Hyperammonemia in children and adolescents usually occurs in the setting of a congenital urea cycle defect, significant portosystemic shunting, or hepatic failure. We present a patient with stage IV hepatocellular carcinoma (HCC) without hepatic failure, known congenital metabolic defect, or obvious portosystemic shunt, who repeatedly demonstrated episodes of hyperammonemic encephalopathy after administration of multiagent chemotherapy. The patient's hyperammonemia was likely caused by a combination of increased protein catabolism from her chemotherapy and intrahepatic shunting of nitrogen-containing compounds away from necrotic and cancerous cells. Her symptoms were initially controlled with hemodialysis and later with intravenous use of arginine.
A 17-year-old Hispanic female with normal physical and cognitive development was referred from a community hospital with a large, painful abdominal mass that had progressed for 6 months. A tissue biopsy showed HCC (without fibrolamellar features), extensive invasion of the portal vasculature, and secondary cholestasis from mechanical bile duct obstruction. Staging computed tomography (CT) and ultrasonography (US) studies revealed bulky disease in the left lobe of the liver with extension into the pelvis, infiltration into the region of the porta hepatis, and no evidence of spread to the right hepatic lobe. Multiple small tissue masses compatible with malignant spread were identified throughout the peritoneum, retroperitoneum, lung bases, and left iliac wing by abdominal and pelvic CT scans. Abdominal US showed the spleen to be of normal size and echogenicity, patency of the inferior vena cava and portal veins, and no evidence of ascites. The hemoglobin was 11.1 g/l, hematocrit was 35%, white blood cell count was 15,900/mm3, and platelets were 592/mm3. Assays for hepatitis B surface antigen/antibody and hepatitis C antibody were nonreactive. There was no history of a prior exposure to hepatitis carriers or blood products. The carcinoembryonic antigen was mildly elevated at 9.0 μg/l (normal range, 0 to 3.0 μg/l), whereas α-fetoprotein and β-hCG levels were both normal at 2.0 IU/l and 3.0 IU/l (normal ranges, <5 IU/l and 5 IU/l for nonpregnant females, respectively). Aminotransferases were mildly elevated, but coagulation studies were normal (Table 1). These laboratory and clinical findings were diagnostic for stage IV HCC without hepatic failure.
Because the patient's tumor was not surgically resectable, she consented to treatment with doxorubicin (90 mg/m2 for 72 hours), cyclophosphamide (2200 mg/m2) with mesna uroprotection (a selective urinary tract protectant for oxazophosphorine-type alkylators such as cyclophosphamide and ifosfamide), vincristine (2 mg/m2), and granulocyte-colony stimulating factor (G-CSF, 5 μg/kg) rescue (cycle 1). This regimen of chemotherapy was generally well-tolerated with only transient febrile neutropenia; however, there was no objective clinical response in the tumor size and associated abdominal pain. Her second cycle of therapy consisted of ifosfamide (3000 mg/m2) with mesna uroprotection, days 1 through 3, carboplatin (635 mg/m2), day 3 only, and etoposide (100 mg/m2) days 1 through 3 (also known as ICE by acronym). During the second day of this therapy, symptoms developed in the patient, initially of involuntary twitching, which escalated into uncontrollable writhing, combativeness, and somnolence. She was admitted in a comatose condition to the Pediatric Intensive Care Unit (PICU) at the University of New Mexico Children's Hospital and was determined to have an arterial ammonia (NH3) level of 120 μM (normal, 0 to 30 μM). The patient's laboratory tests did not show evidence of either hepatic or renal failure (Table 1). Five days after admission, when the concurrent serum NH3 level was 273 μM with IV arginine therapy, serum amino acid analyses showed trace levels of citrulline, a glutamine level of 493 pM (normal range, 200-850 pM), an arginine level of 93 pM (normal range, 14-200 pM), and moderately elevated urinary orotic acid levels. These results were suggestive of a heterozygous ornithine transcarbamylase (OTC) deficiency (1). Peripheral blood lymphocytes were later assayed for abnormalities of the OTC gene using single-strand conformational polymorphism (SSCP) analysis of all 10 OTC gene exons and intron/exon borders. All gene fragments were found to be normal and therefore direct DNA sequencing was not done (2).
The initial management of the patient's hyperammonemia included a trial of lactulose (30 ml nasogastrically every 6 hours), in combination with neomycin (1 gram nasogastrically every 12 hours) (3), and daily hemodialysis. Abdominal magnetic resonance imaging and US studies during this hospital admission did not demonstrate portal venous dilatation nor circumhepatic collateral circulation. Only the addition of arginine (6.6 g continuous IV infusion for 24 hours; 160 mg/kg/day) to this therapeutic regimen caused a gradual improvement in her mental status and reversal of the elevated NH3 levels. Sodium phenylacetate and sodium benzoate were not easily available during the patient's emergent medical care. The lactulose and neomycin were discontinued after 2 weeks, and the patient recovered from the anticipated chemotherapy-associated bone marrow suppression, but her poor appetite necessitated the initiation of total parenteral nutrition (TPN), which contained 10% dextrose, 2% amino acids, and 6.6 g/day of arginine. This TPN formulation did not exacerbate the hyperammonemia and was continued before, during, and after each cycle of chemotherapy for the duration of the patient's lifetime without apparent harmful effects. During the second day of the subsequent ICE regimen (cycle 3), the patient's NH3 levels again became dangerously elevated, but in contrast with the previous episode of hyperammonemia, she did not become frankly encephalopathic. The patient's serum NH3 reached a peak value of 412 μM on day 9 of cycle 3 when her continuous arginine infusion was interrupted for a 4-hour blood transfusion. The hyperammonemia subsequently resolved during 10 days of supportive care that included hemodialysis, arginine by continuous IV infusion, and both oral lactulose and neomycin. Two consecutive cycles of ICE achieved a moderate reduction in the pelvic component of the tumor mass by US and a significant reduction of her abdominal pain.
Cycle 4 consisted of cis-platinum (90 mg/m2 IV for 6 hours) and 5-fluorouracil (600 mg/m2 for 30 minutes on day 2) given in the outpatient setting. On day 6, the patient was readmitted to the PICU with symptoms of encephalopathy and a concurrent serum NH3 level of 332 μM. A bolus infusion of 2.5 g arginine promptly reversed the symptoms of encephalopathy, and within a few hours the serum NH3 level was 90 μM. The patient did not require further hemodialysis and refused further treatment with lactulose and neomycin. All subsequent cycles of chemotherapy were modified to include 2.5-g boluses of arginine IV every 8 hours after the initiation of therapy for a period of approximately 10 days; these boluses were given in addition to 10 g per day (250 mg/kg/day) of arginine-containing TPN. Cycles 5 through 9 were successfully administered in the outpatient clinic without further episodes of encephalopathy despite brief elevations of serum NH3 levels to 190 μM on day 2 of cycle 6 and 217 μM on day 9 of cycle 7 (Fig. 1). Chemotherapy-induced renal dysfunction developed in the patient, and she died of progressive disease approximately 15 months from presentation.
Ammonia is a toxic substance that is transiently produced when proteins are catabolized into urea through multiple enzymatic steps in the Krebs-Henseleit cycle (1,4-5). Elevated ammonia levels cause vomiting, tachypnea, and lethargy in the newborn, whereas disorientation, irritability, combativeness, and behavioral changes tend to occur in older patients (4). Without treatment, uncontrolled hyperammonemia results in coma and eventual death. Hyperammonemia occurs when ammonia is either overproduced or insufficiently cleared from serum. Most endogenously produced ammonia is generated in the large intestine from the breakdown of luminal proteins and amino acids. The kidneys, small bowel, and skeletal proteins can be important sites of ammonia synthesis as well. When serum ammonia levels exceed the urea-forming capacity of the liver, whether from bleeding into the gastrointestinal tract or from chemotherapy-associated protein catabolism, hyperammonemia can occur. If efferent blood flow to the liver is compromised from a portal vein obstruction (extrahepatic shunting) or a bypass of functional hepatocytes (intrahepatic shunting), hyperammonemia can also occur, especially under conditions of excess ammonia synthesis. Congenital enzymopathies in the urea cycle can lead to varying degrees of hyperammonemia depending on the enzyme affected and whether the genetic deficiency is heterozygous or homozygous. A disruption of mitochondrial pathways owing to drug toxicities from L-asparaginase, valproic acid, iron, cyanide, and nucleoside analogues can result in hyperammonemia (5-7). End-stage liver disease or acute hepatic failure often leads to hyperammonemia as a result of one or more of the etiologies described above (4,5).
Our patient presented with stage IV HCC without portal hypertension, and had normal clotting studies, bilirubin levels, glucose metabolism, and only moderately abnormal aminotransferase levels. It seems unlikely that her hyperammonemia was the result of fulminant hepatic failure or previously undiagnosed cirrhosis, as has been described in adult patients with HCC (8,9). Our patient did not have serologic markers for hepatitis B or C. Her age, past medical history, and laboratory data did not suggest any recognizable heterozygous or homozygous metabolic abnormalities. Although she received a variety of chemotherapeutic agents known to be partially effective in the treatment of HCC (10), these drugs are not reported to cause hyperammonemia. Our patient's peak ammonia levels resolved before pancytopenia developed, which is clinically different from other patients in whom hyperammonemia developed during periods of bone marrow depression after high-dose cytoreductive therapy (11). A case has been reported of a patient with HCC and noncirrhotic hyperammonemic encephalopathy who had high urinary orotic acid levels, intrahepatic microvascular shunting, and no response to intravenous arginine therapy (12). Although our patient also had elevated urinary orotic acid levels, her chemotherapy-induced hyperammonemia responded to intravenous arginine therapy. We hypothesize that the agents used in cycles 2 through 9 may have destroyed enough tumor tissue to cause intrahepatic microvascular shunting, in addition to temporarily increasing protein catabolism and secondary ammonia production. The patient's “baseline” level of hyperammonemia appeared to decline after several courses of treatment, possibly as a consequence of an overall decrease in cancer bulk. The OTC SSCP analysis identifies mutations in approximately 75% of presumed OTC-deficient patients (2). Consequently, there is a 25% chance that our patient had an occult heterozygous OTC mutation that might have caused the observed urea cycle abnormalities.
The treatment of a hyperammonemic encephalopathic state is somewhat limited, and when secondary to HCC (9,12,13) or metastatic liver disease (14), control of the underlying malignancy can sometimes lead to an improvement in symptoms. When the encephalopathic changes are mild, lactulose or neomycin have proven helpful in decreasing the ammonia level. Sodium benzoate and sodium phenylacetate for intravenous use or sodium phenylbutyrate for oral use have been helpful in the setting of controlling hyperammonemia as a consequence of urea cycle defects. Arginine can aid in the treatment of hyperammonemia by inducing the formation of argininosuccinate and citrulline, both of which can function as a conduit for nitrogen excretion. Moreover, arginine can facilitate the activation of N-acetylglutamate synthetase, which then induces carbamoyl-phosphatase synthase activity and an increased clearance of ammonia. In the absence of a urea cycle defect, arginine is considered to be a nonessential amino acid and would not be expected to improve the excretion of waste nitrogen (4). Presumably our patient's endogenous stores of arginine were insufficient for nitrogen excretion, especially during periods of chemotherapy-induced protein catabolism, making arginine a conditionally essential amino acid. When the arginine was given as a rapid infusion the excessive ammonia was cleared more efficiently. In some settings, hemodialysis or peritoneal dialysis are the best supportive means to control hyperammonemia when drug therapy is inadequate.
We found that the use of hemodialysis during the acute crisis and a combination of continuous and bolus infusions of arginine later on in the patient's course enabled us to successfully control her hyperammonemia. Chemotherapy-induced acute hyperammonemia is a previously unreported complication of treatment in HCC and it may be controllable if promptly recognized and treated.
Acknowledgment: The authors thank Dr. John Johnson for his scholarly assistance in the preparation of this manuscript.
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