Plasma levels of tumor necrosis factor-alpha and ammonia in patients with liver cirrhosis: correlation with severity of hepatic encephalopathy

ABSTRACT

The pathogenesis of hepatic encephalopathy [HE] is still incompletely understood, and the precise mechanisms causing brain dysfunction in liver failure are still not fully established. Several theories concerning the pathogenesis of HE have been previously suggested, including the ammonia theory, which received the most attention. Ammonia is still the most incriminated substance in the pathogenesis of HE. However, several problems exist with the ammonia theory. It is traditionally considered that circulating ammonia levels do not correlate well with severity of HE, and some patients with HE have normal circulating levels of ammonia. Another theory is that TNF-alpha is implicated in apoptosis of hepatocytes. This study aimed to determine the plasma levels of TNF-alpha and ammonia in patients with liver cirrhosis and their relation to hepatic encephalopathy [HE]. Circulating levels of TNF-alpha and ammonia were measured in 84 patients with liver cirrhosis [due to hepatitis C in 50 patients and due to hepatitis B in 34 patients], 21 of them had no HE and 63 had various clinical grades of HE [grades 1-4]. TNF-alpha concentrations were measured using commercially available solid-phase high sensitivity enzyme-linked immunosorbent assay. Ammonia levels were determined in venous plasma by the Berthelot reaction. Twenty four healthy controls with matched age and sex were included in the study. There were a statistically significant difference between plasma levels of TNF-alpha and ammonia in patients with liver cirrhosis compared to healthy controls. A significant positive correlation was found between circulating levels of TNF-alpha and those of ammonia [r=0.974, P< 0.0001], and also between circulating levels of both substances and severity of HE in all studied patients [r=0.950, P<0.0001, and r=0.900, P<0.0001 respectively]. TNF-alpha and ammonia were both significant independent predictors of severity of HE [P<0.0001 for both variables]. The results of this study demonstrate a significant positive relationship between TNF-alpha and ammonia in patients with chronic liver disease with HE and strengthen the suggestion that TNF-alpha could be strongly involved in the pathogenesis of HE which would stimulate the development of new treatment modalities to decrease this cytokine. This possibility needs further investigation and elucidation