Hyperammonemic Encephalopathy Associated With Fibrolamellar Hepatocellular Carcinoma: Case Report, Literature Review, and Proposed Treatment Algorithm

Abstract

We report a case of a 31-year-old man with metastatic fibrolamellar hepatocellular carcinoma (FLHCC) treated with gemcitabine and oxaliplatin complicated by hyperammonemic encephalopathy biochemically consistent with acquired ornithine transcarbamylase deficiency. Awareness of FLHCC-associated hyperammonemic encephalopathy and a pathophysiology-based management approach can optimize patient outcome and prevent serious complications. A discussion of the management, literature review, and proposed treatment algorithm of this rare metabolic complication are presented. The Oncologist 2016; 21:514-520Implications for Practice: Pathophysiology-guided management of cancer-associated hyperammonemic encephalopathy can improve patient outcome and prevent life-threatening complications. Community and academic oncologists should be aware of this serious metabolic complication of cancer and be familiar with its management.

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

“…As previously reported in the literature, a more convincing explanation to the development of HE in patients with FHC is a disorder in the urea cycle [15–17]. The urea cycle (also known as ornithine cycle) was described by Krebs and Henseleit in 1932, being the first metabolic cycle discovered [19].…”

“…Several chemotherapy agents have been associated with HE, such as oxaliplatin, vincristine, 5-fluorouracil, cyclophosphamide, methotrexate, etoposide, and gemcitabine [15]. Nevertheless, our patient had never received chemotherapy before developing HE.…”

“…In fact, OTC deficiency has been previously associated with FHC [15–17,21]. However, the specific reason for the suppression of OTC enzyme activity or for a deficiency of ornithine availability and consequent decreased ornithine cycle functioning has never been determined [15,22]. The answer to that question probably began to be solved in 1972 by Weber and colleagues [23].…”

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

“…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.…”

“…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 ).…”