Hyperammonemia is a medical condition characterized by elevated levels of ammonia in the blood, a toxic byproduct of protein metabolism. Normally, the liver converts ammonia into urea through the urea cycle for safe excretion by the kidneys. When this detoxification process fails—due to liver disease or a genetic error—ammonia rapidly accumulates in the bloodstream. This build-up is highly damaging to the central nervous system, quickly leading to hepatic encephalopathy. Prompt intervention is necessary because sustained high ammonia levels can result in cerebral edema, irreversible brain injury, coma, and death.
Rapid Removal Techniques
When ammonia levels reach dangerous concentrations during an acute crisis, mechanical filtration of the blood is the fastest method for clearance. Extracorporeal treatments physically draw the small ammonia molecules out of the circulation. This approach is initiated when blood ammonia levels are extremely high or when initial drug therapy has failed to produce a quick reduction.
Hemodialysis (HD) is the most effective and rapid method for ammonia removal, often reducing levels by 50% within the first few hours. Its superior clearance rate is due to the high diffusion gradient created by the dialyzer, which exploits the small molecular size of ammonia. Despite its speed, intermittent HD can be challenging in unstable patients, such as critically ill neonates, because it can cause rapid fluid shifts and hemodynamic instability.
Continuous Renal Replacement Therapy (CRRT) is often the preferred extracorporeal treatment in intensive care settings. While CRRT is slower than intermittent HD, its continuous nature offers better control over fluid balance and blood pressure. This steady, sustained removal minimizes the risk of a rapid ammonia rebound effect that can occur after the cessation of intermittent treatment. CRRT provides safer and more stable management for vulnerable patients.
Pharmacological Ammonia Scavengers
Pharmacological ammonia scavengers introduce alternative pathways for nitrogen excretion, effectively bypassing the dysfunctional urea cycle. This drug therapy is initiated rapidly during an acute hyperammonemic episode and is continued for long-term management. The most common agents are a combination of sodium phenylacetate and sodium benzoate, which provide chemical substrates that bind to nitrogenous compounds.
Sodium benzoate conjugates with the amino acid glycine to form hippurate, sequestering one molecule of nitrogen for safe excretion in the urine. Sodium phenylacetate is metabolized to phenylacetyl-CoA, which then binds with glutamine to create phenylacetylglutamine. This scavenging action is effective because glutamine contains two nitrogen atoms, meaning its excretion removes a significant nitrogen load from the body.
The newly formed compounds, hippurate and phenylacetylglutamine, serve as substitutes for urea, carrying waste nitrogen out of the body through the kidneys. This process helps decrease the plasma concentration of ammonia and its precursor, glutamine, which contributes to neurotoxicity. For patients with Urea Cycle Disorders (UCDs), supplementation with specific amino acids is a necessary part of the pharmacological regimen.
Patients with deficiencies in enzymes like ornithine transcarbamylase (OTC) or carbamoyl phosphate synthetase (CPS) require supplementation with L-arginine or L-citrulline. Arginine is the final amino acid in the urea cycle and is needed to drive the cycle forward, promoting nitrogen excretion even if the cycle is partially impaired. Citrulline is often used as a precursor that the body converts into arginine. This helps maintain adequate levels of the essential compound to support the residual function of the urea cycle.
Dietary Adjustments and Gut Detoxification
Controlling ammonia production within the gut and managing dietary nitrogen intake form the foundation of long-term hyperammonemia management. Since ammonia is primarily produced from the breakdown of protein by intestinal bacteria, a strict, medically supervised protein-restricted diet is necessary. The goal is to limit the nitrogen substrate available for ammonia generation while ensuring sufficient protein and calories to prevent the body from breaking down muscle, which releases an uncontrolled nitrogen load.
Lactulose, a non-absorbable synthetic sugar, is a mainstay for gut detoxification, particularly in acquired hyperammonemia from liver failure. Once it reaches the colon, gut bacteria ferment lactulose into short-chain organic acids, primarily lactic and acetic acid. This fermentation process lowers the pH of the colon, creating an acidic environment.
The lowered pH facilitates the conversion of ammonia (NH3) into the non-absorbable ammonium ion (NH4+), trapping the nitrogen within the colon. Lactulose also acts as an osmotic laxative, increasing bowel movements. This cathartic effect physically flushes the trapped ammonium ions and other nitrogenous waste products out of the body, reducing the time available for ammonia absorption.
Rifaximin, a non-absorbable oral antibiotic, is often used in combination with lactulose for chronic management. Because it is poorly absorbed into the systemic circulation, its effect concentrates entirely within the gastrointestinal tract. Rifaximin works by suppressing the population of ammonia-producing bacteria in the colon, decreasing the overall load of nitrogenous compounds generated.
Treating the Primary Condition
While the immediate focus is to lower toxic ammonia levels, the long-term strategy involves treating the underlying cause to prevent future crises. For severe hyperammonemia resulting from end-stage liver disease or a severe UCD, orthotopic liver transplantation (OLT) remains the only definitive cure. The transplanted liver contains the necessary enzymes to restore a fully functional urea cycle, normalizing the body’s ability to detoxify ammonia.
Successful OLT eliminates the risk of hyperammonemic crises and the need for a highly restrictive diet or daily ammonia-scavenger medication. However, it is a major surgical procedure that requires lifelong immunosuppression to prevent organ rejection. The neurodevelopmental outcome following transplantation largely depends on the extent of brain damage that occurred during the initial hyperammonemic episodes.
For inherited disorders like UCDs, advanced therapies aim to provide a corrective treatment without the risks of major surgery. Gene therapy approaches are being investigated to deliver a functional copy of the defective enzyme gene directly to the liver cells. This involves using specialized viral vectors, such as adeno-associated viruses (AAV), to shuttle the genetic material into the hepatocytes, restoring missing enzyme activity. Advanced gene editing techniques, like prime editing, are also being explored to permanently correct the patient’s disease-causing genetic variant in the liver, offering the potential for a complete, one-time treatment.