Hyperammonemia : Causes, Symptoms, Diagnosis & Treatment

• Causes Of Hyperammonemia
• Pathogenesis
• Classification
• &Nbsp;
• Symptoms
• Congenital Hyperammonemias
• Acquired Hyperammonemias
• Complications
• Diagnostics
• Treatment Of Hyperammonemia
• Forecast And Prevention

Hyperammonemia is a severe pathological condition characterized by an increase in the concentration of ammonia (NH3) in the blood serum of more than 60 µmol / l. The reasons may be genetically determined defects in the 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 levels of ammonia 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 individuals on 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. Most often, the etiology of hyperammonemia (about 90% of cases) is associated with severe liver diseases (alcoholic, viral hepatitis, cirrhosis), in which massive death of hepatocytes occurs, as a result of which the ornithine cycle is disrupted - the process of neutralizing toxic ammonia and turning it into urea.
• Genetic defects in urea synthesis. The main cause of hyperammonemia in neonatal and infant children. In total, 5 enzymes are known to be 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 system (ureters, bladder), which impede the outflow of urine, with the addition of an 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 decay, tissue compression or crush syndrome, purulent-necrotic processes) can also cause hyperammonemia.
• Infections. Some influenza viruses and viruses that cause acute respiratory infections inhibit carbamoyl phosphate synthetase I, one of the key enzymes of the cycle.
• Taking medications. An increase in the content of ammonia can cause salicylates, glucocorticosteroids, thiazide diuretics. Valproate-induced hyperammoniemic 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 a violation of beta-oxidation of fatty acids, transport of organic acids, pyruvate metabolism, etc.

Pathogenesis

The highest concentrations of ammonia are observed in organs with a high consumption of amino acids - in skeletal muscle, 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 the brain cells shifts the conversion of amino acids into keto acids, which significantly slows down the Krebs cycle.

This significantly reduces the production of energy-producing ATP molecules. Inhibition of the synthesis of almost all neurotransmitters - serotonin, norepinephrine, gamma-aminobutyric acid - and a change in the transmembrane potential adversely affect the transmission of nerve impulses. Hyperammonemia stimulates the formation of glutamine, an osmotically active substance.

Fluid is retained 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 for oxygen increases, due to which oxygen penetrates the cells worse, hypoxia occurs. Hyperammonemia also induces lipid peroxidation, which damages cell membranes.

Classification

There are physiological and pathological hyperammonemia. According to etiology, they are distinguished:

1. Primary (hereditary) hyperammonemia. Increased ammonia levels are due to genetic defects in ornithine cycle enzymes. There are 5 forms in total:

• Type I hyperammonemia: inhibition of the production of carbamoyl phosphate synthetase I. It is characterized by manifestation at 1-2 years of age and a severe course.
• Type II hyperammonemia: ornithine carbamoyl transferase defect. The most common type of hereditary hyperammonemia. Symptoms develop during the neonatal period. Mortality in boys reaches 100%.
• Citrullinemia: defect in arginine succinate synthetase. Differs in clinical polymorphism from asymptomatic to fatal forms.
• Argininosuccinaturia: deficiency of arginino-succinate-lyase. May debut in neonatal or early childhood.
• Hyperargininemia: violation of the formation of arginase. More often debuts in the neonatal period.

2. Secondary hyperammonemia. An increase in ammonia concentration due to liver disease, viral infections, medication, 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:

• Light: up to 10 µmol / l.
• Moderate : up to 20 µmol/l.
• Severe: more than 20 µmol/l.

Hyperammonemia

Symptoms

Congenital hyperammonemias

The clinical picture can vary from an asymptomatic course to bright lightning-fast symptoms with a fatal outcome. For hereditary fermentopathies of the ornithine cycle, the age of clinical manifestation is of great importance. In newborns with a complete loss of enzyme activity, breast rejection, vomiting, and motor restlessness are noted from the first days of life.

With further progression, a violation of the activity of the central nervous system occurs - the child becomes drowsy, reacts poorly to external stimuli, convulsions appear, consciousness is depressed up to a coma. These patients have a very high risk 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 mild enzyme defect and gradually developing mild hyperammonemia have symptoms such as emotional lability, aggressive behavior, and cognitive impairment (impaired memory and concentration).

Acquired hyperammonemias

The main symptom is encephalopathy, which has a heterogeneous picture. The severity of symptoms is significantly affected 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. The clinic is dominated by neuropsychic and motor disorders. Psychomotor reactions slow down, visual-spatial orientation suffers.

Acute psychoses with visual, auditory hallucinations, crazy ideas and statements are possible. Impaired gait and coordination. Typical symptoms are asterixis - fast arrhythmic sweeping oscillatory twitches of the distal parts of the arms or legs and sleep inversion (drowsiness during the day, insomnia at night). Asterixis can be either unilateral or bilateral.

Complications

Hyperammonemia is a serious condition with a large number of adverse consequences. With a rapidly increasing concentration of ammonia, reaching high numbers, cerebral edema develops, the patient falls into a coma, which in the vast majority of cases ends in death.

This is most often observed in patients with primary hyperammonemia (with complete enzyme deficiency), liver cirrhosis, and fulminant hepatitis. Due to a pronounced shift in the acid-base balance towards alkalosis, cardiac output and vascular tone decrease, which worsens the perfusion of vital organs and contributes to the development of a state of shock. Rarely, intracranial and pulmonary hemorrhages occur.

Diagnostics

Due to a wide range of etiological factors, doctors of various specialties are involved in 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 the hepatic (ammonia) smell from the mouth, hyperreflexia, yellowness of the skin, enlarged liver. Differential diagnosis is carried out by Gaye-Wernicke-Korsakov encephalopathy, Marchiafava-Bignamimini syndrome, alcoholic dementia.

To assess cognitive impairment, various questionnaires, a number linking test, and psychometric tests are used. The main diagnostic method is the determination of plasma ammonia levels by ELISA or express method. For the diagnosis of some forms of hyperammonemia in the blood, the content of metabolites - glutamine, citrulline - is measured. 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.

The main method for diagnosing hyperammonemia is to determine the level of ammonia in the blood plasma.

Treatment of hyperammonemia

Patients need to be hospitalized. All methods of therapy are aimed at reducing ammoniogenesis, binding, stimulating the excretion of ammonia from the body and treating the underlying disease (antiviral, anticirrhotic, 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 the restriction of animal protein intake 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, which produces ammonia, non-absorbable antibacterial agents are used - neomycin, rifaximin.
• Lactulose. This drug is a synthetic disaccharide that increases the osmolarity in the lumen of the colon, which significantly reduces the absorption of ammonia.
• L -ornithine- L -aspartate ( LOLA ). Being an activator of enzymes for the formation of urea in the liver, LOLA contributes to the neutralization of ammonia.
• drugs that bind ammonia. These medicines include phenylacetate, sodium benzoate.
• Ketoacids. In hereditary fermentopathy, intermediate metabolites of various stages of the ornithine cycle are prescribed - citrulline, arginine, glutamine.

Forecast and prevention

Hyperammonemia is a severe pathological condition with a high mortality rate. Primary forms have a mortality rate of 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 the etiological factor.

Prevention of secondary hyperammonemias consists in timely diagnosis and treatment of the underlying disease. The only effective method for preventing the occurrence of primary forms of this pathology is prenatal diagnosis (determination of the enzymatic activity of amniotic fluid) and termination of pregnancy.