University of Iowa Hospitals & Clinics Iowa City, IA
Bohae R. Lee, MD1, Robert Schoeneich, MD1, Udhayvir S. Grewal, MD1, Rishi R. Patel, BS2, Andrew J. Vegel, MD1, Tanner Simonson, MD1, Mark W. Karwal, MD1, Carlos HF. Chan, MD, PhD1, Naomi H. Fei, MD, MS2 1University of Iowa Hospitals & Clinics, Iowa City, IA; 2University of Iowa Carver College of Medicine, Iowa City, IA Introduction: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare, aggressive liver malignancy that primarily affects young adults and is seldom associated with cirrhosis. Hyperammonemic encephalopathy (HAE) is a rare, often overlooked complication of FLHCC. A deletion on chromosome 19 results in fusion of the genes DNAJB1 and PRKACA, forming a chimeric protein, a hallmark of FLHCC. This disrupts the urea cycle, leading to impaired ammonia clearance and HAE (Figure D).
Case Description/
Methods: A 26-year-old man with known FLHCC — status post hepatic resection and therapy with trastuzumab deruxtecan- nxki — presented to the emergency department with altered mental status. He was nonverbal, disoriented, and required intubation for airway protection. The only notable lab finding was serum ammonia elevated at 339 µmol/L (reference range: 16-60 µmol/L). Imaging showed extensive metastatic nodules in the peritoneal wall and throughout the mesentery along with significant ascites consistent with progression of disease (Figure A). He received ammonia salvage therapy, consisting of citrulline phenylbenzoate, arginine and intravenous dextrose (urea cycle supporters), continuous renal replacement therapy (CRRT) and intermittent dialysis (to facilitate removal of ammonia). Unfortunately, his mentation improved minimally, with ammonia varying from 69-150 µmol/L. He underwent cytoreductive surgery (open greater omentectomy, total peritonectomy, splenectomy, ultralow proctectomy, total colectomy with end ileostomy, resection of abdominal wall mass, resection/fulguration of numerous small bowel tumors). Peritoneal carcinomatosis index was 36. Complete cytoreduction was achieved. Within 24 hours after surgery, serum ammonia level dropped to 30 µmol/L. He was extubated the next day and discharged 10 days later. He was doing well on capecitabine, nivolumab, and ipilumumab 4 months after surgery. Discussion: HAE in FLHCC is often associated with poor outcomes. There should be a high index of suspicion for HAE in FLHCC patients presenting with encephalopathy, even in the absence of liver dysfunction. Aggressive metabolic therapy should be initiated promptly, but early surgical consultation is essential when response is suboptimal. Surgical cytoreduction can be lifesaving by decreasing tumor burden and resolving refractory HAE. This case highlights the potential of cytoreductive surgery as part of multidisciplinary care for HAE in FLHCC.
Figure: Figure A) Prior to admission computed tomography scan of the abdomen and pelvis reveals prior post trisegmentectomy changes along with extensive metastatic nodules in the peritoneal wall and throughout the mesentery, significant ascites. B) Hematoxylin & Eosin section showing cords and clusters of tumor cell with abundant oncocytic cytoplasm in background of dense collagen bundles (100x). C) Intraoperative picture demonstrating metastatic disease within peritoneum and mesentery D) Proposed mechanism of urea cycle dysfunction in FLHCC by Cho et al [2]. OTC activity is higher than ODC in normal physiologic conditions, facilitating the entry of ornithine into the urea cycle. In FLHCC, a mutation chromosome 19 leads to the formation of fusion protein DNAJB1-PRKACA. This increases ODC activity via downstream effects, resulting in increased use of ornithine in polyamine synthesis rather than the urea cycle. [DNAJB1, DnaJ Heat Shock Protein Family (Hsp40) Member B1; PRKACA, Protein Kinase CAMP-Activated Catalytic Subunit Alpha; c-Myc, melocytomatosis oncogene; ODC, ornithine decarboxylase; OTC, ornithine transcarbamylase
Figure: Figure A) Prior to admission computed tomography scan of the abdomen and pelvis reveals prior post trisegmentectomy changes along with extensive metastatic nodules in the peritoneal wall and throughout the mesentery, significant ascites. B) Hematoxylin & Eosin section showing cords and clusters of tumor cell with abundant oncocytic cytoplasm in background of dense collagen bundles (100x). C) Intraoperative picture demonstrating metastatic disease within peritoneum and mesentery D) Proposed mechanism of urea cycle dysfunction in FLHCC by Cho et al [2]. OTC activity is higher than ODC in normal physiologic conditions, facilitating the entry of ornithine into the urea cycle. In FLHCC, a mutation chromosome 19 leads to the formation of fusion protein DNAJB1-PRKACA. This increases ODC activity via downstream effects, resulting in increased use of ornithine in polyamine synthesis rather than the urea cycle. [DNAJB1, DnaJ Heat Shock Protein Family (Hsp40) Member B1; PRKACA, Protein Kinase CAMP-Activated Catalytic Subunit Alpha; c-Myc, melocytomatosis oncogene; ODC, ornithine decarboxylase; OTC, ornithine transcarbamylase
Disclosures: Bohae Lee indicated no relevant financial relationships. Robert Schoeneich indicated no relevant financial relationships. Udhayvir Grewal indicated no relevant financial relationships. Rishi Patel indicated no relevant financial relationships. Andrew Vegel indicated no relevant financial relationships. Tanner Simonson indicated no relevant financial relationships. Mark Karwal indicated no relevant financial relationships. Carlos Chan indicated no relevant financial relationships. Naomi Fei indicated no relevant financial relationships.
Bohae R. Lee, MD1, Robert Schoeneich, MD1, Udhayvir S. Grewal, MD1, Rishi R. Patel, BS2, Andrew J. Vegel, MD1, Tanner Simonson, MD1, Mark W. Karwal, MD1, Carlos HF. Chan, MD, PhD1, Naomi H. Fei, MD, MS2. P3997 - Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma: A Case of Rapid Neurologic Recovery Following Cytoreductive Surgery, ACG 2025 Annual Scientific Meeting Abstracts. Phoenix, AZ: American College of Gastroenterology.
