Editorial Response: Hyperlactatemia and Hepatic Steatosis as Features of Mitochondrial Toxicity of Nucleoside Analogue Reverse Transcriptase Inhibitors

Brinkman, Kees

doi:10.1086/313921

Cited by 62 publications

(42 citation statements)

References 8 publications

(10 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…Thus a liver biopsy could reveal any potential alteration in mitochondrial phosphorylation capacity. Brinkman et al found microvesicular or mixed hepatic steatosis in patients with persistent hyperlactataemia who underwent liver biopsies [8]. Therefore, impaired lactate clearance might be the result of mitochondrial dysfunction in the hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…The patients had been HIV-positive for a median of 2 (range 1-18) years in group 2, for 9 (1-16) years in group 3 and for 7 (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) years in group 4, and both groups 3 and 4 had been treated with HAART for a median of 5 years.…”

Section: Patient Characteristicsmentioning

confidence: 99%

“…The sole pathway for lactate utilization leading to stable lactate concentrations of less than 2 mmol/L is conversion back to pyruvate and then to glucose in the Cori Cycle, which depends on ATP and sufficient oxidative phosphorylation. Thus, impaired lactate clearance may be the result of a mitochondrial dysfunction in the liver [8] or in other tissues, for example skeletal muscle.Skeletal muscle cells, which have high amounts of mitochondria and high oxidative requirements, are the most important producers of lactate, especially during exercise. Elevated lactate levels could also be caused by increased production (see Fig.…”

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confidence: 99%

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Kinetics of lactate metabolism after submaximal ergometric exercise in HIV‐infected patients

et al. 2004

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It is unknown whether high levels of lactate result from enhanced production or decreased degradation. We therefore investigated differences in the kinetics of plasma lactic acid in HIV-infected patients receiving or not receiving highly active antiretroviral therapy (HAART) and in uninfected controls after submaximal ergometric exercise. MethodsTen healthy controls, 11 HIV-infected therapy-naïve patients, 15 HIV-infected patients on HAART with normal baseline lactate levels, and nine HIV-infected patients on HAART with elevated baseline lactate levels >2 mmol/L performed 10 min of ergometric exercise, with a heart rate of 200 beats/min minus age. Lactate levels were measured at baseline, at the end of exercise and 15, 30, 45, 60 and 120 min thereafter. ResultsMean baseline lactate levels were 1.4, 1.5, 1.5 and 2.8 mmol/L in the controls, the therapy-naïve patients, the patients on HAART with normal lactate levels and the patients on HAART with elevated lactate levels, respectively. Maximum lactate levels after exercise were similar in all groups (9.7, 9.4, 9.0 and 10.1 mmol/L, respectively). Significant differences were found in the slope of lactate decline between controls and untreated individuals (P 5 0.038) and between patients on HAART with normal baseline lactate and patients on HAART with elevated baseline lactate (P 5 0.028). ConclusionsDifferences in lactate metabolism do exist between healthy controls and HIV-infected therapy-naïve individuals. Thus, HIV infection in itself may influence lactate levels. Elevated baseline lactate levels are associated with a delayed decline of lactate after exercise. These results could be explained by impaired lactate clearance. Lactate production upon exercise does not seem to be affected by baseline lactate levels. Fig. 1).Mitochondria have a pivotal role in cellular energy homeostasis, producing adenosphine biphosphate (APT) by oxidative phosphorylation. Under normal aerobic conditions, glucose is metabolized to pyruvate, which is further degraded in the mitochondrion to CO 2 , H 2 O and ATP. Lactate production can be induced by anaerobic glycolysis, by a defect in the oxidative phosphorylation of peripheral tissue or as a result of defective mitochondrial DNA (mtDNA)-encoded proteins. The primary site of lactate clearance is the liver and, to a lesser extent, the kidney and the skeletal muscle itself. The sole pathway for lactate utilization leading to stable lactate concentrations of less than 2 mmol/L is conversion back to pyruvate and then to glucose in the Cori Cycle, which depends on ATP and sufficient oxidative phosphorylation. Thus, impaired lactate clearance may be the result of a mitochondrial dysfunction in the liver [8] or in other tissues, for example skeletal muscle.Skeletal muscle cells, which have high amounts of mitochondria and high oxidative requirements, are the most important producers of lactate, especially during exercise. Elevated lactate levels could also be caused by increased production (see Fig. 1). Whether hyperlactataemia associated w...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Patient Characteristicsmentioning

confidence: 99%

mentioning

confidence: 99%

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Kinetics of lactate metabolism after submaximal ergometric exercise in HIV‐infected patients

et al. 2004

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“…34 Nucleoside analogs are well known mitochondrial toxins. 35,36 Long-term use of these drugs including zidovudine, didanosine, stavudine, and fialuridine have been shown to cause hepatic steatosis, fulminant lactic acidosis, ultrastructural abnormalities of mitochondria, and mtDNA depletion. 36 This iatrogenic depletion of mtDNA resembles the genetic MDS, suggesting a common, as yet undefined, underlying pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

The hepatic mitochondrial DNA depletion syndrome: Ultrastructural changes in liver biopsies

et al. 2001

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Mitochondrial respiratory chain disorders are an established cause of liver failure in early childhood. In some patients, the levels of mitochondrial DNA are markedly reduced, a condition referred to as mtDNA depletion syndrome (MDS). We report here on the ultrastructural changes in the livers of 10 infants with the hepatic form of this syndrome. All patients displayed progressive liver failure, neurological abnormalities, hypoglycemia, and lactic acidosis that warranted investigation of respiratory chain disorder in liver tissue, specifically expressing the disease. Decreased activity of respiratory chain complexes containing mtDNA-encoded subunits (complexes I, III, IV) was shown in 5 patients. Mitochondrial DNA depletion was confirmed by Southern blot analysis in the livers of 6 patients. We found hepatocytes filled with mitochondria having aspects of "oncocytic transformation," associated with numerous changes in shape, size, cristae, and matrix. The changes were virtually identical in all specimens. In many hepatocytes, microvesicular steatosis was the salient feature. Additional findings included cholestasis and focal cytoplasmic biliary necrosis (CBN), as well as cytosiderosis in hepatocytes and sinusoidal cells. In some hepatocytes the damage appeared extreme, but fibrosis was identified only in the few patients who died beyond 6 months of age. Although individual ultrastructural findings are not specific, when taken together, they show a diagnostic pattern highly suggestive of a respiratory chain disorder. In the appropriate clinical context, these findings can direct the clinician towards the diagnosis of hepatic MDS. (HEPATOLOGY 2001;34:776-784.)The mitochondrial respiratory chain is a highly organized system involved in the ATP-generating, oxidative phosphorylation (OXPHOS) process. It is composed of 5 enzymatic complexes, which include more than 100 proteins. Thirteen of the polypeptides are encoded by mitochondrial DNA (mtDNA) whereas the remaining subunits by the nuclear genome.

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Mitochondrial Toxicity of Antiviral Drugs: A Challenge to Accurate Diagnosis

Baar¹,

Ronde²

2008

Drug‐Induced Mitochondrial Dysfunction

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Editorial Response: Hyperlactatemia and Hepatic Steatosis as Features of Mitochondrial Toxicity of Nucleoside Analogue Reverse Transcriptase Inhibitors

Cited by 62 publications

References 8 publications

Kinetics of lactate metabolism after submaximal ergometric exercise in HIV‐infected patients

Kinetics of lactate metabolism after submaximal ergometric exercise in HIV‐infected patients

The hepatic mitochondrial DNA depletion syndrome: Ultrastructural changes in liver biopsies

Mitochondrial Toxicity of Antiviral Drugs: A Challenge to Accurate Diagnosis

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