Aims: Brain edema represents a constant finding in patients with hepatic encephalopathy (HE) due to chronic liver failure; however its pathogenetic mechanisms are poorly described. Hyperammonemia is considered the central component in the pathogenesis of HE, but ammonia levels are not correlated with severity of HE. Other factors such as oxidative stress and impaired lactate metabolism are believed to be involved. Temporal resolution of these factors involved in the progression of the disease and brain edema might elucidate the relationship between these pathogenetic factors. The present study investigates temporal resolution of ammonia, oxidative stress and lactate in relation to the development of brain edema in bile-duct ligated rats (BDL), a widely used rat model of chronic liver failure and HE. Methods: Ammonia (commercial kit), reactive oxygen species (ROS) (DCFDA fluorescence), lactate (Amplex Red fluorescence) and brain edema (specific gravimetric technique) were measured in BDL rats vs sham operated controls at 2, 4 and 6 weeks after surgical intervention in plasma and cerebrospinal fluid or brain tissue. Results: See table.Conclusions: Following 2 weeks of BDL, an increase in plasma oxidative stress is observed with no appearance of hyperammonemia, hyperlactataemia, increased brain lactate and ammonia or brain edema. Following 4 weeks of BDL, in addition to an increase in systemic oxidative stress, an increase in plasma and brain ammonia and brain (not plasma) lactate is demonstrated but still no evidence of brain edema. Brain edema appears at 6 weeks, along with an increase in all 3 pathogenetic factors. The further increase in brain lactate and ammonia compared to 4 weeks, superimposed on systemic oxidative stress, may be responsible the development of brain edema in BDL rats. Our results support the multifactorial pathogenesis of brain edema in HE and suggests systemic oxidative stress might be an important “first hit”, followed by increases in ammonia and lactate, in the pathogenesis of brain edema in chronic liver failure.
