Classification and diagnosis
The development of hyperammonemia is generally divided into two main forms:
- Primary. Occurs due to hereditary defects of urea cycle enzymes (ornithine transcarbamylase deficiency is most commonly affected).
- Secondary. Associated with severe liver damage (e.g., viral hepatitis involving up to 80% of the parenchyma or cirrhosis), in which urea synthesis is critically reduced.
The main diagnostic sign is an elevated blood ammonia level. An important clinical feature is that in chronic cases, the basal ammonia level may be normal and increases exclusively after a protein load or against the background of acute complicated diseases. Blood levels of glutamine and alanine, which act as transport forms of nitrogen, also increase. In massive liver damage, serum urea concentration drops (e.g., to 1.4 mmol/L), and its urinary excretion decreases sharply. Additionally, analysis of urea cycle metabolites in urine and determination of enzyme activity in liver biopsies may be required.
Pathogenesis of ammonia neurotoxicity
Excess ammonia has a devastating effect on the central nervous system. This process is mediated through three interrelated mechanisms:
- Neuronal energy starvation. A shift in the glutamate dehydrogenase (GDH) reaction occurs: ammonia binds with α-ketoglutarate and NADH to form glutamate. The depletion of the α-ketoglutarate pool leads to a halt of the citric acid cycle and severe ATP deficiency in nerve cells.
- Cerebral edema. The resulting glutamate attaches another molecule of ammonia and is converted into glutamine. Massive accumulation of glutamine in astrocytes increases intracellular osmotic pressure, causing brain tissue edema.
- Convulsive syndrome. Due to the active consumption of glutamate for glutamine synthesis, the production of its derivative — GABA (gamma-aminobutyric acid) — is suppressed. GABA is the primary inhibitory neurotransmitter. Its deficiency disrupts nerve impulse conduction, reduces inhibitory processes, and causes seizures.
Hereditary enzymopathies of the urea cycle
Blockade of any step of the urea cycle leads to the accumulation of toxic metabolic products. All of the diseases listed below are inherited in an autosomal recessive manner and can manifest as severe hyperammonemia in newborns or in adults after protein consumption.
| Disease | Enzyme defect | Accumulated metabolites |
|---|---|---|
| Citrullinemia | Argininosuccinate synthetase | Citrulline ↑ (blood, urine) |
| Argininosuccinic aciduria | Argininosuccinate lyase | Argininosuccinate ↑ (blood, urine), Gln, Ala, Lys (urine) |
| Hyperargininemia | Arginase | Arginine ↑ (blood, urine), Lys, Ornithine (urine) |
Treatment and condition management
The main goal of therapy is to reduce blood ammonia concentration. The cornerstone of treatment is a low-protein diet, which artificially limits nitrogen intake.
Pharmacotherapy includes the administration of urea cycle metabolites (arginine, citrulline, glutamate). Their mechanism of action is based on stimulating the excretion of ammonia bypassing impaired reactions. Nitrogen is excreted via alternative pathways — for example, as part of phenylacetylglutamine and hippuric acid.
In argininosuccinic aciduria, the administration of high doses of arginine helps restore ornithine levels. Ornithine restarts the urea cycle, binding ammonia and aspartate into argininosuccinate. This substance, containing two nitrogen atoms, is safely excreted in the urine, replacing urea. Additionally, patients may be prescribed keto analogs of valine, leucine, isoleucine, and phenylalanine, which leads to a significant drop in ammonia levels and a decrease in the excretion of pathological metabolites.
Briefly: answers to topical questions
What five main enzymes normally participate in the urea cycle?
Five main enzymes of urea synthesis participate in the urea cycle:
- Carbamoyl phosphate synthetase I;
- Ornithine transcarbamylase;
- Argininosuccinate synthetase;
- Argininosuccinate lyase;
- Arginase.
When urea cycle steps are blocked, toxic products of nitrogen metabolism accumulate.
Which urea cycle enzymes are localized in the mitochondria and which in the cytosol?
Urea cycle enzymes have a distinct compartmentalization and are distributed between the mitochondria and the cytosol of the cell. The first two reactions take place in the mitochondria, and the subsequent three reactions occur in the cytosol.
| Localization | Enzymes |
|---|---|
| Mitochondria | Carbamoyl phosphate synthetase I, Ornithine transcarbamylase |
| Cytosol | Argininosuccinate synthetase, Argininosuccinate lyase, Arginase |
The rule of the three "O"s in ammonia toxicity to the brain: TCA cycle arrest (ATP deficiency), Astrocyte edema (glutamine excess), and Outage of GABA (seizures).
Class and exam questions
Why do severe seizures occur in hyperammonemia?
Excess ammonia binds glutamate, converting it into glutamine. Due to a shortage of glutamate, the synthesis of the crucial inhibitory neurotransmitter, GABA, decreases, which weakens inhibitory processes in the brain and leads to seizures.
How to confirm the diagnosis if the blood ammonia level is normal?
In the chronic course, the basal ammonia level often remains normal. A protein load is used for diagnostics, after which the concentration of the toxin in the blood rises sharply.
What is the rationale behind treating argininosuccinic aciduria with high doses of arginine?
Arginine is cleaved by arginase into ornithine, which restarts the urea cycle. Ammonia is bound into argininosuccinate, which accumulates and is easily excreted in the urine, taking over the role of urea in nitrogen excretion.
What else to study on this topic
- Mechanism of the therapeutic action of amino acid keto analogs in enzymopathies.
- Alternative pathways of nitrogen excretion: biosynthesis of hippuric acid and phenylacetylglutamine.
- Changes in biochemical blood and urine parameters in severe viral hepatitis.
- Features of determining urea cycle enzyme activity in liver biopsy specimens.
- The role of alanine and glutamine as transport forms of ammonia in health and disease.
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