Ammonia is toxic to the body. ITEB knows how to overcome hyperammonemia

1. Ammonia is converted into urea only in the liver, therefore, in case of liver diseases (hepatitis, cirrhosis, etc.) or hereditary defects in ammonia neutralization enzymes, increased levels of ammonia in the blood (hyperammonemia), which has a toxic effect on the body.

Hyperammonemia is accompanied by the following symptoms:

Nausea, vomiting;

Dizziness, convulsions;

Loss of consciousness, cerebral edema (in severe cases).

All of these symptoms are caused by the effect of ammonia on the central nervous system and primarily on the brain.

2. Mechanisms of toxic action of ammonia are related to the fact that:

Ammonia causes decrease in the concentration of α-ketoglutarate, because

shifts the reaction catalyzed glutamate dehydrogenase, towards the formation of glutamate:

It causes oppression of the TCA(hypoenergetic state) and amino acid metabolism (transamination); high concentrations of ammonia cause glutamine synthesis from glutamate to nerve tissue:

decreased glutamate concentration suppresses amino acid metabolism and the synthesis of neurotransmitters, in particular γ-aminobutyric acid (GABA),

main inhibitory mediator:

This disrupts the conduction nerve impulse, causes convulsions. The accumulation of glutamine in nerve cells increases osmotic pressure and, in high concentrations, can cause cerebral edema;

In the blood and cytosol, ammonia is converted to NH ion 4 +:

The accumulation of NH 4 + disrupts the transmembrane transport of monovalent cations Na + and K +, which also affects the conduction of nerve impulses.

3. There are five known hereditary diseases caused by defect of five enzymes of the ornithine cycle(Table 9.5). Disruption of the ornithine cycle is observed in hepatitis and some other viral diseases; for example, the influenza virus inhibits the synthesis of carbamoylphosphate synthetase I.

All violations ornithine cycle lead to significant increase in blood concentrations:

Ammonia;

Glutamine;

Alanina.

Diagnostics The different types of hyperammonemia are made by determining:

Metabolites of the ornithine cycle in the blood and urine;

Enzyme activity in liver biopsies.

The main diagnostic sign serves to increase the concentration of ammonia in the blood. However, in most chronic cases, ammonia levels may increase only after a protein load or during acute complicated illnesses.

To reduce NH concentration 3 in blood and to alleviate the condition of patients, it is recommended:

Low protein diet;

Introduction of metabolites of the ornithine cycle (arginine, citrulline, glutamate), which stimulate the excretion of ammonia bypassing impaired reactions (Fig. 9.13), for example, in the composition of phenylacetylglutamine and hippuric acid.

Topic 9.8. Biosynthesis of non-essential amino acids

1. Carbon skeleton of the eight nonessential amino acids (Ala, Asp, Asn, Ser, Gli, Pro, Glu, Gln) And cysteine can be synthesized from glucose (Fig. 9.15).

The α-amino group is introduced into the corresponding α-keto acids via a transamination reaction. The universal donor of the α-amino group is glutamate.

Directly through transamination of OPA metabolites with glutamate, the following are synthesized:

Rice. 9.15. Pathways for the biosynthesis of non-essential amino acids

2. Partially replaceable amino acids Arg and His synthesized into small quantities, which do not meet the needs of the body, which is especially noticeable in childhood. Arginine synthesis occurs in reactions of the ornithine cycle. Histidine synthesized from ATP and ribose.

Conditionally essential amino acids Tyr and Cys are formed using essential amino acids:

Phenylalanine is converted to tyrosine under the influence of phenylalanine hydroxylase;

For education cysteine sulfur is required, the donor of which is methionine. The synthesis uses the carbon skeleton and α-amino group of serine.

EMA 9.9. METABOLISM OF SERINE AND GLYCINE.

ROLE OF FOLIC ACID

In addition to the metabolic pathways characteristic of most amino acids that make up proteins, for almost all amino acids there are also specific pathways transformations. Let us consider the metabolism of some amino acids, the specific pathways of transformation of which lead to the synthesis of biologically important products and largely determine physiological state person.

1. Serin- a non-essential amino acid, synthesized from an intermediate

glycolysis product - 3-phosphoglycerate in the sequence of reactions of dehydrogenation, transamination and hydrolysis under the action of phosphatase

In the body, serine is used to synthesize:

Phospholipids (phosphatidylserines, sphingomyelins);

Amino acids (glycine, cysteine).

Major pathway of serine catabolism- its deamination with the formation of pyruvate (see topic 9.3).

2. Glycine is formed from serine by the action of serine oxymethyltransferase. Coenzyme this enzyme is tetrahydrofolic acid (H4-folate),

which adds the β-carbon atom of serine, forming methylene - H4-folate

Glycine is a precursor to:

Porphyrins (heme),

Purine bases

Coenzymes,

Glutathione, etc. Glycine catabolism is happening

also with participation N 4 -folate, which binds the a-CH 2 group of glycine (see Fig. 9.18).

3. N 4 -folate formed in the liver from folic acid(folate) with the participation of the enzymes folate reductase and dihydrofolate reductase (Fig. 9.19). The coenzyme of these reductases is NADPH.

Methylene group - CH 2 - in a molecule methylene-H 4 -folate can transform into other one-carbon groups:

N 4 -folate is able to transfer these groups to other compounds and plays a role intermediate carrier of one-carbon groups.

One-carbon fragments are used to synthesize nucleotides and a number of compounds (see Fig. 9.18).

Rice. 9.17. Synthesis of serine from glucose

Rice. 9.18. Biological role one-carbon groups

Rice. 9.19. H synthesis scheme 4 -folate in the liver

4. Folic acid is a vitamin for humans and most mammals (vitamin B WITH or IN 9 ). It is widely distributed in foods and is synthesized by intestinal bacteria. Hypovitaminosis It occurs quite rarely in humans. The reasons for this may be:

Poor nutrition - insufficient consumption of vegetables, fruits and meat products;

Impaired absorption of folic acid in the intestine;

Hepatitis, cirrhosis and other liver lesions that cause a decrease in folate reductase activity.

Folic acid hypovitaminosis leads to disruption of the synthesis of nucleic acids in the body, which primarily affects rapidly dividing blood cells, and the development megaloblastic anemia.

5. Many pathogenic microorganisms are able to synthesize folic acid from para-aminobenzoic acid, which is integral part folate. Based on this bacteriostatic effect of sulfonamide drugs, that are structural analogues n-aminobenzoic acid:

The drugs are competitive inhibitors of folic acid synthesis enzymes in bacteria or can be used as pseudosubstrates, resulting in the formation of a compound that does not perform the function of folic acid. This makes cell division impossible, bacteria stop multiplying and die. Sulfonamides are called antivitamins.

Ending. Beginning in No. 80 Continued in No. 81 Continued in No. 82. Among various forms The most common hyperammonemias are the following (J. Zschocke, G. Hoffman, 1999). Carbamyl phosphate synthetase deficiency (hyperammonemia type I) B

E. Ya. Grechanina, MD, Professor, Head of the Kharkov Interregional Center for Clinical and Prenatal Diagnostics

Ending.
Starts at No. 80
Continued in No. 81
Continued in No. 82.

Among the various forms of hyperammonemia, the most common are the following (J. Zschocke, G. Hoffman, 1999).

Carbamyl phosphate synthetase deficiency (hyperammonemia type I)

In most cases, the defect occurs sporadically, but an autosomal recessive type of transmission cannot be excluded.

Clinical manifestations depend on severity enzyme deficiency. In the complete absence of the enzyme, the disease progresses rapidly and death can occur within 2-3 days. In newborns with an incomplete block of the enzyme, the course of the disease is less severe. Late forms of carbamyl phosphate synthetase deficiency are known, manifested by mental retardation, bouts of vomiting, and lethargy.

The severity of neurological disorders is explained not only by intoxication, but also by damage to the cerebral cortex and cerebellum, neuronal damage, proliferation of fibrillar astrocytes and sclerotic changes.

Laboratory diagnostics:

hyperammonemia without increasing the level of specific amino acids in plasma;
secondary increase in glutamine and alanine;
orotic acid in urine is absent or its content is reduced.

Treatment. Low protein diet - 0.6 g/kg/day per day natural product and 0.6 g/kg/day as essential amino acids. For N-acetylglutamate synthetase deficiency, oral administration of carbamyl glutamate is effective.

Forecast. Children who survive may have developmental delays.

Ornithine transcarbamylase deficiency (hyperammonemia type II)

The enzyme catalyzes the production of citrulline. The enzyme defect is inherited in an X-linked dominant manner.

Homozygous males are more severely affected than heterozygous females. Newborn boys have the same clinical manifestations, as with severe hyperammonemia. Erased forms simulate Reye's syndrome. Changes nervous system are caused by degenerative processes in the gray and white matter of the cerebral hemispheres. Many abnormal astrocytes, pale nuclei, and changes in the cytoplasm of neurons are detected.

Laboratory diagnostics:

increased levels of glutamine and orotic acid, decreased citrulline;
in heterozygous girls, after a protein load, ammonia and ornithine can be detected in the blood plasma and the release of orotic acid in the urine.

The diagnosis can be confirmed by determining the activity of an enzyme normally found only in the liver. Prenatal diagnosis performed using a fetal liver biopsy.

Treatment. Similar to carbamylphosphate synthetase deficiency, except that citrulline can be used instead of arginine.

Forecast. If the enzyme deficiency is less than 2% of the norm in newborns, improvement occurs during the first week; with activity below 14% and timely diet, mental and physical development can proceed satisfactorily. Asymptomatic carriers have moderate central nervous system dysfunction compared to healthy individuals.

Citrullinemia (deficiency of arginine succinic acid synthesis)

The disease is based on deficiency of arginine succinate synthetase, resulting in sharp increase citrulline in plasma and increased excretion of this amino acid in the urine. The disease is inherited autosomal recessive type.

There is significant clinical and genetic polymorphism from asymptomatic forms to severe and fatal forms.

All forms are characterized by mental retardation and neurological symptoms. With a complete block of the enzyme, lethargy, hypotension, convulsions, and coma occur already on the first day of life after breastfeeding. Death can occur in the first day of life. Morphological examination of the brains of deceased children reveals neural degeneration and disturbances in myelination. Glial cells are enlarged and contain significant lipid inclusions.

Laboratory diagnostics:

increase in plasma citrulline concentration. The diagnosis is confirmed by determining enzyme activity in leukocytes, fibroblasts, and liver cells;
Hyperammonemia is not always detected in newborns with citrullinemia. Clinical symptoms do not correlate with plasma ammonia concentrations;
prenatal diagnosis is based on determination of enzyme activity in amniotic fluid culture.

Treatment. Low-protein diet (1.2 to 1.5 g/kg/day) with the addition of arginine (0.4-0.7 g/kg).

Forecast. Newborns with severe clinical symptoms of the disease have an extremely unfavorable prognosis. With erased forms, patients usually respond well to diet therapy with protein restriction.

Argininemia

The disease was first described in 1969 by Terheggen et al.

The type of inheritance is autosomal recessive.

The human liver arginase gene has been mapped to chromosome 6q23.

The primary biochemical defect is a deficiency of the enzyme, arginase, which catalyzes the breakdown of arginine into ornithine and urea.

Symptoms usually appear after 6 months of age: vomiting, irritability, delayed psychomotor development. Common symptoms in older children include progressive spasticity with crossing of the legs, spastic diplegia, ataxia, choreoathetosis and seizures. Clinical manifestations are caused by chronic ammonia intoxication. The toxic effect of arginine accumulation is important, leading to mental retardation after the 2nd year of life.

Laboratory diagnostics:

increased plasma arginine levels;
determination of arginase activity in erythrocytes;
an increased content of orotic acid is determined in the urine;
intrauterine diagnosis is possible by determining enzymatic activity arginase in fetal erythrocytes.

Treatment. Arginine-free diet. Therapy with a mixture of essential amino acids with restriction general admission squirrel.

Arginine succinic aciduria

The disease was first described in 1958 by S. Alan. The type of inheritance is autosomal recessive.

The mutant gene is localized on chromosome 7.

The primary biochemical defect is a deficiency of the enzyme arginine succinase, which catalyzes the formation of arginine and fumarate from arginine succinic acid. The severity of clinical manifestations and biochemical changes varies significantly. In the neonatal form of the disease, severe hyperammonemia develops during the first few days of life, and the mortality rate is very high. After a short asymptomatic period, food refusal and anorexia are observed. Then the newborns become drowsy, there are signs of central nervous system depression, and eventually coma occurs. Respiratory disorders, muscle hypotension, convulsions, hepatomegaly, and vomiting are also observed. The cause of death was apnea and cardiac arrest.

In subacute or late forms of the disease, the first clinical manifestations may occur in early childhood. An important symptom is neurological disorders: seizures, transient ataxia, delayed psychomotor development or mental retardation. Signs such as vomiting, hepatomegaly, increased fragility and dry hair.

Laboratory data:

an increase in the concentration of arginine succinic acid in urine, blood and cerebrospinal fluid;
moderate increase in liver enzyme activity;
arginine succinic acid is also found in increased quantities in the amniotic fluid if the fetus is sick.

Treatment: Based on protein restriction. Counts appropriate use arginine on the background of a low-protein diet.

Among our observations, the following are indicative.

Child G., 2 years 3 months, was sent to the Clinical Clinical Hospital and PD with a diagnosis of cerebral palsy. Delayed psychomotor development.

Complaints upon admission: irritability, aggressiveness, Strong smell urine.

Proband from the 1st pregnancy of the 1st birth. The pregnancy proceeded with the threat of termination from 13 weeks. Conservation therapy was carried out. Delivery at 38 weeks. A girl was born, m=2900 g, L=49 cm, with the umbilical cord wrapped three times around her neck. She was discharged from the maternity hospital on the 8th day with a diagnosis of asphyxia of the 1st degree, NGLD of the 1st degree.

Was on natural feeding up to 7 months. Until she was a year old, she was lethargic and sleepy. He holds his head from 5 months, sits from 9 months, walks from 1 year 2 months. From 4 months a strong smell of urine appeared (“ ammonia"). In the 1st year of life she suffered acute bronchitis. From the age of 11 months, the girl began to refuse food and began to vomit periodically. The child became aggressive, easily excitable, and did not interact well. She was first examined by a neurologist at the age of 1 year 8 months and diagnosed with cerebral palsy, atopic-ataxic form. Treatment was carried out. Treatment is not effective. A gait disorder has been noted since the age of 2: he stumbles and often falls. The child does not play with children, is not interested in toys, and does not talk.

Phenotype features

Child of low nutrition. Skin pale, dry. The hair is thin and light. Head circumference 50 cm, prominent forehead. Palpebral fissures D>S, epicanthus, strabismus. Short nose. High sky. The chest is wide. Joint hypermobility upper limbs. Varus position of the feet. Partial cutaneous syndactyly of fingers II and III. Neurological status: S Laboratory research:

When studying the level of blood amino acids using the PICO TAG method, an increase in lysine and threonine was detected;
TLC of amino acids in 24-hour urine: increased ornithine, arginine, glycine, aspartic acid;
uric acid level is 2 times higher than normal;
a computed tomographic examination of the brain reveals moderate signs of hydrocephalus in the form of slight expansion ventricular system and subarachnoid space with moderate hypoplasia of the cerebral cortex;
Ultrasound of the heart: dysplastic cardiopathy;
Ultrasound of the liver: liver + 3.5 cm edge is compacted, granular parenchyma, significantly increased echogenicity;
Pancreas: capsule thickening, increased echogenicity;
Ultrasound of the kidneys: salt inlay;
when conducting a urine test - nitrogen test = 1.3 (N - 1.1 g/l).

After prescribing a protein-restricted diet, the child's condition improved significantly.

Taking into account the complaints, medical history, and data from additional research methods, the child was diagnosed with ornithine transcarbamylase deficiency (hyperammonemia) with an X-linked dominant type of inheritance. Delayed rate of psycho-speech development. Dysplastic cardiopathy. Dysmetabolic nephropathy.

Despite the fact that periodic anemia and hemolysis are characteristic of a number of organic aciduria and hyperammonemia, we encountered in five patients cases where these symptoms were caused by enzymatic defects in the cells of the erythrocyte germ - hereditary erythrocyte enzymopathies. The most systematized of them are the following.

Glutathione reductase deficiency. Not associated with hemolysis. Most probable cause- riboflavin deficiency.
Glutathione peroxidase deficiency. The connection with hemolysis has not been established.
Insufficiency of glutathione synthetic enzymes. Both erythrocyte and tissue deficiency of these enzymes (gamma-glutamyl-cysteine synthetase and glutathione synthetase) are possible. The clinical picture depends on the degree of reduction in enzyme activity and whether the gamma-glutamine cycle in non-erythroid tissue is affected.
Insufficiency of gamma-glutamyl-cysteine synthetase 2 manifests itself with residual enzyme activity at the level of 5% and is accompanied by periodic jaundice, splenomegaly, stone formation, neurological disorders and generalized aminoaciduria.
Insufficiency of 2 glutathione synthetase with a decrease in enzyme activity only in erythrocytes, signs characteristic of chronic hemolysis are noted; when the tissue enzyme is involved, in addition to these signs, neurological disorders, mental retardation and hyperproduction of 5-oxoproline with oxoprolinuria are noted.
Deficiency of glycolytic enzymes. General clinical signs is chronic anemia, reticulocytosis and intermittent hyperbilirubinemia. Anemia levels increase with viral infections. Most children with glycolytic enzyme deficiencies develop significant hyperbilirubinemia in the neonatal period, the level of which may require replacement blood transfusion. There are no pathognomonic signs of glycolytic enzyme deficiency. Hereditary disorders of this group of enzymes should be assumed when chronic hemolytic anemia cannot be explained by more frequent hereditary reasons- spherocytosis and hemoglobinopathy.
Pyruvate kinase deficiency. Pyruvate kinase is encoded by 2 different genes. One (mapped on chromosome 1) is expressed in the liver and erythrocytes; the other (mapped on chromosome 15) - in muscles and leukocytes. Hemolysis is observed in homozygotes for an abnormal gene located on chromosome 1. Hemolysis can be very pronounced. With splenectomy, there is a decrease in the intensity of hemolysis while maintaining a high number of reticulocytes.
Glucose-phosphate isomerase deficiency. The second most common hereditary enzymopathy. The gene is localized on chromosome 19. The main manifestation of the disease is hemolysis. Hemolytic anemia due to deficiency of this enzyme is considered the cause of neonatal polyhydramnios. In adults, splenectomy is moderately effective.
Hexokinase deficiency. Rare hereditary defect. The gene is localized on chromosome 10.
Phosphoglycerate kinase deficiency. X-linked defect. Women suffer from hemolysis varying degrees gravity. In men, the defect is accompanied by severe hemolysis, mental retardation, speech impairment and other neurological disorders.
Phosphofructokinase deficiency. The enzyme consists of 2 types of subunits - muscle (gene on chromosome 1) and liver (gene on chromosome 21). Hemolysis occurs only when enzyme activity is less than 50%. However, already at 50% of enzyme activity, pronounced muscle hypotension is observed. In addition, there is another type of defect of this enzyme with minor hemolysis and no muscle damage.
Triose phosphate isomerase deficiency. Accompanied by neurological disorders and delayed psychomotor development, developing after 6 months.
Disturbances in the metabolism of purines and pyrimidines, accompanied by hemolysis.
Pyrimidine 5'-nucleotidase deficiency. One of the most common enzymopathies is associated with hemolysis. There is mild to moderate anemia, splenomegaly, and a tendency to form pigment stones in the gall bladder. Splenectomy is ineffective.
Excess adenosine deminase. Inherited in an autosomal dominant manner. In the neonatal period, hyperbilirubinemia is observed. At older ages, mild anemia and reticulocytosis are noted.
Adenylate kinase deficiency. Communication with hemolytic anemia not proven.

The group of intermediate metabolism disorders includes disorders of the metabolism of fatty acids, carbohydrates and their transport, mitochondrial disorders, disorders associated with vitamin deficiency, disorders of amino acid transport, and disorders of mineral metabolism.

The second group consists of disorders of the biosynthesis and cleavage of complex molecules - defects in the metabolism of purines and pyrimidines, lysosomal storage diseases, peroxisomal disorders of the metabolism of isoprenoids and sterols, disorders of the metabolism of bile acids and hemes, congenital disorders of glycosylation, disorders of lipoprotein metabolism.

Changes in this group of metabolic diseases, unlike the previous one, manifest themselves in a slow progressive course and are poorly recognized by generally accepted metabolic studies. To identify them, specific studies are needed.

The third group of metabolic disorders - defects in mediators and related disorders - disorders of the metabolism of glycines and serines, pterins and biogenic amines, gamma-aminobutyrates. We hope to announce this in the near future.

We are trying to break down the standard idea that metabolic disorders can only be understood by biochemists.

If in your life there were such great teachers of biochemistry as Professor Aron Abramovich Utevsky and such colleagues as biochemist Professor Ivan Fedorovich Paskevich, then the conviction that metabolic diseases can be understood by a clinician will always be with you. You just need to try to tell everything clearly.

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When amino acids break down, free ammonia is formed, which has a strong toxic effect on the central nervous system. It is rendered harmless by conversion to urea through a series of reactions called the urea cycle. Urea synthesis occurs with the participation of five enzymes: carbamyl phosphate synthetase, ornithine transcarbamylase, arginine succinate synthetase, arginine succinate lyase and arginase. In total, deficiency of these enzymes occurs with a frequency of 1:30000 and is one of the common reasons hyperammonemia.

Genetic causes

High plasma ammonia levels are observed not only with urea cycle enzyme deficiency, but also with other inborn errors of metabolism.

Clinical manifestations of hyperammonemia

In newborns, hyperammonemia, regardless of the causes that caused it, is manifested mainly by symptoms of impaired brain function. These symptoms of hyperammonemia occur in the first days after starting a protein diet. Breast refusal, vomiting, shortness of breath and lethargy quickly turn into a deep coma. Convulsions are also usually observed. Physical examination reveals hepatomegaly and neurological signs of deep coma. In more late dates Acute hyperammonemia is manifested by vomiting, ataxia, confusion, agitation, irritability, and aggressive behavior. Such attacks are interspersed with periods of lethargy and drowsiness leading to coma.

In cases where hyperammonemia is caused by a deficiency of urea cycle enzymes, routine laboratory research do not reveal any specific deviations. The blood urea nitrogen level is usually low and the pH is normal or slightly elevated. If organic acidemia is accompanied by hyperammonemia, then, as a rule, severe acidosis is recorded. Hyperammonemia in newborns is often confused with sepsis; misdiagnosis threatens the death of the child. At autopsy, nothing specific is usually found. Therefore, every child serious condition which cannot be attributed to overt infection, plasma ammonia must be determined.

Diagnostics

Basic diagnostic criterion- increase in plasma ammonia, the concentration of which usually exceeds 200 µM (normal< 35 мкМ). У детей с недостаточностью карбамилфосфатсинтетазы или орнитинтранскарбамилазы уровень большинства аминокислот в плазме остается в норме. Исключение составляют глутаминовая, аспарагиновая кислоты, аланин, содержание которых воз растает вторично (вследствие гипераммониемии).

With ornithine transcarbamylase deficiency, the level of orotic acid in the urine is sharply increased, which distinguishes this defect from carbamyl phosphate synthetase deficiency.

Treatment of acute hyperammonemia

Acute hyperammonemia requires prompt and vigorous treatment. Its purpose is to remove ammonia and provide the body with sufficient calories and essential amino acids. Nutrients, fluids and electrolytes should be administered intravenously. Lipid preparations are a reliable source of calories for intravenous administration. A minimal amount of nitrogen-containing compounds is added to intravenous solutions, preferably in the form of essential amino acids. Immediately after the condition improves, low-protein feeding begins (0.5-1.0 g/kg per day) nutritional mixtures through a nasal tube.

The kidneys do not excrete ammonia well, and to speed up this process it is necessary to convert it into quickly excreted compounds. Sodium benzoate, interacting with endogenous glycine, forms hippuric acid, and each mole of benzoate removes 1 mole of ammonia from the body in the form of glycine. Phenylacetate, interacting with glutamine, forms phenylacetylglutamine, which easily penetrates into the urine. In this case, 1 mole of phenylacetate removes 2 moles of ammonia in the form of glutamine from the body.

For hyperammonemia due to a disorder of the urea cycle (except for arginase deficiency), arginine should be administered, since it serves as a source of ornithine and acetyl glutamate for this cycle.

If after a few hours, despite all these measures, the concentration of ammonia in the blood does not noticeably decrease, hemodialysis or peritoneal dialysis should be started. Exchange blood transfusion weakly reduces the ammonia content in the body. This method is used only when it is impossible to quickly carry out dialysis or the newborn has hyperbilirubinemia. The hemodialysis procedure is technically complex and not always available. Therefore, the most practical method is peritoneal dialysis. When it is carried out, after a few hours, plasma ammonia is significantly reduced, and in most cases, after 48 hours it is completely normalized. Peritoneal dialysis effectively removes not only ammonia from the body, but also organic acids, so it is also indicated for secondary hyperammonemia.

Early administration of neomycin and lactulose through a nasal tube prevents the production of ammonia by intestinal bacteria. Normalization of ammonia does not immediately lead to disappearance neurological symptoms, sometimes it takes several days.

Long-term therapy for hyperammonemia

As soon as the child has regained consciousness, measures are taken against the underlying cause of hyperammonemia. Regardless of the enzymatic defect, all patients require some form of protein restriction (no more than 1-2 g/kg per day). For urea cycle disorders normal level blood ammonia is maintained by chronic administration of benzoate, phenylacetate and arginine or citrulline. Phenylbutyrate can be used instead of the unpleasant odor of phenylacetate. It is also recommended to add carnitine to the diet, since benzoate and phenylacetate reduce its content in the body. However, the clinical effectiveness of carnitine has not been proven. In case of hyperammonemia, prevention of any conditions that enhance catabolic processes is necessary.

The article was prepared and edited by: surgeon

Metabolic disorders are known that are caused by a deficiency of each of the 5 enzymes that catalyze the reaction of urea synthesis in the liver (Fig. 30.13). The rate-limiting steps are likely to be reactions catalyzed by carbamoyl phosphate synthase (reaction 1), ornithine carbamoyltransferase (reaction 2), and arginase (reaction 5). Because the urea cycle converts ammonia to non-toxic urea, all disturbances in urea synthesis cause ammonia poisoning. The latter is more pronounced when reaction 1 or 2 is blocked, since during the synthesis of citrulline, ammonia is already covalently bound to the carbon atom. Clinical symptoms Common to all urea cycle disorders are vomiting (in children), aversion to protein-rich foods, incoordination, irritability, drowsiness and mental retardation.

The clinical manifestations and treatment methods of all the diseases discussed below are very similar. Significant improvement is observed with restriction of protein in the diet, and many brain disorders can be prevented. Food should be taken often, in small portions, in order to avoid rapid promotion blood ammonia level.

Hyperammonemia type I

A case of a disease associated with a deficiency of carbamonyl phosphate synthase is described (reaction 1, Fig. 30.13). This disease is probably hereditary.

Hyperammonemia type II

Numerous cases of disease associated with ornithine carbamoyltransferase deficiency have been reported (reaction 2, Fig. 30.13). This disease is genetically linked to the X chromosome. The mother also has hyperammonemia and an aversion to protein-rich foods. The only constant laboratory and clinical indicator is an increase in glutamine content in the blood, cerebrospinal fluid and urine. This appears to reflect an increase in glutamine synthesis by glutamine synthase (Fig. 30.8), caused by an increase in tissue ammonia levels.

Citrullinemia

This rare disease is probably inherited in a recessive manner. It is characterized by urinary excretion of large amounts of citrulline (1-2 g-day1); the content of citrulline in plasma and cerebrospinal fluid was significantly increased. One of the patients had complete absence argininosuccinate synthase activity (reaction 3, Fig. 30.13). Another patient was found to have a modification of this enzyme. In the culture of fibroblasts from this patient, the activity of argininosuccinate synthase was characterized by a value for citrulline that was 25 times higher than usual. Probably, there was a mutation that caused a significant, but not “lethal” modification of the structure of the catalytic center of the enzyme.

Citrulline (as well as argininosuccinate, see below) can serve as a waste nitrogen carrier because it contains nitrogen “dedicated” to urea synthesis. Arginine intake increases citrulline excretion in patients with this disorder. Likewise, consumption of benzoate “channels” ammonium nitrogen into hippurate (via glycine) (see Figure 32.2).

Argininosuccinate aciduria

This rare disease, inherited in a recessive manner, is characterized by increased content argininosuccinate in blood, cerebrospinal fluid and urine; it is often accompanied by impaired hair growth. Although there are cases of both early and late onset of the disease, it usually develops around the age of two years and is fatal at an early age.

This disease is associated with the absence of argininosuccinase (reaction 4, Fig. 30.13). In cultured skin fibroblasts of a healthy person, the activity of this enzyme can be recorded, but in patients with argininosuccinate aciduria it is absent. In patients, argininosuccinase is also absent in the brain, liver, kidneys and red blood cells. The diagnosis is established quite easily: the patient’s urine is examined using two-dimensional paper chromatography, and argininosuccinate is detected. If you analyze urine not immediately, but after some time, additional spots appear on the chromatogram belonging to cyclic anhydrides, which are formed from argininosuccinate. To confirm the diagnosis, the content of argininosuccinase in red blood cells is measured. For early diagnosis, blood taken from umbilical cord. Since argininosuccinase is also found in the cells of the amniotic fluid, the diagnosis can be made by amniocentesis (puncture amniotic sac). For the same reasons that were given when considering citrullinemia, when arginine and benzoate are consumed in the patients under consideration, the excretion of nitrogen-containing metabolites increases.

Hyperargininemia

This disorder of urea synthesis is characterized by increased levels of arginine in the blood and cerebrospinal fluid, low levels of arginase in red blood cells (reaction 5, Fig. 30.13) and an increase in the content of a number of amino acids in the urine, as is the case with lysine cystinuria. This may reflect competition between arginine, on the one hand, and lysine and cystine, on the other, during reabsorption in the renal tubules. If the patient is transferred to a low-protein diet, there is a decrease in the level of ammonia in the blood plasma and the content of a number of amino acids in the urine.

LITERATURE

Adams E., Frank L. Metabolism of proline and the hydroxypro-lines, Annu. Rev. Biochem., 1980, 49, 1005.

Batshaw M. L. et al Treatment of inborn errors of urea synthesis. Activation of alternative pathways of waste nitrogen synthesis and expression, N. Engl. J. Med., 1982, 306, 1387. Felig P. Amino acid metabolism in man, Annu. Rev. Biochem., 1975, 44, 933.

Msall M. et al. Neurological outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies, N. Engl. J. Med., 1984, 310, 1500.

Nyhan W. L. Heritable Disorders of Amino Acid Metabolism. Patterns of Clinical Expression and Genetic Variation, Wiley, 1974.

Ratner S. Enzymes of arginine and urea synthesis, Adv. Enzy-mol., 1973, 39, 1.

Ratner S. A long view of nitrogen metabolism, Annu. Rev.

Biochem., 1977, 46, 1.

Rosenberg L. E., Scriver C. R. Disorders of amino acid metabolism, Chapter 11. In: Metabolic Control and Disease, Bondy P. K., Rosenberg L. E. (eds), Saunders, 1980.

Stanbury J.B. et al. The Metaboli Basis of Inherited Disease, 5th ed., McGraw-Hill, 1983.

Torchinsky Y. M. Transamination: Its discovery, biological and clinical aspects (1937-1987), Irends Biochem. Sci., 1987, 12, 115.

Tyler B. Regulation of the assimilation of nitrogen compounds, Annu. Rev. Biochem., 1978, 47, 1127.

Wellner D., Weister A. A survey of inborn errors of amino acid metabolism and transport in man, Annu. Rev. Biochem., 1981, 50, 911.

Hyperammonemia is a metabolic disease manifested by insufficiency of the urea enzyme cycle, leading to ammonia poisoning of the body.
Ammonia is a toxic compound found in the blood in relatively small concentrations (11.0-32.0 µmol/l). Symptoms of ammonia poisoning appear when these limits are exceeded by only 2-3 times. Extremely permissible level ammonia in the blood 60 µmol/l. When ammonia concentrations increase (hyperammonemia) to extreme values, coma and death can occur. With chronic hyperammonemia, mental retardation develops.
types: congenital and acquired

Symptoms Transient hyperammonemia is also called borderline state, inherent in newborn children during the period of adaptation to extrauterine life, usually manifesting itself on the second or third day of life. This type of hyperammonemia occurs most often in premature infants with delayed intrauterine development, with a frequency of up to fifty percent of births, but is sometimes recorded in full-term babies. Some children do not show symptoms clinical picture hyperammonemia: signs of depression of the central nervous system (lethargy, decreased muscle tone, apnea attacks, weakened pupillary response to light, refusal to eat, stupor and coma), as well as disorders respiratory function, jaundice, cramps and dehydration. The cause of hyperammonemia is called oxygen starvation, or hypoxia, during pregnancy and during childbirth.
reasons: 1. The binding of ammonia during the synthesis of glutamate causes the outflow of α-ketoglutarate from the tricarboxylic acid cycle, while the formation of ATP energy decreases and cell activity deteriorates.
2. Ammonium ions NH4+ cause alkalization of blood plasma. At the same time, the affinity of hemoglobin for oxygen increases (Bohr effect), hemoglobin does not release oxygen in the capillaries, resulting in cell hypoxia.
3. The accumulation of free NH4+ ion in the cytosol affects membrane potential and the work of intracellular enzymes - it competes with ion pumps for Na+ and K+.
4. The product of ammonia binding to glutamic acid - glutamine - is osmotically active substance. This leads to water retention in the cells and their swelling, which causes tissue swelling. In the case of nerve tissue, this can cause brain swelling, coma and death.
5. The use of α-ketoglutarate and glutamate to neutralize ammonia causes a decrease in γ synthesis -aminobutyric acid(GABA), an inhibitory neurotransmitter of the nervous system.

QUANTITY METHOD FOR DETERMINING UREA IN BLOOD SERUM

In biological fluids, M. is determined using gasometric methods, direct photometric methods based on the reaction of M. with various substances with the formation of equimolecular quantities of colored products, as well as enzymatic methods using mainly the enzyme urease. Gasometric methods are based on the oxidation of M. with sodium hypobromite in an alkaline medium NH 2 -CO-NH 2 + 3NaBrO → N 2 + CO 2 + 3NaBr + 2H 2 O. The volume of nitrogen gas is measured using special apparatus, most often the Borodin apparatus. However, this method has low specificity and accuracy. The most common photometric methods are those based on the reaction of metal with diacetyl monooxime (Feron reaction).

To determine urea in blood serum and urine, a unified method is used, based on the reaction of urea with diacetyl monooxime in the presence of thiosemicarbazide and iron salts in acidic environment. Another unified method for determining M. is the urease method: NH 2 -CO-NH 2 → urease NH 3 +CO 2. The released ammonia forms indophenol with sodium hypochlorite and phenol, which has Blue colour. The color intensity is proportional to the M content in the test sample. The urease reaction is highly specific; only 20 samples are taken for testing. µl blood serum diluted in a ratio of 1:9 with NaCI solution (0.154 M). Sometimes sodium salicylate is used instead of phenol; blood serum is diluted as follows: to 10 µl blood serum add 0.1 ml water or NaCl (0.154 M). The enzymatic reaction in both cases proceeds at 37° for 15 and 3-3 1/2 min respectively.

Derivatives of M., in the molecule of which hydrogen atoms are replaced by acid radicals, are called ureides. Many ureides and some of their halogenated derivatives are used in medicine as drugs. Ureides include, for example, salts of barbituric acid (malonylurea), alloxan (mesoxalyl urea); heterocyclic ureide is uric acid .