Hepatic encephalopathy: a critical current review

Abstract

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis and/or porto-systemic shunting. The clinical symptoms are widely variable, extending from subtle impairment in mental state to coma. The utility of categorizing the severity of HE accurately and efficiently serves not only to provide practical functional information about the current clinical status of the patient but also gives valuable prognostic information. In the past 20-30 years, there has been rapid progress in understanding the pathophysiological basis of HE; however, the lack of direct correlation between pathogenic factors and the severity of HE make it difficult to select appropriate therapy for HE patients. In this review, we will discuss the classification system and its limitations, the neuropsychometric assessments and their challenges, as well as the present knowledge on the pathophysiological mechanisms. Despite the many prevalent hypotheses around the pathogenesis of the disease, most treatments focus on targeting and lowering the accumulation of ammonia as well as inflammation. However, treatment of minimal HE remains a huge unmet need and a big concerted effort is needed to better define this condition to allow the development of new therapies. We review the currently available therapies and future approaches to treat HE as well as the scientific and clinical data that support their effectiveness.

Keywords: Classification; Hepatic encephalopathy; Pathogenesis; Treatment.

Fig. 1

Factors contributing to the pathogenesis of HE and treatment mechanisms. Factors contributing to the pathogenesis of HE with emphasis on the interorgan effects of ammonia and inflammation arising due to liver disease. The mechanism of action of ornithine phenylacetate (OP), which acts in lowering hyperammonemia through the production of the L-ornithine induced glutamine is depicted in blue (A). Glutamine in then converted to phenylacetylglutamine in the kidney followed by its eventual excretion (B). As a result, this increases the update of available ammonia for the production of glutamine, which consequently lowers the systemic and brain ammonia levels (C). The mechanism of rifaxamin is indicated by green arrows. Lactulose, in orange, effectively targets the gut and lowers bacterial ammonia production. OP ornithine phenylacetate, NO nitric oxide, NH ₃ ammonia, NH ₄⁺ ammonium ions

Fig. 2

Mechanism of action of ammonia on astrocytic and neuronal dysfunction modified by Hadjihambi et al. [108]. (1) Astrocytes entrap plasma ammonia and act as a sink for ammonia detoxification in brain by way of the enzyme glutamine synthetase. (2) This short-circuits potassium buffering, resulting in increased [K⁺]_o. (3) Increase in [NH₄ ⁺]_o and [K⁺]_o stimulate Na⁺–K⁺ ATPase(NKA) activity. (4) The excess [NH₄ ⁺]_o and [K⁺]_o promotes overactivation of neuronal NKCC1, which is the principal neuronal chloride importer. (5) This results in an increase in [Cl⁻] leading to neuronal E_GABA depolarization and therefore neuronal disinhibition. A recent study has also revealed impairment of hemichannel function and lactate release, due to hyperammonemia, which implies limited energy supply to the already compromised neurons