Case 1: Recurrent acute liver dysfunction in a 19-month-old boy

A male infant with an unremarkable family history and medical history presented initially at 12 months of age with vomiting and recurrent otitis media, which was treated successfully with antibiotics. At 16 months of age, he presented again to the emergency room with severe vomiting with hematemesis, in the context of a recurrent otitis under antibiotic treatment. A gastric lavage was performed and his clinical status improved rapidly following treatment with intravenous fluid rehydration and ranitidine. His coagulation profile revealed a mildly increased international normalized ratio (INR) of 1.63 (normal 0.8 to 1.3). On day 6 after the emergency room visit, the coagulopathy was found to have worsened, with his INR increasing to 2.66. Vitamin K therapy was empirically begun, and antibiotic therapy was discontinued. On day 10, the patient’s INR had decreased to 1.61, plasma ammonia level was 39 μM (normal 0 μM to 55 μM) and his hepatic profile showed transaminase elevation up to 767 IU/L for aspartate aminotransferase (normal 22 IU/L to 58 IU/L) and 1108 IU/L for alanine aminotransferase (normal 11 IU/L to 39 IU/L), and a mild increase in alkaline phosphatase and direct bilirubin. At this time, the patient was clinically well. Complementary investigations were performed. Ceruloplasmin and α1-antitrypsin levels were normal. Serology for Epstein-Barr virus, cytomegalovirus and hepatitis A, B and C viruses were negative, as were antinuclear, smooth muscle and antiliver kidney microsome-1 autoantibodies. Abdominal ultrasonography demonstrated an architecturally normal liver. Liver functions gradually normalized over the course of three weeks. It was suspected that the liver dysfunction was related to an idiosyncratic reaction to cephalosporins. At 19 months of age, the infant presented for a third time to the emergency room with vomiting, poor oral intake and lethargy. The patient exhibited tachycardia (heart rate 191 beats/min), tachypnea (respiratory rate 30 breaths/min, oxygen saturation 100%) and dehydration with cold extremities and prolonged capillary refill. He was afebrile. Capillary blood gas analysis showed pH 7.43, partial pressure of carbon dioxide 29 mmHg and a calculated bicarbonate level of 18.7 mM. His lactate levels and anion gap were normal, and his hepatic workup demonstrated a mildly elevated INR of 1.52 and normal transaminase levels. Because of the patient’s lethargy, his plasma ammonia level was tested and was found to be elevated (179 μM). Additional laboratory tests confirmed the diagnosis. Urea cycle defects (UCDs) are rare inborn errors of metabolism that are characterized by impaired conversion of ammonia to urea, causing hyperammonemia (1). Ammonia accumulation causes hyperventilation and respiratory alkalosis, as well as a secondary increase in glutamine, which can cause cerebral edema. In the present case, the hyperammonemia associated with illness and prolonged fasting, the presence of specific amino acid profile changes, the elevation of orotic acid levels and the quick clinical and biochemical response to treatment with increased calories cannot be explained merely by the liver dysfunction itself. These findings support the diagnosis of a UCD. A biochemical diagnosis of ornithine transcarbamylase deficiency (OTCD, Table 1) was made in the context of mild hyperammonemia in the presence of elevated urine orotic acid levels (2345 μmol/mmol creatinine, normal 0 μmol/mmol creatinine to 11 μmol/mmol creatinine) and abnormal plasma amino acid chromatography revealing elevated glutamine (724 μM, normal 473 μM to 689 μM), low ornithine (11 μM, normal 24 μM to 70 μM), normal citrulline (19 μM, normal 16 μM to 34 μM) and low arginine levels (29 μM, normal 45 μM to 95 μM) (2). Homocitrullinuria was absent. It is important to note that plasma amino acid levels can be within the normal range outside of the acute episode and also that expanded newborn screening does not identify OTCD. OTCD (Online Mendelian Inheritance in Man #311250) is the most common inherited disorder of the urea cycle and has a prevalence of approximately one in 60,000 and is transmitted as an X-linked recessive trait (1). In the present case, sequencing of the ornithine transcarbamylase (OTC) gene was normal. However, current methods detect only 80% of mutations in patients with OTCD. In patients without a detected mutation, a liver biopsy can demonstrate reduced OTC activity to further support the diagnosis, but it was declined in the present case. Amino acid profile and orotic acid level in different urea cycle disorders May be elevated; Not high in neonates. ASA Argininosuccinic acid; Arg Arginine; CPS 1 Carbamylphosphate; Cit Citrulline; HHH Hyperammonemia hyperornithinemia homocitrullinuria; LPI Lysinuric protein intolerance; NAGS N-acetylglutamate synthase; N Normal; ND Not detectable; Orn Ornithine; OTC Ornithine transcarbamylase deficiency; P Plasma; U Urine Amino acid profile and orotic acid level in different urea cycle disorders May be elevated; Not high in neonates. ASA Argininosuccinic acid; Arg Arginine; CPS 1 Carbamylphosphate; Cit Citrulline; HHH Hyperammonemia hyperornithinemia homocitrullinuria; LPI Lysinuric protein intolerance; NAGS N-acetylglutamate synthase; N Normal; ND Not detectable; Orn Ornithine; OTC Ornithine transcarbamylase deficiency; P Plasma; U Urine Patients with UCD typically have severe enzyme deficiency and present in the neonatal period with irritability, poor feeding, vomiting and lethargy secondary to severe hyperammonemia. Some patients only have partial enzyme deficiency and present later in childhood, or even adulthood, during times of catabolic stress, such as prolonged fasting or illness. Catabolic stress causes increased protein breakdown that leads to increased ammonia production, which can exceed their residual enzymatic capacity. In OTCD, this late-onset presentation is observed in up to 30% of male patients. Variable symptoms have been reported in these patients, including protein avoidance, psychosis, behavioural changes, recurrent vomiting, episodic ataxia, seizures and hyperammonemic coma (1,3). Acute liver dysfunction has been very rarely described as the sole presentation of UCD, but this presentation may have been under-recognized (4). The present case, which is most likely OTCD, illustrates this very rare presentation and shows that lethargy and hyperammonemia may not be predominant. The laboratory chronology of the patient indicates that the elevated levels of ammonia appear early in the course of liver dysfunction and may not be detected later when liver dysfunction is still observed. Paediatricians should recognize this presentation of a UCD and promptly measure plasma ammonia, plasma amino acid and urinary orotic acid levels to screen for this potentially life-threatening disease. Early recognition of late-onset UCD and appropriate treatment can prevent death and other complications, such as intellectual disability (3). Simple measures should be promptly started while waiting for diagnostic confirmation and include the removal of dietary protein sources and initiation of intravenous fluids containing 10% dextrose at 1.5 to 2 times the maintenance rate to prevent further catabolism. A genetic-metabolic specialist should be consulted to assist with the diagnostic laboratory evaluation and any additional medications that may be required. These medications include the ammonia scavengers, sodium phenylacetate and sodium benzoate, and L-citrulline or L-arginine to ensure an adequate amount of urea cycle intermediates. Failure to respond to these measures during the acute crisis requires hemodialysis. Long-term therapy options are dependent on the residual enzyme activity and can include dietary protein restriction, supplementation with essential amino acids, L-arginine or L-citrulline, and oral ammonia scavenger drugs. Late-onset UCDs are life-threatening but treatable disorders that should be considered in the differential diagnosis of infants and toddlers presenting with protein avoidance, psychosis, behavioural changes, recurrent vomiting, episodic ataxia, seizures, unexplained coma and acute liver dysfunction. Plasma ammonia, plasma amino acid and urinary orotic acid levels should be tested promptly when suspecting UCDs.

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