Hepatic encephalopathy due to liver cirrhosis

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Link to this article online for CPD/CME credits Hepatic encephalopathy due to liver cirrhosis Mark A Ellul, 1 Santosh A Gholkar, 2 Timothy J Cross 3 1 Institute of Infection and Global Health, University
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Link to this article online for CPD/CME credits Hepatic encephalopathy due to liver cirrhosis Mark A Ellul, 1 Santosh A Gholkar, 2 Timothy J Cross 3 1 Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, UK 2 City Health Centre, Manchester M1 1PL, UK 3 Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool L7 8XP, UK Correspondence to: TJ Cross Cite this as: BMJ 2015;351:h4187 doi: /bmj.h4187 thebmj.com Previous articles in this series ЖЖCaring for sex workers (BMJ 2015;351:h4011) ЖЖManagement of sharps injuries in the healthcare setting (BMJ 2015;351:h3733) ЖЖAcute rheumatic fever (BMJ 2015;351:h3443) ЖЖNormal lower limb variants in children (BMJ 2015;351:h3394) ЖЖDementia: timely diagnosis and early intervention (BMJ 2015;350:h3029) Overt hepatic encephalopathy affects approximately 20% of patients with liver cirrhosis each year. 1 It is a pathognomonic feature of liver failure and a common cause of admission to emergency departments. It affects the quality of life of both patient and relatives 2 and signifies a poor prognostic indicator for patients with cirrhosis, with a survival of only 23% at three years from onset. 3 Treatments aimed at interrupting the pathogenesis of hepatic encephalopathy are known to reduce frequency of hospital admissions and improve survival. 4 Studies suggest that the prevalence of chronic liver disease in the United Kingdom is increasing, in part owing to the increasing prevalence of non-alcoholic fatty liver disease (NAFLD), alcohol related liver disease, and hepatitis C. 5 6 Clinicians therefore need to be able to recognise signs and symptoms of hepatic encephalopathy in patients who might not have a diagnosis of chronic liver disease. This review aims to highlight the importance of recognising hepatic encephalopathy in chronic liver failure and outlines a practical and evidence based approach to its management, based on the framework of recent guidelines from the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD). 4 Hepatic encephalopathy in acute liver failure is managed differently, and will not be addressed. What is hepatic encephalopathy and what are its signs and symptoms? Hepatic encephalopathy constitutes a spectrum of neuropsychiatric abnormalities, beginning with subtle psychomotor changes and progressing to confusion with asterixis, somnolence, and then coma, arising in patients with impaired liver function or portosystemic shunting. 7 The first neuropsychological feature to emerge is psycho- HOW PATIENTS WERE INVOLVED IN THE CREATION OF THIS ARTICLE We consulted one of our patients who had experienced hepatic encephalopathy who kindly reviewed our manuscript and made suggestions about aspects of care that were especially important for patients with the condition THE BOTTOM LINE Hepatic encephalopathy is a sign of poor prognosis and correlates with mortality in both in patients with acute liver failure and those with cirrhosis associated with end stage liver disease Patients without overt hepatic encephalopathy can have subtle cognitive deficits affecting quality of life that may be responsive to treatment Hepatic encephalopathy is a clinical diagnosis that can be assisted by neuropsychology and neurophysiology Evidence based treatments, such as lactulose and rifaximin, influence both length and quality of life SOURCES AND SELECTION CRITERIA We searched PubMed up to March 2015 (and updated June 2015) with the terms hepatic encephalopathy and minimal hepatic encephalopathy targeting reviews and studies published in English since We searched the references of identified articles as well as our own files. The selection of references was made based on our assessment of relevance to the topic. motor slowing, which can only be detected on psychometric testing, using, for example, the psychometric hepatic encephalopathy score (PHES). 8 Other neuropsychological tests are outlined in table 1. There is no agreed gold standard test, and patients may score differently on each. The tests therefore need to be used as part of a wider clinical assessment. Which test is chosen depends on availability of equipment, training of examiner, and local preference. 4 Psychomotor slowing may progress to subtle cognitive impairment and difficulties in concentration. 14 Reversal of the sleep-wake cycle is an early sign in some patients. In addition, affective changes including depression and occasionally personality changes are observed (such as irritability and inappropriate behaviour). 15 Agitation and aggression can progress to acute confusion leading to progressive stupor and coma. Asterixis (also known as a liver flap ) constitutes an arrhythmic negative myoclonus and loss of postural tone with a frequency of 3-5 Hz. This may be bilateral or asymmetric and is normally seen in the hands but can affect other parts of the body. It may be more easily felt than seen. Hepatic encephalopathy must be distinguished from other causes associated with a change in cognition such as electrolyte disturbance, intoxication, cerebral hypoperfusion, hypoxia, and sepsis as well as more chronic conditions such as dementia. A differential diagnosis for hepatic encephalopathy is given in table 2. Neurological examination is often normal in stages 1-2 of hepatic encephalopathy, but hyperreflexia and extensor posturing may develop later, together with a positive Babinski sign. 16 In liver cirrhosis seizures are less common than in acute liver failure (when they warn of developing cerebral oedema) and suggest causes such as electrolyte derangement (for example, hypoglycaemia, hypomagnesaemia), alcohol withdrawal, stroke, or encephalitis. 19 How is hepatic encephalopathy classified? There are several methods of classifying hepatic encephalopathy. The syndrome can be seen as comprising three separate clinical entities: type A due to acute liver failure, type B due to portal venous bypass with portosystemic August 2015 the bmj Table 1 Psychometric tests for diagnosis of covert hepatic encephalopathy Test name Description Equipment required Problems Psychometric hepatic encephalopathy score (PHES) 8 Six tests evaluating cognitive and psychomotor processing speed and visuo-motor coordination Pencil and paper Vision must be intact Stroop test 9 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) test 10 Assessment of ability to detect a light source flickering Specialised equipment Vision must be intact Continuous reaction time (CRT) test 11 Motor reaction time to auditory stimuli Computer equipment and additional hardware Hearing must be intact SCAN test 12 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 Some authorities define hepatic encephalopathy as acute or chronic; or as episodic, recurrent, or persistent; others differentiate between non-precipitated and precipitated episodes. Type B hepatic encephalopathy may develop acutely after transjugular intrahepatic portosystemic shunting (TIPS) procedures, 20 in which an iatrogenic portosystemic shunt is created. The likelihood of developing overt hepatic encephalopathy after TIPS varies from 15% to 48%, 21 and is higher in older patients, those with previous episodes of hepatic encephalopathy, and those with a higher Child-Pugh score. 22 If covert hepatic encephalopathy is included the risk is higher. If hepatic encephalopathy does develop, shunt size reduction or embolisation of portosystemic collaterals should be co nsidered. 23 The most common clinical classification used to describe the severity of hepatic encephalopathy is the West Haven criteria (table 3). 7 This describes the continuum of hepatic encephalopathy progressing through its four stages, from mild lack of awareness to coma. Covert hepatic encephalopathy refers to subtle neuropsychological problems, psychomotor slowing, and difficulty with activities of daily living that can be detected on neuropsychological assessment (see table 1). It is not reliably detected by the clinician without investigations. Recent studies have demonstrated that covert hepatic encephalopathy affects up to 50% of cirrhotic patients. 8 Many patients develop covert hepatic encephalopathy in a chronic manner, with subtle neuropsychological changes that may have devastating effects on the patient s ability to function independently. 24 Assessment for covert hepatic encephalopathy using psychometric tests may be particularly considered in patients with known or suspected liver cirrhosis who complain of difficulties functioning in everyday life, whose relatives have noticed attentional difficulties, or when employment is directly affected by cognitive impairment. 4 Covert hepatic encephalopathy also has a poor prognosis, with increased risk of hospitalisation and progression to overt hepatic encephalopathy or mortality. 25 What causes hepatic encephalopathy? Hepatic encephalopathy can develop due to liver failure from any cause. It is postulated that its pathogenesis is Table 2 Differentials differential diagnosis for hepatic encephalopathy Category and diagnosis Metabolic: Diabetic ketoacidosis Hypoglycaemia Hyperosmolar states Endocrine: Hyponatraemia Hypercalcaemia Hypothyroidism Drugs and toxins: Alcohol intoxication or withdrawal Wernicke s encephalopathy Opioids Benzodiazepines Infection: Encephalitis Sepsis related encephalopathy Vascular: Ischaemic stroke Intracranial haemorrhage Cerebral hypoperfusion Others: Non-convulsive status epilepticus Brain lesions Dementia Obstructive sleep apnoea Psychiatric disorder Distinguishing factors Patient s history and results of blood and urine investigations will help to exclude metabolic and endocrine causes Alcohol withdrawal often causes tremor, sweating, and prominent hallucinations. A collateral history of alcohol intake can be helpful Constricted pupils and depressed respiratory drive may indicate opiate toxicity Look for prodromal personality change, fever, focal neurological signs, and seizures as signs of encephalitis Evaluate carefully for a source of underlying sepsis: consider chest x ray and urine microscopy Sudden onset focal neurological signs point to a cerebral vascular event Cerebral hypoperfusion can occur secondary to cardiac failure or reduced circulating volume: consider echocardiography Electroencephalography and brain imaging are vital if non-convulsive status or a space-occupying lesion are considered Overnight pulse oximetry and early morning arterial blood gas analysis can point to obstructive sleep apnoea Depression can cause psychomotor slowing and may coexist with other pathologies: psychiatric evaluation may be warranted Table 3 West Haven criteria for grading severity of hepatic encephalopathy Grade Clinical features Covert hepatic encephalopathy Minimal hepatic encephalopathy (MHE) Grade I Overt hepatic encephalopathy Grade II Grade III Grade IV Evidence of cognitive impairment on neuropsychology Evidence of altered psychomotor speed or executive function Requires psychometric tests to make the diagnosis Trivial lack of awareness Euphoria or anxiety Shortened attention span Impairment of addition or subtraction (for example, serial 7s test) Altered sleep rhythm Lethargy or apathy Disorientation for time Obvious personality change Inappropriate behaviour Dyspraxia Asterixis Somnolence to semi-stupor Response to stimuli Confused Gross disorientation Bizarre behaviour Coma the bmj 15 August A PATIENT S STORY I will attempt to provide an account of the impact of HE by recounting actual occurrences. Most of these have a comic element which disguises the severe anxieties I experienced. In most cases I am paradoxically able to remember what was happening at the time, 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. My episodes of hepatic encephalopathy usually started with the onset of confusion and a state of disorientation. I would start to shake, hold my head in my hands, and become argumentative, unreasonable, and uncooperative. Bizarre behaviour usually followed, such as: Dressing to go out to a dinner party, I presented downstairs with my trousers on back to front. Returning from buying a newspaper I stood in the dark on a freezing winter s night trying to unlock the back door without success until my partner returned home from shopping. I once spent 20 minutes trying to figure out how to put on a pair of gardening clogs (no laces). I forgot how to brush my teeth despite having the brush loaded with paste put in my hand and the tap turned on. I went downstairs one morning to make my partner her cup of tea and returned inexplicably with a knife and no tea. I didn t recognise best friends whom my partner had called for help during one of my episodes. I offered my phone as payment in a shop. I couldn t work out how to read a book. I forgot how to use the computer My handwriting became illegible. Prior to my admission to hospital, I experienced a variety of attempts to diagnose my condition. While I understand the need to cover every possibility before arriving at hepatic encephalopathy, greeting a confused and anxious patient with Hello again, Mr Crawford. Been drinking again have we? cannot help. Hepatic encephalopathy is an awful experience for the patient and the carer. It is unpredictable and challenging and mystifying in the early stages because it is usually impossible to ascribe the episodes to any particular cause. Generally, I was aware of what was happening and what I wanted to say, but I was 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 views and opinions of the patient s carer in trying to assess the impact the condition has on their lives. I had many awful experiences alone on a ward. For example, when I was in bed and wanted a blanket I resorted to miming to a nurse that I was cold because I couldn t retrieve the necessary words. I remember hallucinating and developing irrational fears of what might be planned for me. I even planned an elaborate plot to escape from hospital. Patients are usually seen alone on the wards when they are confused and disorientated. I remember trying to remember key facts for my partner s benefit when she visited. Usually I was unable to recall what I d been told which caused anxiety and embarrassment. Hepatic encephalopathy prohibits clear thought and articulation. Once, I tried to write things down for her benefit, but what I thought was a lucid account was illegible. At this point, I had not been given a formal account of what hepatic encephalopathy was and what I might expect to happen to me. An explanation given to my partner was: Toxins which your liver cannot process travel to your brain and distort its functioning. Clarity is vital if the patient and carer are expecting to come to terms with hepatic encephalopathy. A simple, definitive explanation is beneficial for patients as soon as one is available. Rifaximin worked for me. Being prescribed it during a consultation with my specialist certainly made me feel that I was being dealt with properly at last. Informing the DVLA is really important. I did drive on occasions when I was affected by hepatic encephalopathy. Defiance and bravado were to blame, and I did have one minor collision which could have been avoided. related to the effects of nitrogenous waste products on the brain, particularly ammonia and glutamine. 26 Glutamine is normally metabolised by glutaminase in the small intestine to ammonia and glutamate; ammonia is then converted to urea in the liver. 27 High levels of ammonia in the serum lead to cerebral oedema, which acts synergistically with an inflammatory response in the central nervous system to cause complex cortical and subcortical dysfunction. In cirrhotic patients, portosystemic shunting allows ammonia and other neurotoxins to bypass the liver and enter the systemic circulation, and this may also occur after transjugular intrahepatic portosystemic shunting. Hyponatraemia, common in cirrhosis, may also exacerbate cerebral oedema and astrocyte dysfunction. 28 Muscle volume depletion (sarcopenia) contributes to the development of encephalopathy, since muscle represents an alternative site of ammonia detoxification. 29 Patients with a concomitant systemic inflammatory response syndrome, such as from infection, are predisposed to developing hepatic encephalopathy The gut microbiota has also been implicated in pathogenesis, and there is evidence for gut dysbiosis and small bowel overgrowth, 32 hence the possibility of therapies modulating microbiota, such as probiotics. Which investigations aid diagnosis? There is no specific test for hepatic encephalopathy, and the diagnosis should be made on clinical grounds through the exclusion of other conditions that can mimic or be confused with hepatic encephalopathy (see table 2). Testing of arterial or venous ammonia levels is commonly performed, but levels correlate poorly with the grade of hepatic encephalopathy 33 and should not be used alone for establishing the diagnosis as they are not consistently raised. 34 Computed tomography or magnetic resonance imaging should be performed in all patients in whom a diagnosis of hepatic encephalopathy is being considered, in order to exclude other conditions such as intracranial haemorrhage or space occupying lesions. Hyperintensity of the basal ganglia on magnetic resonance imaging is suggestive of portosystemic shunting. 35 Positron emission tomography has been used experimentally and may have a role, but this remains undefined. 36 Electroencephalography is used to investigate for the presence of seizures and should be considered if subclinical seizures are suspected. 37 It may show characteristic changes in overt hepatic encephalopathy in the form of triphasic waves, as well as more subtle signs in covert hepatic encephalopathy. 38 It may be used together with neuropsychological assessments (see table 1) to aid the diagnosis of covert hepatic encephalopathy. 4 However, the findings are generally non-specific and may be influenced by metabolic and drug factors. How is hepatic encephalopathy managed? The management of hepatic encephalopathy depends on its type and severity. Many patients with covert hepatic encephalopathy may not require treatment unless the condition is thought to be adversely affecting quality of life. 4 Episodes of overt hepatic encephalopathy can be August 2015 the bmj shortened with appropriate treatment, and further events prevented. Many patients presenting acutely with overt hepatic encephalopathy will have an underlying precipitant, such as gastrointestinal bleeding, infection, diuretic overdose, or use of sedating medication. 39 The first stage in management is to address these that is, by stopping precipitating drugs, treating infection, etc. However, a substantial proportion of patients will have no identified cause. All patients with evidence of hepatic encephalopathy should be advised to stop driving and inform the Driver and Vehicle Licensing Authority (DVLA). 4 Studies have shown that even patients with covert hepatic encephalopathy are more prone to road traffic accidents. 40 Failure of the patient to inform the DVLA about the condition may result in a fine. Patients are likely to have their licence revoked until satisfactory recovery is demonstrated. 41 Nutrition Historically, dietary protein restriction has been advis
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