Ammonia (NH3) is a natural byproduct of protein metabolism, created as the body breaks down amino acids for energy or growth. This process constantly generates ammonia, primarily in the gut and muscles. Under normal circumstances, this compound is managed efficiently by the body’s detoxification systems. High ammonia levels in the bloodstream are a serious medical condition known as hyperammonemia.
The presence of elevated ammonia is particularly problematic because the compound is neurotoxic, meaning it is poisonous to the nervous system. If not controlled, this buildup can cause a cascade of neurological problems. Hyperammonemia requires immediate medical attention due to its potential to cause life-threatening complications.
The Body’s Ammonia Processing System
The body safely disposes of the ammonia constantly being produced through a detoxification system centered primarily in the liver, known as the Urea Cycle. The cycle’s purpose is to convert highly toxic ammonia into urea, a much less harmful compound.
The liver cells perform this conversion, which involves a series of five distinct enzymatic reactions. Ammonia and carbon dioxide are combined, consuming energy in the form of ATP, to ultimately synthesize urea. Urea is water-soluble and can circulate harmlessly in the bloodstream.
Once formed, the urea travels through the bloodstream to the kidneys. The kidneys filter the urea from the blood, and it is safely excreted from the body in the urine. This efficient cycle ensures that ammonia levels remain low, protecting the brain from damaging effects.
Primary Causes of Elevated Levels
When ammonia levels rise, it is due to a failure or malfunction in the detoxification process, categorized as acquired or inherited. The most common cause of hyperammonemia in adults is acquired, stemming from severe liver dysfunction, such as cirrhosis or acute liver failure. In these conditions, the liver is too damaged to perform the steps of the Urea Cycle effectively, causing ammonia to bypass the liver and accumulate in the systemic circulation.
Another acquired cause involves blood flow rerouting, known as portosystemic shunting, where blood from the digestive system bypasses the liver entirely and enters the general circulation. Ammonia produced in the gut never reaches the liver for detoxification, leading to elevated levels. Non-hepatic acquired causes can include certain medications, gastrointestinal bleeding, or infections with urease-producing bacteria, which generate more ammonia.
Inherited hyperammonemia is primarily due to Urea Cycle Disorders (UCDs). These are rare genetic conditions where a specific enzyme required for one of the steps in the Urea Cycle is either missing or defective. The most common UCD is Ornithine Transcarbamylase (OTC) deficiency, which prevents the proper synthesis of urea and results in a buildup of ammonia. While UCDs often manifest in infancy or early childhood, some milder forms can present later in life, particularly when triggered by physiological stress like infection or high protein intake.
Recognizable Signs and Neurological Effects
The most concerning effect of high ammonia is its impact on the central nervous system, leading to a condition called Hepatic Encephalopathy (HE). Ammonia readily crosses the blood-brain barrier, where it interferes with neurotransmission and brain function. Inside the brain, ammonia is converted into glutamine within specialized brain cells called astrocytes, which causes them to swell, potentially leading to cerebral edema.
The symptoms of HE often progress through stages that healthcare providers grade for severity. Early signs (Grade I) include mild confusion, poor concentration, and changes in sleep patterns, such as insomnia or daytime sleepiness.
As ammonia levels increase, symptoms progress to Grade II, involving lethargy, disorientation, and noticeable personality changes. Severe hyperammonemia (Grade III and IV) is marked by significant confusion, the inability to perform basic mental tasks, and a flapping tremor in the hands. The most severe stage, Grade IV, results in unresponsiveness and coma. The speed and severity of these neurological symptoms relate directly to how high the ammonia level is and how quickly it rose.
Strategies for Lowering Ammonia
Management involves both acute and long-term strategies to prevent recurrence. For a sudden, severe elevation of ammonia, or hyperammonemic crisis, interventions are necessary to rapidly remove the toxin from the blood. Emergency treatment may include intravenous medications known as ammonia scavengers, which bind to ammonia or its precursors to facilitate their excretion. In severe cases, such as those with cerebral edema or unresponsiveness, hemodialysis may be used to filter ammonia directly from the blood.
The non-absorbable sugar lactulose is a first-line treatment that works in the colon by lowering the pH, which traps ammonia in an unabsorbable form for excretion. Lactulose also acts as an osmotic laxative, speeding up the transit time of gut contents and reducing the time for ammonia absorption.
Specific oral antibiotics, such as rifaximin, target and reduce the number of ammonia-producing bacteria in the gut. Additionally, patients are advised to follow a moderate-protein diet, typically between 0.8 to 1.2 grams per kilogram of body weight per day, to limit the raw material for ammonia production.