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Hyperammoniemia

1. GENERAL INFORMATION

1.1 Incidence, risk factors and pathophysiology

Hyperammonaemia is diagnosed as a ammonia level above 30 ùmol/L. Ammonia is metabolized in the urea cycle, a metabolic pathway that transforms nitrogen to urea in the liver for excretion from the body. Urea cycle defects lead to hyperammonaemia and life-threatening illnesses.

Liver toxicity can be due to metastatic disease, cancer treatment or veno-occlusive disease.
•    In cancer patients, the liver is one of the most common sites affected by metastatic disease. Its functional failure, however, which requires the destruction of more than 70% of the hepatic parenchyma, is usually seen in the end-stage disease. However, in some patients acute liver failure may lead to the identification of a primary or metastatic cancer.
•    Chemotherapy can induce liver toxicity.
o    In patients treated with asparaginase, severe hepatic failure and hyperammonaemia due to chemotherapy have been reported.
o    Idiopathic hyperammonaemia has been described after intensive chemotherapy for leukaemia (2.5% of patients) and following bone marrow transplantation (0.5-1% of patients). This syndrome occurs 2-4 weeks after chemotherapy or bone marrow transplantation and mortality is very high (70-80%). The aetiology is unknown.
o    Hepatic failure secondary to sclerotising cholangitis has been reported after infusion of the hepatic artery with fluorouridine.
•    An increased central venous pressure (e.g. superior vena cava syndrome) can result in hepatic dysfunction. However, clinically significant liver necrosis, which may occur, is probably rare.

2. DIAGNOSIS

2.1 Clinical presentation

Severe hyperammonaemia is associated with a metabolic encephalopathy resulting in lethargy, confusion, disorientation, and agitation. Evolution to coma and seizures is rapid. Due to hepatic failure, jaundice and bleeding may be present.

2.2 Diagnosis

Diagnosis is made by serum ammonia determination. Patients may have a respiratory alkalosis and may show signs of clotting disorders (e.g. bleeding). Liver function tests are abnormal with advanced liver disease.

3. PROGNOSIS

The prognosis of patients with extensive liver metastases of solid tumours and hyperammonaemia is poor and reported mortality is very high (70-80%).

4. TREATMENT

4.1 Treatment of hyperammoniemia

Liver failure observed in cancer patients is primarily related to extensive liver metastases with end-stage disease. Palliative care should be offered to these patients as a standard treatrment , on a type C basis.
Haemodialysis and ammonium-trapping therapy are suitable for individual clinical use, on a type R basis in patients with idiopathic hyperammonaemia following high-dose chemotherapy.
•    Haemodialysis should be started as soon as possible after hospital admission of a patient with severe hyperammonaemia to decrease serum ammonia level below 200 µmol/L and is subsequently discontinued.
•    Pharmacologic therapy of hyperammonaemia consists of administration of sodium phenylacetate and sodium benzoate, that scavenge ammonia by creating an alternate pathway to excrete nitrogen precursors. This treatment option can be considered suitable for individual clinical use, on a type 3 level of evidence. Phenylacetate combines with glutamine to form phenylacetylglutamine and benzoate combines with glycine to form hippurate. These conjugation products are water soluble and are excreted in the urine. Therefore, adequate renal function is essential. Hepatic toxicity due to L-asparaginase requires a decrease of the administered doses, and must be considered as suitable for individual clinical use, on a type R basis.

INDEX

Shih VE. Alternative-pathway therapy for hyperammonemia. N Engl J Med 2007; 356: 2321-2 [Medline]

Dr. Dirk Schrijvers (Reviewer)
University Hospital Antwerp – Antwerp, Belgium
mail: Dirk.Schrijvers@zna.be

Dr. Silvia Spinazzé (Associate Editor)
START Programme
mail: silvia.spinazze@poste.it