Hepatic encephalopathy and orotic aciduria associated with hepatocellular carcinoma in a noncirrhotic liver

Jeffers, Lennox J.; Dubow, Richard A.; Zieve, Leslie; Reddy, K. Rajender; Livingstone, Alan S.; Neimark, Sidney; Viamonte, Manuel; Schiff, Eugene R.

doi:10.1002/hep.1840080116

Cited by 17 publications

(14 citation statements)

References 7 publications

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“…Although initial metabolic investigations suggested inherited OTC deficiency, this was not confirmed by DNA analysis. Similar cases have been reported in the literature of patients with FLC (Jeffers et al 1988;Sethi et al 2009) presenting with hyperammonaemic encephalopathy, in some cases related to chemotherapy (Chan et al 2008;Winter et al 1997). A previous study on rats has shown an inverse relationship between ornithine carbamyl transferase activity and the rate of growth of hepatoma (Weber et al 1972).…”

Section: Discussionsupporting

confidence: 73%

Fibrolamellar Hepatocellular Carcinoma Mimicking Ornithine Transcarbamylase Deficiency

Sulaiman

Geberhiwot

2014

JIMD Reports

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We report an unusual case of recurrent nonhepatic hyperammonaemic encephalopathy in an adult patient. She had a previous history of treated fibrolamellar hepatocellular carcinoma (FLC). This posed a diagnostic challenge, as she had normal liver function tests and normal looking liver on imaging but with extra hepatic metastases. This case highlights the importance of measuring plasma ammonia levels in all patients presenting with unexplained acute confusion. Clinical awareness of non-hepatic hyperammonaemic encephalopathy can contribute to early diagnosis and timely initiation of life-saving treatment. Delay in treatment results in irreversible brain damage, deep coma and death. Treatment of hyperammonaemia must begin prior to confirmation of aetiology, for a favourable outcome. This case also highlights the need for further research to understand the exact mechanism of hyperammonaemia in hepatocellular carcinoma.

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Section: Discussionsupporting

confidence: 73%

Fibrolamellar Hepatocellular Carcinoma Mimicking Ornithine Transcarbamylase Deficiency

Sulaiman

Geberhiwot

2014

JIMD Reports

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“…A recent study in rats showed that OAT2 is responsible for the uptake of orotic acid [24], which reportedly promotes liver carcinogenesis [25,26]. In the clinical setting, orotic aciduria was also observed in HCC patients without liver cirrhosis [27]. Moreover, a previous study using gene-set enrichment analysis revealed that SLC22A7 expression is significantly correlated with mitochondrial oxidoreductase activity and fatty acid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Reduced Organic Anion Transporter Expression Is a Risk Factor for Hepatocellular Carcinoma in Chronic Hepatitis C Patients: A Propensity Score Matching Study

et al. 2014

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Objectives: Recent reports indicated that reduced SLC22A7 (a gene-encoding organic anion transporter 2) expression in noncancerous liver tissue predicts hepatocellular carcinoma (HCC) recurrence after curative resection. Our study aimed to elucidate the association between SLC22A7 expression and HCC development in chronic hepatitis C patients. Methods: HCC recurrence after local ablation therapy and SLC22A7 expression in noncancerous liver tissue were analyzed in 20 patients. Subsequently, the association between de novo HCC development and SLC22A7 expression was examined at baseline in 38 hepatitis C patients without HCC who subsequently developed HCC as well as in 76 hepatitis C patients who did not develop HCC and were matched for age, gender and stage of fibrosis. Results: In the patients whose HCC had been cured, reduced SLC22A7 expression in noncancerous liver tissue was significantly associated with a high incidence of multifocal HCC recurrence. In patients without HCC at baseline, cumulative incidence of de novo HCC development was significantly higher with a reduced SLC22A7 expression than with a normal expression (p = 0.01). This difference remained significant among patients without known risk factors for HCC like age and advanced fibrosis. Conclusion: Reduced SLC22A7 expression in the liver indicates a significant risk for HCC development in chronic hepatitis C, independently of other risk factors.

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“…OTC inhibition can be induced by carcinogens and/or carcinogenesis (McLean, 1964;Jeffers, 1988;Riordan, 1997) although the mechanism is unknown. Of possible relevance to that mechanism is that OTC is known to be negatively regulated by acetylation (Weber, 1972), and deacetylated (activated) by Sirt3 (Xu, 2011).…”

Section: Alternate Pyrimidine Biosynthesis Paths Of Clinical Relevancementioning

confidence: 99%

Multiple Cytoproliferative Effects of Elevated Pyrimidines are DNA-Synthesis-Independent and Include p53 Repression: DNA-Synthesis-Independent Proliferative Mechanisms of Elevated Pyrimidines

Gipson¹

2014

j pharmaceut sci pharmacol

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Several types of cytoproliferative diseases, including cancers and autoimmune diseases, are associated with elevated cellular levels of pyrimidine nucleotides. This review assembles literature evidence supporting a thesis that elevated pyrimidine levels drive cytoproliferation largely through DNA-synthesis-independent mechanisms, which circumstance, it is proposed, inherently limits clinical efficacy of DNA-synthesis-targeting cytostatic drugs. Five hypothetical mechanisms, with supporting literature evidence, are presented: (1) Pyrimidine nucleotides released from ion channels auto/paracrinally and persistently activate the EGFR, PKC and ERK signaling pathway, upregulating cytokines and Cdk2; (2) One effect of ERK activation is reversal of allosteric control of de novo pyrimidine biosynthesis; thus pyrimidines' auto/paracrine ERK activation may reflect positive autoregulation; (3) Elevated intracellular pyrimidine nucleotides preferentially upregulate tumorigenic genes; (4) Elevated pyrimidines promote aberrant glycosylation of transcription factors; and (5) These diverse pyrimidine effects contribute, by different paths yet collectively, to repression of p53 or of its function. Also reviewed are alternate pyrimidine biosynthesis pathways relevant to disease. Based on these hypotheses, a clinical strategy for cytoproliferative disease is proposed that co-targets three cellular processes seen as "linchpins" of pyrimidines' auto/paracrine effects, including targeting alternate pyrimidine biosynthesis pathways.

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Hepatic encephalopathy and orotic aciduria associated with hepatocellular carcinoma in a noncirrhotic liver

Cited by 17 publications

References 7 publications

Fibrolamellar Hepatocellular Carcinoma Mimicking Ornithine Transcarbamylase Deficiency

Fibrolamellar Hepatocellular Carcinoma Mimicking Ornithine Transcarbamylase Deficiency

Reduced Organic Anion Transporter Expression Is a Risk Factor for Hepatocellular Carcinoma in Chronic Hepatitis C Patients: A Propensity Score Matching Study

Multiple Cytoproliferative Effects of Elevated Pyrimidines are DNA-Synthesis-Independent and Include p53 Repression: DNA-Synthesis-Independent Proliferative Mechanisms of Elevated Pyrimidines

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