Hyperammonemia - Causes, Symptoms, Diagnosis, and Treatment

Introduction

Raised amounts of the nitrogen-containing chemical ammonia characterize the metabolic disorder known as hyperammonemia. Age-related differences exist in the body's normal ammonia levels. Several congenital and acquired diseases, in which it may be the main toxin, can lead to hyperammonemia. Additionally, other diseases that include different other metabolic problems may also include hyperammonemia as a symptom. Ammonia is often created in the colon and small intestine and then taken to the liver, where it is transformed into urea by the urea cycle. The water-soluble substance urea can then be eliminated by the kidneys. If the liver experiences an enzymatic problem or hepatocellular damage that prevents it from properly metabolizing this harmful substance, ammonia levels increase.

The levels may also increase if portal blood is diverted away from the liver and into the systemic circulation or if the generation of ammonia increases due to an infection with specific microorganisms. Ninety percent of the time, adults with hyperammonemia have cirrhotic liver disease as the primary cause. But there are many more illnesses that require understanding since they exhibit this metabolic imbalance. According to the underlying problem, elevated blood levels of ammonia can result in neurological signs and symptoms that may be acute or persistent. In order to avoid the emergence of life-threatening consequences such as cerebral edema and brain herniation, hyperammonemia should be detected early and treated immediately. Treatment plans change depending on the etiology.

What Is the Etiology of Hyperammonemia?

Multiple factors can contribute to hyperammonemia, with different causes being more prevalent at various stages of life. The primary culprits, generally speaking, are liver-related complications and urea cycle disorders (UCDs).

Liver Conditions That Can Lead To Hyperammonemia: The liver plays a crucial role in converting ammonia into urea. If the liver is damaged or afflicted by disease, it may struggle to process ammonia effectively, resulting in its accumulation in the bloodstream. Liver-related conditions that can trigger hyperammonemia encompass include the following:

• Liver Disease: When the liver is impaired, its capacity to process ammonia is limited. Severe liver disease is a common scenario, but even individuals with stable liver disease can experience spikes in blood ammonia levels, particularly following triggering events like gastrointestinal bleeding or electrolyte imbalances. The liver disease represents the leading cause of heightened ammonia levels in both adults and children.

• Hepatic Encephalopathy: This condition arises when the liver is extensively diseased or damaged, impairing its ability to process ammonia and causing an escalation of blood ammonia levels that subsequently reach the brain. Symptoms may include confusion, disorientation, and even coma. In some cases, hepatic encephalopathy can be fatal.

• Cirrhosis of the Liver: Cirrhosis arises when scar tissue replaces healthy liver tissue, hampering the organ's normal functionality and potentially leading to hyperammonemia. Cirrhosis is a chronic liver disease that develops over time.

• Acute Liver Failure: This condition arises when the liver suddenly becomes unable to perform its functions adequately. Various diseases and conditions can trigger liver failure, with drug-induced liver injury from substances such as Acetaminophen accounting for 50 percent of acute liver failure cases in the United States. In children, acute liver failure accounts for 64 percent of hyperammonemia cases.

• Reduced Blood Flow to the Liver: If blood flow to the liver is compromised, the transfer of ammonia for processing becomes hindered, resulting in its accumulation in the bloodstream.

• Reye's Syndrome: A rare condition affecting the blood, brain, and liver, Reye's syndrome typically causes an increase in blood ammonia levels and a decrease in blood glucose. Children and teenagers recovering from viral diseases like chickenpox or influenza who took Aspirin to ease their symptoms are most commonly affected. The cause of Reye's syndrome remains unknown, but due to the associated risk, children and teens should refrain from using Aspirin unless specifically recommended by their healthcare provider.

What Are the Urea Cycle Disorders (UCDs) Leading To Hyperammonemia?

The urea cycle is responsible for converting toxic ammonia into urea, which can then be eliminated through urine. This process involves multiple enzymatic steps, each dependent on a specific enzyme:

1. N-acetyl-glutamate synthase (NAGS).

2. Carbamoyl phosphate synthetase (CPS).

3. Ornithine transcarbamylase (OTC).

4. Argininosuccinate synthetase (AS).

5. Argininosuccinic acid lyase (ASL).

6. Arginase (ARG1).

A deficiency in any of these enzymes results in impaired functioning of the urea cycle, leading to the accumulation of ammonia in the bloodstream. Such deficiencies are classified as urea cycle disorders (UCDs). UCDs can result in acute or chronic hyperammonemia.

UCDs are congenital conditions present at birth. Newborns with a complete deficiency in any of the urea cycle enzymes typically develop acute hyperammonemia within 24 to 72 hours after birth. In milder or partial deficiencies of urea cycle enzymes, ammonia buildup may be triggered at any point in life by illness or stress.

UCDs account for 23 percent of cases involving acute hyperammonemia in critically ill children.

Other potential causes of hyperammonemia include:

• Kidney (Renal) Failure: In cases of kidney failure, the kidneys are unable to effectively eliminate urea, leading to the buildup of ammonia in the bloodstream.

• Certain Blood Disorders: Hyperammonemia can be associated with conditions like multiple myeloma and acute leukemia.

• Specific Infections: Infections caused by urease-producing organisms such as Proteus mirabilis, Escherichia coli (E. coli), and Klebsiella can induce severe hyperammonemia in children with congenital urinary tract disorders and older individuals with urinary tract infections (UTIs) leading to urinary retention.

What Are the Signs and Symptoms of Hyperammonemia?

The symptoms of hyperammonemia can vary in severity and age of onset. Symptoms of mild hyperammonemia in children and adults may include:

• Nausea and vomiting.

• Abdominal pain.

• Irritability.

• Headaches.

• Issues with balance, coordination, and speech (ataxia).

• Behavioral changes.

Additional symptoms of mild hyperammonemia, specifically in children, may include:

• Failure to thrive.

• Decreased muscle tone (hypotonia).

• Neurodevelopmental delays.

Symptoms of severe hyperammonemia in children and adults may include:

• Confusion and disorientation.

• Mood swings.

• Excessive sleepiness.

• Changes in consciousness.

• Seizures.

• Hyperventilation.

• Coma.

If an individual is experiencing these symptoms, it is crucial to go to the nearest emergency room immediately. High levels of ammonia in the blood are life-threatening and require urgent medical treatment.

Symptoms of hyperammonemia in newborns typically manifest within 24 to 72 hours after birth and may include:

• Irritability.

• Vomiting.

• Lethargy.

• Seizures.

• Grunting during breathing.

• Hyperventilation.

If the newborn exhibits these symptoms, it is essential to inform their healthcare provider promptly if they are still in the hospital.

How Is Hyperammonemia Diagnosed?

The diagnosis of hyperammonemia varies depending on the age of the individual. One of the primary methods used by doctors to diagnose hyperammonemia is through blood tests to measure ammonia levels. Normal ammonia levels vary based on age, as outlined for different age groups:

• Preterm Infants: Normal levels are around 71 micromoles per liter (mcmol/L) with a deviation of approximately 26 micromol/L. These levels decrease and reach the levels of infants born at term within approximately seven days.

• Full-Term Infants: Normal levels are about 45 micromol/L with a deviation of around 9 micromol/L. The upper limit for typical levels is 80 to 90 micromol/L.

• Children Older Than One Month: Normal levels are below 50 micromol/L.

• Adults: Normal levels are below 30 micromol/L.

If newborns have ammonia levels above 100 to 150 micromol/L, they may experience symptoms of hyperammonemia. In adults, doctors also conduct tests to measure liver enzymes, bilirubin, and prothrombin time to evaluate liver function.

For preterm infants with symptoms of hyperammonemia, additional tests are necessary to exclude other conditions such as sepsis, gastrointestinal bleeding, meningitis, and intracranial hemorrhage.

The synthetic function of the liver is assessed in hepatic encephalopathy patients using liver function tests, which also measure bilirubin, prothrombin time, and liver enzyme levels. If a legitimate clinical suspicion exists, certain tests to identify the underlying cause of non-cirrhotic hyperammonemia should be taken into consideration.

How Is Hyperammonemia Treated?

Acute hyperammonemia is treated by lowering the ammonia level and managing certain side effects, such as cerebral edema and intracranial hypertension. Hyperammonemia with neonatal beginnings or recurrent episodes of hyperammonemia might result from inborn metabolic abnormalities. These call for ongoing therapies that are directed at the particular etiology. Hepatic encephalopathy is treated differently from inborn metabolic abnormalities.

• Medications to Reduce Ammonia: Neonates with inherited metabolic disorders may exhibit hyperammonemic coma, a severe disease requiring urgent treatment. The consumption of all proteins should be halted, and calories should only be obtained through glucose solutions. For the quick elimination of ammonia, hemodialysis is favored over peritoneal dialysis. Ongoing venovenous or arteriovenous hemofiltration is another option. Compounds that transform nitrogenous waste into substances other than urea are employed as the amounts of ammonia decline. These include intravenous versions of Sodium benzoate and Phenylacetate. Additionally, intravenous Arginine needs to be offered.

When levels increase by more than three times the upper limit of normal, hyperammonemia in patients with disguised urea cycle abnormalities should be addressed. All nitrogen intake should be discontinued, and intravenous glucose solutions should be used to deliver calories. Begin administering Phenylacetate and Sodium benzoate intravenously. Only after eight hours of continuous treatment, if ammonia levels have not decreased, may dialysis be considered.

The goal of medical treatment for hepatic encephalopathy is to reduce intestinal ammonia production. Non-absorbable oral disaccharides, such as Lactulose and Lactitol, are the standard first-line treatment for encephalopathy. These sugars function by reducing intestinal ammonia generation and absorption. However, they have little impact on mortality. Along with the non-absorbable disaccharides, the non-absorbable antibiotic Rifaximin is frequently administered as first-line therapy.

• Administration of Complications: For the treatment of elevated intracranial pressure brought on by cerebral edema, hypertonic saline is preferable over Mannitol. Propofol sedation and the use of hyperosmolar medicines are thought to be effective treatments for hyperammonemia brought on by fulminant liver failure, which causes cerebral edema and elevated intracranial pressure. Corticosteroids should not be used to treat elevated intracranial pressure in neonatal-onset hyperammonemia because they cause a negative nitrogen balance. For the treatment of hyperammonemia-related seizures, valproic acid should not be utilized.
• Dietary Control:It makes sense to infer that people with hyperammonemia need to limit their protein consumption. Since individuals with chronic liver disease are already undernourished, protein restriction is not advised in these patients, and it is often advised to maintain a regular intake of proteins instead. Some substances that can be added to the diet may help lower ammonia levels. Patients with urea cycle abnormalities can take L-carnitine to lessen the frequency of episodes. Since it enhances ammonia metabolism in the muscle, L-ornithine-L-aspartate may be helpful in treating hepatic encephalopathy. Patients with urea cycle abnormalities should include arginine supplements in their diets since it becomes an important amino acid.

Conclusion

Ammonia levels that are abnormally high are referred to as hyperammonemia in medicine. Ammonia is hazardous to the nervous system because it is neurotoxic. The problem should be diagnosed and treated as soon as possible since, if untreated, it can result in complications that can be fatal. Genetic conditions or acquired health issues, such as liver disease or kidney failure, maybe the cause of hyperammonemia. Lowering ammonia levels and treating the problems caused by hyperammonemia are the main goals of treatment. Depending on the underlying reason, treatment options may include oral antibiotics, hemodialysis, hemofiltration, intravenous medicines and glucose solutions, and nutritional supplements.