“Ammonia disease” commonly refers to hyperammonemia, a state of abnormally high ammonia levels in the bloodstream. Ammonia is a natural byproduct formed in the body, primarily from protein breakdown in the intestines. Ammonia is also highly toxic, especially to the brain, and must be efficiently removed from the body. When the body’s mechanisms for ammonia removal falter, ammonia can accumulate, leading to severe and life-threatening complications.
The Role of Ammonia and the Urea Cycle
Ammonia is continuously produced as amino acids, the building blocks of proteins, are metabolized. Gut bacteria also contribute to ammonia production through protein digestion in the intestines. To prevent toxic buildup, the body employs a detoxification system known as the urea cycle.
This cycle primarily takes place in the liver, converting nitrogenous waste. In this cycle, toxic ammonia is converted into urea. Urea is water-soluble and transported in the bloodstream to the kidneys, where it is filtered and excreted in the urine. This continuous process is essential for maintaining healthy ammonia levels and preventing neurological damage.
Causes of Elevated Ammonia Levels
Elevated ammonia levels stem from two main categories: inherited metabolic disorders and acquired conditions. Inherited metabolic disorders, particularly Urea Cycle Disorders (UCDs), are a common cause of hyperammonemia, especially in newborns. UCDs are genetic conditions involving a deficiency of specific enzymes or transporter proteins in the urea cycle. For instance, ornithine transcarbamylase (OTC) deficiency is the most common UCD and is X-linked, often severely affecting males from birth. Complete deficiencies can lead to severe ammonia accumulation within 24 to 72 hours of birth.
Acquired conditions are another significant cause, with severe liver disease being the most frequent culprit in adults, accounting for approximately 90% of cases. When the liver is damaged by conditions like cirrhosis or acute liver failure, its ability to perform the urea cycle is compromised, leading to ammonia buildup. This can result from chronic infections like hepatitis B or C, excessive alcohol consumption, or exposure to hepatotoxins. Less common acquired causes include kidney failure, certain infections caused by urease-producing bacteria, and some medications.
Symptoms and Complications
The brain is particularly susceptible to elevated ammonia, and symptoms primarily reflect neurological dysfunction. Symptoms can differ depending on the patient’s age and the severity of ammonia elevation. In infants, early signs of hyperammonemia, typically appearing within 24 to 72 hours after birth, can include lethargy, irritability, poor feeding, and vomiting. As ammonia levels rise, infants may exhibit hyperventilation and seizures.
In older children and adults, symptoms are often less specific and can include confusion, disorientation, headaches, and slurred speech. Patients may also experience tremors, ataxia (impaired coordination), and behavioral or mood changes. If hyperammonemia is not promptly addressed, it can progress to severe complications such as cerebral edema (brain swelling), increased intracranial pressure, and seizures. Untreated, these complications can lead to coma, permanent brain damage, and death. Ammonia levels exceeding 200 micromol/L are associated with severe symptoms including encephalopathy and coma.
Diagnosis and Medical Interventions
Diagnosing hyperammonemia begins with a blood test to measure ammonia levels, with samples needing proper handling to ensure accuracy. Normal blood ammonia levels typically range from 15 to 45 µmol/L in adults, though values can vary by age and laboratory. If elevated levels are found, further tests such as liver function tests, kidney function tests, plasma amino acid analysis, and urinary orotic acid levels are conducted to determine the underlying cause. Genetic testing, including DNA mutation analysis, is commonly used to confirm a Urea Cycle Disorder. Neuroimaging, such as CT or MRI scans of the brain, may also be performed to assess for complications like cerebral edema.
Immediate interventions focus on rapidly reducing ammonia levels and providing supportive care. Patients are advised to stop protein intake, as protein metabolism produces ammonia, and receive intravenous glucose solutions to provide calories. For rapid ammonia removal, emergency treatments like hemodialysis or continuous renal replacement therapy are often initiated, especially in severe cases. Hemodialysis is effective at quickly clearing ammonia from the blood.
Medical management includes medications known as “ammonia scavengers,” such as sodium phenylbutyrate and sodium benzoate. These drugs work by providing alternative pathways for waste nitrogen excretion, binding to nitrogenous compounds to form products safely eliminated in urine, reducing the load on the urea cycle. For long-term management of Urea Cycle Disorders, dietary protein restriction, often tailored to individual needs, is a consistent component of therapy. Nutritional supplementation with amino acids like arginine may also be provided. Liver transplantation offers a definitive cure for Urea Cycle Disorders and hyperammonemia caused by end-stage liver disease, as it replaces the deficient enzyme or damaged organ responsible for ammonia detoxification.