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

Abstract

Summary 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.

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

“…7 It has therefore recently been redefined as covert HE. 8 The prevalence of MHE in patients with cirrhosis has been estimated to lie between 30% and 84%, with variations in the diagnostic criteria thought to be responsible for this wide range. 9 THE ROLE OF AMMONIA IN THE SYNDROME OF HEPATIC ENCEPHALOPATHY Ammonia was first implicated in the pathogenesis of HE by a team of Nobel Prize winning physiologists led by Pavlov and Nencki at the Imperial Institute of Experimental Medicine in Russia in the 1890's.…”

Minim Al Hepatic Encephalopathy in Al Coholic Cirrhosis

“…24 However, after the knowledge on the impact of MHE, great emphasis on OHE (overt hepatic encephalopathy) has recently been shifted towards MHE. Because of psychomotor defects, patients with MHE have been shown to have reduced driving skills, more likely to suffer from falls and develop episodic HE more frequently.…”

Management of Covert Hepatic Encephalopathy

“…There is abundant evidence in the literature that MHE has a profound impact on quality of life, daily functioning, driving ability, [3][4][5][6][7][8][9][10] and nearly half of all patients with MHE may be unfit to maintain employment. 9 Based on the current ISHEN guidelines, 11 patients with MHE and Grade I encephalopathy by WestHaven Criteria were re-classified as having covert hepatic encephalopathy (CHE). Since the prevalence of MHE in patients with cirrhosis varies between 30 and 84%, [12][13][14][15] therapeutic strategies to prevent overt hepatic encephalopathy (OHE) are of major importance.…”