A Proposed Physiopathological Pathway to Hyperammonemic Encephalopathy in a Non-Cirrhotic Patient with Fibrolamellar Hepatocellular Carcinoma without Ornithine Transcarbamylase (OTC) Mutation

Abstract

Patient: Male, 31Final Diagnosis: Fibrolamellar hepatocellular carcinomaSymptoms: EncephalopathyMedication:—Clinical Procedure: —Specialty: Gastroenterology and HepatologyObjective:Rare diseaseBackground:Hyperammonemic encephalopathy is a potentially fatal condition that may progress to irreversible neuronal damage and is usually associated with liver failure or portosystemic shunting. However, other less common conditions can lead to hyperammonemia in adults, such as fibrolamellar hepatocellular carcinoma. Clinical awareness of hyperammonemic encephalopathy in patients with normal liver function is paramount to timely diagnosis, but understanding the underlying physiopathology is decisive to initiate adequate treatment for complete recovery.Case Report:A 31-year-old male with fibrolamellar carcinoma and peritoneal carcinomatosis presented with rapid onset hyperammonemic encephalopathy. Despite usual treatment for hepatic encephalopathy, his hyperammonemia was aggravated. A physiopathological pathway to encephalopathy resulting from hepatocellular dysfunction or portosystemic shunting was suspected and proper treatment was initiated, which resulted in complete remission of encephalopathy. Thus, we propose there is a physiopathology path to hyperammonemic encephalopathy in non-cirrhotic patients with fibrolamellar carcinoma independent of ornithine transcarbamylase (OTC) mutation. An ornithine metabolism imbalance resulting from overexpression of Aurora Kinase A as a result of a single, recurrent heterozygous deletion on chromosome 19, common to all fibrolamellar carcinomas, can lead to a c-Myc and ornithine decarboxylase overexpression that results in ornithine transcarboxylase dysfunction with urea cycle disorder and subsequent hyperammonemia.Conclusions:The identification of a physiopathological pathway allowed adequate medical treatment and full patient recovery from severe hyperammonemic encephalopathy.

Acquired ornithine transcarbamylase deficiency in pediatric and adolescent patients with fibrolamellar hepatocellular carcinoma

“…Presentation of aOTCD is variable and can include altered mental status, fatigue, personality changes, emesis, diarrhea, motor retardation, posturing, and asterixis, associated with elevated serum ammonia, typically >150 μmol/L. Absolute ammonia levels do not necessarily correlate with the severity of encephalopathy . Liver transaminases are normal or mildly elevated, and serum bilirubin is normal .…”

“…Acquired OTCD may be an isolated episode or a recurrent problem. If not readily recognized, symptoms progress to irreversible neurologic damage, intracranial hypertension, coma, seizures, or death . Treatments include hyperhydration with dextrose and electrolyte containing fluids, reduced protein intake, ammonia scavenger therapy (sodium benzoate and/or sodium phenylacetate), rifaximin and lactulose to decrease intestinal ammonia‐producing bacteria and to produce an acidic environment that favors conversion of ammonia to ammonium, at times dialysis, and arginine therapy.…”

“…It has been speculated that aOTCD is due to chemotherapy inducing a catabolic state that overwhelms a patient's ability to clear nitrogenous waste, with alkylating agents, antimetabolites, topoisomerase inhibitors, anthracyclines, and immunotherapy as potential precipitating agents . However, cases of aOTCD have occurred without chemotherapy exposure …”

“…It is hypothesized that with this consequent overexpression of c‐Myc, ornithine decarboxylase is upregulated, leading to increased consumption of ornithine for synthesis of polyamines. As a primary substrate for the urea cycle, decrease in bioavailable ornithine greatly reduces the capacity of the urea cycle and may result in the accumulation of ammonia in FL‐HCC patients . If AURKA mechanistically imparts such biological impact, treating FL‐HCC with AURKA inhibitors may be considered.…”

“…In adults with FL‐HCC, a possible paraneoplastic phenomenon known as acquired ornithine transcarbamylase deficiency (aOTCD), a toxic accumulation of ammonia in the blood causing acute encephalopathy and potentially irreversible neurologic deficits, or death, has been reported . We report two cases of aOTCD in pediatric patients with FL‐HCC (Table ).…”