EASL Clinical Practice Guidelines

Suggestions for future research

This section deals with research into the management of HE. However, such research should always be based on research into the pathophysiology of HE. It is necessary to gain more insight into which liver functions are responsible for maintenance of cerebral functions, which alterations in intestinal function and microbiota make failure of these liver functions critical, which brain functions are particularly vulnerable to the combined effects of the aforementioned events, and, finally, which factors outside this axis that result in the emergence of HE (e.g., inflammation, endocrine settings, or malnutrition). Therefore, the research fields into pathophysiology and clinical management should remain in close contact. Such collaboration should result in new causal and symptomatic treatment modalities that need and motivate clinical trials.

There is a severe and unmet need for controlled clinical trials on treatment effects on all the different forms of HE. Decisive clinical studies are few, although the number of patients and their resource utilization is high. There are no data on which factors and patients represent the higher costs, and research is needed to examine the effect of specific cirrhosis-related complications. At present, there is an insufficient basis for allocating resources and establishing priority policies regarding management of HE. Many drugs that were assessed for HE several decades ago were studied following a standard of care that, at present, is obsolete. Any study of treatment for HE should be reassessed or repeated using the current standard of care. It is critical to develop protocols to identify precipitating factors and ACLF. The benefit of recently assessed drugs is concentrated in the prevention of recurrence, and there is a large need for trials on episodic HE.

There is also an unmet need for research into diagnostic methods that is necessary to form a basis for clinical trials. The diagnosis of MHE and CHE has received enormous interest, but it is still not possible to compare results among studies and the precision should be improved. It may be useful to develop, validate, and implement HE scales that combine the degree of functional liver failure and PSS with more than one psychometric method.

One important area of uncertainty is whether the term CHE, which was introduced to expand MHE toward grade I of oriented patients, is informative and clinically valuable. This needs to be evaluated by a data-driven approach. Likewise, the distinction between isolated liver failure and ACLF-associated HE should be evaluated by independent data.

A closer scientific collaboration between clinical hepatologists and dedicated brain researchers, including functional brain imaging experts, is needed. Likewise, neuropsychologists and psychiatrists are needed to clarify the broad spectrum of neuropsychiatric symptoms that can be observed in patients with liver disease. Syndrome diagnoses should be more precisely classified and transformed into classifiable entities based on pathophysiology and responding to the requirements of clinical hepatology practice and research.

Future studies should fill our gaps in knowledge. They should be focused on assessing the effects of HE on individuals and society, how to use diagnostic tools appropriately, and define the therapeutic goals in each clinical scenario (Table 7).

Table 7
Suggested areas of future research in HE.

Recommendations on future research in HE

The existing literature suffers from a lack of standardization, and this heterogeneity makes pooling of data difficult or meaningless. Recommendations to promote consistency across the field have been published by ISHEN [66]. Following is a synopsis of the recommendations.

Trials in patients with episodic OHE

  1. Patients who are not expected to survive the hospitalization, who are terminally ill or have ACLF should be excluded.
  2. A detailed standard-of-care algorithm must be agreed upon a priori and must be instituted and monitored diligently throughout the trial.
  3. Patients should not be entered into trials until after the institution of optimal standard-of-care therapy and only if their mental state abnormalities persist.
  4. Provided the optimal standard of care is instituted and maintained, the treatment trial can be initiated earlier if they include a placebo comparator; this would allow an evaluation of the trial treatment as an adjuvant to standard therapy.
  5. Large-scale, multicenter treatment trials should be evaluated using robust clinical outcomes, such as in-hospital and remote survival, liver-related and total deaths, completeness and speed of recovery from HE, number of days in intensive care, total length of hospital stay, quality-of-life measures, and associated costs. Markers for HE, such as psycho metric testing, can be employed if standardized and validated tools are available in all centers. Individual centers can utilize additional, accessible, validated markers if they choose.
  6. Proof-of-concept trials will additionally be monitored using tools that best relate to the endpoints anticipated or expected; this may involve use of neural imaging or measurement of specific biomarkers.

Trials in patients with MHE or CHE

Trials in this population should be randomized and placebo controlled.

  1. Patients receiving treatment for OHE or those with previous episodes of OHE should be excluded.
  2. In single-center or proof-of-concept studies, investigators may use tests for assessing the severity of HE with which they are familiar, provided that normative reference data are available and the tests have been validated for use in this patient population.
  3. Further information is needed on the interchangeability and standardization of tests to assess the severity of HE for use in multicenter trials. As an interim, two or more of the current validated tests should be used and applied uniformly across centers.