Urea cycle defects in adulthood: clinical presentation, diagnosis and treatment in genetically encoded hepatic metabolic disorders with a potential for encephalopathy

Abstract

Hyperammonaemia is an important cause for encephalopathy. Ammonia is the waste product of amino acid degradation and cannot be excreted via urine. Ammonia is metabolized to water-soluble urea via the urea cycle. Hyperammonaemia not only occurs during acute liver failure, but also in rare genetically determined defects of enzymes or transporters involved in the urea cycle resulting in elevated ammonia concentrations. Enzyme defects include deficiency of carbamylphosphate synthase, N-acetylglutamate synthase, ornithine transcarbamylase, argininosuccinate lyase and arginase, transporter defects are citrin deficiency and HHH-syndrome. These urea cycle defects (UCD) mostly manifest for the first time during the neonatal period, infancy or childhood, however first clinical manifestations including encephalopathy may be observed in adulthood in milder forms. Therefore, physicians treating adults should be aware of clinical symptoms in UCD to make a timely diagnosis and initiate treatment. In adulthood, clinical symptoms are often uncharacteristic including headache, avoidance of high-protein food, psychiatric symptoms triggered by heavy exercise or delivery of a child, autism, attention deficit, lethargy, developmental delay and epilepsy. Elevated ammonia concentrations in blood are the biochemical hallmark. Some UCDs can be diagnosed at metabolite level, others only at genetic level. Treatment consists of eucaloric, low-protein diet supplemented with essential amino acids and vitamins/trace elements, and intake of arginine or citrulline. Pharmacological scavengers of nitrogen are benzoate and butyrate. If conservative therapy fails, hemodialysis should be considered. Prompt treatment during acute crises is essential for optimal outcome. Liver transplantation is considered in metabolically unstable patients. For arginase deficiency, enzyme replacement therapy is available.

Keywords: Amino acids; Ammonia; Benzoate; Glycerophenylbutyrate; Scavengers; Urea cycle defect.

Fig. 1

Schematic view of the urea cycle. Enzymes, transporters and metabolites involved in the urea cycle. Ammonia resulting from protein degradation is converted to urea. As an example of a UCD, enzyme deficiency of ASS in ASSD is marked by the red bar

Fig. 2

Schematic view of nitrogen scavengers. The mode of action of the nitrogen scavengers phenylbutyrate (left) and benzoate (right). Both compounds are conjugated with amino acids containing nitrogen atoms (circles) and form water-soluble compounds, which can be excreted via urine