“Hyperammonemia” - A Look Beyond the Liver

Abstract

Purpose: A 51-year-old female with history of seizure disorder and stroke presented with decreased level of consciousness and lethargy of one day duration. She did not have other symptoms of neurologic or liver disease. On examination, the patient was drowsy but responsive. Her vital signs and rest of the physical examination was normal except residual weakness in left upper extremity from her previous stroke. The patient had no signs of jaundice and no stigmata of chronic liver disease. Seizures had been well controlled with valproate. Complete blood count, electrolytes, creatinine, liver biochemistry, international normalized ratio and albumin, were normal. The results of a toxicology screen and a head CT scan were unremarkable. The patient's serum valproate level was 77.4 mcg/ml, which was within the therapeutic range (50-120 mcg/ml). An electroencephalogram showed diffuse slowing of background activity consistent with metabolic encephalopathy. Subsequent tests revealed an elevated ammonia level 195 mmol/l (3-37). Her liver biochemistry was normal; thus, valproate-related hyperammonemic encephalopathy (VHE) was suspected. To support the diagnosis, carnitine levels were checked. Her free carnitine level was 4 μMol/l (25-60) and total carnitine level was 9 μMol/l (34-86) both of which were low. Valproate therapy was immediately discontinued, and was started on treatment with L-Carnitine. Over the next week, the patient's level of consciousness and ammonia level returned to normal. Hyperammonemic encephalopathy with normal liver function is an uncommon serious adverse effect of valproate therapy. VHE is characterized by a decreasing level of consciousness, vomiting, and lethargy. Several mechanisms have been postulated to cause hyperammonemia; 1) Propionate, a metabolite of valproate reduces carbamoyl phosphate synthetase 1 activity results in accumulation of ammonia. 2) Reduction of hepatic carnitine levels by valproate which disrupts the urea cycle resulting in ammonia accumulation. Treatment with carnitine supplements can lead to an early favorable clinical response due to the probable carnitine deficiency induced by a valproate (VPA) treatment. In our patient, there was a good correlation between the fall in serum ammonia levels (after VPA withdrawal) and clinical improvement confirming our diagnosis of Valproate induced hyperammonemic encephalopathy. Conclusion: We often attribute encephalopathy and elevated levels of serum ammonia to liver failure. However, other conditions, including valproate-related hyperammonemic encephalopathy, must be considered. In our case, the clues to the correct diagnosis were the patient's normal hepatic synthetic function and the use of valproate therapy.