Clinical Challenges

Clinical Challenges - September 2016
What's Your Diagnosis?

Publish date: September 12, 2016

By Jana G. Hashash, MD, Kavitha Thudi, MD, and Shahid M. Malik, MD. Published previously in Gastroenterology (2012;143[5]:1157, 1401-2).

An 18-year-old white woman with no significant medical history was in good health until 2 days before admission, when she developed nausea, vomiting, and confusion. She was awake but lethargic and disoriented with asterixis. The remainder of her neurologic examination was nonfocal.

A firm liver margin was palpated 4 cm below the costal margin, but no ascites or bruit were appreciated. At presentation, the patient’s serum aspartate and alanine aminotransferases were 86 IU/L and 115 IU/L, respectively, with a total bilirubin of 0.9 mg/dL, alkaline phosphatase of 68 IU/L, albumin of 2.9 g/dL, and International Normalized Ratio of 1.3. Her neurologic status quickly deteriorated with obtundation requiring intubation for airway protection. Computed tomography (CT) of the head revealed no abnormalities.

Laboratory data revealed white blood cell count of 13,000/L, hemoglobin of 13 g, and a platelet count of 300,000/L. A serum venous ammonia level was 342 micromol/L (normal range, 9-33). A urine drug screen was negative, as were her serum acetaminophen and aminosalicylic acid levels. Infectious work-up was unrevealing. Work-up for underlying chronic liver disease, including viral hepatitis serologies, autoimmune serologies, ceruloplasmin level, alpha-1 antitrypsin level, as well as hemochromatosis gene testing, was negative. An electroencephalography revealed burst suppression but no seizure activity. A lumbar puncture was negative.

An abdominal contrast-enhanced CT revealed an 11 × 15-cm heterogeneous, hypervascular mass replacing the majority of the right hepatic lobe (Figure A), right portal vein thrombosis, an enlarged hypervascular portocaval node measuring 2.0 × 2.0 cm, and an 8-mm left lower lobe lung lesion concerning for metastatic disease. Her liver was mildly enlarged, but was noncirrhotic. There was no radiologic evidence of portal hypertension or varices. There was no evidence of extrahepatic portosystemic shunting. Serum tumor markers, including alpha-fetoprotein, were within normal limits (1 ng/mL).

What is the cause of this young patient’s acute hepatic encephalopathy?


 

The diagnosis

Histologic analysis was consistent with a fibrolamellar-hepatocellular carcinoma (HCC). The patient developed decerebrate posturing without cerebral edema on CT of the head. The patient was treated with mannitol, hyperventilation, and therapeutic hypothermia, as well as lactulose, rifaximin, hemodialysis, and “empiric” sodium benzoate/sodium phenylacetate (Ammonul, Ucyclyd Pharma, Scottsdale, Ariz.) for the possibility of a urea cycle disorder. In hopes of decreasing blood flow to the tumor, the patient underwent embolization of the right hepatic artery with no clinical improvement. Given the persistently elevated ammonia level, a work-up for an underlying urea cycle disorder was performed, revealing trace citrulline and increased urine orotic acids and uracil, suggesting an ornithine transcarbamylase (OTC) deficiency. She was started on parenteral nutrition with arginine supplementation, after which her ammonia level normalized with subsequent improvement in her mental status.

Two weeks after her initial presentation, the patient underwent a right hepatic trisegmentectomy, removal of the portocaval lymph node, and thoracoscopic resection of the left lung nodule. The resected liver revealed a fibrolamellar-HCC with extensive lymphovascular invasion and metastatic disease in both the lymph node and pulmonary nodule. The patient’s alpha-fetoprotein level postoperatively remained normal at 1 ng/mL. The patient’s postoperative course was complicated by a deep vein thrombosis. Given the history of the preresection portal vein thrombosis, an underlying hypercoagulable state was investigated and was negative. The patient is currently on anticoagulation with warfarin (Coumadin) for the deep vein thrombosis.

Fibrolamellar-HCC is a rare, malignant, primary liver tumor predominantly affecting young adults with no underlying liver disease. This hypervascular tumor is radiographically characterized by a central scar. 1 Most patients experience vague abdominal pain, weight loss, and fatigue. Fibrolamellar-HCC carries a better prognosis than HCC; in surgically resectable cases, the 5-year survival rates range between 37% and 76% vs. 12-14 months in nonresectable cases. 2 Systemic chemotherapy has been used in case reports and the role of sorafenib remains unexplored and ill defined.

This is the second reported case of metastatic fibrolamellar-HCC with hyperammonemia. 3 Although urea cycle disorders are more commonly diagnosed in newborns and infants, patients with partial enzyme deficiencies may present later in life and manifest in the setting of metabolic decompensation or stress. Our patient’s initial evaluation was consistent with a urea cycle deficiency, but OTC sequencing from the blood was negative. We hypothesize that the patient exhibited a “functional” OTC deficiency as a result of a combination of the massive tumor burden and portal vein thrombus, leading to a decreased expression of the OTC gene and insufficient enzyme production. The patient is doing well 3 months post resection and is being considered for a phase I clinical trial with a telomerase inhibitor, imetelstat.

References

1. Ichikawa, T., Federle, M.P., Grazioli, L., et al. Fibrolamellar hepatocellular carcinoma: Imaging and pathologic findings in 31 recent cases. Radiology. 1999;213(2):352-61 .

2. Ward, S.C. Waxman, S. Fibrolamellar carcinoma: A review with focus on genetics and comparison to other malignant primary liver tumors. Semin Liver Dis. 2011;31(1):61-70 .

3. Sethi, S., Tageja, N., Singh, J., et al. Hyperammonemic encephalopathy: A rare presentation of fibrolamellar hepatocellular carcinoma. Am J Med Sci. 2009;338(6):522-4 .

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