Multiple myeloma-induced hyperammonemic encephalopathy: An entity associated with high in-patient mortality

Pham, Anthony Q.; Reagan, John L.; Castillo, Jorge J.

doi:10.1016/j.leukres.2013.07.014

Cited by 35 publications

(41 citation statements)

References 19 publications

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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

145

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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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

145

156

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“…There exists some data about the probability of occurrence of delirium in MM and acute leukemia involving the hyperammonemic encephalopathy which is characteristic for this disease [25][26][27][28][29][30] . In a systematic study of D. Vybornykh et al (2006) [31] .…”

Section: Somatogenic Psychosesmentioning

confidence: 99%

Psychohematology. Attempt to Summarise

Выборных

Olexenko

Savchenko

2016

International Journal of Hematology Research

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AIM:This article describes studies involving mental and personality disorders in patients with blood diseases -disorders typology, prevalence, risk factors for developing of mental disturbances and their treatment. METHODS:The work is done on the basis of scientific literature search in various databases and analysis of the resulting material. RESULTS: There was obtained information on the prevalence, typologies, risk factors and treatment of blood diseases in the available literature. CONCLUSIONS: The presented data of literature suggests clinical heterogeneity and a wide range (from asthenic reactions to delirious states) of psychopathological disorders detected in blood diseases patients. The main risk factors are severe underlying disease, chemotherapy management (especially corticosteroids), elderly patients. In most cases of adjustment disorders there was observed a combination of several risk factors (both general and specific). In the context of the tolerability and safety of pharmacotherapy preference was given to atypical antipsychotics and new generations of antidepressants (SSRI, SNRI). It remains to study the mental disorders and personality disorders, which are formed in patients with specific malignant and nonmalignant (hemophilia, thrombocytopathy etc.) diseases and to develop differentiated approaches to pharmacotherapy and psychotherapy in such states.

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“…Increased catabolism by plasma cells of amino acids derived from excess protein turnover as well as plasma cell infiltration of liver causing porto-systemic shunting of blood may lead to hyperammonemia [52]. Encephalopathy is associated with development of advanced disease (e.g., myeloma cells in the peripheral blood) and an increased risk of mortality, especially at a level of >114 μmol/L [53,54]. Patients receiving bone marrow transplantation for hematological malignancies [55] and rarely those with lung transplants [56] are also at risk of developing elevated ammonia with encephalopathy due to unclear reasons.…”

Section: Increased Production Of Ammoniamentioning

confidence: 99%

Non-cirrhotic Hyperammonemia—When High Ammonia Is not Always from Cirrhosis

Kumar

Asrani

2015

Curr Hepatology Rep

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Though elevated ammonia is often associated with the presence of intrinsic liver disease, several other causes need to be considered. Elevated ammonia can either be related to increased production of ammonia due to a catabolic state (e.g., protein degradation) or due to decreased clearance. Diagnostic workup of elevated ammonia levels involves consideration of the following questions: (1) Is there evidence of underlying liver disease? (2) Is hyperammonemia due to increased production or decreased clearance of ammonia? (3) Is elevated ammonia simply a bystander to obvious clinical scenarios (e.g., septic shock), or does it imply the need for further workup of unrecognized entities (e.g., urea cycle defect) that need prompt attention?

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Multiple myeloma-induced hyperammonemic encephalopathy: An entity associated with high in-patient mortality

Cited by 35 publications

References 19 publications

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

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

Psychohematology. Attempt to Summarise

Non-cirrhotic Hyperammonemia—When High Ammonia Is not Always from Cirrhosis

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