Hyperammonemic Encephalopathy in Multiple Myeloma

Kwan, Lawrence; Wang, Clifford; Levitt, Lee J.

doi:10.1056/nejm200205233462119

Cited by 45 publications

(24 citation statements)

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“…The pathogenic mechanism is thought to be related to an acquired deficiency of glutamine synthetase of unknown cause. [60][61][62][63][64][65] Miscellaneous causes of hyperammonemia Hypoglycin (Jamaican vomiting sickness) This is caused by a toxin present in the unripe ackee fruit. The Jamaican vomiting sickness, which has a high mortality rate (up to 50%), is characterized by vomiting, lethargy, hallucinations, coma, hypoglycemia, hyperammonemia, and abnormal liver enzymes, which occur when this unripe fruit is ingested [6].…”

Section: Drug Related Causesmentioning

confidence: 99%

Hyperammonemia in review: pathophysiology, diagnosis, and treatment

2011

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Ammonia is an important source of nitrogen and is required for amino acid synthesis. It is also necessary for normal acid-base balance. When present in high concentrations, ammonia is toxic. Endogenous ammonia intoxication can occur when there is impaired capacity of the body to excrete nitrogenous waste, as seen with congenital enzymatic deficiencies. A variety of environmental causes and medications may also lead to ammonia toxicity. Hyperammonemia refers to a clinical condition associated with elevated ammonia levels manifested by a variety of symptoms and signs, including significant central nervous system (CNS) abnormalities. Appropriate and timely management requires a solid understanding of the fundamental pathophysiology, differential diagnosis, and treatment approaches available. The following review discusses the etiology, pathogenesis, differential diagnosis, and treatment of hyperammonemia.

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Section: Drug Related Causesmentioning

confidence: 99%

Hyperammonemia in review: pathophysiology, diagnosis, and treatment

2011

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“…4,5 Hyperammonemia with or without the related encephalopathy has been reported as a possible rare clinical manifestation in relapsed/refractory MM patients with high mortality rate. [6][7][8][9][10][11][12] Recently, multivariate analysis based on 1 H-NMR spectroscopy analysis of serum samples has shown that a specific metabolic profile characterized MM patients vs healthy controls, including Gln levels significantly lower in the MM group. 13 Overall, these data suggest that Gln is highly metabolized in MM cells.…”

Section: Introductionmentioning

confidence: 99%

Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target

Bolzoni

Chiu

Accardi

et al. 2016

Blood

143

156

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Key Points• Myeloma cells produce ammonium in the presence of glutamine, showing high glutaminase and low glutamine synthetase expression.• Myeloma cells show high expression of glutamine transporters and inhibition of ASCT2 transporter hinders myeloma growth.The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138 1 cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gammopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitive to its inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138 1 cells. Gln-free incubation or treatment with the glutaminolytic enzyme L-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138 1 cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 downregulation by a lentiviral approach inhibited HMCL growth in vitro and in a murine model. In conclusion, MM cells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM. (Blood. 2016;128(5):667-679)

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“…One study demonstrated excess production of ammonia in vitro by human myeloma cell lines, although the mechanism is unclear. Whether this overproduction is due to mutations in the enzymes involved in ammonia synthesis or due to excess protein synthesis remains unknown [11]. Hyperammonemic encephalopathy has also been infrequently reported to occur after high dose chemotherapy for treatment of hematologic malignancies [6].…”

Section: Discussionmentioning

confidence: 99%