Hyperammonemic Encephalopathy Induced by Valproic Acid: Don’t Blame the Liver This Time

Brian Dinh, MD
Kyle Ball, DO
Sangeeta Agrawal, MD
Volume 56 - Issue 9 - September 2016

A 60-year-old man with a history of depression, migraines, osteoarthritis, neuropathy, and chronic opioid use for back pain presented to the emergency department with a 1-week history of generalized weakness and altered mental status. His medications included fluoxetine, valproic acid (VPA), sumatriptan, methocarbamol, gabapentin, oxycodone-acetaminophen, and a fentanyl patch.

On physical examination, the patient was afebrile, somnolent, and slow to respond. Strength was 4/5 in the upper and lower extremities, with patchy decreased sensation.

Results of basic laboratory studies were within normal limits. Urine drug screening results were positive for opiates, and the patient’s ammonia level was elevated at 34 µg/dL.

Computed tomography scanning of the head and magnetic resonance imaging of the brain and spine showed no acute abnormalities. Vitamin B12, folate, thyrotropin, and thyroxine levels were within normal limits. The patient’s VPA level was 58 µg/mL (reference range, 50-125 µg/mL).

The hyperammonemia initially was attributed to the presence of underlying liver disease. Lactulose was started, resulting in improvement of his symptoms.

Results of an outpatient liver biopsy performed 2 weeks later were normal. Four months later, the patient’s symptoms recurred, and rifaximin was added to his regimen. VPA was discontinued due to its ineffectiveness in treating the man’s migraines. Follow-up at the gastroenterology clinic showed resolution of weakness and confusion, with normalization of his hyperammonemia.

Discussion

This patient’s case highlights the importance of considering all potential adverse drug reactions. VPA-induced hyperammonemic encephalopathy (VHE) is a rare adverse effect and therefore is commonly overlooked. 

While previous reports describe VHE with toxic VPA levels, this patient’s case stresses the importance of considering VHE despite normal levels of the drug. This patient underwent unnecessary liver biopsy and extensive workup before the diagnosis was made. Because several causes of elevated ammonia levels are possible, the diagnosis of VHE is often overlooked.

Causes

Although VPA has been used for decades for the treatment of seizure disorders and for prophylaxis of migraine, its mechanism for inducing hyperammonemia is not fully understood. Of the 2 possible mechanisms by which VPA causes hyperammonemia, the first is related to VPA’s metabolite. VPA undergoes glucuronic acid conjugation and β-oxidation in the liver, resulting in the production of propionic acid.1 Propionic acid inhibits a urea cycle enzyme, carbamoyl phosphate synthase, which inhibits the body’s ability to excrete ammonia.

Another proposed mechanism is related to carnitine depletion. Carnitine is a required cofactor for transportation within mitochondria for long-chain fatty acid metabolism via β-oxidation.2 Under normal circumstances, VPA primarily undergoes β-oxidation, producing nontoxic metabolites.3 If levels of carnitine are reduced, ω-oxidation begins to predominate, creating toxic metabolites that may increase the ammonia level.2,3

Clinical Manifestations

The commonly reported adverse effects associated with the use of VPA are pancreatitis, teratogenicity, hepatotoxicity, and thrombocytopenia. VHE, when reported, commonly presents without abnormal liver test results.2,4-6 Signs and symptoms of VHE vary from lethargy, weakness, and confusion to as severe as coma and death.4,7,8 VHE has been reported to occur after acute overdose of and chronic use of VPA.2,5,6 Additionally, published studies have shown that VHE may occur at supratherapeutic as well as therapeutic levels of VPA.2

Diagnosis

Making the diagnosis of VHE can present a challenge and lead to unnecessary testing and invasive procedures. Other causes of acute hyperammonemia must be ruled out, including hepatic congestion, cirrhosis, acute hepatitis, drug use, and inborn errors of metabolism. Routine testing should include a comprehensive metabolic panel, including liver function testing, and possibly right upper quadrant ultrasonography; other tests to consider include arterial blood gases and serum amino acids if there is clinical suspicion for congenital metabolic defects.9 Since most cases present with normal results on liver function tests, the diagnosis can be made if there is suspicion for VHE.2,4-6 Therefore, isolated hyperammonemia in a patient taking VPA should lead to a diagnosis of VHE.2

Management

Previous case reports of VHE have focused primarily on ammonia elimination and drug cessation. Carnitine deficiency is a known adverse effect of VPA and is related to several synergistic mechanisms during metabolism of the drug.3 These interactions with carnitine have promoted supplementation with l-carnitine, which is considered to be relatively safe.3,10 However, the benefits of l-carnitine supplementation have not been widely studied, and an optimal dose has not been determined. There is a need for further randomized, controlled studies to determine the role of l-carnitine supplementation in VHE.

Brian Dinh, MD, is a resident in the Department of Internal Medicine at Wright State University in Dayton, Ohio.

Kyle Ball, DO, is a resident in the Department of Internal Medicine at Wright State University in Dayton, Ohio.

Sangeeta Agrawal, MD, is chief of the Division of Gastroenterology at the Dayton Veterans Affairs Medical Center and an associate professor of medicine at Wright State University in Dayton, Ohio.

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