Metabolic acidosis in falciparum malaria

Metabolic acidosis, often associated with hyperlactataemia, has been described in African children with severe falciparum malaria [111, 112]. It is not unique to this disease, being seen in viral, rickettsial and bacterial infections [113] as well as acute gastroenteritis, where its prevalence is higher than in malaria [114]. The terms hyperlactataemia and lactic acidosis are often mistakenly used interchangeably in the malaria literature. As often reviewed in the basic literature [115-118], protons (H+, the basis of acidosis) are not formed when ATP and lactate are generated during glycolysis, but on the subsequent hydrolysis of ATP in tissues. Every time a molecule of ATP undergoes hydrolysis, a proton is released. If this occurs under aero bic conditions, these protons are consumed within ATP regeneration from ADP, and pH remains normal, i.e. acidosis does not occur. In contrast, if the mitochondria are not functioning adequately, whether through insufficient oxygen supply or an inability to use it, ATP regenerates under anaerobic condition, and the protons are not consumed. Hence, once the buffering capacity of the body is exceeded, acidosis occurs. In short, metabolic acidosis requires the ratio of glycolytic (i.e. anaerobic) ATP hydrolysis to mitochondrial (i.e. aerobic) ATP hydrolysis to reach a point at which the buffering systems can no longer cope. Pathological changes in the buffering system can be a major determinant of when this occurs.

Is hyperlactataemia a cause or marker of the acidosis of malaria?

High lactate levels have traditionally been seen not only as a marker for poor oxygen delivery in disease states, but also a consequence of it, and the cause of the acidosis. For some time hyperlactataemia has been regarded as a functionally relevant marker for a poor prognosis in both sepsis [119] and malaria [66, 112, 120]. Although the sepsis world now discusses several origins for the lactate increase, including inflammation-induced mitochon-drial dysfunction [97], in falciparum malaria it is still generally attributed to a reduced oxygen supply, mostly through microvascular occlusion by sequestered parasitised erythrocytes [121]. Other mechanisms are known to contribute to acidosis in malaria, independent of lactate production, e.g. acute renal failure [8]. Impaired hepatic clearance [8, 112], production by parasites, and, in some areas, thiamine deficiency [122] are also argued to contribute to lactate accumulation independent of impaired cellular respiration. Thus, as described below, although acidosis and hyperlactataemia can be associated, they are independent cellular mechanisms.

Lactate anion has complex roles in biology. Hyperlactataemia may be associated with acidosis, a normal pH, or alkalosis [123]. A recent editorial in Critical Care Medicine [124] has lucidly summarised the key points of the mechanism of metabolic acidosis in sepsis, a condition that shares systemic inflammation and a range of its consequences with severe malaria (Tab. 2). These authors argue against lactate as the cause of the acidosis associated with hypoxia. Instead, they note the evidence that during hypoxia, be it from limited oxygen supply or utilisation, the unconsumed protons that cause acidosis arise from the hydrolysis of non-mitochondrial ATP. Since these reactions are independent of lactate levels, it is difficult to see how thera-peutically reducing levels of this anion, as has been proposed [125], could increase survival rate in falciparum malaria any more than in sepsis [126]. Indeed, in theory it could harm comatose patients, since there is evidence that lactate helps brain tissue survive hypoxic and hypoglycaemic episodes [127-129], and the lactate shuttle is proving to be how astrocytes protect neurons from metabolic stress [130].

Even when considerable lactate is generated in acute inflammatory states, other, unidentified, anions contribute much more than it does to the strong ion difference that, through influencing the body's buffering capacity, influences acidosis in sepsis [131, 132] and falciparum malaria [114, 133]. Thus, lactate accumulation can only partially account for the high anion gap observed during the metabolic acidosis associated with severe malaria.

In summary, lactate is an imprecise but useful marker for metabolic acidosis in malaria. In turn, acidosis is an imprecise but useful marker of impaired cellular respiration. Whether impaired cellular respiration arises from (a) poor supply of oxygen to mitochondria (through vaso-occlusion, low circulating volume, anaemia or cardiac insufficiency) or impaired mito-chondrial function (in response to severe systemic inflammation) the outcome is essentially the same. The resulting high anion gap metabolic acidosis is strongly predictive of death in severe malaria. Greater understanding of the multiple factors influencing the metabolic acidosis could provide further insight into the underlying pathophysiological process and may provide additional therapeutic options.

Hypoglycaemia in paediatric malaria

When glycolysis is enhanced for any period glycogen stores are soon depleted, and gluconeogenesis supervenes. However, its substrate supplies are limiting [134], and the hypoglycaemia often reported in severe malaria [135] and sepsis [19, 136] occurs. Hypoglycaemia is therefore a secondary cause of harm in these diseases, and is an inevitable consequence of exuberant, mostly anaerobic, glycolysis.

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