The social and psychological impact of hepatic encephalopathy

Hepatic encephalopathy (HE) is a brain dysfunction caused by liver insufficiency with symptoms ranging from slight cognitive changes detectable only by neuropsychiatric testing to coma. Up to 60% of patients with cirrhosis have mild forms of HE and 35% will at some point experience overt HE. Even in its milder forms, HE impacts the patient’s daily routines, self-sufficiency, quality of life, and, thereby, socio-economic status. HE is a condition affecting the whole household including formal and informal caregivers, who carry a heavy burden. Early identification, prophylaxis, and treatment of HE are essential for relieving patients and informal caregivers.


Introduction
Hepatic encephalopathy (HE) is a brain dysfunction caused by liver insufficiency or portal-systemic shunt (AASLD and EASL 2014;EASL 2022).It is a common complication of late-stage cirrhosis regardless of aetiology that manifests as a broad spectrum of neurological and psychiatric symptoms ranging from subtle neuropsychiatric alterations (covert HE) to coma.Noteworthy, HE is also identified in up to 60% of patients with non-cirrhotic portal hypertension, porto-sinusoidal vascular disease including shunts, and chronic portal vein thrombosis (Gioia et al. 2021).Patients admitted to the hospital with HE have high readmission rates (Di Pascoli et al. 2017) and the one-year mortality rate for patients with alcohol-related cirrhosis who develop HE is 64%, which is higher than that of those who develop ascites, variceal Louissaint and Tapper 2020).Symptoms such as reduced reflexes and lapses of consciousness lead to impaired driving skills, and current guidelines and expert consensus accordingly recommend that patients avoid driving after a bout of overt HE (Kircheis et al. 2009;EASL 2022).Collectively, cognitive problems and the inability to work cause a high rate of unemployment among patients with previous HE, which, along with health care expenses and several other factors related to cirrhosis, negatively impacts financial status which leads to further social isolation (Bajaj et al. 2011).
Patients are often cared for by next-of-kins, close relatives, friends, or neighbours, who act as informal caregivers (Fabrellas et al. 2020;Louissaint and Tapper 2020;Saleh et al. 2022;Shrestha et al. 2020).For many patients and informal caregivers, the first bout of overt HE is frightening and unexpected because they were not aware of the risk of HE associated with cirrhosis.This unpreparedness and the profound, albeit temporary, loss of autonomy caused by HE can lead caregivers to fear the patient's imminent death or severe neuropsychiatric disorders such as fastonset Alzheimer's disease, stroke, or head trauma (Fabrellas et al. 2020;Kunzler-Heule et al. 2016;Orr et al. 2014).For milder forms of HE, symptoms such as altered speech, slow movements, and clumsiness also cause fear, anxiety, and sorrow among both patients and caregivers (Fabrellas et al. 2020;Montagnese et al. 2012;Saleh et al. 2022).There is a clear association between a patient's mental status and the psychological burden on caregivers (Montagnese et al. 2012), and the stress introduced by higher job loss and financial insecurity introduces an even heavier caregiver burden (Shrestha et al. 2020;Bajaj et al. 2011;Schomerus and Hamster 2001).
Despite the availability of many tools that can be used to quantify HE symptoms, monitor treatment response, and assess health-related quality of life, these are, unfortunately, rarely used among clinicians (Orr et al. 2014;Lauridsen and Bajaj 2015).Focused liver-specific questionnaires or longer questionnaires such as the Sickness Impact Profile seem to be better for detecting differences in covert HE, whereas more general questionnaires suffice in overt HE (Montagnese and Bajaj 2019) though simple tools actually perform well (Lauridsen et al. 2020).New app-based technologies hold the potential for closer surveillance of daily functioning and quality of life (Shaw et al. 2023).

Mitigating the impact of HE on daily life
Early identification of HE In general, all patients with chronic liver disease, especially those with active liver disease, are at risk of developing HE.Early identification of patients at risk of developing HE and early diagnosis and treatment of any HE bout have several benefits.Besides affecting the daily lives of patients and informal caregivers, as outlined above, covert HE is also associated with a higher risk of overt HE and, thus, a higher mortality rate, which can be reduced if identified and treated early (Gairing et al. 2024;Parker 2020).
Improving health literacy and self-management strategies HE often catches the patient and caregiver off guard.Further, HE is recurrent in one in three patients, and efforts should be made to provide self-management tools for the  (AASLD and EASL 2014) patient and caregivers (Table 2).Education of patients and caregivers is essential and should include awareness of the disease, prevention, and treatment (Carbonneau et al. 2018;Mikkelsen et al. 2016;Rodenbaugh et al. 2020;Garrido et al. 2017).Up to 75% of patients with chronic liver disease suffer from muscle wasting, and moderate to severe malnutrition and dietary protein deficiency can cause muscle breakdown and contribute to further muscle wasting as well as ammonia production (Amodio et al. 2013;EASL 2022).It is thus important that patients attempt to maintain or rebuild their muscle mass by exercising and proper diet (Aamann et al. 2019;Tandon et al. 2018;Berzigotti et al. 2016).Patients should avoid longer periods of fasting and a late-night snack is recommended (Leoni et al. 2023).Table 2 summarises some topics that should be addressed when educating patients and caregivers.

Quality of life and patient-reported outcomes as clinical endpoints
Despite the profound effects on the quality of life of both patients and informal caregivers, quality of life and patientreported outcomes are rarely included as endpoints in clinical studies.A few sporadic studies have included cognition and quality of life as endpoints in studies of hyponatremia (Ahluwalia et al. 2015) and L-carnitine (Yoon et al. 2022).In a recent systematic review of the effects of lactulose and/or rifaximin on patient-reported outcomes, only 16 studies met the inclusion criteria, most studies on covert HE (Moon et al. 2023).It is worth mentioning that both treatments seemed to improve overall health-related quality of life, social activity, sleep, and, to some extent, physical functioning (Moon et al. 2023).As the only recommended pharmaceutical treatments for HE, lactuose has been used for decades and rifaxmin for a little more than a decade.As such, it is staggering that patient-reported outcomes have not been addressed further in clinical trials.We strongly advocate that future studies address these issues using standardized instruments.
In conclusion, more focus on early detection and information to patients, next-of-kin, and caregivers about HE is strongly encouraged as the condition has a tremendous impact on daily life and survival.Quality of life and the burden on informal caregivers should also be addressed in clinical trials of treatments for HE.Patients and caregivers should be educated about practical tools to help prevent development or recurrence of HE.These include: 1. Early signs of HE -when to contact health care professionals 2. Dietary guidance including protein intake and a late-night snack 3. Rationale for using lactulose and rifaximin including treatment goals 4. Risk and signs of dehydration 5. Signs of infections 6. Abstinence from alcohol and medications such as aspirin, opioids, benzodiazepines, non-steroid anti-inflammatory drugs (NSAIDs)

Table 1
Identification and grading of hepatic encephalopathy in liver disease -West Haven Criteria including minimal

Table 2
Focus on education of patients and caregivers about hepatic