Metabolic intermediates in lactic acidosis: compounds, samples and interpretation

Abstract

A number of acquired conditions including infections, severe catabolic states, tissue anoxia, severe dehydration and poisoning can give rise to hyperlactacidaemia. All these causes should be ruled out before considering inborn errors of metabolism. Carefully collected samples are necessary if artefacts that result in spuriously increased lactate/pyruvate (L/P) and 3-hydroxybutyrate/acetoacetate (B/A) ratios are to be avoided. When properly performed, 24-h studies of L/P and B/A ratios provide a useful tool in making a diagnosis. A few metabolic profiles when present are specific or highly suggestive of a given disorder. When the L/P ratio is normal or low, pyruvate dehydrogenase (PDH) deficiency is highly probable whatever the lactate concentration, which is often only moderately elevated after meal, may be. When the L/P ratio is very high in association with post-prandial hyperketonaemia and in contrast to a normal or low B/A ratio, pyruvate carboxylase (PC) deficiency and alpha-ketoglutarate dehydrogenase (KGDH) deficiency are the most likely diagnoses. The distinction between the two disorders relies upon amino acid and organic acid profiles (glutamate and alpha-ketoglutarate accumulations in KGDH deficiency and hyperammonaemia and hypercitrullinaemia in PC deficiency). When both L/P and B/A ratios are elevated and associated with significant post-prandial hyperketonaemia, respiratory-chain disorders should first be suspected. All other profiles, especially a high L/P ratio without hyperketonaemia, are compatible with respiratory-chain disorders but are not specific; all acquired anoxic conditions should also be ruled out. Clearly, the clinical utility of these profiles needs to be interpreted cautiously in very ill patients in relation to the cardiocirculatory condition and to therapy. Finally, a normal profile, even after stress and loading, does not rule out an inborn error of lactate/pyruvate oxidation.

Measurement of pyruvate in blood by high-performance liquid chromatography with fluorescence detection

“…The preliminary reference range for the lactate/ pyruvate ratio of 9·3-13'9 (17 non-fasting adults) is comparable to that of Poggi-Travert et al 2 (6-14'5; II children, age 1-7 years), Lamers et al 20 (6'4- 2·00 3·00 4·00 5·00 Min 6·00 7·00 8·00 9·00 10·00…”

Cerebrospinal Fluid Lactate and Pyruvate Concentrations and Their Ratio in Children: Age-related Reference Intervals

“…Simultaneous determination of lactate and pyruvate is used to determine cytosolic redox status (i.e., the L/P ratio) in several forms of IEM, and especially PDH deficiency. Both pyruvate and lactate concentrations are increased in PDH deficiency, but the L/P ratio remains normal or only slightly decreased (20 ) because the mitochondrial RC is not impaired. However, CSF appears to be more clinically relevant for pyruvate determinations because pyruvate concentrations in blood may be highly sensitive to sample preparation (13 ), giving rise to artificially low values (attributable to lactate dehydrogenase activity) and therefore to falsely high L/P ratios.…”

Potential Non-Hypoxic/Ischemic Causes of Increased Cerebral Interstitial Fluid Lactate/Pyruvate Ratio: A Review of Available Literature

“…Increased LPR also is described in patients with parenteral nutrition-induced deficiency of thiamine [37], a necessary cofactor for PDH complex function, and has been described in a patient with a mutation in the thiamine transporter gene [38]. However, normal blood LPR also may be observed in patients with PDH deficiency [39]. The clinical implication of the relationship between elevated LPR and PDH abnormalities is uncertain.…”

“…Third, patients with deficiency of pyruvate carboxylase (a gluconeogenic enzyme that converts pyruvate to oxaloacetate through the reaction Pyr + HCO 3 -+ ATP ? OAA + ADP + P i ) also can exhibit increased blood LPR [39]. Fourth, deficiencies of the citric acid cycle enzymes a-ketoglutarate dehydrogenase and succinate dehydrogenase also may be associated with increased LPR in the blood [39].…”