Dr Jez Thompson Provides Six Key Learning Points for Primary Care Based on the EASL Guideline on Hepatic Encephalopathy
|Read This Article to Learn More About:|
In people with cirrhosis, hepatic encephalopathy (HE) is a very common and life-threatening complication;1 the 10-year cumulative incidence of HE in these individuals ranges between 7% and 42%.2
HE is defined as reversible brain dysfunction associated with liver insufficiency and/or porto-systemic shunts.3,4 The exact mechanisms underlying the development of HE remain poorly understood, although disturbance of ammonia metabolism is implicated in its pathogenesis.5
The condition is associated with a wide spectrum of neurological and psychiatric manifestations, ranging from subclinical alterations in cognitive function only detectable on psychometric or neuropsychological tests (termed minimal, subclinical, or covert HE),4 to more clinically evident symptoms (known as overt HE), which can include euphoria or anxiety, altered sleep rhythm, disorientation, confusion, disturbed behaviour, and impaired responsiveness, and can lead to coma.6
As a condition, HE is important for three reasons:
- it is a high-impact disorder with very damaging effects on the lives of patients and their carers
- it results in significant demand on healthcare systems
- it is reversible and often preventable.
It is in this context that the European Association for the Study of the Liver (EASL) has developed EASL clinical practice guidelines on the management of hepatic encephalopathy.4
Rather than taking a systematic approach to the identification and management of HE, the EASL guideline is framed around answers to a number of what are essentially ‘frequently asked questions’.4 Although many of these questions are aimed at those working in specialist hepatology services, a number are also relevant to primary care because they either guide clinical practice or provide useful background information.
Although there are clear challenges in the diagnosis of HE, early identification in primary care can make a real difference to patient outcomes. This article provides six key learning points to aid the recognition of HE in primary care.
1. Screen Patients with Cirrhosis for Covert HE in Primary Care
Diagnosing covert HE is important because the condition occurs in 30–70% of patients with cirrhosis, and it is associated with both a poor quality of life and an increased risk of developing overt HE.4 The EASL guideline therefore recommends screening for covert HE in patients with cirrhosis and no history of overt HE.4 The only simple screening test currently available is the Animal Naming Test (see Box 1).4,7–9
|Box 1: The Animal Naming Test—A Diagnostic Tool for Covert HE9|
The ANT is used to rapidly screen for the presence of covert HE in people who have cirrhosis. It can be used in an office setting or at the bedside.
ANT analyses semantic fluency and the test consists of a person listing as many animal names as possible within 1 minute.
According to Agarwal et al (2020),9 ‘A cut-off of <14 animal names differentiated well between patients with and without [covert HE] with a sensitivity of 89% and specificity of 95%.’
Optimal performance of the ANT requires well-organised verbal recall and retrieval, and also self-monitoring of cognition (i.e. awareness by the person of the names they have already listed). The ANT is very sensitive to functions associated with anterior cortical and prefrontal cortex areas, which are particularly vulnerable to the initial stages of HE.
ANT=Animal Naming Test; HE=hepatic encephalopathy
2. Identify and Correct Precipitating Factors in Patients With Overt HE
The EASL guideline recommends that, in patients with overt HE, the primary intervention ‘is a search for, and correction of, any precipitating factors. This exercise always precedes specific anti-HE treatment.’4
Correction of any precipitating factors is important because up to 90% of people with episodic overt HE can be expected to recover; in addition, specific treatment of HE has little chance of success without management of precipitating factors (see Box 2).4,10
|Box 2: Common Precipitating Factors in HE10|
Poudyal et al (2019)10 analysed 132 people who were admitted to hospital with liver cirrhosis and overt HE to determine the most common precipitating factors. These included:
Primary care prescribers can support the prevention of HE by maintaining a high level of awareness of medications that can precipitate the development of HE in people with cirrhosis. These include:11
- sedative medications such as opioids, benzodiazepines, and gabapentinoids
- proton-pump inhibitors.
It should also be noted that nonsteroidal anti-inflammatory drugs may cause gastrointestinal bleeding in people with cirrhosis,12 and that diuretics can result in electrolyte imbalance.13
3. Understand the Referral Criteria for Patients With Overt HE
The EASL guideline recommends that: ‘Patients with recurrent or persistent HE should be considered for liver transplantation and a first episode of overt HE should prompt referral to a transplant centre for evaluation.’4
Although the majority of patients with cirrhosis and HE will be engaged in regular monitoring and treatment by specialist hepatology services, some may be lost to follow up from outpatient appointments, and others may receive only fragmented care.14 The optimal management of patients with complicated cirrhosis involves a multidisciplinary approach,14 and primary care physicians are well placed to identify those patients who may need further assessment but who are not receiving specialist follow up.
4. Initiate Secondary Prophylaxis in Patients Experiencing Their First Episode of Overt HE
The EASL recommends that lactulose is taken ‘as secondary prophylaxis following a first episode of overt HE, and should be titrated to obtain 2–3 bowel movements per day.’4 The guideline also highlights a systematic review involving over 1800 participants, which showed that lactulose was effective at preventing overt HE with only mild gastrointestinal adverse effects.4 Further information on the rationale for the use of lactulose in the secondary prophylaxis of HE is included in Box 3, and an algorithm detailing the management of severe recurrent HE is included for reference in Figure 1.15
|Box 3: BSG Rationale for the use of Lactulose in the Secondary Prophylaxis of HE15|
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:
BSG=British Society of Gastroenterology; HE=hepatic encephalopathy
McPherson S, Thompson A. Management of hepatic encephalopathy: beyond the acute episode. London: BSG, 2019 (updated May 2022). Available at: www.bsg.org.uk/web-education-articles-list/management-of-hepatic-encephalopathy-beyond-the-acute-episode-dr-mcpherson-and-dr-thompson-provides-insight-into-the-management-of-hepatic-encephalopathy Reproduced with permission.
Figure 1: Management of Severe Recurrent HE15
The EASL guideline also recommends ‘rifaximin as an adjunct to lactulose … as secondary prophylaxis following ≥1 additional episodes of overt HE within 6 months of the first one.’4 Study data, highlighted in the guidance, show that rifaximin (versus placebo) decreased the risk of recurrence of overt HE in people with cirrhosis and two or more episodes of overt HE within the previous 6 months.4
The guideline notes that the use of probiotics for secondary prophylaxis is not supported owing to the poor quality of published trials comparing their use with that of lactulose; in addition, the use of probiotics in the secondary prevention of overt HE has not been investigated in a randomised controlled trial (RCT).4
5. Know When to Discontinue Prophylactic Therapy for HE in Patients With Cirrhosis
To date, no RCT has shown the beneficial impact of stopping prophylactic therapy for HE in patients with cirrhosis. However, patients with a history of overt HE whose liver function and nutritional status have improved, or in whom precipitating factors are unlikely to recur (for example, someone with a history of overt HE precipitated by gastrointestinal bleeding whose varices have been obliterated) may be considered for discontinuation of prophylactic therapy on a case-by-case basis.4 The guideline therefore recommends that discontinuation of anti-HE therapy can be considered on an individual basis ‘in patients with a history of overt HE with improvement of liver function and nutritional status and in whom precipitant factors have been controlled.’4
6. Recognise When Patients With Overt HE or a History of the Condition Should Be Provided With Advice in Relation to Driving
The EASL guideline recommends that people who have had an episode of overt HE ‘should be provided with information on the risks associated with driving and on the appropriateness of formal driving assessment with the relevant authorities.’4
On-road driving tests and driving simulation studies have shown that patients with cirrhosis and HE can experience problems with vehicle handling and other aspects of driving, and that they have more documented road traffic accidents and violations than unimpaired patients with cirrhosis.4 However, the guideline notes two published studies in which there was no increased rate of vehicular accidents in patients with cirrhosis.4
In its guidance, the EASL acknowledges the difficulties associated with drawing up international guidance on whether patients with cirrhosis and HE can continue to drive, owing to different regulatory and legal approaches.4 However, it does recognise expert consensus in this area, which recommends avoidance of driving after an episode of overt HE, as most patients with HE experience significant ‘lapses of consciousness’ during or following an episode.4 The EASL states that patients and their carers should be provided with verbal and written advice on avoiding driving following an episode of overt HE, but also emphasises that clinicians should be aware of their local responsibilities, and be mindful that they are not trained to assess fitness to drive.4 If patients want to resume driving, they should schedule a formal driving reassessment based on local regulations.4
Within the UK, driving for patients with hepatic cirrhosis and chronic encephalopathy is covered under Alcohol-related disorders in Assessing fitness to drive—a guide for medical professionals by the Driving & Vehicle Licensing Agency (see Table 1).16
Table 1: DVLA Guidance for Patients With Hepatic Cirrhosis and Chronic Encephalopathy16
|Group 1: Car and Motorcycle||Group 2: Bus and Lorry|
Must not drive and must notify DVLA
Licence will be refused or revoked until:
Must not drive and must notify DVLA
Licence will be refused or revoked until recovery is satisfactory.
DVLA=Driver & Vehicle Licensing Agency
Driver & Vehicle Licensing Agency. Assessing fitness to drive—a guide for medical professionals. Swansea: DVLA, 2022. Available at: www.gov.uk/government/publications/assessing-fitness-to-drive-a-guide-for-medical-professionals Reproduced with permission.
Primary care clinicians have a number of important roles in the prevention and early diagnosis of HE, and in the long-term management of patients with the condition. The evidence-based answers to questions in the EASL HE guideline will help practitioners to diagnose and manage HE, identify patients lost to follow up, and provide the best possible care and advice to patients and carers about the condition.
HE=hepatic encephalopathy; EASL=European Association for the Study of the Liver; DVLA=Driver & Vehicle Licensing Agency