Glycolic acid is another byproduct of the oxalate pathway and comes from the conversion of glyoxylic acid. Urinary levels of glycolic acid have most commonly been studied in the rare inborn error of metabolism primary hyperoxaluria type 1 (PH1). PH1 is caused by a deficiency of alanine:glyoxylate aminotransferase (AGT) which converts glyoxylic acid into glycine. When this pathway is blocked, due to inborn error, glyoxylic acid ultimately leads to higher production of glycolic acid and oxalic acid.
Clinically, PH1 results in a similar clinical presentation as PH2 with increased oxalic acid excretion and calcium oxalate deposition (oxalosis). This can ultimately progress to renal calcinosis and kidney failure. Aside from inborn error, a large portion of glycolic acid is derived from metabolism of glycine and hydroxyproline. It has been projected that between 20% and 50% of urinary glycolate comes from hydroxyproline in the form of collagen turnover in the body. Supplementation or recent intake of collagen or collagen-rich foods may influence levels of glycolic acid in the urine. Another important source of glycolic acid is the molecule glyoxal. Glyoxal is derived, in part, from oxidative stress in the forms of lipid peroxidation and protein glycation. The majority of this glyoxal is converted into glycolic acid utilizing glutathione as a cofactor.
Lange JN, Wood KD, Knight J, Assimos DG, Holmes RP. Glyoxal formation and its role in endogenous oxalate synthesis. Adv Urol. 2012;2012:819202 [L]
Danpure CJ, Jennings PR. Peroxisomal alanine:glyoxylate aminotransferase deficiency in primary hyperoxaluria type I. FEBS Lett. 1986;201(1):20-24. [L]
Dietzen DJ, Wilhite TR, Kenagy DN, Milliner DS, Smith CH, Landt M. Extraction of glyceric and glycolic acids from urine with tetrahydrofuran: utility in detection of primary hyperoxaluria. Clin Chem. 1997;43(8 Pt 1):1315-1320. [L]
Barratt TM, Kasidas GP, Murdoch I, Rose GA. Urinary oxalate and glycolate excretion and plasma oxalate concentration. Arch Dis Childhood. 1991;66(4):501-503. [L]
Knight J, Jiang J, Assimos DG, Holmes RP. Hydroxyproline ingestion and urinary oxalate and glycolate excretion. Kidney Int. 2006;70(11):1929-1934. [L]
Rabbani N, Thornalley PJ. Dicarbonyls (glyoxal, methylglyoxal, and 3-deoxyglucosone). Uremic Toxins. 2012:177-192. [L]
Knight J, Wood KD, Lange JN, Assimos DG, Holmes RP. Oxalate Formation From Glyoxal in Erythrocytes. Urology. 2016;88:226. e211-225. [L]
Dindo M, Oppici E, Dell’Orco D, Montone R, Cellini B. Correlation between the molecular effects of mutations at the dimer interface of alanine-glyoxylate aminotransferase leading to primary hyperoxaluria type I and the cellular response to vitamin B(6). J Inher Metab Dis. 2018;41(2):263-275. [L]
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The clinical relevance of low levels of urinary glycolic acid has not been fully explored. Low levels of glycolic acid precursors could potentially explain low levels of this end-product. This could be found in lower overall oxidative stress burden or low collagen turnover. Glycine is also a precursor to the glyoxylase system and could theoretically result in low downstream metabolites, such as glycolic acid.
Extremely high levels of urinary glycolic acid are suspicious of a metabolic defect in the glyoxylate pathway such as in PH1. However, this rare inborn error is commonly diagnosed early in life. To note, Genova’s urinary organic acid testing is not designed for the diagnosis of metabolic inborn errors. However, the enzyme defect responsible for PH1 (AGT) is dependent on vitamin B6 as a cofactor. The extent to which urinary glycolic acid could be a functional indicator of vitamin B6 insufficiency has not been studied, however patients with PH1 have shown improvement with B6 intervention.
Aside from inborn error, higher levels of glycolic acid may be indicative of increased oxidative stress. This is because oxidative stress causes higher levels of glyoxal which is ultimately converted into glycolic acid for excretion utilizing glutathione as a cofactor.
Lower levels of glutathione may promote more conversion of glyoxal to oxalic acid.
Lastly, a large proportion of glycolic acid comes from collagen in the form of hydroxyproline. Consumption of foods high in collagen should be considered with unexplained elevations in glycolic acid. The extent to which accelerated turnover of collagen, such as in catabolic conditions, contributed to urinary glycolic acid has not been studied in the literature.
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