Hyperammonemia

What is hyperammonemia?

Hyperammonemia is a metabolic condition that happens when you have elevated levels of ammonia in your blood. Having high levels of ammonia in your blood is toxic to your central nervous system (CNS) (brain and spinal cord).

Ammonia, also known as NH3, is a waste product that your intestines make when they digest protein. Normally, your liver then processes ammonia, where it’s ultimately eliminated in a process known as the urea cycle.

If there’s an issue with any part of the urea cycle or your liver’s ability to process ammonia, ammonia can build up in your blood, causing hyperammonemia.

Hyperammonemia can be life-threatening and requires immediate medical treatment.

Who does hyperammonemia affect?

Hyperammonemia can affect newborns, children and adults.

Approximately 90% of hyperammonemia cases in adults are in people who have cirrhosis of the liver. Newborns can develop hyperammonemia due to a congenital urea cycle disorder (a genetic condition they’re born with). Children can develop hyperammonemia from severe liver failure and inherited metabolic diseases.

How common is hyperammonemia?

Since hyperammonemia occurs as a result of several different conditions, researchers lack data on how common it is. They estimate that urea cycle disorders, one of the causes of hyperammonemia, occur in 1 in 250,000 live births in the United States and 1 in 440,000 live births internationally.

What causes hyperammonemia?

Several conditions can cause hyperammonemia, and certain conditions are more likely to be the cause at different ages. The two most common causes, in general, are liver issues and urea cycle disorders (UCDs).

Liver conditions that can cause hyperammonemia

Your liver is responsible for transforming ammonia into urea. If your liver is damaged or diseased, it may not be able to properly process ammonia, which then leads to ammonia buildup in your blood.

Liver-related conditions that can cause hyperammonemia include:

• Liver disease: Damage to your liver limits its ability to process ammonia. This often happens in severe liver disease, but you can have spikes in ammonia blood levels with stable liver disease, especially following a triggering event such as gastrointestinal bleeding or an electrolyte imbalance. Liver disease is the most common cause of high ammonia levels in adults and children.
• Hepatic encephalopathy: This is a condition that happens when your liver is too diseased or damaged to properly process ammonia, leading to a buildup of ammonia in your blood that travels to your brain. It can cause confusion, disorientation and coma. It can sometimes be fatal.
• Cirrhosis of the liver: Cirrhosis happens when scar tissue replaces healthy liver tissue. This stops your liver from working properly and can cause hyperammonemia. Cirrhosis is a long-term (chronic) liver disease.
• Acute liver failure: Acute liver failure happens when your liver suddenly isn’t working well enough to perform its functions. Many different diseases and conditions can cause liver failure. Drug-induced liver injury, for example, from acetaminophen, accounts for 50% of acute liver failure cases in the United States. Acute liver failure is responsible for 64% of hyperammonemia cases in children.
• Decreased blood flow to your liver: If there’s a lack of blood flow to your liver, your body can’t transfer ammonia to it to be processed. This causes ammonia to build up in your blood.
• Reye’s syndrome: Reye’s syndrome is a rare condition that affects your blood, brain and liver that usually causes an increase in blood ammonia levels and a decrease in blood glucose. It mainly affects children and teenagers who are recovering from viral infections, such as chickenpox or the flu (influenza), and have taken aspirin to manage their symptoms. The cause of Reye’s syndrome is unknown, but because of the risk, children and teens should not take aspirin unless specifically recommended by their healthcare provider.

Urea cycle disorders (UCDs) that cause hyperammonemia

The urea cycle is the process responsible for converting toxic ammonia into urea, which can then be eliminated through your urine (pee). The urea cycle involves multiple steps, each requiring a different enzyme. These enzymes include:

• N-acetyl-glutamate synthase (NAGS).
• Carbamoyl phosphate synthetase (CPS).
• Ornithine transcarbamylase (OTC).
• Argininosuccinate synthetase (AS).
• Argininosuccinic acid lyase (ASL).
• Arginase (ARG1).

A deficiency in any of these enzymes results in impaired function of your urea cycle, which leads to a buildup of ammonia in your blood. A deficiency in any of these enzymes is considered a urea cycle disorder (UCD). UCDs can result in acute and/or chronic hyperammonemia.

UCDs are congenital conditions (conditions you’re born with). Newborns who have a complete deficiency in one of the urea cycle enzymes typically develop acute hyperammonemia within 24 to 72 hours of being born. In milder or partial urea cycle enzyme deficiencies, ammonia buildup may be triggered at almost any time of life by illness or stress.

UCDs are responsible for 23% of acute hyperammonemia cases in critically ill children.

Other causes of hyperammonemia

Other possible causes of hyperammonemia include:

• Kidney (renal) failure: If your kidneys are unable to effectively get rid of urea due to kidney failure, it leads to a buildup of ammonia in your blood.
• Certain blood disorders: Multiple myeloma and acute leukemia can cause hyperammonemia.
• Certain infections: Infections with urease-producing organisms such as Proteus mirabilis, Escherichia coli (E. coli) and Klebsiella may cause severe hyperammonemia in children with congenital disorders of the urinary tract and older people with urinary tract infections (UTIs) leading to urinary retention.

What are the symptoms of hyperammonemia?

Hyperammonemia can cause many different symptoms depending on how mild or severe it is and at which age you develop it.

Symptoms of hyperammonemia in children and adults

Symptoms of mild hyperammonemia that affects children and adults include:

• Nausea and vomiting.
• Abdominal pain.
• Irritability.
• Headaches.
• Issues with balance, coordination and speech (ataxia).
• Behavioral changes.

Additional symptoms of mild hyperammonemia that just affect children

• Failure to thrive.
• Decreased muscle tone (hypotonia).
• Neurodevelopmental delays.

Symptoms of severe hyperammonemia that affect children and adults

• Confusion and disorientation.
• Mood swings.
• Excessive sleepiness.
• Changes in consciousness.
• Seizures.
• Hyperventilation.
• Coma.

If you or a loved one are experiencing these symptoms, call 911 or go to the nearest emergency room as soon as possible. High ammonia levels are life-threatening and require immediate medical treatment.

Symptoms of hyperammonemia in newborns

Newborns affected by hyperammonemia usually have symptoms within 24 to 72 hours of being born, including:

• Irritability.
• Vomiting.
• Lethargy.
• Seizures.
• Grunting when breathing.
• Hyperventilation.

If your baby is displaying these symptoms, it’s crucial to tell their healthcare provider as soon as possible if you’re still in the hospital after their birth. If you’re at home, call 911 or take them to the nearest hospital as soon as possible.

How is hyperammonemia diagnosed?

Healthcare providers typically diagnose hyperammonemia if blood ammonia levels are above 80 micromoles per liter (micromol/L) in infants up to one month old and if blood ammonia levels are above 55 micromol/L in older children. They may diagnose hyperammonemia in adults if blood ammonia levels are above 30 micromol/L.

What tests will be done to diagnose hyperammonemia?

The main test that healthcare providers use to diagnose hyperammonemia is a blood test that measures blood ammonia levels.

If you have elevated ammonia levels, your provider will likely run other blood tests to try to determine the cause, such as liver function tests and kidney function tests. They may also order a urinalysis (urine test).

Since hyperammonemia can damage your central nervous system and be life-threatening, your provider may also order imaging tests to look for complications affecting your brain, such as neuroimaging with a CT (computed tomography) scan or MRI (magnetic resonance imaging).

How is hyperammonemia treated?

The treatment for hyperammonemia depends partly on what’s causing it, such as liver disease or hepatic encephalopathy in adults or a urea cycle disorder (UCD) in newborns.

Treatment of acute hyperammonemia focuses on decreasing the level of ammonia and controlling specific complications, including brain swelling (cerebral edema) and pressure around the brain (intracranial hypertension).

For newborns with hyperammonemia, healthcare providers stop protein intake (since protein digestion produces ammonia) and provide calories by using glucose (sugar) solutions. Healthcare providers also use hemodialysis — a procedure where a dialysis machine and a special filter called an artificial kidney clean your blood — to remove ammonia from your newborn’s blood.

People who have a partial UCD enzyme deficiency that triggers hyperammonemia under stress are also treated by stopping protein intake and providing calories through glucose. Providers only use hemodialysis if their ammonia levels don’t decrease after several hours of initial treatment.

Medical treatment for hepatic encephalopathy involves decreasing the production of ammonia in your gut. The first-line therapy for encephalopathy is an oral medication that includes lactulose and lactitol. These sugars decrease the production and absorption of ammonia in your intestines.

Healthcare providers may also recommend the following dietary supplements to try to reduce the frequency of attacks in people with urea cycle disorders:

• L-carnitine.
• L-ornithine-L-aspartate.
• Arginine.

Can hyperammonemia be prevented?

Since there are several different causes of hyperammonemia, not all cases can be prevented.

You can take steps to prevent some — but not all — types of liver disease, especially those affected by your diet and lifestyle. If you’re at risk for liver disease, your healthcare provider may recommend lifestyle changes, including:

• Avoiding or limiting alcohol.
• Avoiding foods and drinks that contain trans fats or high-fructose corn syrup.
• Carefully managing your intake of prescription and over-the-counter medications to avoid liver damage.
• Getting regular exercise.
• Limiting consumption of red meat.

To try to prevent Reye’s syndrome, a cause of hyperammonemia in children and teenagers, do not give your child aspirin to manage their symptoms of a viral infection (such as the flu or chickenpox) unless it’s specifically recommended by their healthcare provider.

Urea cycle disorders (UCDs) are rare, but there are genetic tests you can get to see if you’re a carrier for genes that cause them. Talk to your healthcare provider about your options.

What is the prognosis for hyperammonemia?

The prognosis (outlook) for hyperammonemia depends on a few factors, including:

• How high your ammonia levels are.
• How long you’ve had elevated ammonia levels.
• The cause of hyperammonemia.

In general, the prognosis for hyperammonemia is poor. People and newborns with untreated hyperammonemia or who receive delayed treatment have a high mortality rate due to irreversible brain swelling. Unfortunately, even with aggressive early therapy, a good outcome for severe hyperammonemia in a newborn can’t be guaranteed.

For people in the U.S. who have urea cycle disorders (UCDs), the 11-year-survival rate is approximately 35% for people who develop hyperammonemia early in life and approximately 87% for people who develop hyperammonemia later in life.

For people who have severe hepatic encephalopathy due to hyperammonemia, the survival probability at one and three years has been reported to be 42% and 23%, respectively.

What are the complications of hyperammonemia?

If hyperammonemia isn’t treated quickly enough, elevated levels of ammonia can result in life-threatening complications due to central nervous system damage. Complications include:

• Brain swelling (Cerebral edema).
• Pressure around the brain (intracranial hypertension).
• Brain herniation (when brain tissue moves) — this is most often caused by brain swelling and intracranial pressure.
• Coma.
• Death.

If a person has chronic mild hyperammonemia, they may develop an intellectual disability and permanent behavioral and psychiatric issues.

When should I see my healthcare provider?

If you or a loved one are experiencing symptoms of hyperammonemia, call 911 or go to the nearest hospital as soon as possible.

If you have liver disease or a partial urea cycle disorder enzyme deficiency, it’s important to see your healthcare provider regularly to manage your condition and monitor your ammonia levels.

A note from Cleveland Clinic

Hyperammonemia is a serious condition that has several causes. If you, your child or infant are experiencing symptoms of hyperammonemia, call 911 or go to the nearest hospital as soon as possible. If you have liver disease or have a family history of urea cycle disorders (UCDs), talk to your healthcare provider about your risk of developing hyperammonemia. They’re there to help you.