An important contributing factor to the progression of hepatic encephalopathy is the accumulation of ammonia in the blood. In general, nitrogenous complexes emitted by the intestinal bacteria are carried to the liver through the portal circulation. There it is metabolized by the urea cycle and it is released in the form of urea through urine. In advanced liver disease, the injured liver causes the excess release of ammonia to the systemic circulation. This condition of excess ammonia bypassing from liver to blood is referred to as Hyperammonemia.
How Hyperammonemia Affects the Brain?
Excess ammonia crosses the blood-brain barrier and metabolized by astrocytes cells to synthesize glutamine. Glutamine increases the osmotic pressure within the astrocyte resulting in morphologic malformations similar to those seen in Alzheimer’s disease Type II. Astrocyte swelling that subsequently results in astrocyte-neuron dysfunction. Glutamine consequences in mitochondrial dysfunction, leading to increased production of reactive oxygen species. Studies have also revealed an association between hyperammonemia and impairment of neurotransmitter.
What Are The Symptoms of Elevated Ammonia Levels?
The early phase of hepatic encephalopathy is challenging to identify clinically but can be revealed by neuropsychological testing. Absent-mindedness, mild confusion, and irritability are observed in affected patients. Patients will have greater disturbances in cognition leading to more drastic personality changes, bad temper, and dis-inhibition. Motor abnormalities such as hypertonia and hyperreflexia as well as extrapyramidal dysfunction such as rigidity, bradykinesia, dyskinesia, hypokinesia, and slowness of speech are also often present. Intermittent ataxia, failure to thrive, gait abnormality, epilepsy, recurrent Reye syndrome, protein avoidance and rarely, episodic headaches and cyclic vomiting also observed in advanced hepatic encephalopathy stages.
The Symptoms Of Hepatic Encephalopathy Can Be Described In Four Stages
- 1st stage – Sleep disturbances with excessive daytime sleepiness and being awake at night is another common manifestation.
- 2nd stage- Lethargy and disposition changes
- 3rd stage – Misperception.
- 4th stage – Progression to coma
- Ammonia-induced Neurotoxicity
The circulating ammonia can increase glutamine, which may have a negative impact on brain cells initiating edema. Brain edema is life-threatening and severe form can lead to death. In acute liver failure, a severe form of edema is observed and in chronic liver failure, mild edema is observed. The presence of edema is described infrequently in Acute-On-Chronic Liver Failure patients where it is only present in 4–8% of patients. Brain edema has been described in all situations of acute hyperammonemia and has been associated with plasma levels of ammonia in fulminant hepatic failure
The effects of increased cerebral ammonia can cause a subsequent increase in oxidative stress, osmotic pressure, and astrocyte swelling. Recent studies have demonstrated that ammonia also has effects on many signal transduction pathways, gene expression, and post-translational protein modifications, which together lead to subsequent impairment in astrocyte function and manifest as abnormal proliferation, neurotransmitter release, and even cellular senescence.
Brain inflammation or neuroinflammation is common in due to ammonia. Microglia and astrocytes were dysregulated, which is responsible for cognitive and motor function impairment. Ammonia blood-brain barrier permeability is increased in type C hepatic encephalopathy condition.
Ammonia is a neurotoxin responsible for hepatic encephalopathy development. Hyperammonemia has a direct effect on the metabolism and functions of the central nervous system. Persistent arterial hyperammonemia increases the risk of complications and mortality in patients with acute liver failure. The effects of increased cerebral ammonia can cause a subsequent increase in brain edema, oxidative stress, osmotic pressure, and astrocyte swelling. Hyperammonemia is the main factor responsible for the brain abnormalities in hepatic encephalopathy. If left untreated it may lead to the development of severe neurological symptoms, seizures, and coma, and at those who survived to mental retardation and paralysis of the brain.