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

Abstract

Ornithine transcarbamylase deficiency (OTCD) disrupts the metabolic pathway responsible for converting nitrogenous waste to urea, allowing for excretion. When impaired, ammonia levels accumulate in the blood resulting in severe, sometimes life-threatening toxicities. Abnormalities of the urea cycle are often inherited, though there are some rarer acquired forms. We describe two cases of acquired OTCD in pediatric patients with fibrolamellar hepatocellular carcinoma (FL-HCC). We detail its presentation and management, explore potential underlying pathophysiology, and propose a practice change to optimize care of FL-HCC patients.

Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma

“…We focused on proteins in ammonia metabolism because hyperammonemic encephalopathy is commonly observed in FLC and is sometimes a cause of death in these patients ( 6 , 7 , 30 , 31 ). In liver disease, ammonia toxicity can result from liver failure or specific mitochondrial dysfunction ( 32 ).…”

“…The observations of both the proteome and metabolome suggest that there are three pathways that contribute to FLC hyperammonemic encephalopathy. FLC has been described as an “acquired” ornithine transcarbamylase deficiency ( 6 , 7 , 31 , 39 , 50 ). In other examples of OTC deficiency generated by mutations ( 34 , 38 ), excess carbamoyl phosphate diffuses out of the mitochondria and is then metabolized.…”

“…Our results suggest that high ammonia in FLC is unlikely due only to the failure of the liver to consume ammonia but a specific generation of ammonia by FLC, potentially explaining the ineffectiveness of lactulose (directed at trapping ammonia in the gut) in treating FLC. Therefore we, and others, have turned to the use of scavengers for ammonia such as sodium benzoate and arginine ( 6 , 7 , 31 , 39 , 40 , 50 , 51 , 55 ). These agents can target tissue and serum ammonia, unlike lactulose that removes only ammonia in the gut.…”

Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma

“…Ornithine transcarbamylase (OTC) localizes in mitochondrial matrix and catalyzes the conversion of ornithine and carbamylphosphate to citrulline. OTC deficiency disrupts the metabolic pathways of urea, resulting in the accumulation of ammonia in the blood which is life-threatening in severe cases 141 . OTC silencing promotes proliferation of HCC SK-HEP-1 and Huh-7 cells.…”

Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses

“…Along these lines, the over-expression of ARG1 affects liver cancer cell behavior by promoting typical morphological changes of EMT and increasing migration and invasiveness [ 138 , 145 ]. The last key enzyme of the urea cycle is the OCT, so much so that its loss of function or down-regulation leads to a gap in the urea cycle with consequent accumulation of ammonia in the blood [ 138 , 146 ]. Low expression of OTC correlates with poor overall survival and shorter disease-free survival in HCC patients [ 143 ].…”