Introduction and setting the scene: New nomenclature of hepatic encephalopathy and American Association for the Study of Liver Diseases/European Association for the Study of the Liver guidelines

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Abbreviations

AASLD

American Association for the Study of Liver Diseases

EASL

European Association for the Study of the Liver

HE

hepatic encephalopathy

ISHEN

International Society for Hepatic Encephalopathy and Nitrogen Metabolism

UTI

urinary tract infection

Hepatic encephalopathy (HE) has emerged in the last decade as one of the leading complications of cirrhosis in terms of patient, caregiver, and healthcare burden.1, 2 In its overt stage, it is a major indication for hospital admission and readmission and death in cirrhotic patients in North America.1 In its covert stage it can adversely affect health‐related quality of life, driving capability, hospitalizations, falls, and survival.3 This series of sessions will cover the American Association for the Study of Liver Diseases/European Association for the Study of the Liver (AASLD/EASL) guidelines, pathogenesis, alterations in the gut‐brain axis, outpatient and inpatient management of HE, as well as future treatment and investigation directions.

Definition

The combined AASLD/EASL HE guidelines4 define HE as follows: “Hepatic Encephalopathy is brain dysfunction caused by liver insufficiency and/or portosystemic shunting; it manifests as a wide spectrum of neurological/psychiatric abnormalities ranging from subclinical alterations to coma.”

Updated Nomenclature of HE

Four Axes for Describing HE Episodes

Given the multidimensional nature of HE, the AASLD/EASL guidelines4 seek to divide each episode into four axes (Fig. 1) that involve the definition of: (1) underlying disease, (2) grade, (3) time course, and (4) spontaneous/precipitated. The definition of each HE episode into these four axes will help in understanding the origin, the current medical needs, and the optimal management strategies, and importantly, will place this HE episode in the context of prior HE episodes.

Figure 1.

Four axes to define an episode of HE.

Case 1

A person with cirrhosis who presents with coma for their second episode in 2 months with a urinary tract infection (UTI) would be classified as type C (for cirrhosis), grade IV (overt and coma), recurrent (more than one episode in 6 months), and precipitated (by the UTI).

This detailed description could help inpatient and outpatient teams to: (1) manage the patient better as an inpatient by applying care for the unconscious patient and treat the UTI, and (2) potentially prevent future recurrence by identifying the source of the recurrent UTIs and resultant HE episodes in this patient.

Case 2

A person with cirrhosis is seen in clinic with his wife, who reports that the patient is “slow and not himself.” Because you are familiar with the patient, on interaction you agree with the wife, even though the patient does not have asterixis and is oriented to time, place, and person. The cognitive tests performed show significant impairment in all fields tested. However, when seen by your colleague subsequently, who has not been following the patient and who did not interview the wife, he was deemed as being “normal.” This patient has grade 1 HE according to the West‐Haven criteria, but that was only apparent to the clinician who was familiar with the patient and not an independent clinician. This is the dilemma between practicability and underlying disease severity. Therefore, this person is classified as type C, covert HE. The axes related to time course and precipitated/spontaneous do not apply to the covert HE stage.

Covert Versus Overt HE

The West‐Haven Criteria, modified from the original Parsons‐Smith Criteria, were meant as a semiquantitative method to define the severity of HE.4 However, because of the absence of other methods to quantify HE that could be readily used clinically, they were co‐opted as clinical endpoints for trials despite having a significant subjective component in the early stages. This subjectivity has been recognized by several regulatory agencies such as the US Food and Drug Administration that have consistently demanded objective criteria for all multicenter HE studies that refine these criteria or define HE in other objective methods.5, 6 The most problematic definition is grade 1, which is characterized by trivial lack of awareness, impaired attention span, altered sleep, euphoria, or depression. This is difficult to define unless one has evaluated a patient over time, and thus is an inappropriate endpoint for multicenter trials of therapies for HE. Changes and classifications are shown in Figure 2.

Figure 2.

(A) Classification according to the West‐Haven criteria for HE severity. (B) Classification according to the ISHEN criteria and AASLD/EASL guidelines for HE severity.

Grade 1 HE is distinct from minimal HE from a disease severity and pathophysiological perspective, as has been known for several decades and reaffirmed recently.7 However, because of the poor interrater variability in defining this stage and also to guide clinicians to define the clearer grade 2 or higher stages, a pragmatic approach was first proposed in 2011 in the ISHEN (International Society for Hepatic Encephalopathy and Nitrogen Metabolism) consensus statement.8 The EASL/AASLD guidelines have proposed continuing this while investigating better approaches to define grade 1 HE.4, 9, 10 Regardless, the definition of grade 2 HE, which includes disorientation and asterixis, is being used in several ongoing clinical trials for HE, and the term “covert HE” returns more than 50 publications on PubMed. Some authors also are using “covert” and “minimal” HE interchangeably.

Summary of the Changes in the Guidelines

Overall, the AASLD/EASL guidelines4 have introduced or modified selected existing concepts, whereas other concepts related to the diagnosis and management of HE have remained the same. These are now summarized in Tables 1 and 2. These guidelines were aimed toward the clinician in order to simplify the diagnosis of HE and introduce the four‐axial concept that places specific HE episodes in the context of the overall prognosis and disease course of the patients, to improve overall outcomes and healthcare burden of HE.

Table 1.

What Is New in the AASLD/EASL HE Guidelines?

• New nomenclature and definition

• Streamlining the diagnosis for overt HE

• Potential diagnostic strategies for covert and minimal HE

• Focus on nutritional therapy for HE

• Differentiating treatment strategies regarding primary and secondary prophylaxis

• Treatments for persistent HE

Table 2.

What Has Remained Unchanged in the AASLD/EASL HE Guidelines?

• Treatment strategies for an acute episode focused on specific and general management

• Need to identify precipitating factors and other causes of altered mental status

• Importance of HE stages that are not apparent clinically

• Evaluation of gut‐based therapies for treatment and prevention of further HE episodes