Hyperammonemia is a severe pathological condition characterized by an increase in the concentration of ammonia (NH3) in the blood serum of more than 60 mmol/l. The causes may be genetically determined defects of ornithine cycle enzymes in the liver or severe liver diseases (hepatitis, cirrhosis). The main clinical symptoms include repeated vomiting, impaired consciousness, convulsions. The condition is diagnosed based on the detection of elevated ammonia content in the blood. Treatment consists in reducing protein intake, stimulating the excretion of ammonia from the body and treating the underlying disease.
Causes of hyperammonemia
An increase in ammonia levels can be observed in healthy people (physiological or functional hyperammonemia). It occurs in people who adhere to a high-protein diet, after intense physical exertion, during pregnancy. Transient hyperammonemia is inherent in newborn children during the period of adaptation to extrauterine life (for 2-3 days). The causes of pathological hyperammonemia are as follows:
- Liver diseases. The most common etiology of hyperammonemia (about 90% of cases) is associated with severe liver diseases (alcoholic, viral hepatitis, cirrhosis), in which massive death of hepatocytes occurs, resulting in a violation of the ornithine cycle – the process of neutralizing toxic ammonia and converting it into urea.
- Genetic defects of urea synthesis. The main cause of hyperammonemia in neonatal and infants. In total, there are 5 enzymes involved in the ornithine cycle. Mutations of the genes encoding the synthesis of these enzymes lead to the accumulation of ammonia in the body.
- Urological pathology. An increase in the concentration of ammonia is possible in patients with congenital anomalies of the lower urinary tract (ureters, bladder), obstructing the outflow of urine, with the addition of infection caused by urease-producing bacteria (klebsiella, morganella, proteus). The resulting ammonia is absorbed into the blood.
- Conditions accompanied by increased catabolism. Severe conditions in which accelerated protein catabolism is observed (tumor disintegration, tissue compression or crushing syndrome, purulent-necrotic processes) they can also cause hyperammonemia.
- Infections. Some influenza viruses and viruses that cause acute respiratory diseases inhibit carbamoyl phosphate synthetase I‒ one of the key enzymes of the cycle.
- Taking medications. Salicylates, glucocorticosteroids, thiazide diuretics can cause an increase in ammonia content. Valproate-induced hyperammonemic encephalopathy occurs in some patients with epilepsy taking valproic acid or its derivatives.
- Genetic diseases. An increase in the concentration of ammonia in the blood is also accompanied by hereditary metabolic diseases, such as impaired beta-oxidation of fatty acids, transport of organic acids, pyruvate metabolism, etc.
The highest concentrations of ammonia are observed in organs with a high consumption of amino acids – in skeletal muscles, nervous tissue and liver. Ammonia has the most damaging effect on the central nervous system. Its toxicity is due to several mechanisms. The penetration of a large amount of ammonia into brain cells shifts the processes of converting amino acids into ketoacids, which significantly slows down the Krebs cycle.
This significantly reduces the production of ATP energy molecules. Inhibition of the synthesis of almost all neurotransmitters – serotonin, norepinephrine, gamma-aminobutyric acid – and a change in the transmembrane potential adversely affects the transmission of nerve impulses. Hyperammonemia stimulates the formation of glutamine, an osmotically active substance.
Fluid is trapped in the cells, causing them to swell and swell. Ammonia binds hydrogen ions, thereby shifting the pH of the blood to the alkaline side (alkalosis). The affinity of hemoglobin to oxygen increases, which is why oxygen penetrates the cells worse, hypoxia occurs. Hyperammonemia also induces lipid peroxidation, which damages cell membranes.
There are physiological and pathological hyperammonemia. According to the etiology , there are:
1. Primary (hereditary) hyperammonemia. The increase in ammonia levels is due to genetic defects of ornithine cycle enzymes. There are 5 forms in total:
- Type I hyperammonemia: inhibition of carbamoyl phosphate synthetase I production. It is characterized by manifestation at 1-2 years of life and severe course.
- Type II hyperammonemia: ornithine carbamoyl transferase defect. The most common type of hereditary hyperammonemia. Symptoms develop during the newborn period. The mortality rate in boys reaches 100%.
- Citrullinemia: arginine-succinate synthetase defect. It differs in clinical polymorphism from asymptomatic to fatal forms.
- Argininosuccinaturia: insufficiency of arginine succinate lyase. It can make its debut in neonatal or early childhood.
- Hyperarginemia: violation of arginase formation. More often it debuts during the newborn period.
2. Secondary hyperammonemia. An increase in the concentration of ammonia due to liver diseases, viral infections, taking medications, etc. The severity of symptoms correlates with the severity of the underlying disease.
According to the level of ammonia in the blood plasma, hyperammonemia is divided into:
- Mild: up to 100 mmol / l.
- Moderate: up to 200 mmol/l.
- Heavy: more than 200 mmol/l.
The clinical picture can vary from an asymptomatic course to bright lightning-fast symptoms with a fatal outcome. For hereditary ornithine cycle fermentopathies, the age of clinical manifestation is of great importance. In newborns with a complete loss of enzyme activity from the first days of life, breast rejection, vomiting, motor anxiety are noted.
With further progression, there is a violation of the activity of the central nervous system – the child becomes drowsy, reacts poorly to external stimuli, convulsions appear, consciousness is oppressed up to a comatose state. Such patients have a very high probability of death. In childhood, a decrease in appetite, impaired coordination of movements, and a delay in physical and psychomotor development are characteristic.
Epileptic seizures and depression of consciousness are possible. Adolescents and adults with a minor enzyme defect and gradually developing mild hyperammonemia have symptoms such as emotional lability, aggressive behavior, cognitive impairment (deterioration of memory and concentration).
The main feature is encephalopathy, which has a heterogeneous picture. The severity of symptoms is significantly influenced not only by the degree of increase in ammonia in the body, but also by the rate of increase in its concentration, as well as the severity of the underlying disease. Neuropsychiatric and motor disorders dominate in the clinic. Psychomotor reactions slow down, visual-spatial orientation suffers.
Acute psychoses with visual, auditory hallucinations, delusional ideas and statements are possible. Gait and coordination of movements are disrupted. Typical symptoms are asterixis – rapid arrhythmic sweeping oscillatory twitching of the distal parts of the arms or legs and inversion of sleep (drowsiness during the day, insomnia at night). Asterixis can be either unilateral or bilateral.
Hyperammonemia is a serious condition with a large number of adverse consequences. With a rapidly increasing concentration of ammonia reaching high numbers, brain edema develops, the patient falls into a comatose state, which in the vast majority of cases ends in death.
This is most often observed in patients with primary hyperammonemia (with complete enzyme deficiency), cirrhosis of the liver, with fulminant hepatitis. Due to the pronounced shift of the acid-base balance towards alkalosis, cardiac output and vascular tone decrease, which worsens the perfusion of vital organs, contributes to the development of a shock state. Intracranial and pulmonary hemorrhages occur less frequently.
Due to the wide range of etiological factors, doctors of various specialties are involved in the curation of patients with hyperammonemia. Most often, such patients are under the supervision of neonatologists, pediatricians and gastroenterologists. During a general examination, attention is paid to hepatic (ammonia) breath odor, hyperreflexia, jaundice of the skin, liver enlargement. Differential diagnosis is performed by Gaye-Wernicke-Korsakov encephalopathy, Markiafava-Binyamin syndrome, alcoholic dementia.
Various questionnaires, a number binding test, and psychometric tests are used to assess cognitive impairment. The main diagnostic method is to determine the level of ammonia in plasma by the ELISA method or the express method. To diagnose some forms of hyperammonemia, the content of metabolites – glutamine, citrulline – is measured in the blood. To clarify the etiology of hyperammonemia , the following studies are prescribed:
- determination of the level of hepatic transaminases, markers of viral hepatitis.
- determination of the activity of urea synthesis enzymes.
- Ultrasound, CT of the liver.
- genetic research.
Treatment of hyperammonemia
Patients need to be hospitalized in a hospital. All methods of therapy are aimed at reducing ammoniogenesis, binding, stimulating the excretion of ammonia from the body and treating the underlying disease (antiviral, anti-cirrhotic, hepatoprotective therapy). The most radical method is liver transplantation. The main conservative ways to correct hyperammonemia are as follows:
- Diet. The first and mandatory stage of treatment is to limit the intake of animal protein in the diet to 0.5-0.6 g / kg per day to ensure a negative nitrogen balance.
- Antibiotics. To influence the microflora of the large intestine, producing ammonia, non–absorbable antibacterial agents are used – neomycin, rifaximin.
- Lactulose. This drug is a synthetic disaccharide that increases osmolarity in the lumen of the large intestine, which significantly reduces the absorption of ammonia.
- L-ornithine-L-aspartate (LOLA). Being an activator of the enzymes of urea formation in the liver, LOLA contributes to the neutralization of ammonia.
- Drugs that bind ammonia. Such medications include phenyl acetate, sodium benzoate.
- Ketoacids. In hereditary fermentopathies, intermediate metabolites of various stages of the ornithine cycle are prescribed – citrulline, arginine, glutamine.
Prognosis and prevention
Hyperammonemia refers to severe pathological conditions with a high percentage of mortality. Primary forms have a mortality rate from 33 to 100%. Higher rates are observed in newborn male children. With secondary hepatic hyperammonemia, approximately 67% of patients die. Mortality in secondary extrahepatic forms is mainly due to an etiological factor.
Prevention of secondary hyperammonemia consists in timely diagnosis and treatment of the underlying disease. The only effective method of preventing the occurrence of primary forms of this pathology is prenatal diagnosis (determination of the enzymatic activity of amniotic fluid) and termination of pregnancy.