Ornithine: Effects in Hepatic Encephalopathy

Ornithine is a non-proteinogenic amino acid that plays a central role in the liver's urea cycle. As a medication, L-ornithine L-aspartate (trade names Hepa-Merz, Ornithine Aspartate, and generics) is used, a salt consisting of L-ornithine and L-aspartate. Its use has become established in hepatology, especially for lowering elevated ammonia levels in hepatic encephalopathy. In Germany, L-ornithine L-aspartate is approved for intravenous acute treatment and oral maintenance therapy.

In chronic liver disease such as cirrhosis, the detoxification function is impaired. Ammonia, which is produced in the intestine from protein breakdown and bacterial metabolism, is no longer efficiently converted to urea and enters the central nervous system. The consequences include concentration disorders, sleep-wake reversal, confusion, balance disorders, tremor, and in advanced stages consciousness disorders up to coma. L-ornithine L-aspartate supports two important mechanisms of ammonia detoxification and can alleviate these symptoms or reduce their frequency.

Mechanism of Action

L-ornithine L-aspartate works via two pathways simultaneously. L-ornithine is a substrate of the urea cycle in the liver and stimulates the formation of urea from ammonia. L-aspartate serves as a substrate for glutamate synthesis in both the liver and muscle, which in turn forms glutamine with ammonia. This glutamine formation is the most important alternative detoxification pathway, especially when liver function is significantly impaired. In muscle, approximately 30 to 50 percent of total ammonia detoxification can occur through glutamine synthesis.

In studies such as the OHE Trial series and multiple meta-analyses, L-ornithine L-aspartate lowers plasma ammonia levels and improves clinical and psychometric tests in hepatic encephalopathy. In patients with manifest encephalopathy, intravenous therapy showed faster symptom improvement than placebo, while in chronic courses, oral maintenance therapy reduced the frequency of recurrent episodes.

Oral bioavailability is high at approximately 90 percent, the half-life is several hours, and metabolism occurs via the natural metabolic pathways of amino acids. Accumulation is practically absent, which is why the safety profile is favorable.

Indications

• Acute hepatic encephalopathy in liver cirrhosis or acute liver failure, intravenously as part of acute treatment
• Chronic hepatic encephalopathy as oral maintenance therapy to reduce recurrent episodes
• Subclinical or minimal hepatic encephalopathy, a form without clinically obvious symptoms but with measurable cognitive deficits
• Adjuvant in hyperammonemia from other causes, such as after valproate overdose or in rare genetic metabolic disorders

L-ornithine L-aspartate is not first-line treatment for acute liver failure without the possibility of liver transplantation, but rather a supplementary measure. In the treatment of encephalopathy, lactulose, rifaximin, and if necessary plasma purification procedures remain established standards.

Dosage and Administration

Acute intravenous therapy: 20 to 40 g L-ornithine L-aspartate per day as slow infusion over several hours. Maximum dose depending on clinical setting up to 80 g per day in specialized settings.

Oral maintenance therapy: usually 9 g (three sachets of 3 g each) three times daily, thus 27 g per day. Dissolve granules in a glass of water and take after meals.

In minimal hepatic encephalopathy: 9 g two to three times daily, in studies for at least four weeks with measurable improvement in psychometric performance.

Renal insufficiency: caution if eGFR is below 30 ml per minute. Very high doses could theoretically lead to accumulation of individual metabolites. Liver insufficiency: therapy is indicated precisely here, dose adjustment is usually not required, but very advanced liver disease hardly allows an effective therapeutic response.

Administration instructions: dissolve oral granule sachets with plenty of fluid, drink sufficient amounts. With intravenous administration, observe infusion duration, as too rapid infusion can intensify nausea and vomiting.

Side Effects

Frequent: nausea, vomiting, abdominal pain, diarrhea, especially with too rapid infusion or too high oral dose.

Occasional: allergic skin reactions, local reaction at the infusion site, minor shifts in acid-base balance.

Rare: paradoxical hyperammonemia at very high doses without adjustment for severity of liver disease, serious allergic reactions.

Note in acute encephalopathy: the effect does not occur abruptly but over hours to days. Pure symptomatology from alertness response is not to be expected, therefore therapy is usually combined with other measures such as lactulose and rifaximin.

Drug Interactions

• Lactulose: synergistic effect in the treatment of hepatic encephalopathy, frequent combination.
• Rifaximin: complementary effect through reduction of ammonia-producing intestinal bacteria, often combined in practice.
• Diuretics: important to consider in patients with ascites, because volume shifts and electrolyte disturbances can trigger encephalopathy.
• Sedatives and opioids: caution in patients with liver disease, because central effects can be intensified and can trigger or worsen encephalopathy.
• Valproate: can itself cause hyperammonemia, in this constellation L-ornithine L-aspartate is an option.
• Other amino acid infusions: individual coordination necessary in parenteral nutrition.

Special Notes

Pregnancy: data limited, use only with strict indication. In acute hepatic encephalopathy of the mother, treatment is necessary, risk-benefit assessment is made individually. Breast-feeding: low data, transition into breast milk not thoroughly researched, individual decision.

Children: in rare metabolic disorders with hyperammonemia, L-ornithine L-aspartate can be used supplementarily to specific therapy, always in specialized centers.

Before starting therapy: history and clinical presentation of hepatic encephalopathy, ammonia levels, liver and kidney values, acid-base balance, electrolytes. Triggering factors such as infections, gastrointestinal bleeding, diuretic therapy, protein overload, constipation, or sedatives should be identified and addressed.

Accompanying measures: lactulose to reduce intestinal transit and pH, rifaximin as non-absorbable antibiotic, treatment of triggering factors such as infections or bleeding, prevention of constipation.

Lifestyle: in chronic liver disease, balanced nutrition with adequate protein (approximately 1.2 to 1.5 g per kg per day from plant and milk-based sources), alcohol avoidance, treatment of underlying liver disease, regular follow-up examinations are essential.

Driving ability: with manifest encephalopathy, driving is prohibited. Even minimal encephalopathies can significantly impair reaction capacity, medical assessment is necessary.

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• Glucagon, metabolic hormone and emergency medication

Frequently Asked Questions

Sources

• Gelbe Liste, L-Ornithine L-Aspartate Active Ingredient Profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines on Liver Cirrhosis and Hepatic Encephalopathy
• German Society of Gastroenterology