Hyperammonemia

What is Hyperammonemia?

Hyperammonemia is a health issue that happens when there’s too much ammonia, a particular chemical, in your body. The amount of ammonia people normally have in their body can depend on their age. Hyperammonemia can be caused by various health problems you are born with (congenital) or pick up (acquired) in which increased ammonia is the main harmful agent. It can also be a part of other health issues that cause different types of metabolic problems.

Under normal circumstances, ammonia is made in your colon and small intestine. It is then taken to the liver where it gets changed into a substance called urea through the ‘urea cycle.’ Urea, which can dissolve in water, is then expelled from your body via the kidneys. If your liver can’t change the toxic ammonia into urea because of an enzyme failure or liver cell damage, then the amount of ammonia in your body can increase. The levels can also go high if the blood carrying nutrients from the intestine to the liver is diverted into the general bloodstream, bypassing the liver or if there is increased production of ammonia due to infection with certain microorganisms.

In adults, hyperammonemia is most commonly associated with liver disease, such as cirrhosis, accounting for 90% of the cases. However, it can also be seen in many other disorders. It’s important to know that ammonia is a potent neurotoxin, which means it can harm your brain and nerves. If the amount of ammonia in your blood gets too high, it can cause symptoms that affect the nervous system. These symptoms can be acute (sudden and severe) or chronic (long term), depending on the root cause of the problem. It’s very important that hyperammonemia is identified early and treated quickly to avoid severe complications like brain swelling (cerebral edema) and brain herniation, which can be life-threatening. The treatment used depends on the cause of the condition.

What Causes Hyperammonemia?

Hyperammonemia, a high level of ammonia in the blood, can have many causes and can be either inherited (congenital) or acquired later in life. The conditions causing high blood ammonia can be split into two categories: those related to liver problems and those not related to liver problems.

Inherited conditions that cause hyperammonemia typically involve enzyme defects. Enzymes are molecules in your body that help speed up chemical reactions. Certain inherited conditions, like urea cycle disorders, organic acidemias, congenital lactic acidosis, fatty acid oxidation defect, and dibasic amino acid deficiencies, are due to problems with specific enzymes. In these conditions, there’s a flaw in the process converting harmful ammonia into harmless urea, which our bodies usually get rid of in urine. This defect results in the buildup of ammonia.

Other inherited conditions causing high blood ammonia levels include transient hyperammonemia of the newborn, neonatal Herpes simplex virus (HSV) infection, and severe lack of oxygen at birth (perinatal asphyxia).

One of the conditions, called Reye syndrome, occurs predominantly in children after coming down with the flu or chickenpox and taking aspirin. With Reye syndrome, along with high blood ammonia levels, liver enzymes and lactic acid levels are also often high, and the liver becomes enlarged.

Liver diseases like hepatic encephalopathy, a condition causing cognitive problems due to liver disease, are also often linked to hyperammonemia. However, not all patients with this condition have high ammonia levels in their blood. Hepatic encephalopathy can be due to acute liver failure, liver disease without cirrhosis, or chronic liver diseases, such as hepatitis B or C virus, biliary atresia, alpha 1 antitrypsin deficiency, Wilson disease, and cystic fibrosis.

Other causes of high ammonia levels in the blood in adults include blood disorders like multiple myeloma and acute leukemia, infections with certain bacteria that produce an enzyme called urease, drugs like valproic acid, and sometimes congenital defects that don’t show symptoms until adulthood. Certain situations like malnutrition or excessive protein load can also precipitate hyperammonemia.

Finally, liver disease might not be present in some patients with an abnormal blood connection (shunt) between the portal vein and another vein, bypassing the liver. However, these patients might display neuropsychiatric features, termed ‘Type B hepatic encephalopathy’.

Risk Factors and Frequency for Hyperammonemia

Hyperammonemia, or high ammonia levels in the blood, happens due to various health disorders, making it hard to get exact numbers on how often it occurs. However, it is estimated that urea cycle disorders, one type of condition that can cause hyperammonemia, occur in about 1 in 250,000 live births in the United States and 1 in 440,000 live births around the world.

Signs and Symptoms of Hyperammonemia

Hyperammonemia mostly shows neurological signs due to the harmful impact of high ammonia levels on the nervous system. Infants can show symptoms such as lethargy, irritability, and vomiting within 24-72 hours of birth, especially if ammonia levels rise above 100-150 micromol/L. As the levels go further up, the infant may start hyperventilating and making grunting noises due to the influence of ammonia on the part of the brain that controls breathing.

If hyperammonemia starts developing later in life, it is usually due to various inborn or acquired disorders. Symptoms include irritability, headache, vomiting, unsteady walk, and abnormal body movements. In severe cases, where ammonia levels exceed 200 micromol/L, patients may suffer seizures, encephalopathy (brain dysfunction), coma, and can even lead to death. People with partial defects in their urea cycle enzymes (the process of removing nitrogen waste from the body) often only develop symptoms during periods of stress such as starvation, pregnancy, surgery, etc. A sudden increase in protein intake, constipation, aggressive removal of body fluid, opioid use, or infections can also trigger these symptoms.

Chronic hyperammonemia (long-lasting high ammonia levels) can lead to intellectual disability and psychiatric symptoms, which are associated with glutamine levels in the brain.

During a physical check-up, the findings are often vague, including increased breathing rate and dehydration due to vomiting. Neurological examinations may show decreased abilities to concentrate and coordinate, slurred speech, confusion and hand tremors. Indications related to the original disease causing hyperammonemia might also be evident. Certain conditions may come with distinctive signs, such as a ‘sweaty feet’ smell in isovaleric acidemia, or fragile hair in argininosuccinic acid lyase deficiency.

Grade 0 Hepatic Encephalopathy: Minor changes in concentration, memory, and thinking abilities.
Grade 1 Hepatic Encephalopathy: Changes in sleeping patterns, lack of awareness and shortened attention span.
Grade 2 Hepatic Encephalopathy: Lethargy, lack of care, personality changes, abnormal hand movement, and slurred speech.
Grade 3 Hepatic Encephalopathy: Can wake up from sleep but can be easily confused and lose sense of time and place.
Grade 4 Hepatic Encephalopathy: Coma. May or may not respond to pain.

For patients with hepatic encephalopathy due to scarring of the liver (cirrhosis), there can be several indications of liver dysfunction and increased blood pressure within the liver’s blood flow system. These signs can include jaundice, bloated stomach, liver enlargement, swollen feet, abnormal blood vessels on the skin, breast enlargement in men, and belly button veins can all be seen.

Testing for Hyperammonemia

The amount of ammonia in your body can fluctuate depending on your age. For example, newborn babies have higher ammonia levels than older children or adults. And even among newborns, the levels can change depending on whether they were born early or late, and how old they are in terms of days or weeks.

The standard ammonia levels are as follows:

For healthy full-term infants, the usual level is 45±9 micromol/L, a maximum of 80 to 90 micromol/L is regarded as normal.
For preterm (born early) infants, it’s 71±26 micromol/L, which drops to term levels in about a week.
For children older than 1 month: less than 50 micromol/L.
For adults: less than 30 micromol/L.

When a newborn has a high level of ammonia (hyperammonemia), it can cause a variety of general signs and symptoms. It’s important to do certain tests to rule out other conditions that may cause similar symptoms like sepsis, bleeding in the brain, or gastrointestinal bleed. The elevated ammonia level would indicate a need for specific tests including ones for blood gases, blood glucose, lactate and citrulline levels, plasma and urinary amino acids, urinary ketones, etc.

There are other tests for diagnosing urea cycle defects that include enzyme assays on liver biopsy specimens, red blood cell samples, and DNA mutation.

When a patient with hepatic encephalopathy (a decline in brain function that occurs as a result of severe liver disease) has hyperammonemia, liver function tests can help in assessing how well the liver is functioning. If hyperammonemia is not caused by cirrhosis, specific tests to identify the underlying cause should be considered.

Brain imaging with CT scans or MRIs can also help in the diagnosis, although they will only show the effects of ammonia on the brain, not the cause of increased ammonia. These effects could range from restriction of diffusion in certain areas of the brain to the development of symmetric hyperintensities in some areas, which could lead to atrophy. Brain changes due to congenital defects causing high levels of ammonia in neonates are also different and could be due to the fact that these areas are more active metabolically. Some studies suggest that the longer and more severe the hyperammonemia, the more abnormalities can be seen on brain imaging.

Treatment Options for Hyperammonemia

If you have high levels of ammonia in your blood (a condition known as hyperammonemia), your doctor will focus on reducing the ammonia level and controlling any related complications. This condition can be caused by certain metabolic disorders which can either appear at birth or later in life. The treatment approaches for these disorders differ from those for liver disease-related hyperammonemia, another possible cause of the condition.

For newborn babies with metabolic disorders, a high ammonia level can lead to a severe condition known as hyperammonemic coma. In this situation, the patient needs immediate medical intervention, and it’s critical to stop all protein intake while providing calories via glucose solutions. Hemodialysis, a treatment that filters waste from your blood, is the preferred way to remove ammonia quickly. Other helpful measures include drugs like sodium benzoate and phenylacetate, which help convert waste into non-urea products, along with intravenous arginine, a type of amino acid.

If you have a hidden (or “masked”) urea cycle defect, a condition that affects ammonia processing in your body, hyperammonemia can occur under stress. For these cases, it’s important to stop all nitrogen intake, provide calories via glucose solutions, and begin treatment with intravenous sodium benzoate and phenylacetate. Hemodialysis would only be considered if the ammonia level doesn’t decrease after 8 hours.

In treating liver disease-related hyperammonemia, the goal is to reduce ammonia production in the gut. Oral non-absorbable disaccharides (a type of sugar), like lactulose and lactitol, are usually the first choice of treatment. They work by reducing the production and absorption of ammonia in your intestine. This type of treatment doesn’t impact mortality, but it can be beneficial when combined with a non-absorbable antibiotic like rifaximin.

If hyperammonemia has caused increased pressure in the skull due to brain swelling (often referred to as cerebral edema), hypertonic saline is usually preferred over mannitol. It’s also recommended to avoid steroids for these cases in newborns. Steroids can worsen the condition by affecting the balance of nitrogen in the body. It’s important to note that a medication known as valproic acid should not be used for treating seizures related to hyperammonemia.

Although it might seem logical to reduce protein intake in those with hyperammonemia, it’s not usually recommended, particularly in patients with chronic liver disease who may already be malnourished. Certain supplements, such as L-carnitine, can help reduce hyperammonemia attacks in patients with urea cycle defects. L-ornithine-L-aspartate may also be useful for liver disease-related hyperammonemia, as it can increase ammonia metabolism in the muscles. Lastly, supplementing the diet with arginine, an essential amino acid, is advisable for those with urea cycle disorders.

Hyperammonemia is a condition that can be caused by a variety of disorders. To confirm or rule out this condition, certain tests and scans might be needed. These help in diagnosing other diseases that can show similar symptoms as hyperammonemia. Some of these diseases include meningitis, sepsis in newborns, and in adults, conditions like encephalitis, brain tumors, and pseudotumor cerebri.

Several conditions may look like hyperammonemia, but the level of ammonia in the body is normal. These conditions may include:

Disorders of carbohydrate metabolism, which present with low blood sugar and high uric acid levels.
Ataxia, caused by hereditary defects affecting the central nervous system at various levels.
Methylmalonic acidemia, a disorder of protein metabolism that often results in a condition similar to stroke, but which is not seen in hyperammonemia patients.
Homocystinuria, a disorder affecting protein metabolism that presents with symptoms of a stroke, lens displacement, and physical characteristics similar to Marfan syndrome.

Other conditions such as Posterior Reversible Encephalopathy Syndrome, diffuse hypoxic-ischemic encephalopathy, and seizure disorders can show similar brain scan findings to hyperammonemia. However, these happen due to different reasons and usually don’t result in increased ammonia levels.

What to expect with Hyperammonemia

The outlook for patients with increased ammonia levels in their bodies depends on the root cause of this condition. For example, in the case of urea cycle defects (which is a group of rare genetic disorders that prevents the body from removing ammonia from the bloodstream), patients diagnosed at a young age have a 35% chance of survival over 11 years. On the other hand, patients diagnosed later in life have a survival rate of 87% over the same period.

For patients suffering from severe hepatic encephalopathy, a complication of liver diseases that affects brain function, the chance of survival after one year is 42% and after three years it’s 23%. These percentages come from medical studies conducted in the United States.

Possible Complications When Diagnosed with Hyperammonemia

High levels of ammonia, a harmful chemical, can cause serious and potentially fatal health problems due to damage to the central nervous system. This can include swelling of the brain, increased pressure within the skull, brain herniation (where part of the brain is squeezed out of its normal position), and coma. Osmotic demyelination syndrome, a condition that damages the protective covering of nerve cells in the brain, is a possible side effect of treating high ammonia levels in patients with a genetic disorder known as ornithine transcarbamylase deficiency.

Common Effects of High Ammonia Levels:

Brain swelling
Increase in pressure within the skull
Brain herniation
Coma
Osmotic demyelination syndrome as a side effect for specific treatments

Preventing Hyperammonemia

Patients need to be aware of the signs and symptoms of a condition called hyperammonemia. These can include feeling very tired, feeling confused, having trouble walking correctly, and vomiting. It’s crucial to always take your medication as prescribed, especially if you have a condition called cirrhosis. Special diet plans should be given to each patient. These diet plans will include certain foods to avoid and this should be strongly emphasized at every visit.

Patients should also be given information about specific dietary supplements. While exercise isn’t entirely off-limits, patients should increase their calorie intake to prevent protein breakdown if they wish to maintain an active lifestyle. For children with urea cycle defects, it’s important to keep track of their growth and development at every visit, with guidance provided to parents as necessary.

If a baby is diagnosed with a urea cycle disorder, the family should be made aware of prenatal tests available for diagnosis. These tests can help determine the presence of the disorder in a baby before it’s born.

Frequently asked questions

Hyperammonemia is a health issue that occurs when there is an excessive amount of ammonia in the body. It can be caused by various congenital or acquired health problems, and it can also be a part of other metabolic issues. Hyperammonemia can be harmful to the brain and nerves, and it is important to identify and treat it early to prevent severe complications.

It is estimated that urea cycle disorders, one type of condition that can cause hyperammonemia, occur in about 1 in 250,000 live births in the United States and 1 in 440,000 live births around the world.

Signs and symptoms of Hyperammonemia include: - Neurological signs such as lethargy, irritability, and vomiting in infants within 24-72 hours of birth, especially if ammonia levels rise above 100-150 micromol/L. - Hyperventilation and grunting noises in infants due to the influence of ammonia on the part of the brain that controls breathing. - Irritability, headache, vomiting, unsteady walk, and abnormal body movements in cases of hyperammonemia developing later in life. - Seizures, encephalopathy, coma, and even death in severe cases where ammonia levels exceed 200 micromol/L. - Symptoms triggered by stress, sudden increase in protein intake, constipation, aggressive removal of body fluid, opioid use, or infections in people with partial defects in their urea cycle enzymes. - Chronic hyperammonemia can lead to intellectual disability and psychiatric symptoms associated with glutamine levels in the brain. - Vague findings during physical check-up, including increased breathing rate and dehydration due to vomiting. - Neurological examinations may show decreased abilities to concentrate and coordinate, slurred speech, confusion, and hand tremors. - Distinctive signs related to the original disease causing hyperammonemia, such as a 'sweaty feet' smell in isovaleric acidemia or fragile hair in argininosuccinic acid lyase deficiency. - Hepatic encephalopathy can have different grades of severity, ranging from minor changes in concentration, memory, and thinking abilities (Grade 0) to coma (Grade 4). - For patients with hepatic encephalopathy due to cirrhosis, indications of liver dysfunction and increased blood pressure within the liver's blood flow system can be seen, including jaundice, bloated stomach, liver enlargement, swollen feet, abnormal blood vessels on the skin, breast enlargement in men, and belly button veins.

Hyperammonemia can be either inherited (congenital) or acquired later in life. It can be caused by various conditions, including enzyme defects, liver problems, blood disorders, infections, certain medications, and congenital defects.

The doctor needs to rule out the following conditions when diagnosing Hyperammonemia: - Meningitis - Sepsis in newborns - Encephalitis - Brain tumors - Pseudotumor cerebri - Disorders of carbohydrate metabolism - Ataxia - Methylmalonic acidemia - Homocystinuria - Posterior Reversible Encephalopathy Syndrome - Diffuse hypoxic-ischemic encephalopathy - Seizure disorders

The types of tests needed for hyperammonemia include: - Blood gases - Blood glucose - Lactate and citrulline levels - Plasma and urinary amino acids - Urinary ketones - Enzyme assays on liver biopsy specimens, red blood cell samples, and DNA mutation tests for diagnosing urea cycle defects - Liver function tests to assess liver function in patients with hepatic encephalopathy - Brain imaging with CT scans or MRIs to show the effects of ammonia on the brain - Hemodialysis to remove ammonia quickly in severe cases - Treatment-specific tests to identify the underlying cause of hyperammonemia if not caused by cirrhosis.

The treatment for hyperammonemia depends on the underlying cause. For newborn babies with metabolic disorders, immediate medical intervention is necessary, including stopping protein intake, providing calories through glucose solutions, and using hemodialysis to quickly remove ammonia. Drugs like sodium benzoate and phenylacetate, along with intravenous arginine, can also be helpful. For hidden urea cycle defects, it is important to stop nitrogen intake, provide calories through glucose solutions, and use intravenous sodium benzoate and phenylacetate. Hemodialysis may be considered if ammonia levels do not decrease. In liver disease-related hyperammonemia, the goal is to reduce ammonia production in the gut using oral non-absorbable disaccharides like lactulose and lactitol. Hypertonic saline is preferred over mannitol for treating increased pressure in the skull due to brain swelling. It is important to avoid steroids and valproic acid for these cases. Protein intake reduction is not usually recommended, and certain supplements like L-carnitine, L-ornithine-L-aspartate, and arginine may be beneficial for specific conditions.

The side effects when treating Hyperammonemia can include: - Brain swelling - Increase in pressure within the skull - Brain herniation - Coma - Osmotic demyelination syndrome as a side effect for specific treatments

The prognosis for hyperammonemia depends on the root cause of the condition. For patients with urea cycle defects, the survival rate over 11 years is 35% for those diagnosed at a young age and 87% for those diagnosed later in life. For patients with severe hepatic encephalopathy, the chance of survival after one year is 42% and after three years it's 23%.

You should see a doctor specializing in gastroenterology or hepatology for hyperammonemia.

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