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The Body Covers: The 3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV
Mitochondrial Function May Be Normal and Not Causative of Lactate Elevation

October 24, 2001

  • Different Lactate Metabolism in Patients with and without HIV-Associated Lipodystrophy Syndrome
    Presenter: Dr. Ove Andersen, Hivdore University Hospital, Copenhagen, Denmark.


Lactic acidosis is a life-threatening condition rarely observed during nucleoside analog therapy. It has been reported during monotherapy use with zidovudine, didanosine, zalcitabine and stavudine and in combinations including all available agents. For acidosis to occur, mitochondrial function must be compromised as the oxidative phosphorylation process performed by mitochondria normal "mops up" and acid. Chronic or episodic elevation of lactate, hyperlactatemia, without acidosis or clinical symptoms has been reported in persons with HIV receiving nucleoside analogs and, less commonly, untreated individuals. The prevalence of this laboratory finding appears to be around 5%-25% in treated persons. These elevations have not been demonstrated to be predictive of the development of lactic acidosis, hence routine screening of lactate in clinical practice is not currently recommended.

Increased lactate levels without acidosis may result from increased lactate production, release or diminished clearance of lactate. Hyperlactatemia may be observed in both normal physiologic circumstances, such as during or immediately after exercise, in hypermetabolic states, and as an accompaniment to pathological conditions. Transient elevation of lactate may in some cases be explained by sampling issues including use of cuffs or tourniquets, recent physical exertion, and sample handling.

Dr. Anderson and colleagues investigated lactate metabolism in people with lipodystrophy (usually with mixed fat accumulation and peripheral fat loss) or with normal body shape. All patients were on a protease inhibitor containing HAART, mostly using indinavir or saquinavir boosted with low (100mg bd) dose ritonavir. Eighteen patients were included in each group. Their baseline characteristics were similar, although those with lipodystrophy had slightly longer protease inhibitor exposure (32 vs. 25 months) and had higher insulin and cholesterol levels. Duration of nucleoside analogs were similar. At baseline, plasma levels of lactate were normal (range usually considered <2.5mmol/l) but slightly higher in the lipodystrophy group (1.78 vs. 1.37mmol/l).

The patients were studied using a procedure called a euglycemic hyperinsulinaemic clamp: this involves infusion of a standard dose of insulin followed by the administration of enough glucose to enable the glucose levels in the blood to remain normal. The disposal of glucose was lower in patients with lipodystrophy thought to be related to diminished uptake of glucose in peripheral muscle and fat cells. In evaluating the fates of glucose in these subjects, Dr. Anderson found that an identical proportion of the glucose was oxidized in the lipodystrophy patients as in those without lipodystrophy. This was true both in the fasted state and the insulin-stimulated state. As oxidation of glucose is a mitochondrial function, these data suggest that mitochondria are working normally in these patients.

In people without lipodystrophy, higher lactate levels were correlated with lower glucose disposal rates. However, in people with lipodystrophy, no correlation between lactate levels and glucose disposal was observed. Additionally, no relationship between duration of nucleoside analog therapy and lactate levels was observed.

What does this mean? Well, the initial hypothesis regarding lactic acidosis and hyperlactatemia was that these are caused by nucleoside analog effects on mitochondria and lie on a continuum from normal through mild (but not clinically important) to severe abnormalities. These data raise the possibility that we may have acidosis, which clearly requires mitochondrial disease and a second event, hyperlactatemia, which may in some people reflect mitochondrial disease but generally appears to involve normal mitochondrial function.

This would mean that either (or both) increased cellular lactate release or decreased lactate clearance are the problems. No data are yet available to answer this. However, in discussion, Dr. Anderson's hunch was that we are looking at reduced lactate clearance in the liver. However, for the physician and patient, we have the reassurance that high lactate does not indicate mitochondrial disease.




  
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