Classification and Diagnosis
Hyperammonemia is generally divided into two main forms:
- Primary. Caused by inherited defects in urea cycle enzymes (ornithine transcarbamylase deficiency is the most common).
- Secondary. Associated with severe liver damage (e.g., viral hepatitis affecting up to 80% of the parenchyma or cirrhosis), which critically impairs urea synthesis.
The main diagnostic feature is an elevated blood ammonia concentration. An important clinical characteristic is that in chronic cases, basal ammonia levels may be normal and rise exclusively after a protein load or during acute complicated illnesses. Blood levels of glutamine and alanine, which act as nitrogen transport forms, are also elevated. In massive liver damage, serum urea concentration drops (e.g., down to 1.4 mmol/L), and its urinary excretion is sharply reduced. Additionally, analysis of urea cycle metabolites in urine and enzyme activity assays in liver biopsies may be required.
Pathogenesis of Ammonia Neurotoxicity
Excess ammonia exerts devastating effects on the central nervous system through three interrelated mechanisms:
- Neuronal Energy Starvation. The glutamate dehydrogenase (GDH) reaction shifts: ammonia binds with $\alpha$-ketoglutarate and NADH to form glutamate. Depletion of the $\alpha$-ketoglutarate pool halts the citric acid cycle (Krebs cycle), leading to severe ATP depletion in nerve cells.
- Cerebral Edema. The newly formed glutamate binds another ammonia molecule to become glutamine. Massive accumulation of glutamine in astrocytes increases intracellular osmotic pressure, causing brain tissue swelling.
- Seizure Activity. 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 triggers seizures.
Inherited Urea Cycle Enzymopathies
Blockade of any step in 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 neonates or in adults following protein ingestion.
| Disease | Enzyme Defect | Accumulated Metabolites |
|---|---|---|
| Citrullinemia | Argininosuccinate synthetase | Citrulline $\uparrow$ (blood, urine) |
| Argininosuccinic aciduria | Argininosuccinate lyase | Argininosuccinate $\uparrow$ (blood, urine), Gln, Ala, Lys (urine) |
| Hyperargininemia | Arginase | Arginine $\uparrow$ (blood, urine), Lys, Ornithine (urine) |
Treatment and Management
The primary goal of therapy is to lower blood ammonia concentration. The cornerstone of treatment is a low-protein diet, which artificially restricts 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 via pathways bypassing the blocked reactions. Nitrogen is excreted through alternative routes—for example, as phenylacetylglutamine and hippuric acid.
In argininosuccinic aciduria, the administration of high doses of arginine restores 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, substituting for urea. Additionally, patients may be prescribed keto analogs of valine, leucine, isoleucine, and phenylalanine, leading to a significant drop in ammonia levels and decreased excretion of pathological metabolites.