Hyperammonemia is characterized by an elevated concentration of ammonia in the blood. Causes include congenital defects of the urea cycle and certain enzymes as well as severe liver disease. If left untreated, the disorder can lead to severe brain damage or even death.
What is hyperammonemia?
Hyperammonemia is the scientific term for an elevated serum concentration of ammonia in the blood. Ammonia is produced as part of amino acid breakdown. In a process called the urea cycle, free ammonia is bound to form urea. The non-toxic urea is in turn excreted in the urine. However, if disorders occur in the urea cycle due to defective enzymes, the ammonia formed often cannot be converted into urea. Ammonia then accumulates in the blood and often causes irreversible damage, especially in the brain. Any form of hyperammonemia can produce the symptoms of hepatic encephalopathy. This disease is always the result of hyperammonemia. Although hepatic encephalopathy is always described in the context of severe hepatic insufficiency, the actual precipitating hyperammonemia may have other causes.
Causes
The causes of hyperammonemia can be diverse. It is merely a symptom of an underlying condition. It is often the result of a genetically determined disorder of the urea cycle. The urea cycle is controlled by several enzymes whose defect or failure can inhibit the synthesis of nontoxic urea from ammonia. These enzymes include ornithine transcarbamylase, carbamoyl phosphate synthetase I, argininosuccinate synthase, argininosuccinate lyase, N-acetylglutamate synthetase (NAGS), and arginase 1. Ornithine transcarbamylase is most commonly affected. Ornithine transcarbamylase catalyzes the conversion of ornithine to citrulline. If this reaction is interrupted, ammonia will accumulate in the blood. The other enzymes presented would also lead to a disruption in the breakdown of ammonia due to their failure. However, these defects occur somewhat less frequently. For example, carbamoyl phosphate synthetase I catalyzes the addition of ammonia, ATP, and carbon dioxide to carbamoyl phosphate. Argininosuccinate synthase is responsible for the conversion of citrulline and aspartate to argininosuccinate. Argininosuccinate in turn serves as a starting material for the synthesis of arginine, which directly controls urea formation from ammonia. The enzyme argininosuccinate lyase catalyzes the cleavage of argininosuccinate into fumarate and arginine. Arginase 1 controls the final step of the urea cycle with the breakdown of arginine to urea and ornithine. While the ornithine transcarbamylase defect is inherited x-linked, all other enzyme defects each follow an autosomal recessive mode of inheritance. There are also metabolic disorders outside the urea cycle that can lead to hyperammonemia. These include organic acidurias, which cause an accumulation of organic acids. These toxic metabolic intermediates in turn disrupt the urea cycle. Secondary causes of hyperammonemia further include severe liver disease, since the conversion of ammonia to urea occurs in the liver.
Symptoms, complaints, and signs
Symptoms of hyperammonemia differ depending on the age of initial manifestation. In neonates, the course is life-threatening with the onset of weakness in drinking, hypotonia, and lethargy. If the disease first appears in infancy, the course is less acute with lethargy and failure to thrive. If it first manifests in infancy through puberty, mental retardation, disturbances in motor coordination, learning problems, headaches, and vomiting are prominent. Overall, the appearance of hyperammonemia corresponds to the symptoms of hepatic encephalopathy. The hepatic encephalopathy described in connection with severe liver insufficiency manifests itself in a spectrum ranging from mild clinical manifestations to coma. Thus, in a first stage, concentration disorders, mood swings, drowsiness, and disturbances in fine motor skills occur, among other symptoms. Stage II is characterized by increased sleepiness, disturbance of speech motor function, apathy, and orientation disorders. In stage III, the patient is usually permanently asleep but can still be awakened. Incoherent speech upon awakening and increased muscle tension are also part of this stage.Stage IV is characterized by hepatic coma (coma hepaticum).
Diagnosis and course of the disease
Hyperammonemia can be diagnosed by the appearance of symptoms of hepatic encephalopathy. Among other tests, a cranial CT is used for differential diagnosis to stroke or a blood glucose test to exclude hypoglycemia. Furthermore, ammonia is determined in the blood.
Complications
Hyperammonemia can cause serious harm to the patient if left untreated, and death can occur in the worst cases. Hyperammonemia primarily causes weakness in drinking. This usually results in dehydration, which generally has a very negative effect on the patient’s body. Furthermore, mental retardation also occurs, so that the affected person may be dependent on the help of other people in everyday life. Thinking processes are also restricted and greatly impeded by the disease. Vomiting, nausea and headaches occur. Coordination and all movements are also disturbed and can no longer be carried out easily. The affected person may lose consciousness or even fall into a coma. Speech disorders and concentration problems also occur. The quality of life is extremely limited by the symptoms. If there is no treatment for hyperammonemia, the patient’s life expectancy is usually reduced, leading to premature death. Treatment does not lead to further complications and is carried out with the help of medication. It is possible to limit the symptoms relatively well. However, it is possible that irreversible damage has already formed as a result of hyperammonemia.
When should you go to the doctor?
Newborns and infants who show refusal to feed should be presented to a physician as soon as possible. If there is a refusal of supply of breast milk or a substitute infant formula, there is cause for concern. If there is weight loss, pallor of the skin, or lack of saliva production, a physician is needed. In the further course, without medical care, there is a risk of an undersupply of the organism and thus the premature death of the newborn. If the child shows behavioral abnormalities, is lethargic or the movements of the limbs are uncoordinated, a doctor must be consulted. If there are fluctuations in mood, severe fatigue, and a very intense need for sleep, a check-up should be done. If an increased tension of the muscles is noticed, this must be medically clarified. If the muscles cannot be relaxed even when the child is lying down or lightly asleep, a visit to the doctor should be made. If the child is in a comatose state, an ambulance should be called because it is an emergency. If the child is conspicuous by disturbances in fine motor skills or coordination problems, a physician should be consulted. If there are interruptions of consciousness or apathy, a doctor must be consulted immediately. Children who can already speak must be presented to a physician as soon as their pronunciation is subject to dropouts or speech regresses.
Treatment and therapy
In the case of acute hyperammonemia, immediate measures must be taken urgently. This requires immediately stopping protein intake for two days. Furthermore, this includes the performance of a sugar infusion, the administration of insulin, and the supply of arginine as well as carnitine. Various drugs such as phenylacetate, phenylbutyrate or benzoate are used to detoxify the blood. Diuretics are used to increase urine output. In some cases, dialysis must also be performed. Lactulose, a disaccharide, is also given. With the help of intestinal bacteria, this carbohydrate is broken down into lactate and acetone. The resulting acidic intestinal environment ensures the binding of ammonia to ammonium salts. For long-term treatment of hyperammonemia associated with enzyme deficiencies, a low-protein diet must be maintained permanently. In addition, the administration of arginine hydrochloride, citrulline or lysine is necessary. If hyperammonemia is the result of liver disease, it must be treated as a matter of course.
Outlook and prognosis
The prospect of recovery from hyperammonemia is tied to the use of treatment as well as the underlying disease present. With drug therapy, detoxification of the blood takes place.This alleviates the discomfort and improves the patient’s health condition. If treatment is refused, the prognosis is unfavorable. In severe cases, permanent impairment of brain activity may occur. In addition, the affected person is at risk of an early death. With treatment, the prognosis improves, but curability is usually not given. The medical care initiated depends on the present cause of the symptoms. In the case of an underlying genetic disease, relief of the symptoms can be achieved. In long-term therapy, the urea cycle is monitored and regulated. This leads to an improvement in the general state of health and a decrease in the existing complaints. However, since the genetic defect cannot be changed for legal reasons, no permanent cure occurs. As soon as the treatment is interrupted or stopped at the patient’s own request, the urea cycle disorders return. In case of an acute condition, intensive medical care of the patient takes place. This improves the patient’s health situation, but is not sufficient for a cure. If organ damage is present, the organism must also receive long-term medical support so that adequate purification of the blood takes place.
Prevention
Severe crises can be prevented in congenital hyperammonemia by a lifelong diet of low-protein food. However, there is no recommendation for prevention of the disease in urea cycle disorder because it is genetic. Human genetic counseling is offered in cases of familial occurrence. However, nongenetic causes of hyperammonemia can be prevented by a healthy lifestyle and avoidance of alcohol.
Follow-up
As a rule, the person affected by hyperammonemia has no or very few measures and options for aftercare. In this regard, the affected person is primarily dependent on early diagnosis with subsequent treatment to prevent further complications or discomfort. Early detection with subsequent treatment always has a very positive effect on the course of the disease. It is possible that hyperammonemia may result in a reduced life expectancy if the disease is detected late or is not treated. Those affected by hyperammonemia are dependent on taking medication. Care must be taken to ensure that the medication is taken regularly and, above all, correctly so that the symptoms can be treated properly. If there are any uncertainties or questions, a doctor should always be contacted first. Regular examinations of the body are also very important in this disease in order to prevent damage to the internal organs or to detect it early. A healthy lifestyle with a healthy diet can also have a positive effect on the course of the disease. In many cases, the disease makes sufferers dependent on the care and help of relatives and family.
What you can do yourself
If acute hyperammonemia is present, protein intake must be stopped immediately. Depending on the medical treatment, the diet should then be changed to prevent a recurrence. The physician will recommend a low-protein diet to the patient, which should be maintained for at least two to three months after diagnosis. In parallel, therapy using various detoxification medications is indicated. This can be supported by the patient through regular fluid intake. In addition, the patient should temporarily refrain from sporting activities. Rest and bed rest are important, especially in the first one to two weeks after diagnosis. If hyperammonemia occurs as a result of liver disease, stimulants must be avoided. In addition, the underlying disease must be treated. In most cases, the underlying condition is treated with medication, but in some cases surgical treatment is necessary. After surgery on the liver, the body is severely weakened. The patient must spend a few days in the hospital and should then recuperate at home. Regular visits to the doctor’s office can ensure close monitoring and targeted treatment of acute complaints.