally and may have 36 of what might be planned for me. I even planned an elaborate plot to escape from a role, but this remains undefined. hospital. Patients are usually seen alone on the wards when they are confused and Electroencephalography is used to investigate for the disorientated. I remember trying to remember key facts for my partner’s benefit when presence of seizures and should be considered if subclini- 37 she visited. Usually I was unable to recall what I’d been told which caused anxiety and cal seizures are suspected. It may show characteristic embarrassment. Hepatic encephalopathy prohibits clear thought and articulation. Once, changes in overt hepatic encephalopathy in the form of I tried to write things down for her benefit, but what I thought was a lucid account was triphasic waves, as well as more subtle signs in covert illegible. hepatic encephalopathy.38 It may be used together with At this point, I had not been given a formal account of what hepatic encephalopathy neuropsychological assessments (see table 1) to aid the was and what I might expect to happen to me. An explanation given to my partner was: diagnosis of covert hepatic encephalopathy.4 However, “Toxins which your liver cannot process travel to your brain and distort its functioning.” the findings are generally non-specific and may be influ- Clarity is vital if the patient and carer are expecting to come to terms with hepatic enced by metabolic and drug factors. encephalopathy. A simple, definitive explanation is beneficial for patients as soon as one is available. How is hepatic encephalopathy managed? Rifaximin worked for me. Being prescribed it during a consultation with my specialist The management of hepatic encephalopathy depends on certainly made me feel that I was being dealt with properly at last. its type and severity. Many patients with covert hepatic Informing the DVLA is really important. I did drive on occasions when I was affected by encephalopathy may not require treatment unless the hepatic encephalopathy. Defiance and bravado were to blame, and I did have one minor condition is thought to be adversely affecting quality of collision which could have been avoided. life.4 Episodes of overt hepatic encephalopathy can be

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shortened with appropriate treatment, and further events TIPS FOR NON-SPECIALISTS prevented. • Patients with previously undiagnosed liver disease are Many patients presenting acutely with overt hepatic increasingly likely to present to primary or secondary care encephalopathy will have an underlying precipitant, such with hepatic encephalopathy, and it should be part of as gastrointestinal , infection, overdose, 39 the differential diagnosis of confusion. for risk or use of sedating . The first stage in manage- factors such as alcohol misuse, exposure to bloodborne ment is to address these—that is, by stopping precipitat- viruses, , and diabetes will help to identify these ing drugs, treating infection, etc. However, a substantial patients proportion of patients will have no identified cause. • Seizures in patients with cirrhosis usually have another All patients with evidence of hepatic encephalopathy cause: evaluate for electrolyte imbalances, infection, should be advised to stop driving and inform the Driver alcohol history and stroke 4 and Vehicle Licensing Authority (DVLA). Studies have • Early nutritional review is vital for patients with hepatic shown that even patients with covert hepatic encepha- encephalopathy and can improve outcome 40 lopathy are more prone to road traffic accidents. Failure • If patients fail to respond to medical therapies, discussion of the patient to inform the DVLA about the condition may with a liver transplant centre is advised when clinically result in a fine. Patients are likely to have their licence appropriate for the patient revoked until satisfactory recovery is demonstrated.41 • For patients who are not fit for transplant and who are clinically deteriorating, consider shifting the emphasis of Nutrition care to maintaining comfort Historically, dietary restriction has been advised • Patients who are diagnosed with hepatic encephalopathy for patients with hepatic encephalopathy as this was should stop driving and inform the Driver and Vehicle thought to decrease intestinal ammonia production, but Licensing Authority (DVLA)

FUTURE PROSPECTS IN THE TREATMENT OF HEPATIC a small randomised trial suggests that normal protein ENCEPHALOPATHY diets are safe, and protein malnutrition may contribute L--L-aspartate (LOLA)—A preparation containing to sarcopenia, potentially worsening the condition.42 43 the amino acids ornithine and aspartic acid, given by Thus it is recommended by the International Society for intravenous infusion Hepatic Encephalopathy and that Evidence: A meta-analysis including 20 randomised 1.2-1.5 g/kg of protein is given in small meals distributed controlled trials showed LOLA to be as effective as non- throughout the day, with a late night snack of complex absorbable disaccharides, with a trend towards superiority, .44 A nasogastric feeding tube should be 63 with few adverse effects considered if the patient is unable to achieve the dietary Branched chain amino acids (BCAA)—A preparation of targets. amino acids (valine, leucine, and isoleucine) normally given orally or by nasogastric tube, postulated to alter the Non-absorbable disaccharides and probiotics balance of amino acids in the brain as well as to provide Lactulose is a non-absorbable disaccharide that is metab- energy supplementation olised to lactic and acetic acid in the colon, reducing the Evidence: A recent Cochrane review considered 16 pH and promoting the excretion of ammonia as well randomised clinical trials and found high quality evidence as the utilisation of ammonia in the metabolism of gut of clinical benefit but no effect on mortality, quality of life, or bacteria.45 46 Although a Cochrane review did not find nutrition parameters64 a significant difference in outcomes associated with its Human solution (HAS)—Albumin is a use in acute hepatic encephalopathy,47 results from a well crucial plasma protein that is reduced in liver failure. conducted randomised controlled trial support the use of Supplementing albumin intravenously may help to address lactulose in the secondary prophylaxis of hepatic enceph- circulatory dysfunction alopathy.48 The EASL-AASLD guidelines recommend that Evidence: A small randomised trial suggested that lactulose is used as a first line agent in episodes of overt intravenous HAS does not improve resolution of hepatic 65 hepatic encephalopathy and then continued to prevent encephalopathy, but it may improve survival 4 further episodes. The patient should take 25 mL of Glyceryl phenylbutyrate—An oral preparation which lactulose twice daily, aiming to achieve three soft bowel provides an alternative for waste nitrogen excretion, motions a day.4 is an alternative and is used in reducing ammonia production some centres on the basis of poor quality evidence from Evidence: A recent randomised controlled trial showed a small meta-analysis of four small trials suggesting that a reduction in episodes of hepatic encephalopathy and it may be better tolerated than lactulose.49 66 hospital admissions therapy was found to decrease overt hepatic Ornithine phenylacetate—L-ornithine acts as a substrate encephalopathy in a meta-analysis of six randomised con- for glutamine synthesis from ammonia in skeletal muscle, trolled trials.50 Probiotics can be administered in yoghurt and phenylacetate excretes ornithine-related glutamine as 67 drinks or tablets, commonly containing Lactobacillus phenylacetylglutamine in the kidneys rhamnosus and Saccharomyces boulardii. A Cochrane Evidence: A trial is currently recruiting to examine safety and review examining seven trials found insufficient evi- efficacy versus standard of care in hospitalised patients dence to recommend the routine use of probiotics, largely (NCT01966419) because of methodological concerns.51 the bmj | 15 August 2015 29 EDUCATION CLINICAL REVIEW

What treatments are available for resistant hepatic ADDITIONAL EDUCATIONAL RESOURCES encephalopathy? Resources for health professionals Patients whose hepatic encephalopathy does not respond • EASL clinical practice guideline Hepatic Encephalopathy in to optimal medical treatment, in the form of lactulose and Chronic Liver Disease: 2014—www.easl.eu/research/our- rifaximin, may be considered for embolisation of porto- contributions/clinical-practice-guidelines/detail/hepatic- systemic shunts, which can be undertaken percutane- encephalopathy-in-chronic-liver-disease-2014 ously. Evidence from two retrospective studies suggests Useful guide to diagnosis, management, and follow-up. that the procedure decreases hospital admissions and • Felipo V. Hepatic encephalopathy: effects of liver failure on brain function. Nature Reviews Neuroscience 2013;14:851- improves survival, but adverse effects include de novo 8—www.nature.com/nrn/journal/v14/n12/full/nrn3587. gastro-oesophageal varices, worsening , and renal 56 57 html dysfunction due to contrast-induced nephropathy. Accessible recent review of pathophysiology and new should be considered in all suit- approaches to treatment. Requires institutional access able candidates presenting with hepatic encephalopathy, rights. and discussion with a liver transplant centre initiated.58 Resources for patients Patients can be considered for a transplant if they have • British liver trust—www.britishlivertrust.org.uk had two admissions for hepatic encephalopathy in the Provides information and support for patients with liver past six months in the absence of comorbidities that disease and their families would preclude .59 Patients with must be abstinent and sign an agreement indi- cating intention of continued abstinence.60 QUESTIONS FOR FUTURE RESEARCH • What is the most appropriate diagnostic strategy in covert Hepatic encephalopathy and end of life care hepatic encephalopathy? For patients who are not candidates for liver transplanta- • Do patients with covert hepatic encephalopathy benefit tion, particularly those for whom hepatic encephalopathy from treatment, and if so which treatment is most effective? is refractory to treatment or leads to an increasing num- • Are probiotics an effective treatment for hepatic ber of hospital admissions, it is important that clinicians encephalopathy? recognise that a switch in the emphasis of care may be • What is the role of neuroinflammation in hepatic required. Discussions with the patient, family members, encephalopathy, and can it be targeted with anti- and carers are important to inform them what hepatic inflammatory drugs? encephalopathy is, what causes it and, importantly, what its implications are. In the context of liver cirrhosis and Polyethylene glycol is a purgative agent which in the face of clinical deterioration, the clinician may ask produces catharsis of the gut, theoretically reducing the the “surprise” question—that is, “Would I be surprised if numbers of ammonia producing bacteria. In a recent this patient were not alive in 12 months’ time?”61 If the well designed randomised controlled trial, it was shown answer is no, then consider placing the patient on an end to be as effective as, and possibly superior to, lactulose in of life registry, informing his or her general practitioner terms of speed of resolution of hepatic encephalopathy and the community team. and reduction in length of hospital stay.52 However, more The “Amber care bundle” is a set of evidence based data are required before it can be routinely recommended interventions which provides a framework for clinicians in preference to lactulose. to follow to ensure that the correct steps are taken.62 The emphasis of care may then shift to maintaining the and rifaximin patient’s comfort, wishes, and dignity, providing sup- Advances in treatment in recent decades have been due port to the family and carers, and trying to avoid hos- to the use of oral to modulate gut flora, thus pital admissions. Carers should be educated about the reducing ammonia production. Neomycin is an aminogly- causes of hepatic encephalopathy and how to prevent coside which is poorly absorbed and reaches them, such as by preventing and avoiding high concentrations in the gut, acting as a glutaminase sedating . If constipation develops, then inhibitor.53 It was the first antibiotic agent to be widely increasing doses of should be considered. If this used in hepatic encephalopathy, although significant does not lead to an improvement, carers should either be adverse events compared with newer agents now pre- taught how to administer phosphate or contact clude its use. a district nurse to assist with this. For patients who wish Rifaximin is a semisynthetic antibiotic derived from to be cared for at home, when they enter the dying phase . The National Institute of Health and Care of their disease, their carers and the primary care team Excellence (NICE) recently recommended rifaximin for should be fully informed and receive written informa- the prevention of episodes of overt hepatic encepha- tion as to how to respond to the complications of end lopathy based on evidence from a large well conducted stage disease such as variceal bleeding, ascites, wors- randomised controlled trial.54 55 Both NICE and the EASL- ening hepatic encephalopathy, and sepsis. At this stage AASLD guidance recommend rifaximin for secondary the main aim is to reduce distress rather than preserve prophylaxis of overt hepatic encephalopathy in patients lucency, thus administering opiates, benzodiazepines, who have had further episodes while taking lactulose.4 and other sedating medications can be considered where There is no evidence for the use of rifaximin alone. appropriate.

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