Ammonia is described as an important factor in producing hepatic encephalopathy. It is a toxic byproduct of the gut microbial metabolism of protein and nitrogenous substances. About 80% of the ammonia is cleared from the colon through portal vein blood, which is referred as “the first pass” from the gut. Once it reaches the liver, along with endogenous nitrogenous compound it starts the urea cycle. The final product is the generation of urea, which is excreted in the urine. A small proportion of ammonia is left to be metabolized in the muscles, brain, heart, and kidneys. In diseased condition, less ammonia is metabolized into urea and more of it reaches the astrocytes in the brain. The brain does not have a urea cycle but metabolizes ammonia to glutamine by glutamine synthase, an enzyme that is unique to astrocytes.
Ammonia causes swelling of astrocytes and brain edema by the production of glutamine, an osmotically active substance.
Can High Ammonia Levels Cause Permanent Brain Damage?
Patients with hepatic encephalopathy have an increased diffusion of ammonia into the brain. In advanced stages, ammonia adversely affects both astrocytes and neurons. In astrocytes, the enzymes successfully eliminate ammonia in the brain. But in neurons, the absence of enzyme make defenseless. Neurons are easily susceptible against increased ammonia concentrations and therefore are likely to suffer ammonia–related damage.
Neuro-inflammation, oxidative stress, GABA-ergic or benzodiazepine pathway abnormalities, manganese neurotoxicity, brain energetic disturbances, interruption in neurotransmission and brain blood flow abnormalities are considered to be involved in the development of hepatic encephalopathy due to ammonia–related neuron damage. But, patients with this condition are treated with combination therapy and had a complete reversal of hepatic encephalopathy.
Cerebral Ammonia Detoxification in Astrocytes
Glutamine has been shown to have a key role in the brain toxicity induced by ammonia. It has long been accepted that the conversion of glutamate to glutamine, catalyzed by glutamine synthetase, a cytoplasmic enzyme largely localized in astrocytes in the brain, represents the principal way of cerebral ammonia detoxification.
How Ammonia Metabolized in Astrocytes?
Astrocytes occupy one-third of the volume of the cerebral cortex. Their foot processes surround brain capillaries, where they contribute to blood-brain barrier function. Ammonia then crosses the blood-brain battier and is metabolized by astrocytes to synthesize glutamine from glutamate via glutamine synthetase. Glutamine increases the osmotic pressure within the astrocyte resulting in morphologic malformations similar to those seen in Alzheimer’s disease Type II. Astrocyte swelling stimulates the formation of reactive oxygen species that further increases astrocyte swelling.
Systemic Inflammatory Response Syndrome Triggers Inflammation In Hepatic Encephalopathy
In some studies, it is proved that hyper-ammonia induces hepatic encephalopathy only if systemic inflammatory response syndrome is present. It is widely accepted that sepsis is able to trigger hepatic encephalopathy in cirrhotic patients as a result of altered nitrogen metabolism and also by releasing pro-inflammatory mediators. In another study, it is suggested that, in acute liver failure patients, the presence of systemic inflammatory response syndrome resulted in a poorer neurological outcome. The canonic study also demonstrated the clear role of systemic inflammation in patients with advanced hepatic encephalopathy which also correlated with mortality.
Neurons are easily susceptible against increased ammonia concentrations and therefore are likely to suffer ammonia–related damage than astrocytes. Neuro-inflammation, oxidative stress, GABA-ergic or benzodiazepine pathway abnormalities, manganese neurotoxicity, brain energetic disturbances, interruption in neurotransmission and brain blood flow abnormalities are consequences of ammonia–related neuron damage.
Ammonia induces astrocyte swelling which in turn stimulates the formation of reactive oxygen species that further increases astrocyte swelling. However, these factors are treated with combination therapy and can completely reverse the hepatic encephalopathy.