Review article: the design of clinical trials in hepatic encephalopathy--an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement

Abstract

Background: The clinical classification of hepatic encephalopathy is largely subjective, which has led to difficulties in designing trials in this field.

Aims: To review the current classification of hepatic encephalopathy and to develop consensus guidelines on the design and conduct of future clinical trials.

Methods: A round table was convened at the 14th International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting. Key discussion points were the nomenclature of hepatic encephalopathy and the selection of patients, standards of care and end-points for assessing the treatment and secondary prevention of hepatic encephalopathy.

Results: It was generally agreed that severity assessment of hepatic encephalopathy in patients with cirrhosis, whether made clinically or more objectively, should be continuous rather than categorical, and a system for assessing the SONIC (Spectrum of Neuro-cognitive Impairment in Cirrhosis) was proposed. Within this system, patients currently classified as having minimal hepatic encephalopathy and Grade I hepatic encephalopathy would be classified as having Covert hepatic encephalopathy, whereas those with apparent clinical abnormalities would continue to be classified as overt hepatic encephalopathy. Some aspects of the terminology require further debate. Consensus was also reached on the patient populations, standards of care and endpoints to assess clinical trial outcomes. However, some compromises had to be made as there is considerable inter- and intravariability in the availability of some of the more objective surrogate performance markers.

Conclusions: The objectives of the round table were met. Robust, defendable guidelines for the conduct of future studies into hepatic encephalopathy have been provided. Outstanding issues are few and will continue to be discussed.

Figure 1

Proposed classification of HE as part of inpatients with cirrhosis, by severity of the cognitive impairment. Patients with minimal HE and Grade I change using the West-Haven criteria would be classified, as having COVERT HE. Patients with West-Haven Grade II changes or above would be classified as having OVERT HE. Patients with no clinical, neurophysiological or neuropsychometric changes would be classified as UNIMPAIRED.

Figure 2

Categorical and continuous approaches to the classification of hepatic encephalopathy in patients with cirrhosis. The assessment of cognitive function in HE can be performed using (a) categorical or (b) continuous approaches. (a) In the categorical approach, the criteria used to define the categories are arbitrary and have high inter-rater variability. (b) In the continuous approach, there are no fixed boundaries. Patients may be unimpaired or impaired; the impairment may be stable or unstable, and patients may move from one state to another over time. Those who are unstable would experience episodes of HE ranging from an acute confusional syndrome, by degrees to coma. Those that are impaired but stable may have no clinically discernable abnormalities but would exhibit neuro-psychometric/neurophysiological abnormalities on testing – covert HE or else would have obvious but stable clinical feature – overt HE. Individuals who have recovered from an episode of episodic HE may retain features of stable impairment, which may be either covert or overt. Those with prolonged and severe cognitive/motor deficits correspond to the patients who are currently classified as having persistent HE or acquired hepatocerebral degeneration. There is some overlap between the grades of the categorical approach and the situations defined in the continuous approach, but there is no direct correspondence. In the continuous approach, the assessment method is not limited by predefined reference categories.